Manejo Del Samgrado Perioperatorio

Eur J Anaesthesiol 2017; 34:332395
GUIDELINES
Management of severe perioperative bleeding: guidelines

from the European Society of Anaesthesiology
First update 2016
Sibylle A. Kozek-Langenecker, Aamer B. Ahmed, Arash Afshari, Pierre Albaladejo, Cesar Aldecoa,
Guidrius Barauskas, Edoardo De Robertis, David Faraoni, Daniela C. Filipescu, Dietmar Fries,
Thorsten Haas, Matthias Jacob, Marcus D. Lance, Juan V.L. Pitarch, Susan Mallett,
Jens Meier, Zsolt L. Molnar, Niels Rahe-Meyer, Charles M. Samama, Jakob Stensballe,
Philippe J.F. Van der Linden, Anne J. Wikkels, Patrick Wouters, Piet Wyffels and Kai Zacharowski
The management of perioperative bleeding involves update, electronic databases were searched without
multiple assessments and strategies to ensure appropriate language restrictions from 2011 or 2012 (depending on
patient care. Initially, it is important to identify those the search) until 2015. These searches produced 18 334
patients with an increased risk of perioperative bleeding. articles. All articles were assessed and the existing 2013
Next, strategies should be employed to correct preopera- guidelines were revised to take account of new evidence.
tive anaemia and to stabilise macrocirculation and micro- This update includes revisions to existing recommen-
circulation to optimise the patients tolerance to bleeding. dations with respect to the wording, or changes in the
Finally, targeted interventions should be used to reduce grade of recommendation, and also the addition of new
intraoperative and postoperative bleeding, and so prevent recommendations. The final draft guideline was posted on
subsequent morbidity and mortality. The objective of these the European Society of Anaesthesiology website for four
updated guidelines is to provide healthcare professionals weeks for review. All comments were collated and the
with an overview of the most recent evidence to help guidelines were amended as appropriate. This publication
ensure improved clinical management of patients. For this reflects the output of this work.
From the Department of Anaesthesiology & Intensive Care, Evangelical Hospital Vienna, Vienna, Austria (SAKL), Department of Anaesthesiology & Intensive Care, Glenfield
Hospital, Leicester, United Kingdom (ABA), Department of Anaesthesiology, University Hospital of Copenhagen, Copenhagen, Denmark (AA, JS), Department of
Anaesthesiology & Intensive Care, CHU De Grenoble Hopital, Michallon, Grenoble, France (PA), Department of Anaesthesiology & Intensive Care, Hospital Universitario
Rio Hortega, Valladolid, Spain (CA), Department of General Surgery, Lithuanian University of Health Sciences, Kaunas, Lithuania (GB), Department of Anaesthesiology &
Intensive Care, University Hospital Federico II, Napoli, Italy (EDR), Department of Anaesthesiology, Boston Childrens Hospital, Boston, Massachusetts, United States
(DFa), Department of Anaesthesiology & Intensive Care, Emergency Institute for Cardiovascular Disease, Bucharest, Romania (DCF), Department of Anaesthesiology,
University Hospital of Innsbruck, Innsbruck, Austria (DFr), Department of Anaesthesiology, Childrens University Hospital Zurich, Zurich, Switzerland (TH), Department of
Anaesthesiology & Intensive Care, Klinikum Straubing, Straubing, Germany (MJ), Department of Anaesthesiology & Pain Medicine, Maastricht University Medical Centre,
Maastricht, the Netherlands (MDL), Department of Anaesthesiology & Intensive Care, Hospital Clinico Universitario Valencia, Valencia, Spain (JVLP), Department of
Anaesthesia, Royal Free Hospital, London, United Kingdom (SM), Department of Anaesthesiology & Intensive Care, General Hospital Linz, Linz, Austria (JM), Department of
Anaesthesiology & Intensive Care, University Hospital of Szeged, Szeged, Hungary (ZLM), Department of Anaesthesiology & Intensive Care, Franziskus Hospital, Bielefeld,
Germany (NRM), Department of Anaesthesiology & Intensive Care, Groupe Hospitalier Cochin, Paris, France (CMS), Department of Anaesthesiology, CHU Brugmann,
Brussels, Belgium (PJFVDL), Department of Anaesthesiology, Herlev University Hospital, Herlev, Denmark (AJW), Department of Anaesthesiology, Ghent University
Hospital, Ghent, Belgium (PWo, PWy) and Department of Anaesthesiology & Intensive Care, University Frankfurt/Main, Frankfurt am Main, Germany (KZ)
Correspondence to Sibylle A. Kozek-Langenecker, Department of Anaesthesiology & Intensive Care, Evangelical Hospital Vienna, Hans-Sachs-Gasse 10-12, 1180
Vienna, Austria; E-mail: [email protected]
0265-0215 Copyright # 2017 European Society of Anaesthesiology. All rights reserved. DOI:10.1097/EJA.0000000000000630
Copyright European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.

Management of severe perioperative bleeding 333
CONTENTS
1 Summary: Recommendations, Suggestions and Statements ........... ................ . . . . . . 334
1.1 Evaluation of coagulation status ........................... ................ . . . . . . 334
1.2 Preoperative and postoperative correction of anaemia ........... ................ . . . . . . 334
1.3 Optimising circulation .................................. ................ . . . . . . 335
1.4 Oxygen fraction ....................................... ................ . . . . . . 335
1.5 Monitoring tissue perfusion .............................. ................ . . . . . . 335
1.6 Transfusion of labile blood products ........................ ................ . . . . . . 335
1.7 General coagulation management .......................... ................ . . . . . . 336
1.8 Algorithms in specific clinical fields ......................... ................ . . . . . . 337
1.9 Antithrombotic drugs ................................... ................ . . . . . . 338
1.10 Comorbidities involving haemostatic derangement ............. ................ . . . . . . 340
1.11 Patients with congenital bleeding disorders .................. ................ . . . . . . 340
2 Introduction ............................................ ................ . . . . . . 341
3 Methods ............................................... ................ . . . . . . 342
3.1 Task force selection .................................... ................ . . . . . . 342
3.2 Search for evidence .................................... ................ . . . . . . 342
3.3 Guideline preparation ................................... ................ . . . . . . 342
4 Evaluation of coagulation status .............................. ................ . . . . . . 343
4.1 Perioperative coagulation testing ........................... ................ . . . . . . 343
4.2 Evaluation of platelet function ............................ ................ . . . . . . 345
5 Anaemia management ..................................... ................ . . . . . . 346
5.1 Preoperative correction of anaemia ......................... ................ . . . . . . 346
6 Optimising circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 348
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 348
6.2 Evidence-based medicine and perioperative fluid therapy . . . . . . . . . . . . ................ . . . . . . 349
6.3 Optimising macrocirculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 349
6.4 Considerations for microcirculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 349
7 Transfusion of labile blood products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 350
7.1 Infectious risk of allogeneic blood components. . . . . . . . . . . . . . . . . . . . ................ . . . . . . 350
7.2 Immunological and non-immunological complications associated with the transfusion of labile
blood components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 351
7.3 Storage lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 353
7.4 Cell salvage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 353
7.5 Plasma and platelet transfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 354
8 General coagulation management ............................. ................ . . . . . . 354
8.1 Indications, contraindications, complications and doses .......... ................ . . . . . . 354
8.2 Correction of confounding factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 355
8.3 Cost implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 355
9 Algorithms in specific clinical fields . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 355
9.1 Cardiovascular surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 355
9.2 Gynaecological (non-pregnant) surgery . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 359
9.3 Obstetric bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 359
9.4 Orthopaedic surgery and neurosurgery . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 362
9.5 Paediatric surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 363
9.6 Visceral and transplant surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 363
10 Antithrombotic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 364
10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 364
10.2 Antiplatelet agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 365
10.3 Anticoagulant agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 366
11 Comorbidities involving haemostatic derangement . . . . . . . . . . . . . . . . . . . ................ . . . . . . 369
11.1 Patients with comorbidities involving haemostatic derangement . . . . . ................ . . . . . . 369
11.2 Patients with congenital bleeding disorders . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 371
Acknowledgements relating to this article . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 379
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ . . . . . . 380

334 Kozek-Langenecker et al.
1. Summary: recommendations, suggestions 1.1.1. Evaluation of platelet function

and statements We suggest preoperative platelet function testing only in
Grade of recommendation shown in bold type (Table 1) association with a positive bleeding history. 2B
We suggest that preoperative platelet function testing be
used to identify decreased platelet function caused by
1.1. Evaluation of coagulation status medical conditions or antiplatelet medication. 2B
Before surgery or invasive procedures, we recommend
Bleeding time is influenced by many variables and is not
the use of a structured patient interview or standardised
useful for stratifying bleeding risk. C
questionnaire which considers clinical and family bleed-
ing history and detailed information on the patients
medication. 1C
1.2. Preoperative and postoperative correction
We recommend the use of standardised questionnaires of anaemia
on bleeding and drug history as preferable to the routine Preoperative anaemia in adults and children appears to be
use of conventional coagulation screening tests such as a strong predictor for perioperative blood transfusion
activated partial thromboplastin time (aPTT), inter- across various types of conditions and surgeries and
national normalised ratio (INR) and platelet count in may be associated with adverse events. B
elective surgery. 1C
We recommend that patients at risk of bleeding are
We recommend the application of intervention algor- assessed for anaemia 3 to 8 weeks before surgery. 1C
ithms incorporating pre-defined triggers and targets
If anaemia is present, we recommend identifying the cause
based on viscoelastic haemostatic assay (VHA) coagu-
(iron deficiency, renal insufficiency or inflammation). 1C
lation monitoring to guide individualised haemostatic
intervention in the case of perioperative bleeding. 1C We recommend treating iron deficiency with iron supple-
mentation. 1B
If VHA is not available we recommend the application of
intervention algorithms incorporating pre-defined trig- We recommend the use of intravenous iron in preference
gers based on conventional coagulation tests. 1C to oral iron. 1C
Table 1 Grades of recommendation Grading of Recommendations Assessment, Development and Evaluation system
Clarity of risk/benefit Quality of supporting evidence Implications

1A Strong recommendation. Benefits clearly outweigh risk Consistent evidence from well performed Strong recommendation, can apply to
High-quality evidence. and burdens, or vice versa. randomised, controlled trials or overwhelming most patients in most circumstances
evidence of some other form. Further without reservation.
research is unlikely to change our confidence
in the estimate of benefit and risk.
1B Strong recommendation. Benefits clearly outweigh risk Evidence from randomised, controlled trials with Strong recommendation, likely to apply to
Moderate-quality evidence. and burdens, or vice versa. important limitations (inconsistent results, most patients.
methodological flaws, indirect or imprecise),
or very strong evidence of some other form.
Further research (if performed) is likely to have
an impact on our confidence in the estimate of
benefit and risk and may change the estimate.
1C Strong recommendation. Benefits appear to outweigh Evidence from observational studies, Relatively strong recommendation; might
Low-quality evidence. risk and burdens, or vice unsystematic clinical experience, or from change when higher quality evidence
versa. randomised, controlled trials with serious becomes available.
flaws. Any estimate of effect is uncertain.
2A Weak recommendation. Benefits closely balanced with Consistent evidence from well performed, Weak recommendation, best action may
High-quality evidence. risks and burdens. randomised, controlled trials or overwhelming differ depending on circumstances or
evidence of some other form. Further patients or societal values.
research is unlikely to change our confidence
in the estimate of benefit and risk.
2B Weak recommendation. Benefits closely balanced with Evidence from randomised, controlled trials with Weak recommendation, alternative
Moderate-quality evidence. risks and burdens, important limitations (inconsistent results, approaches likely to be better for some
some uncertainty in the methodological flaws, indirect or imprecise), patients under some circumstances.
estimates of benefits, or very strong evidence of some other form.
risks and burdens. Further research (if performed) is likely to have
an impact on our confidence in the estimate of
benefit and risk and may change the estimate.
2C Weak recommendation. Uncertainty in the estimates of Evidence from observational studies, Very weak recommendation; other
Low-quality evidence. benefits, risks and unsystematic clinical experience, or from alternatives may be equally reasonable.
burdens; benefits may be randomised, controlled trials with serious
closely balanced with flaws. Any estimate of effect is uncertain.
risks and burdens.

If other causes of anaemia have been excluded or treated, 1.4. Oxygen fraction
we suggest erythropoietin-stimulating agents. 2B We recommend that the inspiratory oxygen fraction
should be high enough to prevent arterial hypoxaemia
If autologous blood donation is performed, we suggest
in bleeding patients, while avoiding excessive hyperoxia
treatment with iron and/or erythropoietin-stimulating
[PaO2 >26.7 kPa (200 mmHg)]. 1C
agents to avoid preoperative anaemia and increased over-
all transfusion rates. 2C
1.5. Monitoring tissue perfusion
In patients with preoperative anaemia, we recommend We recommend repeated measurements of a combi-
the use of combined therapy with intravenous iron and nation of haematocrit (Hct)/haemoglobin, serum lactate,
erythropoietin along with a restrictive transfusion policy. and base deficit to monitor tissue perfusion, tissue
1C oxygenation and the dynamics of blood loss during acute
bleeding. These parameters can be extended by
In non-cancer patients with preoperative anaemia sched-
measurement of cardiac output, dynamic parameters of
uled for elective major surgery, we recommend postpon-
volume status [e.g. stroke volume variation (SVV), pulse
ing surgery until anaemia has been corrected. 1C
pressure variation (PPV)], CO2 gap and central venous
In patients who are anaemic following surgery, we oxygen saturation. 1C
suggest the use of intravenous iron. 2C
1.5.1. Normovolaemic haemodilution
1.3. Optimising circulation We suggest the use of acute normovolaemic haemodilu-
We recommend aggressive and timely stabilisation of tion (ANH) in selected settings. 2C
cardiac pre-load throughout the surgical procedure, as
this appears beneficial to the patient. 1B We recommend against ANH in combination with con-
trolled hypotension. 1B
In cases of uncontrolled bleeding we suggest lower
thresholds for cardiac pre-load and/or permissive hypo- In patients with pre-existing or acquired coagulopathy
tension may be considered. 2C we suggest that the use of ANH is considered
carefully. 2C
We recommend the avoidance of hypervolaemia second-
ary to crystalloids or colloids to a level exceeding the
1.6. Transfusion of labile blood products
interstitial space in steady state, and beyond an optimal
We recommend that all countries implement national
cardiac pre-load. 1B
haemovigilance quality systems. 1B
We recommend against the use of central venous pres-
We recommend a restrictive transfusion strategy which is
sure (CVP) and pulmonary artery occlusion pressure as
beneficial in reducing exposure to allogeneic blood pro-
the only variables to guide fluid therapy and optimisation
ducts. 1A
of pre-load during severe bleeding. Dynamic assessment
of fluid responsiveness and non-invasive measurement of We recommend pathogen inactivation for fresh frozen
cardiac output should be considered instead. 1B plasma (FFP) and platelets. 1C
We suggest the replacement of extracellular fluid losses We recommend that labile blood components used for
with isotonic crystalloids in a timely and protocol-based transfusion are leukodepleted. 1B
manner. 2C
We recommend that blood services implement standard
Compared with crystalloids, haemodynamic stabilisation operating procedures for patient identification and that
with iso-oncotic colloids, such as human albumin and staff be trained in early recognition of, and prompt
hydroxyethyl starch, causes less tissue oedema. C response to, transfusion reactions. 1C
Infusion of colloids in patients with severe bleeding can We recommend a male-only donor policy for plasma-
aggravate dilutional coagulopathy by additional effects on containing blood products to prevent the onset of
fibrin polymerisation and platelet aggregation. C transfusion-related acute lung injury (TRALI). 1C
We suggest the use of balanced solutions for crystalloids We recommend that all red blood cell (RBC), platelet
and as a basic solute for iso-oncotic preparations. 2C and leukocyte donations from first-degree or second-
degree relatives be irradiated even if the recipient is
1.3.1. Transfusion triggers immunocompetent, and all RBC, platelet and leukocyte
We recommend a target haemoglobin concentration of 7 products be irradiated before transfusing to at-risk
to 9 g dl1 during active bleeding. 1C patients. 1C
Continuous haemoglobin monitoring can be used as a Allogeneic blood transfusion is associated with an
trend monitor. C increased incidence of nosocomial infections. B

1.6.1. Storage lesions We recommend treatment of hypofibrinogenaemia in

We recommend that RBCs should be transfused accord- bleeding patients. 1C
ing to the first-in, first-out method in the blood services to
We suggest an initial fibrinogen concentrate dose of 25 to
minimise wastage of erythrocytes. 1A
50 mg kg1. 2C
1.6.2. Cell salvage In cases wherein fibrinogen concentrate is not available
We recommend the use of red cell salvage which is we suggest cryoprecipitate at an initial dose of 4 to 6 ml
helpful for blood conservation in major cardiac and kg1. 2C
orthopaedic surgery. 1B Plasma transfusion alone is not sufficient to correct hypo-
We recommend against the routine use of intraoperative fibrinogenaemia. C
platelet-rich plasmapheresis for blood conservation In cases of bleeding and low factor XIII activity (e.g.
during cardiac operations using cardiopulmonary bypass
<30%) we suggest administration of factor XIII concen-
(CPB). 1B trate (30 IU kg1). 2C
We recommend that cell salvage is not contraindicated in
In severe perioperative bleeding we recommend that
bowel surgery, provided that the initial evacuation of
patients on vitamin K antagonists (VKAs) should be given
soiled abdominal contents is undertaken, additional cell
prothrombin complex concentrate (PCC) and intrave-
washing is performed and broad-spectrum antibiotics are
nous vitamin K before any other coagulation manage-
used. 1C
ment steps. 1B
We suggest that cell salvage is not contraindicated in
Prolonged INR/prothrombin time (PT) or VHA clotting
cancer surgery, provided that blood aspiration close to the
times alone are not an indication for PCC in bleeding
tumour site is avoided and leukodepletion filters are
patients not on oral anticoagulant therapy. C
used. 2C
We recommend against the prophylactic use of recombi-
1.6.3. Plasma and platelet transfusion nant activated factor VII (rFVIIa) due to increased risk of
We recommend against the use of plasma transfusion for fatal thrombosis. 1B
pre-procedural correction of mild-to-moderately elevated
We suggest that off-label administration of rFVIIa can be
INR. 1C
considered for life-threatening bleeding which cannot be
We recommend early and targeted treatment of coagu- stopped by conventional, surgical or interventional radio-
lation factor deficiencies in the plasma. Sources of coagu- logical means and/or when comprehensive coagulation
lation factors are coagulation factor concentrates, therapy fails. 2C
cryoprecipitate or high volumes of plasma, depending
We recommend tranexamic acid to prevent bleeding
on the clinical situation, type of bleeding, type of
during major surgery and/or treat bleeding due to (or
deficiency and resources provided. 1B
at least suspected) hyperfibrinolysis (e.g. a dose of 20 to
In the treatment of acquired coagulation factor 25 mg kg1). 1B
deficiency, we suggest the consideration of a ratio-driven
We suggest the use of desmopressin (DDAVP) under
protocol (RBC : plasma : platelet concentrates) early in
specific conditions [acquired von Willebrand syndrome
uncontrolled massive bleeding outside the trauma
(VWS)]. 2C
setting followed by a goal-directed approach as soon as
possible. 2C Based on the current literature there is no evidence to
recommend antithrombin supplementation in elective
We suggest coagulation factor concentrates for the
surgical patients while they are bleeding.
primary treatment of acquired coagulation factor
deficiency due to their high efficacy and their minimal We recommend structured staff education and training.
infectiousness. 2C 1C
We recommend against indiscriminate use of plasma
transfusion in perioperative bleeding management. 1C
1.7.1. Correction of confounding factors
We suggest platelet concentrate transfusion in bleeding
We recommend maintaining perioperative normothermia
situations clearly related to antiplatelet drugs or throm-
because it reduces blood loss and transfusion require-
bocytopaenia less than 50 109 l1. 2C
ments. 1B
1.7. General coagulation management We recommend that pH correction should be pursued
Fibrinogen concentration of less than 1.5 to 2 g l1 is during treatment of acidotic coagulopathy, although pH
considered as hypofibrinogenaemia in acquired coagulo- correction alone cannot immediately correct acidosis-
pathy and is associated with increased bleeding risk. C induced coagulopathy. 1C

We recommend that rFVIIa should only be considered In complex cardiovascular surgery we recommend fibri-
alongside pH correction. 1C nogen concentrate infusion guided by VHA monitoring to
reduce perioperative blood loss. 1B
We recommend that calcium should be administered
during massive transfusion if calcium concentration is We suggest that rFVIIa may be considered for patients
low, to preserve normocalcaemia (>0.9 mmol l1). 1B with intractable bleeding during and after cardiovascular
surgery once conventional haemostatic options have been
We suggest that endovascular embolisation is a well
exhausted. 2B
tolerated alternative to open surgical intervention after
failed endoscopic treatment for non-variceal upper We suggest that antiplatelet therapy with aspirin or
gastrointestinal bleeding (UGIB). 2C clopidogrel may be administered in the early postopera-
tive period without increasing the risk of postoperative
We suggest super-selective embolisation as primary
bleeding. 2C
therapy for treatment of angiogram positive lower gastro-
intestinal tract bleeding. 2C We recommend the use of standardised VHA-guided
haemostatic algorithms with pre-defined intervention
We suggest embolisation as first-line therapy for arterial
triggers. 1B
complications in pancreatitis. 2C
1.8.2. Gynaecological (non-pregnant) surgery
1.7.2. Cost implications We suggest that normovolaemic haemodilution should
Both bleeding and transfusion of allogeneic blood pro- not be used as it does not reduce allogeneic transfusion.
ducts independently increase morbidity, mortality, 2B
length of stay in ICU and hospital and costs. B
Cell salvage may reduce allogeneic transfusion in gynae-
Tranexamic acid can reduce perioperative blood loss and cological (including oncological) surgery. B
transfusion requirements; this can be highly cost-effec-
We suggest using preoperative intravenous iron to reduce
tive in several major surgical and trauma settings. B
allogeneic transfusion requirements in anaemic gynaeco-
We recommend restricting the use of rFVIIa to its logical cancer patients receiving chemotherapy. 2B
licensed indication as, outside these indications, the
We suggest using intravenous iron to correct preoperative
effectiveness of rFVIIa to reduce transfusion require-
anaemia in women with menorrhagia. 2B
ments and mortality remains unproven and the risk of
arterial thromboembolic events, as well as costs, are high. Tranexamic acid may reduce perioperative bleeding in
1A gynaecological cancer surgery. C
Cell salvage can be cost-effective in selected patients. A
1.8.3. Obstetric bleeding
The cost-effectiveness of a ratio-driven transfusion pro- We recommend that peripartum haemorrhage (PPH)
tocol has not been investigated. should be managed by a multidisciplinary team. 1C
Goal-directed therapy with coagulation factor concen- We recommended the use of an escalating PPH manage-
trates (fibrinogen and/or PCC) may reduce transfusion- ment protocol including uterotonic drugs, surgical and/or
associated costs in trauma, cardiac surgery and liver endovascular interventions and procoagulant drugs. 1B
transplantation. C
Risk awareness and early recognition of severe PPH are
essential. C
1.8. Algorithms in specific clinical fields
We suggest that patients with known placenta accreta be
1.8.1. Cardiovascular surgery
treated by multidisciplinary care teams. 2C
Withdrawal of aspirin therapy increases the risk of cor-
onary thrombosis; continuation of aspirin therapy Cell salvage is well tolerated in obstetric settings, pro-
increases the risk of bleeding. B vided that precautions are taken against rhesus isoimmu-
nisation. C
Withdrawal of clopidogrel therapy increases the risk of
coronary thrombosis; continuation of clopidogrel therapy We suggest that using perioperative cell salvage during
increases the risk of bleeding. A caesarean section may decrease postoperative homolo-
gous transfusion and reduce hospital stay. 2B
We recommend prophylactic administration of tranexa-
mic acid before CPB in patients undergoing coronary Intravenous iron supplementation improves fatigue at 4,
artery bypass grafting (CABG) surgery. 1A 8 and 12 weeks postpartum. B
We suggest tranexamic acid can be applied topically to We suggest assessing fibrinogen levels in parturients with
the chest cavity to reduce postoperative blood loss fol- bleeding, as levels less than 2 g l1 may identify those at
lowing cardiac surgery. 2C risk of severe PPH. 2B

Dynamic platelet count decrease or a level less than We recommend a low CVP and restrictive fluid admin-
100 109 l1 at the onset of labour, particularly if com- istration during liver surgery to reduce bleeding. 1B
bined with plasma fibrinogen level less than 2.9 g l1, may
We recommend tranexamic acid for treatment of
indicate an increased risk of PPH. C
fibrinolysis (evident from microvascular oozing or
At the beginning of labour aPTT and PT are of little VHA clot lysis measurement) but not for routine
predictive value for PPH. C prophylaxis. Marginal grafts (e.g. donation after
cardiac death) increase the risk of fibrinolysis postre-
VHA can identify obstetric coagulopathy. B
perfusion. 1C
We recommend against pre-emptive fibrinogen replace-
We suggest that tranexamic acid should be considered in
ment; however, in ongoing PPH with hypofibrinogenae-
cirrhotic patients undergoing liver resection. 2C
mia we recommend fibrinogen replacement. 1C
In severe PPH we suggest a VHA-guided intervention 1.8.7. Acute upper gastrointestinal bleeding
protocol. 2C We recommend that acute variceal bleeding should be
managed by a multidisciplinary team. A specific multi-
We suggest that tranexamic acid be considered before
modal protocol for upper gastrointestinal haemorrhage
caesarean section and in cases of antepartum bleeding. 2B
should be available. 1C
We recommend the administration of tranexamic acid in
Transjugular intrahepatic portosystemic stent-shunt
PPH at a dose of 1 g intravenously (IV) as soon as
(TIPSS) can be suggested as an option for rescue
possible, which can be repeated if bleeding continues. 1B
therapy after initial medical and endoscopic therapy
fail. 2B
1.8.4. Orthopaedic surgery and neurosurgery
Reduced platelet activity is associated with early haema- We recommend early interventional endoscopy and the
toma growth, more intraventricular haemorrhage and immediate use of vasopressors (somatostatin or terlipres-
worse 3-month outcomes following intracranial haemor- sin) to reduce bleeding. 1B
rhage (ICH). C Tranexamic acid reduces mortality but not re-bleeding. B
Low platelet count, low plasma fibrinogen concentration
and factor XIII deficiency are predictive of bleeding 1.8.8. Coagulopathy and renal disease
complications in ICH, intracranial surgery and major spine Point-of-care tests of platelet function and bleeding
surgery, particularly when they occur in combination. C time provide no reliable platelet function assessment
in uraemia and no prediction of bleeding in this
setting. C
1.8.5. Paediatric surgery
We suggest low-volume sampling for standard coagu- We suggest that conjugated oestrogen therapy should be
lation tests and VHA-guided interventions. 2C used in uraemia. 2C
We recommend the use of isotonic and balanced resus- We suggest that DDAVP should be considered for redu-
citation fluids in bleeding children. 1C cing bleeding during surgery and for managing acute
bleeding in uraemic patients. 2C
Except for premature babies and cyanotic newborns, haemo-
globin targets in bleeding children are 7 to 9 g dl1. C 1.9. Antithrombotic drugs
1.9.1. Antiplatelet agents
1.8.6. Visceral and transplant surgery We recommend that aspirin therapy should continue
Despite PT, aPTT and INR indicating coagulopathy in perioperatively in most surgical settings, especially car-
chronic liver disease (CLD), global coagulation tests diac surgery. 1C
(thrombin generation and VHA) suggest that haemostasis
Where aspirin withdrawal before surgery is considered,
is balanced in stable CLD. C
we recommend a time interval of 3 days. 1C
Mild-to-moderate prolongation of the preoperative PT
In patients with risk factors for vascular complications
and INR do not predict bleeding in patients with CLD. C
nave of any antiplatelet treatment, it is not recom-
We recommend that, in acute liver failure, moderately mended that treatment with aspirin be initiated preo-
elevated INR should not be corrected before invasive peratively. 1B
procedures, with the exception of intracranial pressure
In patients treated chronically with aspirin for the sec-
monitor insertion. 1C
ondary prevention of cardiovascular events, except those
Fluid restriction, phlebotomy, vasopressors and transfu- patients with coronary stents, we recommend aspirin
sion protocols may be associated with low transfusion interruption for procedures where there is a very high
rates during orthotopic liver transplant (OLT). C bleeding risk. 1B

In patients chronically treated with aspirin for secondary 1.9.2. Heparin

prevention of cardiovascular events, we recommend We recommend that severe bleeding associated with
aspirin be maintained during and after low and medium intravenous unfractionated heparin (UFH) should be
bleeding risk procedures. 1B treated with intravenous protamine at a dose of 1 mg
per 100 IU UFH given in the preceding 2 to 3 h. 1A
We suggest careful consideration of postoperative bleed-
ing complications when timing the first postoperative We suggest that severe bleeding associated with subcu-
administration and dose of anticoagulants along with taneous (SC) UFH unresponsive to intravenous prota-
resumption of aspirin. 2C mine at a dose of 1 mg per 100 IU UFH could be treated
by continuous administration of intravenous protamine,
For intraoperative or postoperative bleeding clearly
with the dose guided by aPTT. 2C
related to aspirin, we suggest that platelet transfusion
be considered (dose: 0.7 1011 per 10 kg body weight in We suggest that severe bleeding related to SC low
adults). 2C molecular weight heparin (LMWH) should be treated
with intravenous protamine at a dose of 1 mg per 100
We recommend that aspirin be continued for at least 4
antifactor Xa units of LMWH administered and, if unre-
weeks after bare metal stent (BMS) implantation and 3 to
sponsive, with a further 0.5 mg protamine per 100 anti-
12 months after drug-eluting stent (DES) implantation,
factor Xa units. 2C
unless the risk of life-threatening surgical bleeding on
aspirin is unacceptably high. 1A
1.9.3. Fondaparinux
We suggest that P2Y12 inhibitor treatment be considered We suggest that the administration of rFVIIa could be
for at least 4 weeks after BMS implantation and 3 to 12 considered to treat severe bleeding associated with SC
months after DES implantation, unless the risk of life- administration of fondaparinux (off-label treatment). 2C
threatening surgical bleeding on this agent is unaccep-
tably high. 2A 1.9.4. Vitamin K antagonists
We recommend that VKAs should not be interrupted in
If clinically feasible, we suggest postponing (semi-
patients undergoing low bleeding risk procedures: skin
urgent) surgery for at least 5 days after cessation of
surgery, dental and oral procedures, gastric and colonic
ticagrelor and clopidogrel, and for 7 days in the case of
endoscopies (even if biopsy is scheduled, but not poly-
prasugrel, unless the patient is at high risk of an ischaemic
pectomies), nor for most ophthalmologic surgery [i.e.
event. 2B
mainly anterior chamber (cataract)]. 1C
We recommend that antiplatelet agent (APA) therapy
We recommend that for low or moderate thrombotic risk
should resume as soon as possible postoperatively to
patients [e.g. atrial fibrillation patients with CHADS2
prevent platelet activation. 1C
score 4; patients treated for >3 months for a non-
We suggest that the first postoperative dose of clopidogrel recurrent venous thromboembolism (VTE)] undergoing
or prasugrel should be given no later than 24 h after skin procedures requiring INR less than 1.5, VKA should be
closure. We also suggest that this first dose should not be a stopped 3 to 5 days before surgery (acenocoumarol,
loading dose. 2C warfarin). No bridging therapy is needed. Measure
INR on the day before surgery and give 5 mg oral vitamin
We recommend that a multidisciplinary team meeting
K if INR exceeds 1.5. 1C
should decide on the perioperative use of APAs in urgent
and semi-urgent surgery. 1C We recommend bridging therapy for high thrombotic risk
patients (e.g. atrial fibrillation patients with a CHADS2
We suggest that urgent or semi-urgent surgery should be
score >4; patients with recurrent VTE treated for less
performed under aspirin/clopidogrel or aspirin/prasugrel
than 3 months; patients with a prosthetic cardiac valve).
combination therapy if possible, or at least under aspirin
Warfarin: last dose 5 days before surgery; 4 days before
alone. 2C
surgery, no heparin; 3, 2 and 1 day before surgery,
We suggest that platelet transfusion be considered (dose: LMWH (last dose 24 h before surgery) or SC UFH twice
0.7 1011 per 10 kg body weight in adults) in cases of or thrice daily; day 0, surgery. Acenocoumarol: 3 days
intraoperative or postoperative bleeding clearly related to before surgery, last dose; 2 and 1 day before surgery, same
clopidogrel or prasugrel. 2C protocol as for warfarin. 1C
According to pharmacological characteristics, we suggest We suggest that the therapeutic dose of LMWH or UFH
that the management of ticagrelor may be comparable to should be tailored for each patient, depending on the
clopidogrel (i.e. withdrawal interval of 5 days). 2C respective thrombotic and bleeding risks. 2C
Platelet transfusions may be ineffective for treating We recommend that for low bleeding risk patients, VKAs
bleeding related to ticagrelor if given within 12 h of should be restarted during the evening or the day after
the drugs administration. C the procedure (at least 6 h after). Therapeutic doses of

LMWH should be given postoperatively until the target We suggest that for low bleeding risk procedures, when
INR is observed in two following measurements. 1C haemostasis is achieved, DOACs should be recom-
menced during the evening after the procedure (at least
We recommend that for moderate to high thrombotic risk
6 h after). 2C
patients, prophylactic doses of heparin (UFH or LMWH)
should be started during the evening or the day after the We suggest that for intermediate and high bleeding risk
procedure (at least 6 h after) and given for up to 48 to 72 h, procedures, prophylactic doses of LMWH or DOACs
and then therapeutic anticoagulation should be resumed. (according to specific indications) should be given post-
VKA can restart at that time or later, only when surgical operatively whenever VTE prophylaxis is requested and
haemostasis is achieved. 1C then the full therapeutic dose of DOAC should be
resumed up to 72 h postoperatively, when surgical haemo-
In VKA-treated patients undergoing an emergency pro-
stasis is achieved. 2C
cedure, we recommend that INR must be measured on
the patients admission to the hospital, with the admin-
1.10. Comorbidities involving haemostatic
istration of four-factor PCC to reverse VKA anticoagulant
derangement
effects (e.g. at an initial dose of 25 IU factor IX kg1 at an
1.10.1. Systemic, metabolic and endocrine diseases
INR of 4) rather than the transfusion of plasma. 1B
We suggest that patients with haemostatic derangements
In bleeding patients where VKA-induced coagulopathy is associated with systemic, metabolic and endocrine dis-
considered a contributing factor, we recommend the eases should be managed perioperatively in collaboration
administration of four-factor PCC 25 to 50 IU factor IX with a haematologist. 2C
kg1 plus 5 to 10 mg IV vitamin K. 1B
We suggest individualised preoperative discontinuation
If PCC is not available, then in bleeding patients where of selective serotonin reuptake inhibitor (SSRI) treat-
VKA-induced coagulopathy is considered a contributing ment. 2B
factor, we recommend the transfusion of plasma (15 to
We suggest individualised preoperative discontinuation
20 ml kg1 plus 5 to 10 mg IV vitamin K). 1C
of antiepileptic agents, such as valproic acid, which may
increase bleeding. 2C
1.9.5. Direct oral anticoagulants We do not recommend preoperative discontinuation of
We recommend assessment of creatinine clearance in gingko biloba extracts. 1B
patients receiving direct oral anticoagulants (DOACs)
who are scheduled for surgery. 1B 1.11. Patients with congenital bleeding
disorders
We suggest that DOACs should only be withheld the day
1.11.1. Preoperative assessment
before surgery for patients undergoing low bleeding risk
We suggest referring the patient to a haematologist for
procedures such as skin surgery, dental and oral pro-
assessment and planning of the intervention if inherited
cedures, gastric and colonic endoscopies (even if biopsy
bleeding disorders (IBDs) are suspected preoperatively. 2C
is scheduled, but no polypectomies) and most ophthal-
mological surgery. 2C We recommend the use of bleeding assessment tools
(BATs) for detecting and predicting the perioperative risk
For intermediate and high bleeding risk procedures
of bleeding before surgery and invasive procedures. 1C
(1) we recommend that rivaroxaban, apixaban and 1.11.2. General perioperative management
edoxaban should not be given for 2 days before Surgery can be safely performed in patients with IBDs
the procedure (i.e. last oral intake 3 days before), when there is appropriate careful preoperative planning,
pending a creatinine clearance (CockcroftGault appropriate replacement/substitution therapy, and multi-
formula) above 30 ml min1. No bridging therapy is disciplinary team management. C
needed. 1C
(2) we recommend that dabigatran should not be given We recommend that patients with IBDs be managed
for 3 days before the procedure (i.e. last oral intake 4 perioperatively in collaboration with a haematologist,
days before), if the creatinine clearance is above 50 preferably in dedicated centres with expertise in coagu-
ml min1 and 4 days before the procedure (i.e. last lation disorders. 1C
oral intake 5 days before), if the creatinine clearance We suggest preoperative haemostatic correction in
is between 30 and 50 ml min1. No bridging therapy patients with IBDs depending on the type of surgery. 2C
is needed. 1C
1.11.3. Von Willebrand disease
We suggest that in severe bleeding patients treated with We recommend DDAVP as a first-line treatment for
dabigatran, a specific antidote (idarucizumab) should be minor bleeding/surgery in patients with von Willebrand
considered. 2C disease (VWD), after a trial testing. The standard

regimen is 0.3 mg kg1 dissolved in 50 ml saline and If rFVIIa is given to control perioperative bleeding in
infused IV over 20 to 30 min, repeated every 12 to inherited factor VII deficiency, we suggest lower doses
24 h usually for no more than 3 days. 1C (e.g. 20 to 25 mg kg1 every 4 to 6 h) than in haemophilia
patients with inhibitors. 2C
We recommend replacement of von Willebrand factor
(VWF) with plasma-derived products for major bleeding/ There are insufficient data to recommend rFVIIa in
surgery. Treatment regimens are specified by published perioperative bleeding for patients with other RBDs.
guidelines. 1C
There are insufficient data to recommend peri-
We suggest that antifibrinolytic drugs be used as haemo- procedural DDAVP or antifibrinolytic drugs in patients
static adjuncts. Treatment regimens are specified by with mild RBDs.
published guidelines. 2C
1.11.4. Platelet defects 2. Introduction

We suggest that DDAVP be used to prevent/control Perioperative bleeding management is a complex and
perioperative bleeding in patients with mild inherited changing field requiring multiple assessments and appro-
platelet defects. 2C priate strategies to optimise patient care. There is an
ongoing drive to find new alternatives to transfusion, a
We suggest that antifibrinolytic drugs be used as haemo- desire to reduce unnecessary use of blood products and a
static adjuncts in procedures involving patients with focus towards more evidence-based perioperative practice.
inherited platelet defects. 2C In this dynamic area of medicine it is imperative to provide
We recommend that rFVIIa treatment should be con- healthcare professionals with clinically useful and up-to-
sidered in patients with Glanzmann thrombasthenia date data concerning the diagnosis and treatment of
undergoing surgery. 1C patients with perioperative bleeding. As such, the Euro-
pean Society of Anaesthesiology (ESA) strongly supports
We recommend against routine platelet transfusion in the development of high-quality, evidence-based clinical
patients with inherited platelet disorders. 1C practice guidelines to help standardise the approach to
patient care and to improve overall clinical practice.1
1.11.5. Haemophilia A and B In 2013, the ESA developed an extensive set of evidence-
We recommend adequate perioperative replacement based guidelines2 for the management of severe perio-
therapy to ensure well tolerated surgery in haemophilia perative bleeding with the overall aim of providing an up-
patients. 1C to-date review and synthesis of the evidence and recom-
We suggest that perioperative replacement therapy (tar- mendations to help guide clinicians towards safer and more
get factor level and duration) in haemophilia patients cost-effective strategies for minimising severe periopera-
follows published guidelines. 2C tive bleeding and thus maximising blood conservation.
The current guidelines update provides additional infor-
We recommend either recombinant products or plasma- mation to assist the clinician to PREPARE, PLAN and
derived concentrates for perioperative replacement take ACTION. PREPARE for any potential bleeding risks
therapy in haemophilia patients. 1C by performing preoperative assessments, particularly to
We suggest that coagulation factors be given periopera- detect anaemia and allow time for its correction. PLAN for
tively by continuous infusion. 2C any intraoperative bleeding that may occur by utilising
transfusion algorithms that incorporate pre-defined trans-
We suggest either rFVIIa or activated PCCs for haemo- fusion triggers to help guide haemostatic intervention, by
philia patients with inhibitors. 2C being aware of the limitations of standard coagulation tests
We suggest antifibrinolytic drugs as perioperative adjunct and by modifying the approach accordingly to use point-of-
therapy in haemophilia patients. 2C care testing and others. If potential bleeding risks are
known in advance and a plan of treatment is in place,
We suggest DDAVP as first-line perioperative therapy in the necessary ACTION can be set in motion as required.
patients with mild haemophilia A as long as factor VIII Because of the increasing evidence in this field, an update
can be raised to an appropriate therapeutic level. 2C of the guidelines was planned every 2 years.
This document not only details the retained recommen-
1.11.6. Rare bleeding disorders
dations, suggestions and statements from the original
There are insufficient data to recommend routine peri-
guidelines published in 20132 but also includes new
operative supplementation of deficient factors in patients
recommendations as well as revisions to the wording
with rare bleeding disorders (RBDs).
and grades of some of the original recommendations.
We suggest that rFVIIa be used in perioperative bleeding Additional clinical questions have been included in
due to inherited factor VII deficiency. 2C the update.

3. Methods recommendations are still valid and should be considered

3.1. Task force selection as clinically relevant.
In the planned process of revising the guideline, Man-
agement of severe perioperative bleeding: Guidelines Guidance in the clinical fields of anaemia management,
from the European Society of Anaesthesiology pub- optimisation of haemostasis, and blood conservation mod-
lished in 2013,2 the ESA Guideline Committee (Chair- alities makes these ESA guidelines the first European
man, EDR) re-nominated the ESA Task Force guidelines on patient blood management (PBM). The
previously selected, chaired by SAKL, and composed World Health Organization encouraged all member states
of AA, PWo, CA, and EDR. The ESA Guideline Com- to implement PBM programmes employing such multiple
mittee and the task force defined the scope of the combined strategies to increase and preserve autologous
guideline revision, which prompted the core group to erythrocyte volume to minimise the transfusion of blood
invite scientific societies involved in the field to suggest components such as RBCs, platelets, FFP.3 Anaemia is
experts to join the task force as affiliate co-authors associated with increased morbidity and mortality and
(advisory group). The first meeting of the extended panel may also be a condition that prompts medical professionals
was held during the Euroanaesthesia meeting in Berlin in to initiate RBC transfusion.4 The latter itself may be
May 2015. associated with increased morbidity due to infectious,
immunological or pulmonary complications.58 These com-
plications are also recorded following the administration of
3.2. Search for evidence platelets and/or FFP.8
For this update we searched Medline (Ovid), Embase
(Embase.com), the Cochrane Library (Wiley), BIOSIS General guidance on the management of severe perio-
(Web of Science), Science Citation Index Expanded perative bleeding is applicable across all clinical settings.
(Web of Science), Conference Proceedings Citation Therefore, to reduce redundancy, the section on general
Index Science (Web of Science), and PubMed (for coagulation management is relevant to all patient
non-Medline contents). The searches were conducted categories whereas guidelines that are specific to a
between March and July 2015 and limited to publication particular setting are detailed in separate sections. Any
dates since 2011 or 2012 (depending on the search). guidance for therapeutic interventions is always based on
Guidelines, case reports, editorials and commentaries the prerequisite of severe bleeding manifestations: in
were excluded from the search result. No other limita- the absence of bleeding the correction of a laboratory
tions were used. As with the original guidelines, we result indicating a pathological coagulation parameter is
conducted 12 separate searches, using both free text not recommended.
terms and subject headings: one general search on the The final draft of the guideline was reviewed by external
topic of perioperative bleeding, one search for systematic reviewers and posted on the ESA website for four weeks,
reviews, and one search for each topic within these and all individual and national ESA members were
guidelines. A total of 18 334 references were retrieved. invited to comment. The final manuscript was approved
The exact search strategies and numbers of references for by the Guidelines Committee and the ESA Board before
each search are reported in Appendix 1 (Supplemental submission for publication.
Digital File: ESA POB guidelines update search
Nov2016.docx, http://links.lww.com/EJA/A118). Both The overall aim of these updated guidelines is to provide
task force members and the extended panel members healthcare professionals with the most recent evidence to
reviewed the selected articles relevant to their sections help ensure improved clinical management of patients
and evaluated these according to the ESA policy on with perioperative bleeding. The search strategy was
guidelines development.1 A total of 733 references were based on pre-defined criteria, and supplementary
included for the guideline update. searches were performed to make this process as robust
as possible. The authors assessed all publications relevant
to their sections and the existing 2013 recommendations
3.3. Guideline preparation were revised with respect to wording or changes to the
To revise the guidelines, the task force referred to the grading of the quality of evidence, as appropriate. New
same series of key clinical questions about the manage- recommendations were also prepared to reflect additional
ment of severe perioperative bleeding as used for the clinical questions.
previous guideline. These questions formed the basis for
reviewing the evidence published after 2012 and, when The guideline uses the same grading system as in the
the new evidence was strong enough, for developing new previous guidelines the Grading of Recommendations
recommendations or modifying the existing recommen- Assessment, Development and Evaluation (GRADE)
dations. Downgrading of the quality of evidence occurred system2 (Table 1). Therefore, recommendations and
for some existing recommendations; this was due to suggestions are assigned a number (relating to the
methodological issues in the studies and not because strength of the recommendation) and a letter (relating
of new contradictory evidence. All downgraded to the quality of the supporting evidence). Statements are

accompanied only by a letter, to indicate the quality of concluded that, when measured on CPB prior to wean-
the evidence supporting the statement. ing, a FIBTEM A10 (clot amplitude at 10 min) 10 mm
or less may be an early alert for post-CPB fibrinogen
It is important to emphasise that these recommendations
levels below, or within, the range for supplementation
can be adopted, modified, or not implemented, depend-
(1.5 to 2.0 g l1) recommended in case of post-CPB
ing on the requirements of different institutions
coagulopathic bleeding.
or countries.
There are indications that EXTEM (extrinsic throm-
4. Evaluation of coagulation status boelastometry), INTEM (intrinsic thromboelastometry)
4.1. Perioperative coagulation testing and APTEM (aprotinin thromboelastometry) are associ-
New evidence supports the existing recommendations ated with fibrinogen and platelet levels: INTEM
and this is detailed below for the relevant sections. clotting time (CT) correlated significantly with aPTT
and FIBTEM correlated significantly with fibrinogen,
4.1.1. Standard laboratory tests for coagulation whereas factor VIII (FVIII) correlated significantly
monitoring with all ROTEM (rotational thromboelastometry)
4.1.1.1. Fibrinogen concentration parameters except EXTEM CT, INTEM CT, FIB-
Fibrinogen concentration is often determined indirectly TEM CT and APTEM clot formation time (CFT)
using the Clauss method.9 In a recent paper, considerable and maximum clot firmness (MCF).14 However, other
differences were found between Clauss-based plasma publications have found it difficult to find a clear corre-
fibrinogen measured using different detection lation between findings from VHA [TEG (thromboelas-
methods.10 However, the similarity between measure- tography) and ROTEM] monitoring to SLTs such as PT
ments, shortly before weaning from CPB and after CPB and aPTT perioperatively and overall haemostatic
within the same centres, indicated that on-pump measurement.15 17
measurements could provide an early estimation of fibri-
nogen deficit after CPB. 4.1.3. Which approaches can be used for
preoperative evaluation of coagulation status?
Fibrinogen levels may be linked with postoperative
4.1.3.1. Standardised bleeding history and clinical
blood loss and a recent systematic review reports a
evaluation
significant but weak-to-moderate correlation between
Recommendations
preoperative and postoperative fibrinogen levels and
postoperative blood loss in cardiac surgery.11 Before surgery or invasive procedures, we recommend the use of
a structured patient interview or standardised questionnaire
4.1.2. Viscoelastic haemostatic assay coagulation which considers clinical and family bleeding history and
monitoring detailed information on the patients medication. 1C
VHA coagulation monitoring uses whole blood and is
We recommend the use of standardised questionnaires on
performed in the emergency room, operating theatre, or
bleeding and drug history as preferable to the routine use of
the central laboratory. In a recent systematic review,
conventional coagulation screening tests such as aPTT, INR
VHA coagulation monitoring was found to be cost-saving
and platelet count in elective surgery. 1C
and more effective than standard laboratory tests (SLTs),
in both patients undergoing cardiac surgery and trauma Structured patient interviews are a primary tool for
patients.12 preoperative assessment of bleeding risk, and physical
examination should focus on signs of bleeding or diseases
4.1.2.1. Commonly used blood modification agents for which may cause haemostatic failure. Comorbidities,
viscoelastic haemostatic assay coagulation monitoring including renal dysfunction, are independent risk
VHA coagulation monitoring can be performed using factors for bleeding and transfusion; for example, a
recalcified, citrated blood alone [native thromboelasto- recent systematic review found that chronic kidney
metry (NATEM) assay with no activation enhancement disease is associated with perioperative bleeding
or additional modifications, and clotting is initiated but not bleeding that required reoperation.18 Among
intrinsically by the surface of the cup and pin]. More cardiac surgery patients, patient-related predictors of
usually, activators are added to accelerate coagulation, excessive bleeding after surgery were reported to be
and modifying agents can suggest the cause of the male gender, higher preoperative haemoglobin levels,
observed coagulopathy. The most commonly used VHAs lower BMI, diabetes mellitus, impaired left ventricular
to measure fibrin clot quality include the functional function, lower amount of pre-bypass thrombin gener-
fibrinogen and FIBTEM (Fibrinogen thromboelastome- ation, lower preoperative platelet counts, decreased pre-
try) assays. These assays measure the strength of the operative platelet aggregation, preoperative platelet
fibrin-based clot and a low functional fibrinogen/FIB- inhibition level more than 20%, preoperative thrombo-
TEM clot strength usually indicates fibrinogen cytopaenia, and lower preoperative fibrinogen concen-
deficiency. In a study by Erdoes et al. 13 the authors tration.19

4.1.3.2. Preoperative use of standard laboratory tests between measurements shortly before weaning from
Preoperative use of SLTs is not recommended by current CPB and after weaning suggests that on-pump measure-
ESA guidelines. Furthermore, in patients without a ments could provide an early estimation of a likely deficit
previous history of bleeding or bleeding disorders, SLTs in fibrinogen post-CPB, and therefore guidance for any
are not generally recommended.20 In the neurosurgical haemostatic therapy. In paediatric non-cardiac surgery
setting, the value of preoperative PT testing is limited in patients, SLTs correlate poorly with intraoperative acti-
patients awaiting elective procedures in whom a normal vated clotting time (ACT).28
bleeding history can be established.21
4.1.4.2. Intraoperative use of viscoelastic haemostatic
A recent meta-analysis reported a significant but weak-to-
assay coagulation monitoring
moderate correlation between preoperative and post-
A recent health technology assessment reports findings
operative fibrinogen levels and postoperative blood loss
from a meta-analysis showing that perioperative VHA
in cardiac surgery.11 Preoperative measurement of fibri-
monitoring is associated with a reduced need for transfu-
nogen may be useful to identify those patients at risk of
sion of RBCs, platelets and FFP compared with monitor-
postoperative bleeding.
ing by SLTs.12 If using VHA coagulation monitoring,
Recent evidence indicates that patients with end-stage appropriate transfusion triggers should be considered
liver disease and an elevated INR can safely undergo carefully.29
invasive cardiac procedures as elevated INR does
not predict catheterisation-related bleeding compli- 4.1.4.2.1. Intraoperative viscoelastic haemostatic assay
cations.22 However, in paediatric living donor liver trans- monitoring in trauma
plantation, preoperative INR was the only predictive risk In paediatric patients with traumatic brain injury, hypo-
factor for massive blood transfusion.23 In adult OLT coagulation measured by TEG is associated with
recipients, a higher preoperative INR was also found mortality and hypercoagulation is associated with survi-
to be associated with increased RBC administration val.30 The timing of sampling and pre-hospital haemo-
(both autologous and cell salvage). Each INR increase static assessment was investigated in a prospective study
of 1 unit resulted in a 36% increase in the predicted of 50 trauma patients and no additional information was
number of units of RBCs required.24 However, there is gained by pre-hospital assessment.31 A small randomised
currently little evidence to support additional, routine controlled trial (RCT) of 30 patients with surgical exci-
application of point-of-care INR testing in the preopera- sion of burn wounds performed on the third day after
tive setting to predict bleeding tendency. For example, burn trauma showed a reduced need for allogeneic blood
point-of-care INR measurements for trauma patients transfusions when a bleeding management algorithm
during various stages of admission and resuscitation based on thromboelastometry was used.32 A recent
could not be used to identify or exclude patients with Cochrane systematic review investigating the diagnostic
acute traumatic coagulopathy.25 test accuracy of TEG and ROTEM in patients with
clinically suspected trauma-induced coagulopathy found
4.1.3.3. Preoperative use of viscoelastic haemostatic no evidence on the accuracy of TEG and very little
assay coagulation monitoring evidence on the accuracy of ROTEM: this was due to
VHA is used for rapid diagnosis of bleeding causes and is the small number of included studies and concerns about
of most value intraoperatively. Indiscriminate preopera- the risk of bias.33 These results are supported by other
tive coagulation monitoring using VHAs is unlikely to be studies.34,35
cost-effective, but it may be warranted in combination
with SLTs in patients with bleeding disorders such as 4.1.4.2.2. Intraoperative viscoelastic haemostatic assay
VWD, factor XIII (FXIII) deficiency, and haemophilia A monitoring in cardiovascular surgery
with dysfibrinogenaemia, or in patients with preoperative The value of VHA monitoring to guide haemostatic
anticoagulant treatment.26,27 therapy following CPB has been demonstrated in several
RCTs.3646 The majority of published randomised trials
4.1.4. Which coagulation monitoring tests can be investigating VHA-guided transfusion have been per-
used to guide intraoperative haemostatic therapy? formed in cardiac surgery and several reviews have
4.1.4.1. Intraoperative use of standard laboratory tests reported a reduced need for allogeneic blood transfu-
For laboratory measurement of fibrinogen to be useful in sion.12,47,48 Thus, 11 randomised trials have been pub-
cardiovascular surgery, analysis would need to begin lished investigating different algorithms and triggers,
before the patient is taken off CPB. Such measurement different devices, and different subgroups of cardiac
is prevented by the sensitivity of the Clauss assay to surgery patients.47 Special attention has been given to
heparin. However, a study by Solomon et al.10 demon- the study by Weber et al.45 which was terminated pre-
strated that there were no significant differences in maturely after an interim analysis showed a significantly
fibrinogen concentration before and after weaning from improved survival using VHA-guided therapy. The study
CPB, for most centres and methods used. The similarity specifically investigated the use of a VHA-guided

algorithm in patients with coagulopathy or severe post- Long turnaround times may preclude the use of some
operative bleeding. Meta-analysis of pooled data from tests in emergency situations. However, implementation
1089 patients suggests a benefit in terms of reduced blood of VHA monitoring appears rational if the alternative is
requirements, even if insufficient data were available on haemostatic management guided by clinical judgement
mortality.12 However, most trials have a high risk of alone. In a recent analysis, the use of VHAs was found to
bias.47,48 Finally, in cardiac surgery with CPB, it might be effective in reducing RBC transfusion, platelet trans-
be an advantage to combine VHA with platelet function fusion and FFP transfusion.12 VHAs were also cost-saving
assays.37,45,46,49 and more effective than SLTs in patients undergoing
cardiac surgery and in trauma patients.
4.1.5. Postoperative evaluation of coagulation status Antithrombin III (AT III), a potent anticoagulant with
Potential complications following surgery include throm- independent anti-inflammatory properties, irreversibly
boembolic events and, conversely, recurrent or excessive inhibits serine proteases (e.g. activated factor X and
bleeding. Postoperative coagulation monitoring in the thrombin). There have often been arguments to increase
ICU can provide information regarding appropriate the antithrombin concentration to supranormal values
haemostatic interventions or further procedures which because the activity of pro-inflammatory and pro-coagu-
may be required. lant molecules are increased in critically ill patients.54
Currently, it remains uncertain whether low postopera- However, in a recent Cochrane systematic review, the
tive fibrinogen levels are causally associated with post- effect of supplementation with AT III in critically ill
operative bleeding.50 In paediatric cardiac surgery, post- patients was found to be of questionable value based on
CPB plasma fibrinogen concentration appears to influ- the available evidence, and there was an increased risk of
ence blood loss, with a fibrinogen concentration of at least bleeding in those receiving AT III to attain supranormal
1.5 g l1 or an MCF of at least 3 mm accurately predicting values.55
excessive blood loss.51 Prediction of postoperative bleed- Nevertheless, supplementation with AT III in a cardiac
ing volume using haemostatic assessment, including surgical setting to avoid FFP transfusion may be con-
VHAs, is not convincing.52,53 However, haemostatic sidered as an option, although one has to consider the
deficiencies are not the sole cause of postoperative bleed- extensive cost and the risk of heparin rebound in the early
ing and attempts to predict bleeding are often thwarted postoperative period.56
by the presence of more obvious surgical causes. The
ability to rapidly exclude haemostatic impairment is of In the paediatric liver transplantation population, the AT
great value as normal haemostasis in a patient with post- III levels are often found to be reduced postoperatively
operative bleeding would indicate a surgical cause of but there is still controversy as regards management of
bleeding and this differentiation might speed up the this deficit.57
decision to re-operate. Two RCTs, with a total of 192
patients, investigated the use of VHAs in the treatment of 4.2. Evaluation of platelet function
excessive postoperative bleeding or suspected coagulo- Identification of platelet function is important for inform-
pathy in cardiac surgery patients.42,45 Both studies ing perioperative haemostatic management. There are
suggest a reduced need for allogeneic transfusion and several methods for assessing platelet function, each with
the study by Weber et al.45 showed reduced mortality. its own limitations. The number of existing devices and
Six other RCTs investigating intraoperative use of their clinical validation is constantly evolving, as is their
VHA-monitored haemostatic treatment also applied the utility in various settings.
interventional algorithm to the beginning of the post-
Recommendations
operative period from 2 h postoperatively up until the
entire ICU stay.32,36,37,39,40,46 We suggest preoperative platelet function testing only in associ-
ation with a positive bleeding history. 2B
4.1.6. Are patient outcomes improved by algorithms We suggest that preoperative platelet function testing be used to
that incorporate monitoring for perioperative identify decreased platelet function caused by medical conditions
haemostatic management? or antiplatelet medication. 2B
Recommendations
Bleeding time is influenced by many variables and is not useful
We recommend the application of intervention algorithms for stratifying bleeding risk. C
incorporating pre-defined triggers and targets based on VHA
coagulation monitoring to guide individualised haemostatic
intervention in the case of perioperative bleeding. 1C 4.2.1. Which platelet function tests can be used
preoperatively for identifying disturbances of primary
If VHA is not available we recommend the application of haemostasis?
intervention algorithms incorporating pre-defined triggers based In thrombocytopaenic patients, several tests such as
on conventional coagulation tests. 1C platelet indices, Multiplate, Cone and Plate(let) Analyser

(CPA, Impact-R), viscoelastic methods and PFA-100 comparing VerifyNow, TEG, AggreGuide, Platelet-
(Platelet function analyser-100) are rapid and easy to works, vasodilator-stimulated phosphoprotein (VASP)
perform.58 However, PFA-100 lacks sensitivity for known phosphorylation and light transmission aggregometry
platelet secretion defects and, while others appear (LTA).66 However, they observed little correlation
superior in this regard, the evidence remains sparse in among the platelet function tests and little correlation
thrombocytopaenic patients. Current evidence indicates between those assays and perioperative bleeding.
that the flow cytometric marker for activation of P-selec-
tin and surface coverage by the Cone and Plate(let)
analyser may predict bleeding in selected 4.2.2.3. Neurointerventional procedures
thrombocytopaenic populations. Despite the increasing use of point-of-care platelet func-
tion assays, in a recent guideline, the authors state that
4.2.2. Preoperative platelet function testing in most of the current evidence is extrapolated from other
different clinical settings settings and there is insufficient data to recommend
4.2.2.1. Trauma routine platelet function testing prior to neuroinvasive
In the setting of traumatic brain injury with trauma- procedures.67
induced coagulopathy, multi-modality monitoring of pla-
telet function appears to detect patients at risk of bleed-
4.2.3. Genetic testing of patients with suspected
ing and may, together with TEG/ROTEM, guide platelet function disorders
transfusion management.26,59 Inherited platelet function disorders (PFDs) may be
associated with normal or reduced platelet counts. PFDs
4.2.2.2. Cardiac surgery account for a significant proportion of bleeding diatheses
Preoperative platelet function testing may increase the and the identification of the underlying genetic defects
predictive value of postoperative bleeding in patients remains challenging.68,69 The majority of patients with
undergoing CABG surgery.60 Platelet dysfunction PFDs have normal platelet counts and mild bleeding
measured during re-warming and postprotamine has been symptoms but are at increased risk of bleeding in the
shown to be independently associated with high blood context of trauma, surgery or childbirth.70 In these
loss in cardiac surgery.61 patients, a significant number of mutations are hetero-
In a recent large observational study in adult cardiac zygous and, in isolation, are unlikely to cause extensive
surgery examining the predictive value of multiple elec- bleeding. The genetic complexity of PFDs highlights
trode platelet aggregometry (Multiplate), the ADP test plausible candidate genes for targeted analysis.71
(adenosine diphosphate test) and the TRAPtest (throm-
bin receptor activator peptide test) were found to predict 5. Anaemia management
the requirement for perioperative blood transfusion.62 5.1. Preoperative correction of anaemia
5.1.1. Introduction
A recent systematic review on the role of point-of-care Perioperative anaemia increases the risk of numerous
platelet function testing in predicting postoperative complications, such as acute kidney injury.72 Preopera-
bleeding concluded that incorporation of point-of-care tive anaemia has been shown to be predictive for peri-
platelet function tests into transfusion management operative transfusion of allogeneic blood products such as
algorithms was associated with a reduction in blood RBCs, which itself carries a significant risk of adverse
loss and transfusion requirements following cardiac events and mortality.73 A large study estimated the
surgery.63 However, this has been disputed by others prevalence of preoperative anaemia to be 31.1% in
due to the lack of high-quality studies.64 women and 26.5% in men.74 High rates have been
In a recent European guideline on the role of platelet reported in some orthopaedic procedures such as total
function testing in patients undergoing percutaneous knee arthroplasty (TKA), whereas lower rates have been
coronary intervention, the authors advocate the use of observed in other orthopaedic procedures such as treat-
VerifyNow and Multiplate as point-of-care tests to pre- ment of hip fracture.75
vent methodological errors during testing and to allow for
easier generalisation of test results.65 Nevertheless, the
5.1.2. Preoperative assessment of anaemia
authors recommend that platelet function results should
Recommendation
only be interpreted in the clinical and angiographic
context of each individual as platelet reactivity to ADP Preoperative anaemia in adults and children appears to be a
should not be the only criterion on which to base the strong predictor for perioperative blood transfusion across
clinical decision. various types of conditions and surgeries and may be associated
with adverse events. B
In an observational study of patients undergoing off-
pump CABG surgery the authors sought to compare We recommend that patients at risk of bleeding are assessed for
the role of preoperative platelet function testing by anaemia 3 to 8 weeks before surgery. 1C

If anaemia is present, we recommend identifying the cause (iron Two recent publications, a consensus statement86 and
deficiency, renal insufficiency or inflammation). 1C practical recommendations,87 both advocate correction of
iron levels before orthopaedic surgery.
Anaemia is associated with prolonged bleeding times,
probably caused by the rheological effect of RBCs Oral iron supplementation may be suitable for a high
on the margination of platelets inside the vessel, proportion of patients, and any side-effects are usually
which ultimately influences platelet interaction with mild.88
the endothelium and thus primary haemostasis. The
In a prospective study, female patients with gynaecolo-
degree of anaemia and the impact of low Hct on
gical ailments and anaemia were treated preoperatively
VHA values remain somewhat unclear, but this may
with iron sucrose and haemoglobin concentration
ultimately illustrate the inability of VHA devices
increased by a mean average of 5.15 g dl1 (P < 0.001)
to reflect the haemostatic impact of the vascular endo-
within 30 days of treatment.89
thelium.76,77
Also, in another prospective study of 20 patients with
In a recently published retrospective study of 1928
colorectal cancer, a single dose of intravenous ferric
paediatric trauma patients, the initial Hct values were
carboxymaltose given preoperatively increased haemo-
found to correlate significantly with conventional signs of
globin levels by 1.8 g dl1 (P < 0.001).90
shock and were a strong independent predictor for blood
transfusion with a better predictability for the latter than A systematic review concluded that patients with pre-
other clinical factors.78 In an observational retrospective operative iron deficiency anaemia may have an earlier and
study, the RBC volume was found to be a predictor for more robust recovery of haemoglobin concentration with
perioperative blood cell transfusion in orthopaedic major preoperative intravenous iron than with oral iron supple-
joint replacement.79 Similarly, among 843 women under- mentation.91
going major gynaecological surgery, retrospective
analysis showed that preoperative anaemia was a com- Recommendation
mon finding and was associated with increased RBC If other causes of anaemia have been excluded or treated, we
transfusion.80 In cardiac surgery, retrospective data from
suggest erythropoietin-stimulating agents. 2B
943 patients demonstrated a high prevalence of preo-
perative anaemia which significantly correlated with A meta-analysis evaluated the effectiveness of erythro-
higher transfusion rates.81 poietin-stimulating agents in patients undergoing knee or
hip arthroplasty. Preoperative use of erythropoietin-sti-
The implementation of a patient blood management mulating agents reduced autologous blood transfusion,
(PBM) programme, which included patient assessment
relative risk 0.48 (P < 0.0001), and mean haemoglobin
4 weeks before surgery, was shown to be effective in levels were 0.71 g dl1 higher than for control groups
reducing the rate of preoperative anaemia and lowering
(P < 0.00001).92 A systematic review also concluded that
the rate of transfusion as compared to before implementa-
a short preoperative regimen of erythropoietin may sig-
tion of the programme.82 Other groups have successfully nificantly reduce transfusion rates.91
used PBM programmes with testing at about 3 weeks
preoperatively.8385 The effect of erythropoietin on transfusion rates has been
shown to be significant in two separate studies of hip
Assessment of patients 3 to 8 weeks before elective replacement patients with preoperative haemoglobin
surgery provides enough time to initiate treatment and
levels of 10.0 to 13.0 g dl1.93,94
for this to take effect. This recommendation is also in
agreement with current consensus86 and practical recom- Based on the available data, erythropoietin-stimulating
mendations.87 agents have been recommended for orthopaedic surgery
patients with anaemia, in whom nutritional deficiencies
Accurate diagnosis of anaemia requires investigation after
are absent or have been corrected.86
it has been determined that haemoglobin levels are low.86
In a simulation of 50 000 individual patients, based on
5.1.3. Preoperative treatment data from controlled trials, preoperative administration of
Recommendation erythropoietin was predicted to be more cost-effective
than either autologous blood donation or an allogeneic
We recommend treating iron deficiency with iron supplement- blood transfusion strategy.95
ation. 1B
We recommend the use of intravenous iron in preference to oral Recommendation
iron. 1C
If autologous blood donation is performed, we suggest treatment
Most (though not all) studies report that preoperative oral with iron and/or erythropoietin-stimulating agents to
iron supplementation is effective in raising haemoglobin avoid preoperative anaemia and increased overall transfusion
concentration and decreasing perioperative transfusion. rates. 2C

5.1.3.1. Other possible treatment approaches and folic acid. As compared with before implementation
Recommendations of the program, the rate of transfusion decreased signifi-
cantly for all three types of surgery and the incidence of
In patients with preoperative anaemia, we recommend the use of
anaemia immediately before surgery decreased signifi-
combined therapy with intravenous iron and erythropoietin
cantly for patients undergoing hip and knee surgery. Also
along with a restrictive transfusion policy. 1C
of note, improved surgical technique played a significant
In non-cancer patients with preoperative anaemia scheduled for role in reducing the intraoperative blood loss.82
elective major surgery, we recommend postponing surgery until
anaemia has been corrected. 1C 5.1.4. Postoperative anaemia
In a prospective study, patients undergoing hip or Recommendation
knee arthroplasty were treated, according to a blood In patients who are anaemic following surgery, we suggest the
conservation algorithm, with oral or intravenous iron use of intravenous iron. 2C
and erythropoietin if they had preoperative haemoglobin
concentration less than 12 g dl1 (women) or 13 g dl1 Evidence from two randomised, controlled studies in
(men).96 Compared with a retrospective comparison patients undergoing TKA75 or total hip arthroplasty100
group, significantly fewer patients received blood trans- showed that, compared with placebo, iron supplement-
fusions for both hip and knee procedures (P < 0.001 and ation significantly reduced the rate of transfusion. Both
P 0.001, respectively). The length of stay in hospital studies showed that the reduction in transfusion was
and rate of readmission also decreased significantly for more pronounced in anaemic patients compared with
both procedures. non-anaemic patients.75,100 In addition, administration
of intravenous iron sucrose and ferric carboxymaltose
Results from a retrospective study described total preparations of iron were found to be cost-neutral.100
hip arthroplasty in Jehovahs Witnesses following a
perioperative blood management strategy.84 Patients In contrast to these results, multiple randomised,
with preoperative haemoglobin (Hb) less than 12.0 g placebo-controlled studies have shown that iron supple-
dl1 were treated with erythropoietin for 3 weeks before mentation for anaemia after surgery had no effect on
surgery, plus oral iron and folate. None of the 53 patients transfusion requirements in the settings of cardiac
received blood transfusion and there were no mortalities. surgery,101104 orthopaedic surgery,103,105108 or surgery
Also, a retrospective study of patients undergoing cardiac in colorectal cancer patients.109
valve replacement showed that erythropoietin and intra- It is possible that surgery induces changes in iron metab-
venous iron, given for 4 weeks preoperatively, signifi- olism, which could explain why postoperative iron
cantly decreased the rate of RBC transfusion (P 0.01) supplementation is ineffective.110
and was associated with decreased perioperative morbid-
ity and in-hospital mortality.97 A recent consensus There is limited evidence to suggest that intravenous iron
statement also advocated the preoperative use of ery- may be advantageous in treating postoperative anaemia.
thropoietin plus iron in patients who are anaemic, likely In a randomised, controlled study, intravenous iron
to refuse blood products (e.g. Jehovahs Witnesses), achieved normal haemoglobin levels significantly more
or who are considered likely to have postoperative frequently than in patients receiving oral iron.75 In
anaemia.98 another randomised, controlled study, serum ferritin
levels were higher at hospital discharge in patients
Leahy et al.99 described the introduction of a periopera- who had taken intravenous iron compared with those
tive PBM programme to a tertiary hospital. The PBM who had received oral iron.102
programme included optimising erythropoiesis, minimis-
ing blood loss and bleeding and optimising the reversal of 6. Optimising circulation
anaemia with intravenous iron. The mean number of 6.1. Introduction
RBC units transfused per patient decreased by 26% Massive bleeding affects delivery of blood to organs and
compared with before the PBM programme was intro- tissues (due to hypovolaemia), as well as the oxygen-
duced. In another study of patients undergoing knee, hip, carrying capacity of blood (due to anaemia). Because
or spinal surgery a PBM programme consisting of the normal haemoglobin concentrations provide a large oxy-
management and treatment of preoperative anaemia, the gen carrying reserve, priority goes to intravascular volume
reduction of intraoperative blood loss by surgical, anaes- replacement with plasma substitutes devoid of RBCs.
thesiological and pharmacological techniques, and a low- Transfusion of RBCs is required only when the haemo-
ering of the transfusion threshold to a Hb 8.0 g dl1 or less globin concentration decreases to levels at which overall
was investigated retrospectively.82 Anaemic patients nutrient demands cannot be met. This section focuses on
were treated daily for 4 weeks before surgery with intra- rational fluid substitution techniques and anaemia man-
venous iron carboxymaltose, erythropoietin, vitamin B12 agement in patients suffering severe haemorrhage.

6.2. Evidence-based medicine and Recommendation

perioperative fluid therapy
We recommend against the use of CVP and pulmonary artery
Creating reliable and generally acceptable outcome-
occlusion pressure as the only variables to guide fluid therapy
based evidence on perioperative fluid management is
and optimisation of pre-load during severe bleeding. Dynamic
currently not feasible due to a lack of adequately pow-
assessment of fluid responsiveness and non-invasive measure-
ered controlled studies, the limited representation of
ment of cardiac output should be considered instead. 1B
clinical scenarios and the absence of a consistent termi-
nology. Several meta-analyses have assessed studies CVP remains the most widely used clinical marker of
that evaluated the impact of perioperative fluid therapy volume status, despite numerous studies showing no
on patient outcomes111 115; however, few of these stu- association between CVP and circulating blood
dies qualify to serve as a basis for recommendations. volume.121 Several studies have demonstrated that
Better and more recent studies have been performed in dynamic parameters such as SVV or PPV provide better
abdominal surgery,116,117 where perioperative fluid prediction of fluid responsiveness in mechanically venti-
needs may differ considerably from other surgical lated patients with a normal heart rhythm, even when a
procedures. Patients at high risk are often excluded, grey zone to determine the ideal threshold of these
even if they represent the typical collective.113 The dynamic parameters is taken into account.122 To use
impact of perioperative fluid management on these dynamic parameters correctly there are some pre-
outcome cannot be isolated from other interventions118 requisites.123 Fluid challenges and the leg-raising test
and only a few prospective trials included details of represent simple and valid alternatives.124
therapeutic strategy beyond fluid therapy. Perioperative
The most extensively studied and successfully used
fluid management must be embedded in a larger
method to maximise cardiac pre-load is the oesophageal
perioperative therapeutic concept to impact on
Doppler device. No data prove the superiority of substi-
patient outcome.
tution regimens guided by specific devices or
specific algorithms.
6.3. Optimising macrocirculation
6.4. Considerations for microcirculation
6.3.1. Pre-load optimisation
6.4.1. Crystalloids versus colloids
Recommendations
Recommendations
We recommend aggressive and timely stabilisation of cardiac
We suggest the replacement of extracellular fluid losses with
pre-load throughout the surgical procedure, as this appears
isotonic crystalloids in a timely and protocol-based manner. 2C
beneficial to the patient. 1B
Compared with crystalloids, haemodynamic stabilisation with
In cases of uncontrolled bleeding, we suggest lower thresholds for
iso-oncotic colloids, such as human albumin and hydroxyethyl
cardiac pre-load and/or permissive hypotension. 2C
starch, causes less tissue oedema. C
Hypovolaemia decreases cardiac output and tissue oxy-
Infusion of colloids in patients with severe bleeding can aggra-
gen supply. Both the extent and duration of tissue hypo-
vate dilutional coagulopathy by additional effects on fibrin
perfusion determine the severity of cellular damage and
polymerisation and platelet aggregation. C
should be kept to a minimum with timely volume sub-
stitution. The most recent meta-analyses111,112,114,115 We suggest the use of balanced solutions for crystalloids and as a
concluded that a goal-directed approach, where therapy basic solute for iso-oncotic preparations. 2C
aims to maintain tissue perfusion by flow-based haemo-
dynamic monitoring and therapeutic interventions, 6.4.2. Transfusion target
reduces mortality, postoperative organ failure and surgi- Recommendations
cal complications, especially in high-risk surgical
We recommend a target haemoglobin concentration of 7 to 9 g
patients.113
dl1 during active bleeding. 1C
Recommendation
Continuous haemoglobin monitoring can be used as a trend
We recommend the avoidance of hypervolaemia secondary to monitor. C
crystalloids or colloids to a level exceeding the interstitial space
During bleeding, patients may be less able to tolerate
in the steady state, and beyond an optimal cardiac pre-load. 1B
anaemia because compensatory mechanisms may be
The relationship between risk and total volume trans- impaired. However, it is not known whether the lowest
fused appears to follow a U-shaped curve (infusing too tolerable haemoglobin concentration is determined by
much can be as deleterious as infusing too little).119 volume status. Data from patients undergoing surgery or
Artificial hypervolaemia predisposes patients to intersti- in intensive care indicate that a restrictive transfusion
tial oedema, which appears to be associated with peri- regimen (Hb concentration maintained at 7 to 8 g dl1) is
operative mortality.120 as effective and well tolerated as a liberal transfusion

regimen (Hb concentration maintained at 9 to 11 g Although transfusion of labile blood products may save
dl1).125,126 One RCT in surgical oncology patients lives, it can also do harm, resulting in poorer patient
favoured a more liberal transfusion trigger.127 Consider- outcomes. At the end of the 1980s, the emergence of
ing the lack of benefits from higher haemoglobin con- HIV, and the discovery that it could be transmitted by the
centrations, and the potential side-effects of transfusing transfusion of labile blood components, put into question
allogeneic blood,128 blood transfusions to raise haemo- the safety of blood. Pioneer work started in France with
globin concentrations above 9 g dl1 cannot be sup- the development of blood transfusion committee
ported. monitoring systems, resulting in a national haemovigi-
lance network in 1994,131 followed by similar pro-
6.4.3. Oxygen fraction grammes in other European countries, Canada, and
Recommendation recently the United States.132 On a European level,
haemovigilance began with the Resolution of the Euro-
We recommend that the inspiratory oxygen fraction should be pean Council, published in 1995, with the aim of improv-
high enough to prevent arterial hypoxaemia in bleeding patients, ing public confidence in the safety of blood products.
while avoiding excessive hyperoxia [PaO2 >26.7 kPa (200 European Blood Directives that give mandatory rules
mmHg)]. 1C for collection, testing, processing, storage, and distri-
The use of high inspiratory oxygen fractions during bution of human blood and blood components and
artificial ventilation [hyperoxic ventilation (HV)] is which include Directives dealing with haemovigilance
traditionally advised for emergencies on the basis that were published between 2003 and 2005.133,134 The word
severe arterial hypoxaemia could endanger oxygen deliv- haemovigilance is derived from the Greek haema
ery. However, it has been demonstrated that the side- (blood) and the Latin vigilans (watchful). According
effects of HV (e.g. vasoconstriction) may worsen patient to de Vries et al.135 haemovigilance is defined as a
outcomes during acute myocardial infarction129 or set of surveillance procedures covering the whole trans-
surgery.130 Overall, current evidence supports the use fusion chain from the collection of blood components to
of HV to achieve physiological arterial oxygen partial the follow-up of its recipients, intended to collect and
pressures during haemorrhagic shock. assess information on unexpected or untoward effects
resulting from the therapeutic use of labile blood pro-
6.4.4. Monitoring tissue perfusion ducts and to prevent their occurrence and their recur-
Recommendation rence.
We recommend repeated measurements of a combination of Hct/ Several reports have been published by different national
haemoglobin, serum lactate and base deficit to monitor tissue haemovigilance systems.136139 From these different
perfusion, tissue oxygenation and the dynamics of blood loss reports it can be concluded:
during acute bleeding. These parameters can be extended by
measurement of cardiac output, dynamic parameters of volume (1) Blood transfusion is relatively well tolerated when
status (e.g. SVV, PPV), CO2 gap and central venous oxygen compared with medicinal drugs
saturation. 1C (2) The majority of preventable adverse reactions are
due to clerical errors
(3) Some adverse reactions have to be considered as an
6.4.5. Normovolaemic haemodilution inherent risk of blood transfusion as they are often not
Recommendations avoidable (e.g. anaphylactic reactions)
We suggest the use of ANH in selected settings. 2C (4) Although current haemovigilance systems show
significant conceptual and organisational differences,
We recommend against ANH in combination with controlled they may report similar outcomes
hypotension. 1B (5) Haemovigilance systems may be used to improve not
In patients with pre-existing or acquired coagulopathy we only the safety of blood transfusion, but also
suggest that the use of ANH is considered carefully. 2C appropriate use
(6) Successful haemovigilance systems not only indi-
cated how safety should be improved but also
7. Transfusion of labile blood products
reported on the relative efficacy of various measures
7.1. Infectious risk of allogeneic blood
(7) Haemovigilance systems could be used to assess the
components
safety of alternatives for allogeneic blood transfusion
Recommendations
such as the use of cell savers.
We recommend that all countries implement national haemo-
vigilance quality systems. 1B Recommendation
We recommend a restrictive transfusion strategy which is We recommend pathogen inactivation for FFP and platelets.
beneficial in reducing exposure to allogeneic blood products. 1A 1C

Although contamination of blood components with infec- System) and the RBC chemical inactivation using S-
tious agents represents a continuing challenge in transfu- 303 and glutathione (GSH: Intercept system).150
sion medicine, rates of infection with known blood-
Recommendation
transmitted pathogens (e.g. HIV, HBV, HCV) are low
following the implementation of high sensitivity testing We recommend that labile blood components used for transfu-
methods. However, (re-) emerging pathogens remain a sion are leukodepleted. 1B
concern. Potential donors are asked questions on travel
Leukodepletion refers to the process of removing white
history, drug abuse, sexual behaviour, and others; how-
blood cells from a unit of RBCs or platelets to a standar-
ever, residual risks remain.140 There is also a risk that
dised degree. This is accomplished through either
laboratory testing of donated blood is not effective. There
removal of the buffy coat following centrifugation or
is usually a period during which the donation is infectious
pre-storage filtration. The current consensus is that leu-
but will screen negative because the infectious marker is
kodepletion has defined indications in the prevention of
not present at detectable levels. Shortening of this win-
three complications of blood transfusion: febrile non-
dow period is a major target of all screening programmes.
haemolytic transfusion reactions (HTRs), platelet refrac-
The introduction of molecular biology with the nucleic
toriness due to alloimmunisation to human leukocyte
acid amplification testing (NAT) assays has reduced the
antigen and transmission of cytomegalovirus.151 In these
classical window period to what is now called the
indications, leukodepletion has been shown to be clini-
eclipse phase in which detectable concentrations of
cally effective and cost-effective.151
viral nucleic acid are present in plasma.141 These NAT
assays are generally applied to classical transfusion-trans- Most European countries adopted universal leukodeple-
mitted viruses HIV, HBV and HCV.142144 tion in the late 1990s on the suggestion that leukodeple-
tion might reduce the transmission of CreutzfeldtJacob
Blood monitoring systems must develop procedures
disease and on the basis of accumulating evidence of
allowing the identification and recognition of a transfu-
leukocyte-mediated transfusion-related immunomodula-
sion-transmission threat, the quantification of the risk,
tion. Although leukocyte depletion shows a reduction in
and finally, the reduction of the associated risk to transfu-
blood prion infectivity of between 58 and 72%,152 it does
sion recipients.145
not constitute a definite solution for removal of prions
Despite improvements in laboratory diagnostics, donor from blood components. The development of comp-
selection and blood collection techniques, the risk of lementary methods, such as prion removal filters, would
bacterial and insect-borne contamination, mainly in pla- further minimise the blood-borne risk of Creutzfeldt
telet units (but also in RBC units), and the risk of Jacob disease transmission.153 However, discordant
transmission of untested and emerging transfusion-trans- results of several meta-analyses suggest that if universal
mitted viruses remain. Application of pathogen inacti- leukodepletion does diminish transfusion-related immu-
vation techniques addresses this problem. Current nomodulation, then the clinical effects are difficult to
methods either target nucleic acids or cell membranes.146 capture in clinical studies. Since 1998, only one double-
They are active on bacteria, protozoa, contaminating blind RCT reported reduced infection rates and in-hos-
leukocytes, known viruses and unknown transfusion- pital mortality rates after cardiac surgery in patients
transmissible agents, but not on prions. They include randomised to pre-storage leukodepleted blood com-
solvent/detergent (SD), methylene blue, amotosalen and pared with buffy-coat depleted blood.154 As a result of
riboflavin technologies: apart from the SD method, all the limited evidence, the rationale for applying universal
require the use of visible or ultraviolet light. Although leukodepletion remains highly debated by the scientific
these methods slightly reduce the concentration of community.155,156 Unfortunately, this debate is not likely
coagulant proteins in the plasma, the concentrations to be resolved, as universal leukodepletion has become
remain within accepted ranges.147 the standard of care in most Western countries.
Platelet components are treated either with the amoto-
salen or the riboflavin methods. The therapeutic efficacy
7.2. Immunological and non-immunological
and safety of pathogen-reduced platelets appear to be
complications associated with the transfusion
similar to conventional platelets.146,148 However, in most
of labile blood components
trials, transfusion of pathogen-reduced platelets resulted
Recommendations
in lower platelet count increments, a shorter interval
between platelet transfusions and an increased number We recommend that blood services implement standard operat-
of platelet transfusions per patients.146 ing procedures for patient identification and that staff be trained
in the early recognition of, and prompt response to, transfusion
Pathogen inactivation of RBC products appears more
reactions. 1C
challenging.149 Two methods are currently in commercial
development: the whole blood photochemical inacti- We recommend a male-only donor policy for plasma-containing
vation using riboflavin and ultraviolet light (Mirasol blood products to prevent the onset of TRALI. 1C

We recommend that all RBC, platelet and leukocyte donations opinions with poor handover.162 In 2014, the estimated
from first-degree or second-degree relatives be irradiated even if risk of death associated with the transfusion of a labile
the recipient is immunocompetent, and all RBC, platelet and blood component was calculated at 5.6 per million com-
leukocyte products be irradiated before transfusing to at-risk ponents issued and the estimated risk of major morbidity
patients. 1C was 63.5 per million components issued. Most of these
cases were acute transfusion reactions, which included
Allogeneic blood transfusion is associated with an increased
anaphylaxis/hypersensitivity and febrile non-haemolytic
incidence of nosocomial infections. B
reactions. Acute transfusion reactions are now the leading
One of the most effective ways to reduce transfusion- cause of major morbidity associated with transfusion of
related complications is to introduce a restrictive transfu- labile blood components.162 RBCs are usually associated
sion protocol, that is transfuse only what is really necess- with febrile-type reactions, plasma (methylene-blue and
ary (RBCs, plasma or platelets) and only when it is really SD-treated FFP) with allergic reactions, and platelets
necessary. Two recent meta-analyses assessed the effects with both.162
of transfusion thresholds (based on a specified haemo-
HTRs are typically caused by transfusion of RBCs carry-
globin or Hct value) on the use of RBC transfusions and
ing antigens to which the recipient has significant alloan-
on clinical outcomes.157,158 These meta-analyses
tibodies. The most frequent cause of intravascular HTRs
included 19 trials (n 6264 patients)157 and 31 trials
is ABO incompatibility attributable to procedural errors.
(n 9813 patients),158 respectively, and they demon-
In the 2014 SHOT report, there were 10 ABO-incompa-
strated that restrictive transfusion strategies are well
tible RBC transfusions, all due to clinical errors.162
tolerated in most clinical settings and are associated with
a reduction in the number of patients being transfused The objective of haemovigilance systems is to improve
and in the number of RBC units transfused. In patients patient safety: it is therefore important that hospitals
with UGIB, a restrictive transfusion strategy (Hb con- complete their reporting process with an appropriate
centration maintained at 7 g dl1) was associated with incident investigation in order that lessons may be
improved outcomes compared with a liberal one (Hb learned and practice improved.163 It should be noted
concentration maintained at 9 g dl1).126 In patients with that two thirds of ABO-incompatible red cells transfusion
septic shock, a restrictive transfusion strategy did not do not result in harm. They will be included in future
alter outcomes, although it significantly reduced patients SHOT reports as never events.162
exposure to allogeneic RBC transfusion.159 However, the
Despite the very useful information gained about trans-
best transfusion strategy still remains to be determined in
fusion reactions, the main risks remain human factors.
some particular populations, for instance patients under-
Correct patient identification and adherence to basic
going cardiovascular surgery.160 After cardiac surgery, a
procedures remains the key to safer practice.138
restrictive transfusion strategy was not found to be
superior to a liberal one with respect to postoperative TRALI is potentially life-threatening and occurs within
morbidity, and might even be associated with an 6 h of transfusion of plasma-containing blood products.164
increased 90-day mortality.161 Also, in patients with acute The 2014 SHOT report includes nine cases of suspected
coronary disease, the question remains unanswered, as TRALI (from a total of 1681 reviewed cases) resulting in
there are no prospective randomised trials, and the same two possible/probable related deaths, and seven major
is true for patients with traumatic brain injury. In a small morbidities.162 In one of these cases, cryoprecipitate was
study of surgical oncology patients, de Almeida et al.127 implicated: the patient received a pool in which three
reported that, compared with a restrictive transfusion female donors had concordant class 1 and class 2 anti-
strategy (Hb concentration maintained at 7 g dl1), a bodies.
more liberal RBC transfusion strategy (Hb concentration
Plasma from female donors has been particularly impli-
maintained at 9 g dl1) could be associated with fewer
cated in the pathogenesis of antibody-mediated
major postoperative complications.
TRALI. Therefore, most blood collection organisations
Although blood transfusion in most Western countries is have implemented the preferential use of plasma from
very well tolerated, patients continue to be put at risk by male donors as a precautionary measure to reduce
human errors at all stages of the transfusion process. TRALI. A recent meta-analysis including 10 studies
The 2014 annual SHOT report analysed 3017 reports.162 which implemented a 95 to 100% male-only plasma
The majority of incidents were caused by human error donation policy reported a significant reduction for
and these accounted for 77.8% of reports: a steady the risk of TRALI after the introduction of this
increase from 2011, and an ongoing major concern for strategy.165 Although none of these studies were
transfusion safety. In addition to instances of failures in randomised trials and only two of them were prospec-
patient identification, communication and documen- tive, the risk of bias of patient selection was low.
tation, several reports indicated poor clinical decision- Heterogeneity was high for all studies combined, and
making, or confusion as a result of too many clinical low for pre-defined subgroup analysis.

Transfusion-associated graft-versus-host disease (TA- infusion rate. The use of pre-transfusion diuretics has
GVHD) is a generally fatal immunological complication been also suggested. Most authors recommend careful
of transfusion, involving the engraftment and clonal monitoring and supervision of the transfusion process in
expansion of viable donor lymphocytes contained in high-risk individuals.169171
labile blood components in both immunocompetent
and compromised hosts.166 Typical features of TA- 7.3. Storage lesions
GVHD include fever, maculopapular skin rash affecting Recommendation
the palms, diarrhoea, liver dysfunction, pancytopaenia
and bone marrow hypoplasia occurring less than 30 days We recommend that RBCs should be transfused according to the
following transfusion. A total of 14 cases of TA-GVHD first-in, first-out method in the blood services to minimise
have been reported to SHOT since 1996: all were fatal.167 wastage of erythrocytes. 1A
The potential link between prolonged duration of storage
Transfusion-associated circulatory overload (TACO) is
of RBCs and adverse clinical outcomes has been highly
increasingly being recognised as an important cause of
debated in the literature. Several meta-analyses have
mortality and morbidity by European haemovigilance
resulted in conflicting results.173175 However, three
systems. The 2014 SHOT report analysed 91 cases
recent large multi-centre prospective studies did not
compared with 96 in 2013.162 The age of patients ranged
demonstrate any significant effect of red cell storage
from 1 to 98 years. Most of the cases occurred on the
duration on major morbidity and mortality in high-risk
wards and followed routine transfusion. However, the
patients. In the first double-blind controlled trial (ARIPI
incidence of perioperative TACO appears similar to
trial: n 377) premature infants with birth weight less
previous estimates in non-surgical populations.168 In
than 1250 g were randomised to receive transfusions of
the 2014 SHOT report, TACO was associated with six
RBCs stored for 7 days or less (mean age, 5.1 2.0 days)
out of the 13 deaths recorded and with 36 cases of major
or standard-issue RBCs in accordance with standard
morbidity. It should be noted that the true extent of
blood bank practices (mean age, 14.6 8.3 days).176
TACO remains unclear, as a formal definition of it
There was no difference between the two groups regard-
appears hard to achieve. The current International
ing the primary outcome, which was a composite measure
Society of Blood Transfusion (ISBT) definition of TACO
of major neonatal morbidities. In the second blinded trial,
(revision in progress) includes the combination of any
critically ill adult patients (ABLE trial: n 2430) were
four of the following five items within 6 h of transfusion:
randomised to receive either RBCs stored for less than 8
acute respiratory distress, tachycardia, increased blood
days (mean age, 6.1 4.9 days) or standard-issue RBCs
pressure, acute or worsening pulmonary oedema, and
(mean age, 22.0 8.4 days).177 There was no difference
evidence of positive fluid balance. As for other compli-
between the two groups regarding the primary outcome
cations associated with blood transfusion, human errors
(90-day mortality), or in any of the secondary outcomes
are common, which support the role of haemovigilance
(major morbidity and hospital length of stay). In the third
systems and of adequate education in transfusion medi-
trial, patients at least 12 years of age, who were under-
cine.169
going complex cardiac surgery (RECESS trial, n 1098),
The key to reducing TACO is to prevent its occurrence, were randomised to receive either RBCs stored for 10
which begins with the identification of at-risk days or less (mean age, 7.8 4.8 days) or for 21 days or
patients.168172 Identified risk factors include being at more (mean age, 28.3 6.7 days) for all intraoperative or
an extreme of age, female sex, having a positive fluid postoperative transfusions.178 There was no difference
balance in the 24 h preceding the transfusion, pre-trans- between the two groups regarding the primary outcome
fusion left ventricular dysfunction leading to congestive (a change in the Multiple Organ Dysfunction Score), or 7-
heart failure, renal dysfunction and the rate of transfu- day and 28-day mortality. Although these studies did not
sion. Interestingly, transfusion volume did not appear to address the issue of whether the use of RBCs stored for
be a risk factor, although the proportion of events associ- very prolonged periods (up to 42 days) results in harm,
ated with death or severe morbidity tended to increase they did not observe any clinically important improve-
with the number of transfused units. In Europe, the ments in outcomes with fresh RBC transfusions.
incidence of TACO was higher with RBCs than FFP
and lowest with platelet concentrates.169,171 In the US, 7.4. Cell salvage
FFP is considered the higher-risk transfusion product.170 Recommendations
This difference might be because in the US, FFP is used We recommend the use of red cell salvage, which is helpful for
to neutralise VKAs as PCCs are not available.171 blood conservation in major cardiac and orthopaedic surgery.
Once high-risk individuals have been identified, preven- 1B
tion of TACO will require the widespread use of pre- We recommend against the routine use of intraoperative plate-
transfusion checklists and the implementation of non- let-rich plasmapheresis for blood conservation during cardiac
emergency transfusion protocols170,171 including a slow operations using CPB. 1B

We recommend that cell salvage is not contraindicated in bowel 7.5. Plasma and platelet transfusion
surgery, provided that the initial evacuation of soiled abdomi- Recommendations
nal contents is undertaken, additional cell washing is performed
We recommend against the use of plasma transfusion for pre-
and that broad-spectrum antibiotics are used. 1C
procedural correction of mild-to-moderately elevated INR. 1C
We suggest that cell salvage is not contraindicated in cancer
We recommend early and targeted treatment of coagulation
surgery, provided that blood aspiration close to the tumour site
factor deficiencies in the plasma. Sources of coagulation factors
is avoided and leukodepletion filters are used. 2C
are coagulation factor concentrates, cryoprecipitate or high
Intraoperative and postoperative cell salvage reduces the volumes of plasma, depending on the clinical situation, type
need for allogeneic RBC transfusion in major orthopaedic of bleeding, type of deficiency and resources provided. 1B
surgery, such as hip and knee replacement.179181 Other
In the treatment of acquired coagulation factor deficiency, we
indications for intraoperative cell salvage (ICS) may
suggest the consideration of a ratio-driven protocol (RBC:plas-
include spinal surgery, hepatic transplant and abdominal
ma:platelet concentrates) early in uncontrolled massive bleeding
aortic aneurysm repair.182,183 However, evidence for the
outside the trauma setting followed by a goal-directed approach
use of cell salvage in individuals undergoing abdominal or
as soon as possible. 2C
thoracic trauma surgery remains equivocal.184
We suggest coagulation factor concentrates for the primary
In cancer surgery, there is concern about the risk of re- treatment of acquired coagulation factor deficiency due to their
infusing malignant cells, which could cause metastases. high efficacy and their minimal infectiousness. 2C
Certainly, aspiration of blood from close to the tumour
site should be avoided. Leukodepletion filters appear to We recommend against indiscriminate use of plasma transfu-
be an effective method for removal of malignant cells sion in perioperative bleeding management. 1C
from ICS blood.185 More recent non-randomised studies We suggest platelet concentrate transfusion in bleeding situations
in urological cancer surgery and metastatic spinal surgery clearly related to antiplatelet drugs or thrombocytopaenia less
have shown ICS to decrease the need for allogeneic RBC than 50 109 l1. 2C
transfusion with no apparent risk of decreased long-term
survival from an oncological perspective.186188 A small RCT of pre-procedural FFP and/or platelet
support (n 60) in patients with cirrhosis demonstrated
Contamination of the surgical field (e.g. bowel surgery, that a transfusion strategy based on TEG parameters
penetrating abdominal trauma or infected wounds) has resulted in a substantial reduction in transfusion and
typically been considered as a contraindication for ICS. no increase in bleeding complications.192
However, after laparotomy for abdominal trauma, the
literature shows no difference in infection rates in
patients receiving allogeneic blood components or cell- 8. General coagulation management
salvaged blood. An RCT in patients undergoing lapar- 8.1. Indications, contraindications,
otomy for abdominal injuries demonstrated that ICS complications and doses
significantly reduced allogeneic blood usage, without Recommendations
increasing postoperative infection or fatality rates.189
Fibrinogen concentration of less than 1.5 to 2 g l1 is considered
During the peripartum period, shed blood can be con- as hypofibrinogenaemia in acquired coagulopathy and is associ-
taminated with amniotic fluid and foetal blood, so rein- ated with increased bleeding risk. C
fusion carries a theoretical risk of amniotic fluid embolus
and alloimmunisation of the mother.190 However, We recommend treatment of hypofibrinogenaemia in bleeding
amniotic fluid embolism is no longer regarded as an patients. 1C
embolic disease but rather as a rare anaphylactoid reac- We suggest an initial fibrinogen concentrate dose of 25 to
tion to foetal antigens. The contamination of the sal- 50 mg kg1. 2C
vaged blood by foetal Rh-mismatched RBCs can be dealt
with using Rh immunoglobulins, and ABO incompat- In cases where fibrinogen concentrate is not available we suggest
ibility tends to be a minor problem as ABO antigens are cryoprecipitate at an initial dose of 4 to 6 ml kg1. 2C
not fully developed at birth. Although the role of cell Plasma transfusion alone is not sufficient to correct hypofibrin-
salvage as a blood-saving measure in obstetrics is becom- ogenaemia. C
ing more common, the published evidence of its quality
and safety remains weak (800 documented procedures In cases of bleeding and low factor XIII activity (e.g. <30%) we
and about 400 patients transfused with salvaged suggest administration of factor XIII concentrate (30 IU kg1).
blood).190,191 Therefore, ICS in obstetrics should be 2C
considered in patients at high risk of haemorrhage or In severe perioperative bleeding we recommend that patients on
in cases where allogeneic blood transfusion is difficult VKAs should be given PCC and intravenous vitamin K before
or impossible. any other coagulation management steps. 1B

Prolonged INR/PT or VHA clotting times alone are not an We recommend restricting the use of rFVIIa to its licensed
indication for PCC in bleeding patients not on oral antic- indications because, outside these indications, the effectiveness
oagulant therapy. C of rFVIIa to reduce transfusion requirements and mortality
remains unproven and the risk of arterial thromboembolic
We recommend against the prophylactic use of rFVIIa due to
events, as well as costs, are high. 1A
increased risk of fatal thrombosis. 1B
Cell salvage can be cost-effective in selected patients. A
We suggest that off-label administration of rFVIIa can be
considered for life-threatening bleeding which cannot be stopped The cost-effectiveness of a ratio-driven transfusion protocol has
by conventional, surgical or interventional radiological means not been investigated.
and/or when comprehensive coagulation therapy fails. 2C
Goal-directed therapy with coagulation factor concentrates
We recommend tranexamic acid to prevent bleeding during (fibrinogen and/or PCC) may reduce transfusion-associated
major surgery and/or treat bleeding due to (or at least suspected) costs in trauma, cardiac surgery and liver transplantation. C
hyperfibrinolysis (e.g. a dose of 20 to 25 mg kg1). 1B
9. Algorithms in specific clinical fields
We suggest the use of DDAVP under specific conditions (acquired
9.1. Cardiovascular surgery
VWS). 2C
9.1.1. Which therapies influence perioperative
Based on the current literature, there is no evidence to recom- bleeding when administered in the preoperative
mend antithrombin supplementation in elective surgical period?
patients while they are bleeding. Recommendations
We recommend structured staff education and training. 1C Withdrawal of aspirin therapy increases the risk of coronary
thrombosis; continuation of aspirin therapy increases the risk of
8.2. Correction of confounding factors bleeding. B
Recommendations Withdrawal of clopidogrel therapy increases the risk of coronary
We recommend maintaining perioperative normothermia thrombosis; continuation of clopidogrel therapy increases the
because it reduces blood loss and transfusion requirements. 1B risk of bleeding. A
We recommend that pH correction should be pursued during We recommend prophylactic administration of tranexamic acid
treatment of acidotic coagulopathy although pH correction before CPB in patients undergoing CABG surgery. 1A
alone cannot immediately correct acidosis-induced coagulopa-
thy. 1C 9.1.1.1. Antiplatelet therapies
9.1.1.1.1. Aspirin
We recommend that rFVIIa should only be considered alongside There may be some benefit to aspirin administration up
pH correction. 1C until the day of surgery. A recent, small RCT (n 20)
We recommend that calcium should be administered during found that continuing aspirin treatment until the day of
massive transfusion if calcium concentration is low, to preserve surgery reduced oxidative and inflammatory responses, as
normocalcaemia (>0.9 mmol l1). 1B measured from radial artery and coronary sinus blood
samples, and myocardial biopsies.193 The authors also
We suggest that endovascular embolisation is a well tolerated highlighted a potentially beneficial effect on cardiac
alternative to open surgical intervention after failed endoscopic tissue injury resulting from surgery. Recent research
treatment for non-variceal UGIB. 2C has also suggested that aspirin therapy may be well
We suggest super-selective embolisation as primary therapy for tolerated up to the time of surgery. A series of 709
treatment of angiogram-positive lower gastrointestinal tract consecutive CABG patients who used aspirin until the
bleeding. 2C time of surgery was compared with 709 matched controls
who discontinued aspirin therapy more than 5 days before
We suggest embolisation as first-line therapy for arterial com- surgery.194 The authors found no significant difference
plications in pancreatitis. 2C between the two groups in intraoperative and postopera-
tive blood loss. Furthermore, there were no significant
8.3. Cost implications differences between the groups in terms of postoperative
Recommendations major cardiac event-free survival estimates and cardiac
readmissions at 4-year follow-up. The angina-free survi-
Both bleeding and transfusion of allogeneic blood products val rate was significantly higher in the group who had
independently increase morbidity, mortality, length of stay in taken aspirin up to the time of surgery.
ICU and hospital, and costs. B
Tranexamic acid can reduce perioperative blood loss and 9.1.1.1.2. Clopidogrel
transfusion requirements; this can be highly cost-effective in A recent meta-analysis of 20 observational studies (23 668
several major surgical and trauma settings. B patients) concluded that clopidogrel exposure within 7

days increases the risk of RBC transfusion and bleeding- interventions. Another recent meta-analysis of 20 studies
triggered re-operations, without any benefit on myo- reiterated that only a weak-to-moderate correlation
cardial infarctions postoperatively.195 The overall between fibrinogen and postoperative bleeding existed,
mortality rate in those who took clopidogrel up to the and suggested further RCTs are necessary before making
time of surgery was also higher. The findings of RCTs recommendations on treatment.11
have been reflected in a recent retrospective analysis of
CABG patients (n 715): a significant association was 9.1.2. Which therapies can be used to control
observed between bleeding and clopidogrel exposure bleeding intraoperatively?
within 5 days before surgery.196 Recommendations
A recent meta-analysis of 12 studies reported that con- We suggest tranexamic acid can be applied topically to the chest
tinuing antiplatelet therapy (aspirin, clopidogrel) until cavity to reduce postoperative blood loss following cardiac
the time of cardiac surgery was associated with increased surgery. 2C
blood loss, but carried a low risk of surgical re-exploration
for bleeding.197 The authors concluded that in patients at In complex cardiovascular surgery, we recommend fibrinogen
a high risk of stent thrombosis, this may be acceptable. concentrate infusion guided by VHA monitoring to reduce
One retrospective, multi-centre, observational study perioperative blood loss. 1B
(n 666) reported that discontinuation of antiplatelet We suggest that rVIIa may be considered for patients with
therapies significantly increased major adverse cardiac intractable bleeding during and after cardiovascular
events (MACEs), myocardial infarction and death, and surgery once conventional haemostatic options have been
did not significantly reduce bleeding.198 However, this exhausted. 2B
study reported cases of both cardiac and non-cardiac
surgery, which may be associated with a smaller risk of
9.1.2.1. Heparin
blood loss.
A recent RCT in elective cardiac valve surgery patients
(n 38) compared heparin and protamine dosage based
9.1.1.2. Antifibrinolytic therapy (aprotinin, tranexamic
on either heparin monitoring using a point-of-care
acid and e-aminocaproic acid)
haemostasis management system, or the standard
A meta-analysis of 106 RCTs and 11 observational studies
ACT-based approach.203 The study found that dosing
(totalling 43 270 patients) was performed to assess the
heparin and protamine based on the haemostasis manage-
safety of aprotinin in comparison with other antifibrino-
ment system decreased the incidence of severe blood loss
lytic treatments.199 The analysis was largely inconclusive,
compared with the ACT approach.
although the authors did observe that there were, on
average, higher mortality and renal failure or dysfunction
rates in patients who had been given aprotinin compared 9.1.2.2. Protamine
with other drugs or no treatment. The authors concluded A recent double-blind RCT investigated the effect of
that concerns about the safety of aprotinin in cardiovas- basing protamine dosages on protamineheparin
cular surgery still remain, and clinicians should be aware titrations in valve replacement patients (n 60).204
of the benefits and risks of the drug. The authors found that basing protamine measurements
on two separate protamineheparin titrations, the first at
A meta-analysis of 33 501 patients suggested that
termination of CPB and the second five minutes after the
mortality may be increased by aprotinin in low-risk to
first dose of protamine, can reduce postoperative blood
medium-risk cases but not in high-risk cases compared
loss by reducing protamineheparin mismatch.
with tranexamic acid and e-aminocaproic acid (EACA).200
9.1.1.3. Coagulation factor replacement therapy 9.1.2.3. Antifibrinolytic therapy (tranexamic acid and e-
9.1.1.3.1. Antithrombin concentrate aminocaproic acid)
An RCT of 200 patients showed that preoperative infu- Recent studies have shown varying results. One retro-
sion of antithrombin to levels of 120% reduced heparin spective study compared aprotinin to EACA in a con-
resistance with no adverse effects and prevented a post- secutive infant patient population (n 227) undergoing
operative reduction of antithrombin activity.201 cardiac surgery requiring CPB.205 Chest-tube output was
significantly higher in the EACA group, although this did
9.1.1.3.2. Fibrinogen concentrate not affect transfusion requirements. Sensitivity analysis
A recent systematic review of four studies (n 2154) revealed lower efficacy with EACA compared with apro-
found that preoperative fibrinogen levels are poor pre- tinin. A prospective randomised study in a consecutive
dictors of postoperative bleeding and could lead to inap- group of adults (n 64) undergoing thoracic aortic
propriate treatment in over 80% of treated patients.202 surgery requiring CPB found that both EACA and tran-
The authors suggested a plasma fibrinogen cut-off value examic acid were effective in reducing postoperative
of 2.5 g l1, which could reduce the rate of inappropriate blood loss.206 However, EACA significantly increased

the risk of renal injury and failure, whereas tranexamic maintenance dose of 5 mg kg1 h1; a high dose con-
acid increased the risk of seizures. sisting of a bolus of 30 mg kg1 and a maintenance dose of
16 mg kg1 h1; and a sodium chloride control.212 The
Evidence of the benefits of tranexamic acid is less clear-
study found no differences in bleeding outcome or fibri-
cut in paediatric versus adult cardiovascular surgery. A
nolysis between any of the three groups.
systematic review and meta-analysis of eight studies
(n 848) concluded that while there was a small Tranexamic acid may also be used topically. A meta-
reduction in blood transfusions across the population that analysis of four randomised, double-blind, controlled
were administered tranexamic acid, the quality of the trials (n 371) on topical tranexamic acid use in cardiac
evidence was weak and much of it was too heterogeneous surgery found a significant reduction in 24-h postopera-
to be analysed in the meta-analysis.207 tive blood loss, but could not prove a significant reduction
in transfusion.213 A more recent prospective, double-
Not all studies have shown positive results. One pro-
blind, clinical trial (n 71) found similar results, with a
spective, double-blind, randomised, placebo-controlled
significant reduction in blood loss; there was also a non-
clinical trial (n 90) compared tranexamic acid with low-
significant reduction in RBC transfusion, but no signifi-
dose aprotinin and a control in adult cardiac valve surgery
cant difference in blood component transfusion.214 One
patients.208 The chest drain output was significantly
retrospective cohort study (n 160) examined the effects
lower in the aprotinin group; the quantity of RBC and
of using combined intravenous and topical tranexamic
platelet transfusions was significantly lower in the apro-
acid doses compared with an intravenous tranexamic acid
tinin and tranexamic acid groups compared with the
regimen in CABG patients.215 Blood loss was significantly
control; and the quantity of FFP transfusion was signifi-
decreased at 3, 6 and 12 h postoperatively in the com-
cantly lower only in the aprotinin group. The authors
bined dose group: the authors recommend further RCTs
concluded that low-dose aprotinin was superior to
in this area.
tranexamic acid in reducing blood loss.
In a recent prospective, double-blind, placebo-con-
A prospective clinical trial (n 1182) investigated the
trolled, randomised clinical trial (n 231), adult patients
efficacy of giving small and medium single shots of
undergoing off-pump CABG were treated with either a
tranexamic acid in CPB priming volume (1 g and 5 g,
1 g bolus of tranexamic acid followed by 400 mg h1
respectively), and a medium dose (3 g)plus 15 mg kg1
during surgery, or a sodium chloride placebo.216 The
h1) infusion in elective cardiac surgical patients.209 The
results showed significant reductions in post-surgical
trial found no significant differences between the groups
chest-drain volume at 6 h, and in transfusion require-
in postoperative blood loss, and the authors concluded
ments for RBC and FFP, compared with the control
that the higher doses were no more effective than the
group. One study has assessed the use of EACA as a
single low dose of tranexamic acid.
topical treatment intraoperatively in off-pump cardiac
Several randomised studies have compared high and low surgery. The study was a prospective, double-blind,
continuous doses of tranexamic acid during surgery. A RCT (n 26) which compared topical EACA with a
prospective, randomised, double-blind trial (n 175) in placebo; there were no significant differences in blood
cardiac valve surgery patients compared tranexamic acid loss or transfusion requirements.217
at a low dosage which consisted of a loading dose of
10 mg kg1, followed by a maintenance dose of 2 mg kg1
9.1.2.4. Allogeneic blood products (fresh frozen plasma,
h1, and a CPB prime of 40 mg; to a high dosage which
platelets and cryoprecipitate)
consisted of a loading dose of 30 mg kg1, maintenance
One small, prospective study (n 13) reported that cryo-
dose of 16 mg kg1 h1, followed by a CPB prime of
precipitate increased fibrinogen levels and fibrin-based
2 mg kg1.210 The study found that the lower dose was as
clot strength in aortic surgery patients undergoing deep
effective as the higher dose in preventing postoperative
hypothermic circulatory arrest.218
bleeding. A multi-centre, double-blinded, randomised,
controlled study (n 568) compared a low dose A recent prospective, cohort study named PLASMA-
(10 mg kg1 loading dose followed by maintenance with CARD (n 967), concluded that FFP usage in cardiac
1 mg kg1 h1 until the end of the operation) with a high surgery has no beneficial impact on 30-day mortality
dose (30 mg kg1 loading dose followed by maintenance rates.219 Evidence from another study, a retrospective
with 16 mg kg1 h1).211 The results showed no signifi- analysis of 685 patients, suggests that using autologous
cant difference between the two doses in the incidence of platelet-rich plasma may be an effective haemostatic
overall transfusions up to 7 days post-surgery, but the option in thoracic aortic surgery. Significantly reduced
higher dose did reduce blood loss, the need for transfu- allogeneic blood transfusions were reported, together
sions, and further surgery. A small double-blind, random- with a decrease in major adverse events among patients
ised, controlled pilot trial (n 33) compared a low dose, receiving autologous platelet-rich plasma, compared with
consisting of a loading dose of 5 mg kg1 followed by a controls.220 However, a large RCT is needed to confirm

the efficacy of autologous platelet-rich plasma as a investigated a PCC containing small amounts of factor
haemostatic option. VIIa and found it to significantly reduce the need for FFP
and platelet transfusions.227 One retrospective study
9.1.2.5. Desmopressin (n 168) has compared the efficacy of FEIBA and
A recent double-blind RCT (n 102) tested the effects of rFVIIa.228 No significant difference was found between
DDAVP on postoperative blood loss and platelet aggre- the two procoagulants in terms of morbidity and
gation.221 The intervention group was treated with mortality. Platelet transfusion was higher among patients
0.3 mg kg1 during surgery and a control group received receiving rFVIIa, but no other differences in transfusion
saline. The results showed a significant decrease in post- requirements were identified.
operative blood loss and FFP transfusions in the DDAVP
group during the first 6 h post-surgery (the duration of 9.1.2.6.4. Recombinant activated factor VII
drug activity). However, by 24 h there was no significant A recent RCT, conducted to compare a group of CABG
difference between the groups. No effects on platelet patients receiving rFVIIa after weaning from CPB
aggregation, RBC or platelet transfusion were observed. (n 30) with a control group, found significant decreases
in chest drain output and transfusion requirements in the
9.1.2.6. Coagulation factor replacement therapy intervention group.229 The authors highlighted the need
9.1.2.6.1. Factor XIII concentrate for more larger-scale RCTs. Research into dosing has
A recent double-blind, placebo-controlled, multi-centre progressed very little, but one retrospective study
trial (n 409) investigated whether replenishing factor (n 69) has compared dosing and efficacy between adult
XIII levels has an effect on postoperative transfusion and paediatric patients, with intraoperative and post-
rates in CPB patients.222 No effect on transfusion avoid- operative treatment.230 Prophylactic therapy tended to
ance, transfusion requirements or surgical re-exploration be more effective, and adults benefited from a much
was observed. smaller dose per kilogram of body mass than children,
due to the shorter half-life of the factor in children.
9.1.2.6.2. Fibrinogen concentrate Although rFVIIa is efficacious in reducing perioperative
A secondary analysis of data from a randomised, double- bleeding, a limited body of research suggests that rFVIIa
blind, placebo-controlled trial performed in patients might increase morbidity and mortality. A single-centre,
undergoing complex cardiovascular surgery (n 61) retrospective review (n 16) of paediatric patients who
investigated the effect of FIBTEM-guided fibrinogen received rFVIIa intraoperatively or postoperatively found
supplementation on the rate of intraoperative bleed- a 56% mortality rate, attributed to neurological, bleeding
ing.223 It was found that fibrinogen concentrate was more and septic events.231 In an observational case control
effective than placebo or one cycle of transfusion with study with patients who received rFVIIa (n 144) intra-
FFP and platelets in reducing the rate of bleeding. operatively or postoperatively and matched controls
Fibrinogen concentrate has also been compared with (n 359), the in-hospital mortality was 40% in the group
cryoprecipitate in a randomised study (n 63) performed receiving rFVIIa and 18% in the control group.232 Renal
in bleeding paediatric cardiac surgery patients with low morbidity was also increased in the group receiving
fibrinogen levels after CPB.224 The results showed no rFVIIa (31 versus 17%, respectively).
significant differences between the agents, and the
authors concluded that fibrinogen was as well tolerated 9.1.2.6.5. Antithrombin
and effective as cryoprecipitate in controlling blood loss A review56 comparing antithrombin with FFP for the
up to 48 h postoperatively. Not all studies have shown treatment of patients with heparin resistance found a
favourable results with fibrinogen concentrate use. One lower risk of TRALI, superior efficacy and a lower
large, retrospective cohort analysis (n 1075) of non- volume of administration with antithrombin. However,
randomised fibrinogen intervention in complex cardiac there was a paucity of good quality evidence with
surgery found no effect on blood loss or transfusion rate, only three case reports, one RCT and one retrospective
but no increased risk of adverse events.225 The authors analysis.
concluded that the low dose and late administration may
have affected the results, and have initiated an RCT to 9.1.2.6.6. Factor IX
investigate further. A retrospective study of 11 patients receiving 35 mg kg1
versus controls showed that factor IX produced a signifi-
9.1.2.6.3. Prothrombin complex concentrate cant reduction in chest tube drainage, but it had no
A small, prospective study (n 14) using a bolus of significant effect on blood product usage.233
commercially available PCC found it was effective at
reducing postoperative bleeding and RBC transfusions in 9.1.2.7. Fibrin sealant (fibrin glue)
paediatric cardiac surgery patients.226 Another prospec- A recent non-randomised, prospective study (n 42)
tive study performed in cardiac surgery patients (n 25) compared the haemostatic efficacy of a surgical patch

containing thrombin and fibrinogen with a conventional 9.2. Gynaecological (non-pregnant) surgery
treatment control in patients undergoing cardiothoracic 9.2.1. Treatment of perioperative anaemia
surgery.234 The authors observed reduced RBC transfu- 9.2.1.1. Minimising gynaecological RBC transfusion
sions in the intervention group compared with the control Recommendation
group, but there was no reduction in intraoperative or
We suggest that normovolaemic haemodilution should not be
postoperative blood loss.
used as it does not reduce allogeneic transfusion. 2B
9.1.3. Which therapies influence bleeding in the 9.2.1.2. Should cell salvage be used in gynaecological
postoperative period? surgery?
Recommendation Recommendation
We suggest that antiplatelet therapy with aspirin or clopidogrel Cell salvage may reduce allogeneic transfusion in gynaecological
may be administered in the early postoperative period without (including oncological) surgery. B
increasing the risk of postoperative bleeding. 2C
9.2.1.3. Should intravenous iron or erythropoietin be
9.1.4. What is the evidence for the use of used to correct perioperative anaemia?
haemostatic management algorithms in Recommendations
cardiovascular surgery? We suggest using preoperative intravenous iron to reduce
Recommendation allogeneic transfusion requirements in anaemic gynaecological
We recommend the use of standardised VHA-guided haemostatic cancer patients receiving chemotherapy. 2B
algorithms with pre-defined intervention triggers. 1B We suggest using intravenous iron to correct preoperative
The most recent systematic review of 12 studies anaemia in women with menorrhagia. 2B
(n 6835), observed a reduction in transfusion require-
ments in patients managed by TEG-guided or ROTEM- 9.2.2. Coagulation monitoring and treatment
guided therapy.48 Transfusion of FFP, platelets and RBC 9.2.2.1. What are the indications for antifibrinolytics
were all reduced; this may have been due to TEG-/ (tranexamic acid)?
ROTEM-guided therapy being more restrictive than Recommendation
control therapy, or control therapy being too liberal.
Tranexamic acid may reduce perioperative bleeding in gynae-
The authors concluded that evidence for the use of
cological cancer surgery. C
TEG-guided/ROTEM-guided intervention algorithms
is still lacking.
9.3. Obstetric bleeding
Two recent RCTs, published in 2015, have also found 9.3.1. Treatment of postpartum anaemia
that preoperative and intraoperative point-of-care test- Anaemia develops in up to 29% of pregnancies in the
ing can reduce transfusion requirements. One RCT third trimester.238 Peripartum bleeding is the major risk
(n 249) was conducted in patients undergoing CABG factor for severe postpartum anaemia239 but peripartum
surgery.235 Preoperative platelet function testing was transfusions may complicate delivery.240242 Here, we
used in a control group and two intervention groups: assess whether correction of anaemia is required as part
one tested using multiple electrode aggregometry and of treating obstetrical haemorrhage and the therapeutic
the other using TEG Platelet Mapping. The results options available.
showed a significant reduction in blood product transfu-
sions in the intervention groups compared with the Related topics of PPH such as diagnosis of PPH, treat-
control. The authors also reported a greater effect in ment of uterine atony, retained placental tissue, arterial
patients who had been treated with an ADP-receptor embolisation and others are beyond the scope of this
antagonist within 5 days before undergoing surgery. The guideline. We recommend other evidence-based clinical
other RCT, conducted in paediatric patients (n 100), guidelines such as the WHO guidelines for the manage-
found that intraoperative ROTEM-guided therapy ment of PPH and retained placenta.243
(EXTEM A10 and FIBTEM A10) post-CPB signifi-
cantly reduced postoperative blood loss and RBC trans- 9.3.1.1. Obstetric triggers for red blood cell transfusion
fusion, both postoperatively and throughout intensive Recommendations
care stay.41 In addition to these RCTs, two recent
We recommend that PPH should be managed by a multi-
observational studies have demonstrated significant
disciplinary team. 1C
reductions in transfusion requirements after imple-
mentation of a blood product utilisation algorithm and We recommended the use of an escalating PPH management
a point-of-care monitoring-based intervention algor- protocol including uterotonic drugs, surgical and/or endovas-
ithm, respectively.236,237 cular interventions, and procoagulant drugs. 1B

Risk awareness and early recognition of severe PPH are moderate (Hb <9.5 g dl1) to severe (Hb <8.5 g dl1)
essential. C anaemia may benefit from intravenous iron therapy,
which elicits more rapid recovery from shorter treatment
We suggest that patients with known placenta accreta be treated
compared with oral therapy.256
by multidisciplinary care teams. 2C
9.3.2. Peripartum haemorrhage: coagulation
9.3.1.2. Should cell salvage be used in obstetrics? monitoring and management
Recommendations 9.3.2.1. Fibrinogen measurement
Cell salvage is well tolerated in obstetric settings, provided that Recommendation
precautions are taken against rhesus isoimmunisation. C We suggest assessing fibrinogen levels in parturients with bleed-
We suggest that using perioperative cell salvage during caesar- ing, as levels less than 2 g l1 may identify those at risk of severe
ean section may decrease postoperative homologous transfusion PPH. 2B
and reduce hospital stay. 2B Fibrinogen levels decrease with increasing blood loss and
may serve as a marker of haemostatic impairment.257,258
9.3.1.3. Intravenous iron or erythropoietin in the Functional markers of fibrinogen such as FIBTEM MCF
treatment of postpartum anaemia and FIBTEM A5 seem to be equally associated with
Recommendation morbidity and the need for transfusion during PPH.259,260
Intravenous iron supplementation improves fatigue at 4, 8 and However, it is not known whether a low fibrinogen level
12 weeks postpartum. B per se, or a low fibrin-based clot firmness, causes pro-
gression of PPH or reflects the severity of the bleed and
PPH should be treated promptly. Delayed recognition of the resuscitation effort required.259 Evaluation of fibrino-
and response to acute bleeding is a leading cause of gen at the onset of labour is of less predictive value.261,262
maternal mortality and near misses.244 A protocol-based Fibrinogen concentration is correlated with estimated
intervention grants an early access to blood pro- blood loss, kaolin-TEG maximum amplitude,263,264 FIB-
ducts.245,246 Suboptimal Hct during the acute phase of TEM MCF and FIBTEM A5.265
PPH is associated with end organ dysfunction.247,248
Blood transfusions have increased substantially in the last 9.3.2.2. Platelet count
decade.249 Although no clinical studies of transfusion Recommendation
trigger Hb thresholds in life-threatening obstetric Dynamic platelet count decrease or a level less than 100 109
haemorrhage were retrieved, a general observance of l1 at the onset of labour, particularly if combined with plasma
an Hb threshold of 8.1 g dl1, to ensure a haemoglobin fibrinogen level less than 2.9 g l1, may indicate an increased
level of 7 to 8 g dl1, has been reported.250 However, in a risk of PPH. C
study of French maternity units, it was reported that RBC
transfusion for PPH was not given in a large proportion of Low platelet count is associated with increased RBC and
women with very low haemoglobin levels.251 FFP transfusion.266 When blood loss reaches 2000 ml,
platelet count is significantly reduced.263
Haemoglobin levels and health-related quality-of-life
physical fatigue scores correlate in the first week post- 9.3.2.3. Activated partial thromboplastin time and
partum. Nevertheless, transfusion in patients with low prothrombin time
haemoglobin concentration without clinical signs of anae- Recommendation
mia has little effect on physical fatigue.252,253 In this
context, a restrictive strategy (haemoglobin threshold: At the beginning of labour aPTT and PT are of little predictive
7 g dl1) seems equally well tolerated and justified. value for PPH. C
aPTT and PT show a small but significant correlation
9.3.1.4. Should cell salvage be used in obstetrics? with estimated blood loss in PPH.267,268
Perioperative cell salvage has been used in obstetric
surgery but is not widely established due to technology 9.3.2.4. Viscoelastic haemostatic assays
issues and a lack of staff training.254 In obstetric haemor- Recommendation
rhage, the routine use of cell salvage is associated with
more salvaged blood returned to the patients, and the costs VHA can identify obstetric coagulopathy. B
may be partly offset by reduced allogeneic blood use.255 VHAs provide results in 5 to 15 min and are faster than
SLTs.264 FIBTEM, a bedside thromboelastometric
9.3.1.5. Intravenous iron or erythropoietin in the fibrin-clot quality test, can indicate a reduced contri-
treatment of postpartum anaemia bution of fibrinogen to clot strength.269,270 FIBTEM
Alternatives to RBC transfusion for maintaining haemo- maximum clot firmness is significantly decreased during
globin concentrations are required. Patients with PPH.270,271

Kaolin-TEG maximum amplitude is correlated with esti- In an RCT involving patients with postpartum haemor-
mated blood loss and fibrinogen concentration.263,264 rhage, a mean estimated blood loss of 1500 ml and
When blood loss reaches 2000 ml, TEG shows decreased normofibrinogenaemia found no benefit of early pre-
maximum amplitude, decreased clot initiation (prolonged emptive treatment with 2 g of fibrinogen concentrate
r-time) and reduced fibrinolytic activity (LY30%).263,264 compared with placebo.285,291 FIBTEM-guided fibrin-
ogen substitution might improve patient outcomes.288,292
Thromboelastometric measurements can identify the
hypercoagulability seen in normal pregnancy,272,273 in No serious adverse events were reported with fibrinogen
caesarean section,274,275 and in pre-eclampsia and concentrate in the obstetric setting.285
HELLP syndromes, as well as cases of impaired haemo-
stasis due to other causes.276 These measurements can 9.3.3.2. Guiding therapy in obstetric bleeding
allow rapid recognition of hyperfibrinolysis and guide Recommendation
therapy with tranexamic acid, fibrinogen concentrate,
PCC, FFP and platelets.263 In severe PPH we suggest a VHA-guided intervention protocol.
2C
9.3.2.5. Hyperfibrinolysis 9.3.3.3. What are the indications for the use of
Split products of fibrin (D-dimer) may increase during antifibrinolytic therapies (tranexamic acid) in obstetrics?
PPH,277 but there is little evidence of hyperfibrinolysis in Recommendations
severe PPH versus non-severe PPH.263
We suggest that tranexamic acid be considered before caesarean
section and in cases of antepartum bleeding. 2B
9.3.3. Haemostatic treatment of obstetric
haemorrhage We recommend the administration of tranexamic acid in PPH
Transfusion of FFP, platelets and cryoprecipitate may be at a dose of 1 g IV as soon as possible, which can be repeated if
a marker for bleeding severity and volume of RBCs bleeding continues. 1B
required.278 An algorithm for managing obstetric haemor- Fibrinolysis is decreased during pregnancy263,264; how-
rhage279 suggests transfusion with FFP if INR is more ever, abnormal fibrinolysis is associated with compli-
than 1.5, with platelets if platelet count is less than cations, for example placental abruption with
25 109 l1, and with cryoprecipitate if fibrinogen is less antepartum bleeding.293
than 100 mg dl1. A high RBC:FFP ratio is associated
with lower risk of advanced interventional procedures to Antifibrinolytic therapy, used prophylactically for vagi-
arrest the postpartum bleeding.280 nal294 or caesarean delivery, or when postpartum bleed-
ing evolves,295 may prevent such complications. A recent
Pregnancy-related hypertensive disorders seem to RCT found that tranexamic acid administered before
increase the risk of TRALI in patients in need of post- caesarean section may reduce perioperative blood loss.296
partum blood transfusions.281,282
Tranexamic acid reduces blood loss, bleeding duration
and possibly transfusion requirements in PPH.297300 In a
9.3.3.1. What are the indications for fibrinogen recent meta-analysis, only a few trials observed adverse
replacement with fibrinogen concentrate or events including thromboembolic complications and sei-
cryoprecipitate? zures; gastrointestinal adverse events were more common
We recommend against pre-emptive fibrinogen replacement; in those patients receiving tranexamic acid compared
however, in ongoing PPH with hypofibrinogenaemia we recom- with placebo.300
mend fibrinogen replacement. 1C
Fibrinogen levels are typically elevated (approximately 9.3.3.4. What are the indications for other coagulation
5 g l1) in pregnancy; however, we are currently unaware factor concentrates (prothrombin complex concentrate
whether trigger levels above 1.5 to 2 g l1 should be and factor XIII)?
applied in obstetrics.283285 Fibrinogen functionality In two cases of amniotic fluid embolism, sufficient
might be impaired by dilution, local or disseminated haemostasis was achieved by thromboelastometric-
consumption.286 The underlying obstetrical cause of guided coagulation therapy comprising tranexamic acid,
bleeding should guide the clinical suspicion of impaired fibrinogen concentrate, platelets and PCC, as well as
haemostasis.287 Trigger levels for fibrinogen substitution RBC and FFP in a 1 : 1 ratio, and rFVIIa.301
vary between 1 and 2 g l1 and FIBTEM A5 less than
12 mm, with a mean administered dose of 2 to 9.3.3.5. What are the indications for the use of
4 g.265,284,288 One retrospective study suggests that recombinant factor VIIa?
fibrinogen concentrate is equally efficacious in treating rFVIIa can be considered as second-line haemostatic
hypofibrinogenaemia compared with cryoprecipitate but therapy alongside intrauterine tamponade, uterine com-
seems faster to use.289,290 pression sutures, pelvic vessel ligation and interventional

radiology.302 Case reports303305 and retrospective stu- doses for emergency VKA reversal in life-threatening
dies302,306309 support off-label use of rFVIIa for severe bleeding range between 25 and 50 IU kg1.338
obstetric coagulopathic bleeding.
In comparison with other reversal strategies, four-factor
An RCT showed reduced need for interventional second- PCCs provide quicker and more controlled correction of
line therapies following administration of 60 mg rFVIIa INR and improved bleeding control than FFP, with a
for postpartum haemorrhage, but also increased risk of favourable safety profile.339344
thromboembolism in 1 of 20 patients.310
Because thromboembolic events after the administration
of PCC have been related to high doses, it is advisable
9.4. Orthopaedic surgery and neurosurgery that the repeated administration of PCC should be
9.4.1. Bleeding risk due to pre-existing coagulation
guided by the effect on the INR: if INR is less than
disorders and medications
1.5 we suggest not administering another dose of PCC,
Elective orthopaedic surgery following the implantation
although clinical parameters should also be assessed.345
of a coronary stent could result in a prohaemostatic
condition and increases the risk of stent thrombosis. Activated PCCs are not indicated for the reversal of VKA-
To minimise this thrombotic risk, elective orthopaedic induced anticoagulation even in emergency bleeding
surgery should be postponed for a minimum of 4 weeks situations. Their use should be restricted to patients with
and optimally for up to 3 months after BMS implantation haemophilia A and B with inhibitors to coagulation
and up to 12 months after DES implantation.311,312 factors VIII or IX for control and prevention of bleeding
episodes, perioperative management or routine prophy-
9.4.2. Screening tests to predict bleeding in laxis to prevent or reduce the frequency of bleeding
orthopaedics and neurosurgery episodes.
Recommendations
ICH is a medical emergency. Quick diagnosis and man-
Reduced platelet activity is associated with early haematoma agement of ICH to limit its expansion is of primary
growth, more intraventricular haemorrhage and worse 3-month importance because clinical deterioration is common in
outcomes following ICH. C the first few hours after ICH onset. Patients on VKA
anticoagulation are at risk of ICH, with worse outcomes
Low platelet count, low plasma fibrinogen concentration and
than non-anticoagulated patients.346 The poorer out-
factor XIII deficiency are predictive of bleeding complications in
comes are mainly related to the volume of the initial
ICH, intracranial surgery and major spine surgery, particu-
haemorrhage and its speed of growth. The general recom-
larly when they occur in combination. C
mendation is to reverse the VKA anticoagulation as
rapidly as possible.
9.4.3. Antifibrinolytics
There is growing evidence for the well tolerated and PCCs are preferable to FFP for rapidly reversing INR,
beneficial use of tranexamic acid to reduce perioperative improving haemostasis and increasing levels of vitamin-K
blood loss, allogeneic blood transfusions and associated dependent coagulation factors in patients requiring
costs in major orthopaedic surgery such as total hip or urgent restoration of haemostasis.347,348
knee arthroplasty, and spine surgery.313326
DOACs (dabigatran, rivaroxaban, apixaban or edoxaban)
However, tranexamic acid is not recommended in patients may increase surgical bleeding. In orthopaedic surgery
with hypersensitivity or allergy to the drug, history of venous they are indicated as thromboprophylaxis in selected
or arterial thrombosis, or thrombophilia, cardiovascular dis- procedures (total hip or knee arthroplasty), with admin-
ease, acute renal failure or subarachnoid haemorrhage, or in istration in the early postoperative period.
patients with a history of seizures or epilepsy.327
Although some antidotes are in the advanced stages of
There is emerging evidence that topical administration of development,349,350 they are not generally available for
tranexamic acid may be beneficial in reducing the rate of routine clinical use. Four-factor PCC, activated PCC and
blood transfusions in both total hip replacement and total rFVIIa have all been investigated for reversing the antic-
knee replacement surgery.315,328333 oagulant actions of DOACs.351354 However, there is
limited evidence that these agents provide clinical
9.4.4. Prothrombin complex concentrate and non- benefit, and a definite lack of evidence regarding optimal
vitamin K-dependent oral anticoagulants dosing and possible thrombotic risk. In some animal
For life-threatening bleeding or ICH among oral anti- models and ex vivo studies, the administration of such
coagulation patients receiving VKAs, with INR more than haemostatic agents has been demonstrated to improve
1.5, guidelines recommend the administration of four- coagulation parameters and/or decrease haemor-
factor PCCs over FFP or rFVIIa for immediate reversal of rhage.351,355362 In cases of life-threatening bleeding or
INR, with co-administration of vitamin K (5 to 10 mg by ICH, it is unclear whether the administration of these
slow intravenous infusion).334338 In general, initial PCC powerful haemostatic agents would be effective in

clinical practice363365 because the correction of haemo- targeted fibrinogen concentration, have been proven by
static laboratory parameters does not necessarily high-quality data.
correlate with bleeding control.349 Another option in
FFP may not provide an adequate increase in plasma
bleeding patients under the effect of dabigatran is hae-
fibrinogen concentrations, and a minimum volume of 20
modialysis.365,366
to 30 ml kg1 should be administered before expecting a
significant increase in fibrinogen concentration.382 No
9.5. Paediatric surgery study has assessed the response observed in fibrinogen
9.5.1. Coagulation monitoring concentration after the administration of FFP in children.
Recommendation
We suggest low-volume sampling for standard coagulation tests 9.5.4.2. Antifibrinolytics
and VHA-guided interventions. 2C Based on tranexamic acid pharmacokinetic data, a loading
dose of 10 mg kg1 over 15 min followed by a 5 mg kg1
There is growing evidence to support the use of VHA- h1 maintenance infusion may be sufficient to maintain
guided paediatric coagulation management, including adequate plasma concentrations during craniosynostosis
three RCTs.41,51,212,367378 In children undergoing car- surgery.383 However, further RCTs are needed to assess
diac surgery, Nakayama et al.41 randomised 100 children the efficacy of this dose regimen. In a recent compre-
to be treated using a ROTEM-guided algorithm or a hensive pharmacokinetic study performed in neonates
routine approach based on standard coagulation assays. and children undergoing cardiac surgery, different dose
The utilisation of a ROTEM-guided approach signifi- schemes based on patients ages and the targeted plasma
cantly reduced chest tube drainage output measured at 12 concentration were recommended.384 As the minimum
and 24 h postoperatively. Although no difference in the plasma concentration required to completely inhibit fibri-
total amount of blood products transfused was observed, nolysis in different surgical settings is not known, further
the ROTEM-guided algorithm was associated with studies are needed before we can recommend the optimal
increased intraoperative blood products transfusion, dosing schemes based on pharmacokinetics and pharma-
and a decrease in postoperative transfusion. These results codynamics.385
confirmed that the use of ROTEM-guided algorithm
allows for an earlier treatment of coagulopathy, leading
9.6. Visceral and transplant surgery
to decreased postoperative bleeding.
9.6.1. Should coagulopathy associated with chronic
liver disease be corrected before invasive
9.5.2. Fluid resuscitation procedures?
Recommendation 9.6.1.1. What is the evidence that haemostasis is re-
We recommend the use of isotonic and balanced resuscitation balanced in chronic liver disease?
fluids in bleeding children. 1C Despite PT, aPTT and INR indicating coagulopathy in CLD,
global coagulation tests (thrombin generation and VHA) suggest
Recent studies suggest that intraoperative positive fluid that haemostasis is balanced in stable CLD. C
balance could contribute to postoperative fluid overload,
which has been shown to significantly affect patient 9.6.1.2. What is the evidence that INR reflects bleeding
outcome.379381 Although most of these studies were risk in patients with chronic liver disease?
performed in children undergoing cardiac surgery, fluid Mild-to-moderate prolongation of the preoperative PT and
overload should be avoided in all clinical contexts; INR do not predict bleeding in patients with CLD. C
fluid administration and balance should be monitored
carefully. 9.6.2. Acute liver failure and invasive procedures
Recommendation
9.5.3. Red blood cell transfusion
We recommend that, in acute liver failure, moderately elevated
Recommendation
INR should not be corrected before invasive procedures, with the
Except for premature babies and cyanotic newborns, haemo- exception of intracranial pressure monitor insertion. 1C
globin targets in bleeding children are 7 to 9 g dl1. C
9.6.3. Orthotopic liver transplantation
9.5.4. Coagulation factor concentrates 9.6.3.1. Intraoperative fluid management
9.5.4.1. Fibrinogen concentrate Recommendations
Intraoperative administration of fibrinogen concentrate
Fluid restriction, phlebotomy, vasopressors and transfusion
(50 mg kg1) has been used effectively to treat hypofi-
protocols may be associated with low transfusion rates during
brinogenaemia (ROTEM FIBTEM maximum clot firm-
OLT. C
ness 7 mm) during major paediatric surgery.367,372,378
However, neither the optimal threshold for initiation of We recommend a low CVP and restrictive fluid administration
fibrinogen replacement nor the dose required to reach the during liver surgery to reduce bleeding. 1B

Maintenance of low CVP during hepatic resection 9.6.6.1. Fluid resuscitation and pharmacological
reduces blood loss and transfusion requirements.386,387 interventions
Low transfusion rates (<80%) during OLT have been A single-centre study of over 900 patients randomised to a
reported using fluid restriction, phlebotomy, vasopressors restrictive (70 g l1) or liberal (90 g l1) transfusion
and transfusion protocols.388 strategy demonstrated that the risks of death and re-
bleeding were lower with the restrictive threshold.126
9.6.4. Coagulation monitoring However, the study was unblinded and no subgroup
Conventional coagulation tests do not reliably predict analysis for coronary artery disease was performed.
bleeding,389 nor does an elevated INR exclude hyper- Another single-centre RCT with 921 patients, found that
coagulability.390 a restrictive transfusion strategy significantly improved
outcomes compared with a liberal transfusion strategy.397
9.6.4.1. Global coagulation tests: thrombelastography/ A large cluster, randomised feasibility study performed in
thromboelastometry six UK centres demonstrated decreased transfusions with
Other evidence suggests TEG/ROTEM monitoring may restrictive (80 g l1) compared with liberal (100 g l1)
help reduce bleeding and transfusion of FFP and plate- strategies, but no differences in patient outcomes were
lets in liver transplantation.391,392 observed.398 It is too early for these studies to inform
clinical practice directly, as the safety of low transfusion
thresholds in patients with ischaemic heart disease
9.6.5. Pharmacological therapy
remains a key area of uncertainty. However, two recently
9.6.5.1. Antifibrinolytic drugs
published guidelines both recommend that a restrictive
Recommendations
transfusion threshold of 70 to 80 g l1 should be
We recommend tranexamic acid for treatment of fibrinolysis used.399,400
(evident from microvascular oozing or VHA clot lysis measure-
ment) but not for routine prophylaxis. Marginal grafts (e.g.
donation after cardiac death) increase the risk of fibrinolysis 9.6.7. Coagulopathy and renal disease
post-reperfusion. 1C 9.6.7.1. Assessment of platelet function
Recommendation
We suggest that tranexamic acid should be considered in cir-
rhotic patients undergoing liver resection. 2C Point-of-care tests of platelet function and bleeding time provide
no reliable platelet function assessment in uraemia and no
A treatment strategy of administering antifibrinolytic prediction of bleeding in this setting. C
therapy based on the presence of fibrinolysis on viscoe-
lastic testing does not appear to result in increased PFA-100 is not useful for the prediction of bleeding
bleeding compared with a prophylactic regime.393 complications.401
9.6.6. Acute upper gastrointestinal bleeding

9.6.7.2. Correction of bleeding diathesis and treatment
A large multi-centre trial (HALT-IT) of the efficacy and
of bleeding
safety of tranexamic acid is in progress.394
Recommendations
Recommendations
We suggest that conjugated oestrogen therapy should be used in
We recommend that acute variceal bleeding should be managed uraemia. 2C
by a multidisciplinary team. A specific multimodal protocol for
We suggest that DDAVP should be considered for reducing
upper gastrointestinal haemorrhage should be available. 1C
bleeding during surgery and for managing acute bleeding in
TIPSS can be suggested as an option for rescue therapy after uraemic patients. 2C
initial medical and endoscopic therapy fail. 2B
DDAVP can treat platelet dysfunction in uraemic
We recommend early interventional endoscopy and the immedi- patients. DDAVP induces VWF release, improving pla-
ate use of vasopressors (somatostatin or terlipressin) to reduce telet adhesion/aggregation, and has been shown to be
bleeding. 1B effective for both prophylaxis and the treatment of peri-
operative bleeding.402,403 However, it can cause signifi-
Tranexamic acid reduces mortality but not re-bleeding. B
cant dilutional hyponatraemia.404
In a systematic review it has been shown that TIPSS can
reduce failure to control bleeding and re-bleeding, as well 10. Antithrombotic drugs
as mortality.395 In high-risk cirrhotic patients, an RCT 10.1. Introduction
also demonstrated that early use of TIPSS is associated Antithrombotic therapies have a range of indications, and
with a significant reduction in treatment failure and in this section we describe how they are managed in
mortality.396 anaesthesia and intensive care.

10.2. Antiplatelet agents factorial trial design (exploring also the efficacy and safety
Perioperative interruption and maintenance of APAs are of clonidine to prevent cardiovascular events), 10 010
associated with increased thrombotic or haemorrhagic patients at risk of vascular complications and who were
complications, respectively. Recommendations for peri- undergoing non-cardiac surgery were included. The
operative APA therapy are based on only one large patients were stratified according to whether they had
controlled study, along with small observational studies, not been taking aspirin before the study (aspirin initiation
case reports and expert opinion, so most recommen- group, 5628 patients) or they were already on an aspirin
dations are weak. In patients with coronary stents, inter- regimen (aspirin continuation group, 4382 patients).
ruption of APA is a risk factor for stent thrombosis. If Patients in the continuation group stopped their usual
these patients require surgery, the optimum delay aspirin 3 days before surgery. Then all started taking
between stent implantation and surgery is unclear, as aspirin (at a dose of 200 mg) or placebo just before surgery
is the need for (or optimal duration of) interruption of and continued it daily (at a dose of 100 mg) for 30 days in
APA therapy. the initiation stratum and for 7 days in the continuation
stratum, after which patients resumed their regular
10.2.1. Aspirin aspirin regimen. The primary outcome, a composite of
Recommendations death or non-fatal myocardial infarction at 30 days,
occurred in 7.0% of patients in the aspirin group and
We recommend that aspirin therapy should continue periopera-
in 7.1% of patients in the placebo group (P 0.92). Major
tively in most surgical settings, especially cardiac surgery. 1C
bleeding was more common in the aspirin group than in
Where aspirin withdrawal before surgery is considered, we the placebo group [230 patients (4.6%) versus 188
recommend a time interval of 3 days. 1C patients (3.8%); hazard ratio, 1.23; 95% CI, 1.01 to
1.49; P 0.04]. A majority of patients included in this
In patients with risk factors for vascular complications nave of
study had only risk factors for perioperative cardiovas-
any antiplatelet treatment, it is not recommended that treatment
cular events including a majority of aged or hypertensive
with aspirin be initiated preoperatively. 1B
and/or diabetic patients. Less than 35% of patients had a
In patients treated chronically with aspirin for the secondary history of vascular disease. The majority of patients were
prevention of cardiovascular events, except those patients with Revised Cardiac Score Index 1. As a result, most patients
coronary stents, we recommend aspirin interruption for pro- included in the initiation group would not have been
cedures where there is a very high bleeding risk. 1B otherwise treated by aspirin.
In patients chronically treated with aspirin for secondary Major bleeding was significantly higher in the aspirin
prevention of cardiovascular events, we recommend aspirin group; however, this was significant only in the initiation
be maintained during and after low and medium bleeding risk group. An interaction between antiplatelet and post-
procedures. 1B operative anticoagulant therapy may explain a higher
major bleeding rate in the aspirin group. In addition, a
We suggest careful consideration of postoperative bleeding
lack of antithrombotic efficacy of aspirin was observed
complications when timing the first postoperative adminis-
but, as the postoperative use of NSAIDs was allowed
tration and dose of anticoagulants along with resumption of
(>40% of the patients), this may have interfered with
aspirin. 2C
aspirin efficacy by blocking access to the COX-
For intraoperative or postoperative bleeding clearly related to inhibitor pathway.
aspirin, we suggest that platelet transfusion be considered (dose:
In summary, aspirin should not be withdrawn periopera-
0.7 1011 per 10 kg body weight in adults). 2C
tively unless the risk of bleeding exceeds the thrombotic
We recommend that aspirin be continued for at least 4 weeks risk from withholding the drug.
after BMS implantation and 3 to 12 months after DES
implantation, unless the risk of life-threatening surgical bleeding 10.2.2. P2Y12 receptor inhibitors: clopidogrel,
on aspirin is unacceptably high. 1A prasugrel and ticagrelor
Recommendations
Treatment discontinuation increases thrombotic risk.
Following aspirin withdrawal, aspirin treatment should We suggest that P2Y12 inhibitor treatment be considered for at
resume as soon as possible postoperatively to prevent least 4 weeks after BMS implantation and 3 to 12 months after
platelet activation. A risk of surgical bleeding is also DES implantation, unless the risk of life-threatening surgical
associated with APA therapy; however, this has been bleeding on this agent is unacceptably high. 2A
poorly evaluated.
If clinically feasible, we suggest postponing (semi-urgent) surgery
In a large RCT, POISE 2, patients undergoing non- for at least 5 days after cessation of ticagrelor and clopidogrel,
cardiac surgery were randomised to receive aspirin and for 7 days in the case of prasugrel, unless the patient is at
or placebo before and after surgery.405 Using a 2-by-2 high risk of an ischaemic event. 2B

We recommend that APA therapy should resume as soon as No studies on efficacy of platelet transfusion in patients
possible postoperatively to prevent platelet activation. 1C treated with ticagrelor were retrieved. However, when
ticagrelor is administered within the preceding 12 h, its
We suggest that the first postoperative dose of clopidogrel or
presence in plasma may render platelet transfusion inef-
prasugrel should be given no later than 24 h after skin closure.
fective.409
We also suggest that this first dose should not be a loading dose.
2C
10.2.3. Dual antiplatelet therapy
We recommend that a multidisciplinary team meeting should The prognosis of stent thrombosis appears to be worse
decide on the perioperative use of APAs in urgent and semi- than for de novo coronary occlusion, and premature cessa-
urgent surgery. 1C tion of dual antiplatelet therapy (DAPT) in patients with
recent coronary stent implantation is the most powerful
We suggest that urgent or semi-urgent surgery should be per-
predictor for stent thrombosis. The management of anti-
formed under aspirin/clopidogrel or aspirin/prasugrel combi-
platelet therapy in patients who have undergone recent
nation therapy if possible, or at least under aspirin alone. 2C
coronary artery stent treatment, and are scheduled for
We suggest that platelet transfusion be considered (dose: non-cardiac surgery, should be discussed to balance the
0.7 1011 per 10 kg body weight in adults) in cases of intra- risk of procedural bleeding on antiplatelet therapy and
operative or postoperative bleeding clearly related to clopidogrel the risk of MACE, including stent thrombosis. Most
or prasugrel. 2C studies exploring the risk of stent thrombosis following
DAPT interruption have been performed in patients
According to pharmacological characteristics, we suggest that the
implanted with first-generation stents. Duration of
management of ticagrelor may be comparable to clopidogrel (i.e.
DAPT for these first-generation stents was 12 months.
withdrawal interval of 5 days). 2C
Recent publications from new-generation DES (zotaro-
Platelet transfusions may be ineffective for treating bleeding limus-eluting and everolimus-eluting stents), suggest
related to ticagrelor if given within 12 h of the drugs admin- that shorter durations (3 to 6 months) of DAPT may
istration. C be sufficient.410,411 Current guidelines recommend
delaying elective non-cardiac surgery until completion
In a systematic review of 37 studies (31 cardiac and six
of the full course of DAPT and, whenever possible,
non-cardiac surgery; three randomised, 34 observational),
performing surgery without discontinuation of aspirin.312
postoperative outcomes in patients who were or were not
exposed to thienopyridine in the 5 days before surgery Regarding BMS, several studies confirm that the first
were compared.406 Exposure to thienopyridine in the 5 month following BMS placement is a high-risk period for
days preceding surgery (compared with no exposure) was non-cardiac surgery. However, most guidelines on stent
not associated with any reduction in postoperative myo- type, surgical timing for both DES and BMS and anti-
cardial infarction, but was associated with increased risks platelet cessation should probably be re-evaluated, as
of stroke, re-operation for bleeding and all-cause other underlying factors may explain postoperative
mortality. Results were similar when analyses were MACE in these patients. In a large national, retrospective
restricted to long-term users of thienopyridines who cohort study of 41 989 operations occurring in the 24
continued versus those who withheld the medication months after a coronary stent implantation between
in the 5 days before surgery. Although all associations 2000 and 2010, a nested casecontrol study assessed
were similar for the subset of patients undergoing non- the association between perioperative antiplatelet cessa-
cardiac surgery, 97% of the outcome data in this meta- tion and MACE.412 Within 24 months, 28 029 patients
analysis came from cardiac surgery trials. underwent non-cardiac operations resulting in 4.7%
MACE. After adjustment, the three factors most strongly
A large phase 3 study (TRITON-TIMI 38) compared
associated with MACE were non-elective surgical admis-
prasugrel with clopidogrel in patients with acute coronary
sion, history of myocardial infarction in the 6 months
syndrome (ACS) scheduled to undergo percutaneous
preceding surgery, and revised cardiac risk index more
coronary intervention. In a subset of patients requiring
than 2. Of the 12 variables in the model, timing of surgery
CABG, platelet transfusions were administered to sig-
ranked fifth in explanatory importance measured by
nificantly more patients, and at a significantly higher
partial effects analysis, and stent type ranked last.
dose, in patients in the prasugrel arm than in patients
allocated to the clopidogrel arm.407 Platelet aggregation
10.3. Anticoagulant agents
recovery period after prasugrel interruption took longer
10.3.1. Heparin
than after clopidogrel interruption.408 This antiplatelet
Recommendations
effect lasts for the lifespan of the platelets (7 days).
Recommendations for clopidogrel should be applicable We recommend that severe bleeding associated with intravenous
to prasugrel, except for the duration of withdrawal (7 days UFH should be treated with intravenous protamine at a dose of
of interruption for prasugrel). 1 mg per 100 IU UFH given in the preceding 2 to 3 h. 1A

We suggest that severe bleeding associated with SC UFH postoperatively until the target INR is observed in two following
unresponsive to intravenous protamine at a dose of 1 mg per measurements. 1C
100 IU UFH could be treated by continuous administration of
We recommend that for moderate to high thrombotic risk
intravenous protamine, with the dose guided by aPTT. 2C
patients, prophylactic doses of heparin (UFH or LMWH)
We suggest that severe bleeding related to SC LMWH should be should be started during the evening or the day after the
treated with intravenous protamine at a dose of 1 mg per 100 procedure (at least 6 h after) and given for up to 48 to 72 h,
antifactor Xa units of LMWH administered and, if unrespon- and then therapeutic anticoagulation should be resumed. VKA
sive, with a further 0.5 mg protamine per 100 antifactor Xa can restart at that time or later, only when surgical haemostasis
units. 2C is achieved. 1C
In VKA-treated patients undergoing an emergency procedure, we
10.3.2. Fondaparinux recommend that INR must be measured on the patients admis-
Recommendation sion to the hospital, with the administration of four-factor PCC
to reverse VKA anticoagulant effects (e.g. at an initial dose of 25
We suggest that the administration of rFVIIa could be con-
IU factor IX kg1 at an INR of 4) rather than the transfusion of
sidered to treat severe bleeding associated with SC adminis-
plasma. 1B
tration of fondaparinux (off-label treatment). 2C
In bleeding patients where VKA-induced coagulopathy is con-
Although some research is ongoing,413 currently there is
sidered a contributing factor, we recommend the administration
no available drug acting as an antidote to fondaparinux.
of four-factor PCC 25 to 50 IU factor IX kg1 plus 5 to 10 mg
rFVIIa has been proposed to control severe bleeding, but
IV vitamin K. 1B
limited data support this.414
If PCC is not available, then in bleeding patients where VKA-
induced coagulopathy is considered a contributing factor, we
10.3.3. Vitamin K antagonists
recommend the transfusion of plasma (15 to 20 ml kg1 plus 5
Recommendations
to 10 mg IV vitamin K. 1C
We recommend that VKAs should not be interrupted in patients
Preoperative interruption of VKA therapy with substi-
undergoing low bleeding risk procedures: skin surgery, dental
tution by a short-acting anticoagulant such as LMWH or
and oral procedures, gastric and colonic endoscopies (even if
UFH (so-called bridging therapy) is common practice.
biopsy is scheduled, but not polypectomies), nor for most
However, recent studies have indicated that it may
ophthalmologic surgery [i.e. mainly anterior chamber (catar-
increase perioperative bleeding without decreasing throm-
act)]. 1C
botic events.415417 Nevertheless, practice guidelines
We recommend that for lowmoderate thrombotic risk patients which have not taken these more recent studies415417
(e.g. atrial fibrillation patients with CHADS2 score 4; into account support bridging therapy when there is a
patients treated for >3 months for a non-recurrent VTE) high thrombotic risk, especially in mechanical valve
undergoing procedures requiring INR less than 1.5, VKA should patients.418
be stopped 3 to 5 days before surgery (acenocoumarol, war-
For urgent control of the anticoagulant effects of VKA,
farin). No bridging therapy is needed. Measure INR on the day
the administration of PCC provides faster and more
before surgery and give 5 mg oral vitamin K if INR exceeds 1.5.
effective reversal than FFP.419422 The optimal dosing
1C
of PCC has not been fully elucidated, so the dose should
We recommend bridging therapy for high thrombotic risk be individualised to maximise effectiveness without
patients (e.g. atrial fibrillation patients with a CHADS2 score compromising safety. Overcorrection should be avoided
>4; patients with recurrent VTE treated for <3 months or as this may increase thrombotic risk. Dose selection
patients with a prosthetic cardiac valve); warfarin: last dose 5 may be influenced by the patients clinical status, pre-
days before surgery; 4 days before surgery, no heparin; 3, 2 and 1 treatment INR, target INR and other laboratory values.
day before surgery, LMWH (last dose 24 h before surgery) or SC
UFH twice or thrice daily; day 0, surgery; acenocoumarol: 3 10.3.4. Direct oral anticoagulants
days before surgery, last dose; 2 and 1 day before surgery, same Recommendations
protocol as for warfarin. 1C
We recommend assessment of creatinine clearance in patients
We suggest that the therapeutic dose of LMWH or UFH should receiving DOACs who are scheduled for surgery. 1B
be tailored for each patient, depending on the respective throm-
We suggest that DOACs should only be withheld the day before
botic and bleeding risk. 2C
surgery for patients undergoing low bleeding risk procedures
We recommend that for low bleeding risk patients, VKAs should such as skin surgery, dental and oral procedures, gastric and
be restarted during the evening or the day after the procedure (at colonic endoscopies (even if biopsy is scheduled, but no poly-
least 6 h after). Therapeutic doses of LMWH should be given pectomies) and most ophthalmologic surgery. 2C

For intermediate and high bleeding risk procedures: fatal bleeding events than the twice-daily 5 mg dose (0.1
versus 0.4%; P 0.04).
(1) we recommend that rivaroxaban, apixaban and edoxaban
should not be given for 2 days before the procedure (i.e. last 10.3.4.2. Apixaban
oral intake 3 days before), pending a creatinine clearance Apixaban is an oral, reversible, direct factor Xa inhibitor
(CockcroftGault formula) above 30 ml min1. No related to rivaroxaban. AMPLIFY was a randomised,
bridging therapy is needed. 1C double-blind study that compared apixaban (10 mg twice
(2) we recommend that dabigatran should not be given for 3 daily for 7 days, followed by 5 mg twice daily for 6
days before the procedure (i.e. last oral intake 4 days months) with conventional therapy (SC enoxaparin, fol-
before), if the creatinine clearance is above 50 ml min1 lowed by warfarin) in 5395 patients with VTE.426 The
and 4 days before the procedure (i.e. last oral intake 5 days primary efficacy outcome (recurrent symptomatic VTE or
before), if the creatinine clearance is between 30 and 50 ml death related to VTE) occurred in 59/2609 patients
min1. No bridging therapy is needed. 1C (2.3%) in the apixaban group compared with 71/2635
(2.7%) in the conventional-therapy group (relative risk,
We suggest that in severe bleeding patients treated with dabiga-
RR, 0.84). Major bleeding was reported in 0.6% of
tran, a specific antidote (idarucizumab) should be considered.
patients receiving apixaban and in 1.8% of those receiv-
2C
ing conventional therapy (RR, 0.31; P < 0.001 for super-
We suggest that for low bleeding risk procedures, when haemo- iority). The composite outcome of major bleeding and
stasis is achieved, DOACs should be recommenced during the clinically relevant non-major bleeding occurred in 4.3%
evening after the procedure (at least 6 h after). 2C of patients in the apixaban group, compared with 9.7%
of those in the conventional-therapy group (RR, 0.44;
We suggest that for intermediate and high bleeding risk pro-
P < 0.001). In another study (ADOPT), apixaban was
cedures, prophylactic doses of LMWH or DOACs (according to
given at a dose of 2.5 mg twice daily for 30 days
specific indications) should be given postoperatively whenever
and was compared with an enoxaparin regimen of
VTE prophylaxis is requested and then the full therapeutic dose
40 mg daily for 6 to 14 days in hospitalised patients
of DOAC should be resumed up to 72 h postoperatively, when
with a risk factor for thrombosis.427 The results
surgical haemostasis is achieved. 2C
showed that apixaban was as effective as enoxaparin in
preventing VTE; however, an increase in bleeding epi-
10.3.4.1. Rivaroxaban sodes was observed in the apixaban group. In comparison
Rivaroxaban is an orally active oxazolidone derivative and with these positive results in patients with ACS, the
the first available oral antifactor Xa agent. results of the APPRAISE-2 study, in which patients
received apixaban 5 mg twice daily in combination with
In the EINSTEIN_PE study, rivaroxaban was as effec-
an antiplatelet regimen or a standard dual antiplatelet
tive as enoxaparin plus adjusted-dose VKA, but the major
regimen, were not so encouraging.428 Apixaban plus
bleeding rate was halved in the rivaroxaban group.423
antiplatelet therapy was associated with an increase in
Rivaroxaban has also been studied in patients hospital-
major bleeding events and fatal intracranial bleedings,
ised for acute medical issues and/or infection with elev-
without any significant reduction in recurrences of
ated risk factors for VTE (MAGELLAN study).424 In
coronary incidents.
these patients, a 10-mg dose of rivaroxaban once daily for
35 days was compared with a once-daily prophylactic
10.3.4.3. Edoxaban
dose of enoxaparin (40 mg) for only 10 days. The efficacy
Edoxaban is the third oral antifactor Xa agent to be
of rivaroxaban was non-inferior to that of enoxaparin, but
marketed. ENGAGE-AF was a randomised trial compar-
the frequency of bleeding was significantly higher in the
ing two once-daily regimens of edoxaban (60 and 30 mg)
rivaroxaban group (4.1 versus 1.7%; P <0.0001).
with warfarin in 21 105 patients with a moderate-to-high-
The ATLAS-TIMI 51 trial was a randomised, double- risk of atrial fibrillation (median follow-up, 2.8 years).429
blind study in patients with ACS.425 Patients received the The primary efficacy endpoint (stroke or systemic embo-
antiplatelet therapy chosen by their cardiologist in lism, annualised rate) was 1.5% with warfarin (median time
addition to rivaroxaban (2.5 or 5 mg twice daily) or in the therapeutic range: 68.4%), compared with 1.18%
placebo. The efficacy endpoint was incidence of cardi- with high-dose edoxaban (P < 0.001 for non-inferiority)
ovascular death, myocardial infarction or ischaemic and 1.61% with low-dose edoxaban (P 0.005 for non-
stroke. Compared with placebo, patients receiving either inferiority). In the intention-to-treat analysis, there was a
dose of rivaroxaban had a reduced frequency of these trend favouring high-dose edoxaban versus warfarin and an
events. Moreover, the lower dose of rivaroxaban (2.5 mg unfavourable trend with low-dose edoxaban versus war-
twice daily) was also associated with a reduction in farin. The annualised rate of major bleeding was 3.43%
cardiovascular mortality and all-cause mortality. Treat- with warfarin versus 2.75% with high-dose edoxaban
ment with the twice-daily 2.5 mg dose resulted in fewer (P < 0.001) and 1.62% with low-dose edoxaban

(P < 0.001). The HOKUSAI-VTE study was a random- 10.3.5. Management of patients scheduled for a
ised, non-inferiority study that enrolled 8240 patients with procedure and treated with direct oral anticoagulants
acute VTE (4921 with deep vein thrombosis and 3319 with (emergency procedures excluded)
pulmonary embolism) who had initially received Physicians from outside the field may be unaware of the
heparin.430 Study participants received either edoxaban pharmacological characteristics of many DOACs. The
60 mg once daily (30 mg once daily for patients with European Society of Cardiology and several other groups,
creatinine clearance of 30 to 50 ml min1 or a body weight such as the Groupe dInteret en Hemostase Periopera-
<60 kg) or warfarin for 3 to 12 months. Edoxaban was non- toire, have issued proposals for managing patients treated
inferior to warfarin with respect to the primary efficacy with DOACs.437,438 The following patient groups are
outcome (recurrent symptomatic VTE), which occurred in considered: atrial fibrillation or VTE patients treated
130 patients in the edoxaban group (3.2%) and 146 patients with DOACs and undergoing an invasive procedure.
in the warfarin group (3.5%) (P < 0.001 for non-inferiority).
The safety outcome (major or clinically relevant non-major
bleeding) occurred in 349 patients (8.5%) in the edoxaban 11. Comorbidities involving haemostatic
group and 423 patients (10.3%) in the warfarin group derangement
(P 0.004 for superiority). 11.1. Patients with comorbidities involving
haemostatic derangement
11.1.1. Systemic, metabolic and endocrine diseases
Recommendation
10.3.4.4. Non-specific reversal agents and specific
antidotes We suggest that patients with haemostatic derangements associ-
As a first option, activated charcoal (50 g) has been shown ated with systemic, metabolic and endocrine diseases should be
to be very effective in healthy volunteers treated with managed perioperatively in collaboration with a haematologist.
apixaban 20 mg.431 The mean elimination half-life for 2C
apixaban alone (13.4 h) decreased to 5 h when activated
Systemic, metabolic and endocrine diseases (e.g. amyloi-
charcoal was administered at 2 or 6 h post-dose. For
dosis, hypothyroidism) are associated with haemostatic
dabigatran, charcoal has only been tested in vitro. One
derangements. Optimal management strategies for these
case report is available for rivaroxaban.432
coagulopathies remain unclear.
Treatments proposed for the reversal of the anticoagulant
Acquired factor X deficiency causes the most frequent
activity, or the control of bleeding in patients treated with
bleeding manifestations in amyloidosis439 and is
DOACs include PCC and activated PCC (aPCC or
treated similarly to inherited factor X deficiency. Overt
FEIBA). Pre-clinical studies performed in rabbits and
hypothyroidism appears to be associated with a bleeding
pigs have provided very positive data regarding the use of
tendency, whereas all other endocrine diseases appear to
PCC for reversal of dabigatran and rivaroxaban364 but not
be associated with thrombotic tendency.440
for apixaban. The efficacy of PCC has been demonstrated
in healthy volunteers for rivaroxaban433 but not for dabi- A decrease in VWF synthesis or a decreased response to
gatran. In some registries, PCC (and aPCC) appear to be adrenergic stimulation due to hormone deficiency could
effective for reversing the anticoagulant effects of all be involved in the pathogenesis of hypothyroidism-
DOACs, although the lack of a control group limits the associated VWS.441 These mechanisms are supported
strength of this evidence. by the reversal of VWS following hormone replacement
therapy.442 Other coagulation abnormalities described in
Idarucizumab, the antidote which is being developed for
hypothyroidism are: impaired platelet function,
dabigatran etexilate, is a fully humanised monoclonal
reduction in coagulation factors, acquired inhibitors to
antibody fragment. It completely reverses the anti-IIa
VWF and coagulation factors, and increased fibrinolytic
activity of dabigatran. An initial series of 90 patients
activity.441 It seems that the pattern of fibrinolytic
(either bleeding patients or patients scheduled for an
abnormality depends on the severity of hypothyroidism,
invasive procedure) have been treated, and complete
with increased fibrinolysis in overt hypothyroidism
reversal of the anticoagulant activity was observed.
and hypofibrinolysis in subclinical hypothyroidism.443
However, there was a safety concern because mortality
However, other authors have found hypofibrinolysis in
reached 20%.434,435 Further phase 3 studies are manda-
both overt and subclinical hypothyroidism444 and con-
tory to confirm the benefits and risks of this compound.
clude that the association between subclinical hypothy-
A factor Xa analogue (andexanet alpha), which reverses roidism and haemostasis abnormalities requires further
the effects of all antifactor Xa agents, is currently being studies.444 The coagulation and fibrinolysis abnormalities
developed. An injectable drug, it appears to be very are corrected by hormone therapy.445 DDAVP was
effective despite having a short half-life (<90 min). This also effective in patients with VWS undergoing thyroid
agent is not yet available in clinical practice.436 surgery.446

Patients with autoimmune and malignant disorders can with agents with lower affinity or non-selective reuptake
develop autoantibodies affecting the activity or acceler- inhibition.461
ating the clearance of clotting factors (acquired inhibi-
Moreover, when used alongside APAs, perioperative use
tors). Such inhibitors are most frequently directed against
of SSRIs should be individualised. Although a French
factor VIII or VWF but acquired inhibitors against other
database analysis did not demonstrate any significant
clotting factors were also described. Recommendations
association between bleeding adverse drug reactions
for the diagnosis and management of acquired inhibitors
and exposure to SSRI and APAs versus APAs alone,462
of clotting factors were recently issued.447
another database analysis found a high rate of adverse
reactions of SSRIs related to drugdrug interactions.463
11.1.2. Patients on chronic medication associated
Some SSRIs may interfere with warfarin metabolism and
with haemostatic derangements
increase INR.464
It is estimated that half of the general surgical population
take medication unrelated to surgery.448 Medications In both large population-based cohort studies,465 and
other than antiplatelet and anticoagulant agents may meta-analyses of cohort and casecontrol studies466,467
potentially affect haemostasis, including SSRIs, antiepi- SSRIs are associated with an increased risk of UGIB. The
leptic drugs and herbal agents. risk is higher even after short-term use, especially in male
patients.468 Combination with NSAIDs466,467 and anti-
Recommendation
platelet drugs467 significantly increases the risk of UGIB.
We suggest individualised preoperative discontinuation of The use of acid-suppressing drugs significantly reduces
SSRI treatment. 2B the risk.467
SSRIs have been associated with an increased bleeding Recommendation
tendency, due to serotonin depletion from plate-
lets.449,450 Bleeding frequency was proportionate to the We suggest individualised preoperative discontinuation of anti-
degree of serotonin reuptake inhibition451 and withdra- epileptic agents, such as valproic acid, which may increase
wal of SSRI medication was recommended according to bleeding. 2C
their half-life if patients were submitted to procedures Drug interactions may involve antiepileptic drugs and
with a high risk of operative bleeding.452 warfarin.464 Most commonly used antiepileptic drugs
However, further studies showed variable and contra- are either potent hepatic enzyme inducers or inhibitors
dictory clinical effects of SSRIs on haemostasis, with both and they affect the metabolism of warfarin. The anti-
increases and decreases of bleeding and/or transfu- epileptic drug valproic acid may displace warfarin from
sion.453457 the protein binding sites resulting in significant INR
changes, but this type of drug interaction is less well
Interestingly, the risk of bleeding has been reported known.469
differently for various types of surgery. In an analysis
of 10 studies, intraoperative and postoperative bleeding The effect of valproic acid on haemostasis is controver-
and transfusion were higher in serotonin antidepressants sial. Decreased platelet function and numbers, as well as
(SAD) users before orthopaedic and breast surgery but reduced levels of factors VII, VIII, XIII, VWF, fibrinogen,
not in CABG or facial surgery.458 protein C and antithrombin were described in some
studies.470472 However, in one prospective controlled
Although analysis of two pharmacovigilance databases study, there were no statistically significant differences in
suggested that SSRIs were not associated with an any of the studied haemostasis parameters in cases versus
increased risk of bleeding,459 a recent systematic review controls.473 Any clinically relevant detriment to haemo-
including 13 relevant studies across a variety of surgical stasis is uncommon.474
procedures showed that SADs were associated with
increased risk of perioperative bleeding (odds ratio 1.21 Recommendation
1.21 to 4.14) and blood transfusions (odds ratio 0.93 to We do not recommend preoperative discontinuation of gingko
3.71).460 Clinicians should be aware of this increased biloba extracts. 1B
bleeding risk with SAD use and carefully weigh it against
the psychiatric benefits in all patients undergoing Although herbal remedies are used to treat a large variety
surgery. Discontinuation of SADs should be planned 2 of diseases, the safety of many products has not been
weeks before the operation in patients with a high risk of proven, nor has their effect on blood parameters been
bleeding and who are in a stable phase of depression. determined. As a number of herbal preparations have
Alternatively, changing to an antidepressant that inhibits been reported to cause alteration of haemostasis, some
less serotonin reuptake should be considered in case of authors recommend their discontinuation before under-
exacerbation of depression.458 Another database analysis going any surgical procedure.475 Moreover, some
provides preliminary evidence that SSRIs may be associ- Chinese herbal medicines (such as danshen, dong quai,
ated with an increased risk of bleeding as compared ginger, ginkgo, liquorice and turmeric) demonstrate

pharmacodynamic interactions with conventional A bleeding score more than 3 could generally be con-
anticoagulant/antiplatelet drugs resulting in increased sidered as suggestive of a bleeding diathesis in adults494
bleeding risk.476 but age and gender differences have been reported.495
The validity of the bleeding score has never been proven
A recent narrative review provides an exhaustive list of
in patients having a severe bleeding disorder.
the potential effects on haemostasis of different herbal
medicines.477 Many of them reduce platelet aggregation In patients with a suspected IBD, further testing should
in vitro. In addition, some interact with antiplatelet and be carried out by the haematologist as the efficacy of
anticoagulant drugs. laboratory testing in patients with mucocutaneous bleed-
ing is low.496 It is also of paramount importance to
Ginkgo biloba is one of the most widely used herbal
distinguish between trivial bleeding symptoms, which
medicines in Europe. Although in vitro studies show
are frequently reported by normal subjects, and clinically
inhibition of platelet aggregation, clinical trials currently
relevant bleeding symptoms that should be more care-
do not support its use as an antiplatelet drug. Although
fully considered.497 The discriminative power of a bleed-
case reports of spontaneous bleeding after taking ginkgo
ing score to differentiate significant from trivial bleeding
preparations have been reported,478 a randomised
has been recently assessed in healthy children.498 When
placebo controlled, double-blind study in healthy volun-
children with a total bleeding score of at least 3 were
teers found no effect of an extract of ginkgo biloba on
predicted to have VWD, the sensitivity, specificity,
bleeding time and coagulation.479 A meta-analysis of 18
positive predictive value and negative predictive value
RCTs did not indicate a higher bleeding risk associated
were 97.2, 97.1, 48.6 and 99.9%, respectively, making the
with standardised ginkgo biloba extracts provided as daily
bleeding score a reliable tool for evaluating children with
oral therapy.480 Neither the combination of ginkgo biloba
suspected VWD.
with aspirin,481,482 cilostazol483 nor ticlopidine484 affects
coagulation indices. In a prospective observational cohort study including 796
patients with different types of VWD, a bleeding score
Diet and nutrients may also alter platelet function and
more than 10 could predict bleeding events that were
preoperative testing of platelet function may be
severe enough to require treatment.499 Similar results
required.485 Omega 3 polyunsaturated fatty acids reduce
were also observed in patients with type 2 VWD, where
fibrin generation measured by overall coagulation poten-
those patients with a bleeding score more than 9 showed a
tial in healthy subjects.486 The clinical perioperative
nearly 6-fold higher risk of bleeding than those with a
significance of these in vitro studies is unknown.
bleeding score in a normal range.500
11.2. Patients with congenital bleeding

disorders 11.2.2. General perioperative management
11.2.1. Preoperative assessment Recommendations
Recommendations Surgery can be safely performed in patients with IBDs when
We suggest referring the patient to a haematologist for assess- there is appropriate careful preoperative planning, appropriate
ment and planning of the intervention if IBDs are suspected replacement/substitution therapy, and multidisciplinary team
preoperatively. 2C management. C
We recommend the use of BATs for detecting and predicting the We recommend that patients with IBDs be managed periopera-
perioperative risk of bleeding before surgery and invasive tively in collaboration with a haematologist, preferably in
procedures. 1C dedicated centres with expertise in coagulation disorders. 1C
IBDs can be classified as primary or secondary haemo- We suggest preoperative haemostatic correction in patients with
static defects, which include VWD, platelet disorders and IBDs depending on the type of surgery. 2C
coagulation factor deficiencies, respectively. It is esti-
Once considered an absolute contraindication, surgery in
mated that at least 1% of the population have an IBD.487
patients with IBDs is still challenging due to the risk of
However, there are probably many more individuals with
haemorrhagic complications. However, recent data
undiagnosed IBDs. They can be detected preoperatively
demonstrated that good surgical results are achievable
by using BATs, which include a structured patient inter-
over a range of procedures when there is appropriate
view and an interpretation grid to score for the most
careful preoperative planning, appropriate replacement/
severe presentation of each bleeding symptom resulting
substitution therapy, and multidisciplinary team manage-
in an individual bleeding score.488
ment.501506 Although surgery is a highly demanding
Prospective studies found that structured bleeding intervention in patients with severe IBDs, especially in
questionnaires have a high negative predictive value low-resource countries,507 it often represents a life or
but a low/moderate positive predictive value both in limb-saving and quality of life-improving measure, which
adults488491 and in children referred for diagnosis.492,493 has to be taken.

In one survey performed in 26 comprehensive haemo- IBDs, the global bleeding rate after circumcision was
philia centres in Europe, the mean rate of haemorrhagic 57%, in contrast with no bleeding complications in 151
complications in major surgery was 10%.508 Despite patients correctly managed.
higher perioperative bleeding complications in patients
Low rates of bleeding were also reported in dental
with IBDs,509 postoperative outcomes similar to matched
extraction in patients with IBDs.545548 However, there
pairs without IBDs was also reported.504,510513
are concerns about the best pathway of treatment, and
During recent decades, total knee replacement has been guidelines for the provision of dental treatment in
the most common surgical intervention performed in patients with IBDs were recently issued.549,550 Although
adult patients with haemophilia. The medium and long- patients with mild IBDs can be allowed the majority of
term results of primary TKA in 74 patients with routine non-surgical dental treatment is in a community-
haemophilia showed good prosthetic survival at 5 and based dental practice and successful management
10 years, with an excellent relief of pain.514 However, an involves close collaboration between dental services
analysis of a US database for postoperative complications and haemophilia centres.551
up to 8 years after TKA in patients with haemophilia Surgery in patients with IBDs should be performed under
(n 3396) and VWD (n 1379), compared with a the supervision of, or in consultation with, a haematol-
matched cohort of patients without bleeding disorders ogist specialised in coagulation disorders, preferably in
(n 427 132 and n 384 657, respectively), found signifi- dedicated centres with appropriate facilities for investi-
cantly higher rates of infection, transfusion of blood gation and treatment.506,508,552 558 A multidisciplinary
products, medical complications and revision after team approach and individualised preoperative manage-
TKA in patients with IBDs.515 ment plan with surgery performed in haemophilia treat-
Outcomes in general and abdominal surgery,516,517 ment centres is highly recommended to minimise the
pseudo-tumour518,519 and cancer surgery,520 urological risks.525,559,560 The methodology of certification of these
interventions,511 laparoscopic surgery,504 cardiac inter- centres in Europe has been recently published.561
ventions,521523 and colonoscopies524 have also been There is insufficient evidence from RCTs to assess the
reported. Different types of surgery are performed suc- most effective and well tolerated treatment to prevent
cessfully in patients with inhibitors, too.525527 However, bleeding in patients with IBDs562; however, major and
delivery outcome in women with IBDs is unsatisfactory, minor surgeries are performed in these patients following
given the high PPH incidence despite specialised care.528 national and international recommendations based on
Further evidence of the safety and efficacy of surgical data from observational, uncontrolled studies.
procedures comes from reviews of surgical outcomes in The mainstay of perioperative therapy in patients with
children with IBDs.529531 The most frequent interven- IBDs is to provide the deficient factor both at the time of
tions are circumcision, dental procedures, insertion of invasive procedures and afterwards: 1 to 5 days for minor
central venous access devices and tonsillectomy. surgery and 7 to 14 days for major surgery.508,557,559 The
In the largest national cohort, including 508 tonsillectomy specific requirements of such patients in the periopera-
in patients with either VWD or haemophilia, the immedi- tive period will be discussed below in the setting of the
ate haemorrhage rate was 1.6%, similar to the rate in the underlying condition.
general healthy population. However, delayed haemor-
rhage occurred in 15%, substantially higher than the 1 to 11.2.3. Specific perioperative management
3% reported in healthy patients.530 Small case series 11.2.3.1. Von Willebrand disease
studies in children with IBDs undergoing adenotonsillar Recommendations
procedures report variable rates of haemorrhage: We recommend DDAVP as a first-line treatment for minor
lower,532535 similar,536,537 or higher538 than in healthy bleeding/surgery in patients with VWD, after a trial testing. The
patients. These data suggest that perioperative protocols standard regimen is 0.3 mg kg1 dissolved in 50 ml saline and
could be improved to reduce bleeding risk further. infused IV over 20 to 30 min, repeated every 12 to 24 h usually
Circumcision is frequently performed in children with for no more than 3 days. 1C
IBDs, with variable outcomes.529,539 The rate of bleeding We recommend replacement of VWF with plasma-derived
complications in haemophilia patients varies from low products for major bleeding/surgery. Treatment regimens are
(06%)512,540542 to high incidence543 depending on the specified by published guidelines. 1C
centre and protocol used. However, when the IBD is not
diagnosed before intervention, the bleeding rate can be We suggest that antifibrinolytic drugs be used as haemostatic
even higher.541 The importance of sufficient replacement adjuncts. Treatment regimens are specified by published guide-
therapy and peri-procedural collaboration with a haema- lines. 2C
tologist is supported by the result of a large retrospective VWD is the most common hereditary bleeding disorder
study performed in Iran.544 Among 423 cases with various with an estimated prevalence of 0.6 to 1.3%.557 Bleeding

in VWD is due to impaired platelet adhesion and/or VWD.576 However, prevention of bleeding during
reduced levels of factor VIII. Acquired VWS comprises surgery, especially in emergency situations where higher
defects in VWF concentration, structure or function levels of coagulant factors are needed promptly, is better
arising from medical disorders or treatments. achieved with products that have a higher concentration
of factor VIII.557 A combination of high purity factor VIII
Reviews and guidelines covering the management of
and high purity VWF concentrate could be also used in
VWD have been published.563,564 These state that
emergencies.563
patients should be managed in specialised centres where
experienced haematology and laboratory support is avail- Plasma-derived VWF concentrates may prevent exces-
able. However, recommendations for the diagnosis and sive bleeding in more than 90% of VWD patients.576 The
treatment of VWD are based on observational studies and efficacy has been confirmed in surgical paediatric577581
case series, and are therefore of low grade. and adult patients with VWD.566,577,580,582594 However,
type 3 and type 2 VWD variants may be extremely
There are three strategies to prevent or control bleeding
difficult to manage and there is no guarantee that homeo-
in VWD: release stored endogenous VWF by stimulating
stasis will be achieved even when plasma concentrations
endothelial cells with DDAVP; replace VWF using
have apparently been corrected into the normal range.563
plasma-derived concentrates; and promote haemostasis
with antifibrinolytic drugs or platelet transfusion. For bleeding treatment/prevention in major surgery, a
loading dose of 40 to 60 U kg1 is recommended, with 20
Despite a lack of RCTs investigating DDAVP in VWD,
to 40 U kg1 every 8 to 24 h for maintenance for 7 to 14
DDAVP has been shown to increase plasma VWF and
days.557 For minor surgeries, the doses are slightly lower,
factor VIII from two-fold to more than five-fold over
given less frequently and for a shorter duration (1 to 5
baseline levels, with good or excellent results in most
days). However, the regimen should be individualised as
surgical adult patients565567 as well as chil-
the dosing of a concentrate is dependent on the patients
dren.533,537,568,569 Although the use of DDAVP during
own basal VWF level, the pharmacokinetics of a specific
pregnancy is controversial,570 efficacy has been reported
product, and the nature and severity of the bleeding or
in obstetrical bleeding in women with bleeding dis-
the procedure.579,580,595,596
orders.571
Perioperative monitoring of factor VIII : C and
A literature and current practice survey performed by the
VWF : RCo may help determine appropriate dosing.557
European Haemophilia Therapy Strategy Board confirms
For severe bleeding or prophylaxis for major surgery,
that DDAVP can be used effectively to cover minor
VWF : RCo and factor VIII levels should be 100 to 200
surgery and dental procedures in most VWD patients.572
IU dl1 and 100 to 250 IU dl1, respectively.557 Sub-
The standard DDAVP dose is 0.3 mg kg1 dissolved in 50
sequent dosing should maintain VWF : RCo and factor
ml saline and infused intravenously over 20 to 30 min,
VIII levels above 50 IU dl1 for 7 to 10 days.557,563,580 For
repeated every 12 to 24 h,557 usually for no more than 3
prophylaxis for minor surgery, VWF : RCo and factor VIII
days unless the patient is monitored closely, and switched
levels should be more than 30 IU dl1 (preferably >50 IU
to factor concentrate if tachyphylaxis occurs.572 The peak
dl1) maintained for 1 to 5 days.557 Bleeding time and
response is registered at 1 h and the plasma concen-
PFA-100 time are not reliable methods for perioperative
trations of factor VIII and/or VWF should be checked
monitoring563 and their use is controversial.597
again at 4 h to identify patients in whom clearance is
increased.572 As not all VWD patients are responsive to Adverse reactions to VWF concentrates include allergic
DDAVP, a test infusion is recommended. A positive and anaphylactic reactions.577 VWF concentrates contain
response to DDAVP is defined as increases of factors factor VIII, so carry a potential thromboembolic
VIII : C and VWF : RCo to more than 0.3 to 0.5 IU risk.598,599 Maintaining levels less than 250% for factor
dl1.570,572 Response rates are reduced in children less VIII : C and less than 200% for VWF : RCo may reduce
than 2 years old.568 thrombogenicity.557 Antithrombotic prophylaxis should
be considered when other risk factors exist, particularly
Tachyphylaxis570 and hyponatraemia573 are frequent but
during periods when VWF and factor VIII levels are in
not sustained adverse effects of DDAVP.
the normal or supranormal range.600
VWF can be supplied by cryoprecipitate or human
Antifibrinolytic therapy may facilitate effective clotting.
plasma-derived concentrates. A phase 3 trial of recombi-
Outcomes with regimens using EACA in addition to
nant VWF has been recently published.574
DDAVP in adenotonsillar surgery have been vari-
Currently licensed plasma-derived VWF concentrates in able.537,538 For adults, a dose of 4 to 5 g EACA (oral or
all countries are virally inactivated formulations with intravenous) is recommended, followed by 1 g h1 until
varying ratios of VWF to factor VIII ranging from approxi- bleeding is controlled, or for 5 to 7 days postoperatively.
mately 1 : 1 to 2.4 : 1.575 Products with a VWF/factor VIII Tranexamic acid is given intravenously at a dose of
ratio more than 1 are preferred in the management of 10 mg kg1 every 8 to 12 h.557,601

11.2.4. Platelet defects that DDAVP shortened bleeding time and was sufficient
Recommendations for perioperative management in selected patients,
particularly in those with normal dense platelet granule
We suggest that DDAVP be used to prevent/control perioperative
stores. In a prospective study of 5649 unselected patients
bleeding in patients with mild inherited platelet defects. 2C
for elective surgery, 254 patients were diagnosed with
We suggest that antifibrinolytic drugs be used as haemostatic either acquired or inherited impaired primary haemo-
adjuncts in procedures involving patients with inherited platelet stasis using a PFA-100 device. Preoperative treatment of
defects. 2C these 254 patients with DDAVP led to normalisation of
platelet dysfunction in 90% of cases and there was no
We recommend that rFVIIa treatment should be considered in
statistically significant difference in blood transfusion
patients with Glanzmann thrombasthenia undergoing surgery.
compared with the patients without impaired haemo-
1C
stasis.611 Further case series support the efficacy of
We recommend against routine platelet transfusion in patients DDAVP in perioperative bleeding prophylaxis manage-
with inherited platelet disorders. 1C ment in some mild IPDs.612
Although rare, the prevalence of inherited platelet dis- The DDAVP-induced improvement of primary haemo-
orders (IPDs) is probably underestimated due to under- stasis in patients with aspirin-like defect is mainly due to
diagnosis.602 IPDs are heterogeneous in severity, the marked increase of the VWF.613 However, the quan-
mechanisms and frequency and few are characterised titative laboratory measurement of the response to
at the molecular level. IPDs can alter platelet production, DDAVP in patients with IBDs other than VWD or
morphology and function and many classification haemophilia is still uncertain, and the use of DDAVP
schemes have been proposed.555,603 remains empirical.570 Recently, it was shown that
DDAVP selectively enhances the platelet procoagulant
Prominent IPDs include Glanzmann thrombasthenia activity which appears to be an additional mechanism to
(defective platelet integrin alpha IIb b3 receptor) and the increase of VWF level.614
BernardSoulier syndrome (dysfunction or absence of
receptor GPIb/IX/V). Both conditions may cause severe Efficacy has rarely been shown in Glanzmann throm-
bleeding.555,604 Bleeding with other platelet abnormal- basthenia.604 If DDAVP is contraindicated or is not
ities is usually mild/moderate, so they are described as effective, patients should receive platelet transfusion
mild bleeding disorders (MBDs);555 VWD is included in or rFVIIa.555
this category. Typically they are manifested as mucocu- A recent review of the literature identified one registry,
taneous bleeding, or bleeding following trauma, or inva- one open-label study and 40 case reports, including a
sive surgical or dental procedures. total of 172 bleeding episodes and 62 procedures, in
Diagnosis of platelet defects is challenging as they may patients with Glanzmann thrombasthenia treated with
be undetectable via bleeding history.555 No relationship rFVIIa.615 Reported efficacy in perioperative bleeding
is apparent between bleeding severity and VWF/platelet management was more than 90%. However, this may not
function variables and in one study the diagnostic efficacy be solely due to rFVIIa but due to combined multi-modal
of laboratory testing for hereditary mucocutaneous bleed- therapy. There were five thromboembolic events regis-
ing was only 40%.496 PFA-100 has a high rate of false tered.
positive and false negative results and does not predict An international post-marketing registry of rVIIa usage
bleeding risk.555,605 PFA-100 clotting times are not suffi- included 96 patients with Glanzmann thrombasthenia
ciently sensitive to be recommended as a haemostasis treated for 216 surgical procedures (minor 179, major
screening test,606 although they correlate with the sever- 37) between 2007 and 2011.616 In total, 49 patients had
ity-of-bleeding history.607 Recently, international recom- antibodies/refractoriness to platelet transfusion. For all
mendations on the laboratory diagnosis of IPDs were patients, regardless of platelet antibody or refractoriness
issued.608 status, rFVIIa administered with or without platelets and/
or antifibrinolytics provided effective haemostasis with a
Guidelines on the management of patients with IPDs,
low frequency of adverse effects. In patients without
including for during the perioperative period, were also
antibodies/refractoriness, rFVIIa showed 100% effective-
published.555,609 The therapies include DDAVP, rFVIIa,
ness for both minor and major procedures, similar to that
platelet transfusions and antifibrinolytics.
for platelet transfusion. In patients with platelet anti-
In a review of DDAVP use in IPDs efficacy appears bodies/refractoriness, the effectiveness of rFVIIa was
variable in both mild and severe platelet defects.603 Most 91% and 100% for minor and major procedures respect-
evidence supporting the clinical efficacy of DDAVP in ively, comparable to that for platelets. rFVIIa was also
IPDs comes from case reports or small case series,555 and effective in the treatment of non-surgical bleeding in
one old placebo-controlled study.610 The latter found patients with Glanzmann thrombasthenia.617

No reliable data exist concerning rFVIIa in bleeding due clotting factor genes, and affect male offspring of the
to platelet dysfunction, and the drug is not licensed for carrier females.559 The estimated frequency is 1 : 10 000
other IPDs. births, with haemophilia A representing 80 to 85% of the
total haemophilia population.
In the registries mentioned above, platelet transfusion
was also effective in the treatment of both surgical and Haemophilia patients may develop spontaneous bleed-
non-surgical bleeding in patients with Glanzmann throm- ing into joints and/or bleed excessively after injury or
basthenia.616,617 The effectiveness of platelets in patients surgery.559 The clinical severity of the bleeding correlates
with antibodies or refractoriness may be due to the with the degree of deficiency. The severity of haemo-
transient nature of the inhibitors. philia is currently classified according to the plasma levels
of factors VIII or IX activity: severe if less than 1%,
Eltrombopag, an oral agonist of the thrombopoietin
moderate if between 1 and 5% and mild if between 5
receptor, has been used successfully instead of platelet
and 40% of normal.621 Mildly affected patients bleed
transfusion for raising the platelet count in patients with
excessively only after trauma or surgery and may have
MYH9-related disease.618
normal routine coagulation test results.622 Some carrier
The use of antifibrinolytic drugs in IPDs is not evidence- females have reduced coagulation factor levels and this is
based. They stabilise the clot and are useful as adjunctive important when specific replacement therapy may be
therapy.555,604 However, tranexamic acid was shown to required.559
partially reverse effects of clopidogrel in cardiac
surgery.619 This effect may contribute to the effective- Factor replacement therapy can induce antifactor VIII or
ness of antifibrinolytics alone in surgical and non-surgical antifactor IX antibodies, known as inhibitors. These are
bleeding in patients with IPDs, such as Glanzmann more common in severe forms of haemophilia.556 Devel-
thrombasthenia.616,617 In another study, patients with opment of inhibitors in mild haemophilia can change the
Glanzmann thrombasthenia with bleeding episodes or bleeding phenotype from mild to severe.622
undergoing dental surgery were treated with antifibrino- Acquired haemophilia is a rare but potentially life-threa-
lytic drugs, with or without additional rFVIIa. In most tening haemorrhagic disorder caused by the development
cases of mild/moderate mucocutaneous bleeding, antifi- of auto-antibodies against factors VIII or IX. It may be
brinolytic drugs and local measures were considered associated with malignancy, autoimmune disorders, drug
sufficiently effective, rendering rFVIIa unnecessary.620 reactions, or pregnancy.623
Factor assays are necessary to determine the diagnosis
11.2.5. Haemophilia A and B and monitor the therapy.559 Global assays have the
Recommendations potential to offer a more objective measure of both the
We recommend adequate perioperative replacement therapy to haemophilic phenotype and the response to treatment, in
ensure well tolerated surgery in haemophilia patients. 1C particular in patients who develop inhibitors to deficient
clotting factors and who require bypassing agents (e.g.
We suggest that perioperative replacement therapy (target factor FEIBA) for haemostasis.624
level and duration) in haemophilia patients follows published
guidelines. 2C Haemophilia therapy involves infusion of deficient
coagulation factors, either prophylactically or during
We recommend either recombinant products or plasma-derived bleeding. Mild haemophilia may be treated with DDAVP
concentrates for perioperative replacement therapy in haemo- and tranexamic acid rather than coagulation factors.556
philia patients. 1C
Although high-quality studies are lacking, in a literature
We suggest that coagulation factors be given perioperatively by review and survey of European practice, replacement
continuous infusion. 2C therapy appeared efficacious in the perioperative man-
We suggest either rFVIIa or activated PCCs for haemophilia agement of haemophilia A.508 In most settings there was
patients with inhibitors. 2C agreement on the intensity and duration of replacement
therapy between published data and clinical practice.
We suggest antifibrinolytic drugs as perioperative adjunct The lack of consensus on the optimal replacement
therapy in haemophilia patients. 2C therapy is more evident for children and the types of
We suggest DDAVP as first-line perioperative therapy in procedures that may be performed in this age group.529
patients with mild haemophilia A as long as factor VIII can Furthermore, in the youngest children the half-lives of
be raised to an appropriate therapeutic level. 2C factors VIII and IX are shorter and more frequent dosing
is required.529
Haemophilia is a recessive X-chromosome-linked IBD,
characterised by deficiency of coagulation factor VIII The clinical effects of different coagulation factor levels
(haemophilia A) or factor IX (haemophilia B). These have not been investigated, and the minimum required
deficiencies are due to mutations of the respective haemostatic levels for individual factors cannot be

defined.625 Consequently, the World Federation of Continuous infusion is used in nearly half of patients
Hemophilia (WFH) guidelines recommend different undergoing major orthopaedic surgery.508 A non-inter-
regimens for factor replacement depending on the ventional study in 12 centres, including 12 patients with
availability of resources.559 Conversely, a high-level severe haemophilia A having 28 surgeries, indicated that
clotting factor replacement regimen which maintains 95% of factor VIII measurements were on target, with
the preoperative high level for a longer period appeared efficacy and tolerability rated as good/excellent.648 Short-
to favour wound healing and to decrease the infection term central catheters can be used perioperatively for
rate in TKA.626 continuous infusion.649
In rare situations where monitoring factor VIII activity is Continuous infusion of factor IX has also been associated
not possible in patients with haemophilia undergoing with excellent haemostasis and safety.502,639
elective or emergency orthopaedic surgery, the feasibility
Bleeding in haemophilia patients with inhibitors is
and safety of a standardised regimen (50 to 70 IU kg1
usually treated with bypassing agents such as PCC
preoperatively, followed by 30 to 40 IU kg1 every 8 to
(either activated, which can produce thrombin without
12 h for 1 to 3 days, 20 to 30 IU kg1 every 8 to 12 h for
any requirement for factor VIII, or non-activated) or
days 4 to 10 and then every 24 h until end of intensive
rFVIIa.650653
rehabilitation) has been reported.506
Retrospective654 and prospective655 studies have con-
FFP and cryoprecipitate have relatively low levels of
firmed the efficacy of aPCC, with criteria for satisfactory
clotting factors and also have the potential for viral
haemostasis met in over 80% of cases. Very few serious
transmission. These products are indicated only if con-
adverse events were reported in these series.
centrates are not available.559
For PCC, recent consensus publications recommend 75
Although both plasma-derived and recombinant factor
to 100 IU kg1 given preoperatively, and then at 8 h
VIII products proved efficacious for preventing/treating
intervals for 7 days and following this, at 12 h intervals for
bleeding episodes in haemophilia patients, the prefer-
up to three weeks.503,656 Despite concerns about poten-
ence for one or another product has been highly
tial thrombogenic risks, concomitant use of tranexamic
debated.627,628 The WFH recommendations do not
acid is increasingly used.657
express a preference for either recombinant or plasma-
derived products,559 and a 4-year surveillance study did An updated evaluation of rFVIIa in perioperative bleed-
not detect a class or brand differences in inhibitor devel- ing in patients with inhibitors reported an overall effec-
opment.629 The safety and efficacy of recombinant factor tiveness of 84% and an incidence of thrombotic events of
VIII have been shown in further observational studies in 0.025% for the procedures included in that analysis.658
patients undergoing surgery.630,631 Further post-marketing surveillance,659 analysis of data-
bases, 653,660,661 and literature reviews662 found similar
Moreover, a prospective cohort study showed that the
results in patients undergoing surgery.
degree of factor VIII purity, but not the source of the
product, influences inhibitor development indepen- The safety of higher than licensed doses of rFVIIa has
dently from other risk factors.632 A recent meta-analysis been recently supported by other studies.663 Children
showed that high-intensity treatment is a strong risk have a faster clearance of rFVIIa and higher doses are also
factor for inhibitor development; the effect of the type advocated.529
of factor VIII was largely due to confounding.633
Adjunctive tranexamic acid was found to be safe, well
In haemophilia B, there is also evidence that both plasma- tolerated and effective in patients with haemophilia and
derived and recombinant products are effective in peri- inhibitors664 and is highly recommended, provided there
operative management,591,634639 providing similar out- are no contraindications.659
comes to those observed among non-haemophiliacs.640
The relative effectiveness of rFVIIa and aPCC for the
Continuous infusion of replacement factors may reduce treatment of acute bleeding in haemophilia patients with
wasteful peaks followed by sub-therapeutic low con- inhibitors was investigated by Cochrane reviews.650,665
centrations, when compared with bolus infusion.641 For Similar haemostatic effects for rFVIIa and aPCC were
severe haemophilia A patients undergoing surgery, con- reported, without increasing thromboembolic risk. In
tinuous infusion has been shown to reduce factor VIII contrast, a Bayesian meta-regression indicated rFVIIa
dosage by 36% compared with bolus infusion, while as being more effective in the treatment of joint bleeds
reducing major bleeding complications to zero (compared in patients with inhibitors.666 However, the UK guide-
with a 17% incidence in patients receiving bolus infusion; lines recommend both bypass agents at recommended
P 0.06). The efficacy of continuous infusion has been licensed doses and, if the original therapy fails, the use of
confirmed in other studies.642645 Increased risk of inhibi- the alternative agent.667 Further studies document that
tor development has been linked with continuous infu- both rFVIIa and aPCC can be used successfully perio-
sion,646 but other data do not confirm this risk.630,647 peratively.525,668,669

In the absence of comparative studies carried out minor surgical procedures performed on haemophilia A
in the surgical setting, then personal experience, avail- patients. In an otherwise normal pregnancy, DDAVP can
ability and cost may guide the choice of the bypassing also be used safely during delivery and in the peripartum
agents.670 The choice of product in patients with high- period in haemophilia carriers.559
titre inhibitors is highly individualised, and depends on
the age of the patient, prior exposure to plasma products, DDAVP does not affect factor IX levels and is of no value
type of bleeding, volume of reconstitution, cost, in haemophilia B.559
efficacy and safety.503 In patients who are plasma Acknowledging clot instability as a key part of the
nave or those with haemophilia B and inhibitors, rFVIIa haemostatic dysfunction in haemophilia,688 it is common
is used to achieve rapid haemostasis. However, for practice in Europe to use antifibrinolytics as perioperative
patients with haemophilia A who have been previously adjunct therapy.508 Recently it was shown that tranexa-
exposed to plasma products, either aPCC or rFVIIa may mic acid added to factor VIII or rFVIIa normalises clot
be used. stability, even when combined with the lowest dose of
The use of bypassing agents has a substantial economic factor concentrates, supporting the concept of a more
impact.671 rFVIIa appears to be cost-neutral672 or even efficient, reliable and cost-effective treatment of patients
cost-effective673 relative to aPCC, for mild/moderate with haemophilia.689
bleeds in this patient population. Antifibrinolytic drugs are not recommended for treat-
Evaluation of haemostatic response to bypassing agents ment of patients with factor IX deficiency already receiv-
using thrombin generation testing or viscoelastic tests has ing large doses of PCCs.559 However, a recent report on
been proposed as a means to optimise the haemostatic clinical experience combining tranexamic acid and aPCC
management of individual patients with inhibitors for for bleeds and during surgery in patients with inhibitors,
surgery.674676 suggested that haemostasis was achieved in nearly all
cases without any thromboses or disseminated intravas-
Potential thromboembolic risks associated with rFVIIa cular coagulation.657 When added to bypass therapy
and aPCC have been discussed.677,678 Currently, both (aPCC or rFVIIa), tranexamic acid normalised clot
rFVIIa679 and aPCC680,681 administration in haemophilia stability in patients with haemophilia with inhibitors
patients with inhibitors is considered well tolerated. as compared with healthy controls without clinical
DDAVP boosts plasma levels of both VWF and factor or laboratory adverse effects.688 It seems that the
VIII. Consequently it could be the treatment of choice for effect is limited to fibrin clot resistance to fibrinolysis,
patients with mild haemophilia A when factor VIII can be as tranexamic acid was found to have no effect on
raised to appropriate therapeutic levels.559 Each patient thrombin generation induced by aPCC.690 In a recent
should be tested before surgery as there are significant literature review, concomitant therapy with anti-inhibitor
differences between individuals.682 Response to DDAVP coagulant complex and tranexamic acid therapy was
is correlated with age (higher in responders),683,684 found to be safe, well tolerated and effective in haemo-
endogenous factor VIII:C levels,683 and type of philia patients with inhibitors.664 Also, adjuvant EACA
mutation.683686 Advantages over factor products include may help to control bleeding in haemophilia patients
lower costs, absence of risks of transmission of viral with inhibitors.691 Interestingly, EACA was also effective
infections and the avoidance of other potential hazards in cases where aPCC was either not available or had been
of using clotting factors. The decision to use DDAVP ineffective.691
must be based on the baseline concentrations of factor The antifibrinolytics alone are particularly indicated in
VIII, the increment achieved and the duration of treat- dental care, where the high fibrinolytic activity of saliva
ment required.559 A recent review describes the few may more easily destabilise the relatively weak clot.691
prospective and retrospective studies on the use of WFH recommends that EACA or tranexamic acid be
DDAVP in a surgical setting in patients with haemophilia started before replacement therapy.559 The dose of
A, for both minor and major procedures.570 Another EACA, which should be started the night before or in
analysis of 48 patients with non-severe haemophilia A the morning of the procedure, is 50 to 100 mg kg1 every
evidenced a complete or partial response to DDAVP 4 to 6 h for 5 to 10 days (maximum 24 g per 24 h). The
(factor VIII:C > 0.3 IU ml1) in 77% of cases, sustained dose for tranexamic acid is 25 to 50 mg kg1 orally every 6
at 3 h post-administration in 50% of cases.687 DDAVP was to 8 h for 10 days. A liquid preparation of these drugs may
also haemostatically effective in 96% of bleeding events be used as a mouthwash.559
in haemophilia A patients tested as responders to
DDAVP.684 In a review of 114 adenotonsillectomy Tranexamic acid, without prophylactic factor replace-
patients with mild bleeding disorders, including haemo- ment or DDAVP pre-procedure, was also effective in
philia, DDAVP was successfully used.536 However, it preventing bleeding following standard endoscopic pro-
seems that children are less responsive at a younger cedures (without biopsy) in patients with IBDs, including
age.683 These results support the use of DDAVP in short, mild and severe haemophilia.692

Antifibrinolytics for 7 days and DDAVP given before bleeds. The utility of standard coagulation screening
circumcision and the day after is a suitable approach in tests is limited by the tests sensitivity at very low residual
patients responsive to DDAVP.529 Fibrin glue and/or factor levels.698 Tests evaluating global haemostatic
antifibrinolytics seem to be routine practice for most capacity can assess more effectively the rate or total
centres performing circumcision.529 thrombin generated, whole blood clot formation, and/or
fibrin polymerisation. Thrombin generation tests702,703
When perioperative factor substitution is adequate, the
and thromboelastography704 may provide accurate evalu-
risk of venous thrombosis might be considered.693 An
ation of in vivo haemostasis and treatment response and
analysis of pooled data from a published series of haemo-
be better suited to predict clinical phenotype, particularly
philia patients undergoing arthroplasty showed an esti-
in factor XI deficiency where standard assays fail to
mated incidence of symptomatic VTE of 0.5%.694
correlate with bleeding risk.698
Although routine pharmacological thromboprophylaxis is
controversial in haemophiliac patients undergoing major The best treatment options, doses and management
orthopaedic surgery, half of the comprehensive haemo- approaches for patients with RBDs published in different
philia centres in Europe reported using pharmacological guidelines and reviews are based on descriptive
antithrombotic prophylaxis after major orthopaedic studies and expert opinion with low levels of evi-
surgery,508 in contrast to 37% of respondents to a US dence.556,698,699,704706 The treatment mainstay for RBDs
survey695 and 4% in a retrospective analysis of one US is replacement of the deficient coagulation factor and use
centre.696 However, one centre reported that 82% of of adjunctive therapies (antifibrinolytics, oestrogen/pro-
haemophiliacs received perioperative VTE prophylaxis gestogen) where appropriate. Unfortunately, as regards
after the year 2000 with no evidence of increased bleed- RBDs, compared with haemophilia, the safety and effi-
ing complications.517 Individualised antithrombotic cacy data for the few available products are limited, as is
therapy, based on local clinical experience, guidelines experience in their optimal use.
for non-haemophilia patients and the patients clinical Coagulation factor supplementation is generally advisa-
characteristics is recommended.697 ble for less than 0.5 to 1 g l 1 fibrinogen699 and less than
20 to 30% for other coagulation factors.698 For specific
11.2.6. Rare bleeding disorders factor deficiencies, plasma-derived concentrates are
Recommendations available for fibrinogen, factor VII, factor XI, and factor
XIII but also, recombinant factors are available for factor
There is insufficient data to recommend routine perioperative VII and factor XIII. rFVIIa is the treatment of choice for
supplementation of deficient factors in patients with RBDs. factor VII deficiency. If rFVIIa is not available, plasma-
We suggest that rFVIIa be used in perioperative bleeding due to derived factor VII is favoured over PCC because of PCCs
inherited factor VII deficiency. 2C potential thrombogenicity.556 PCCs are recommended
for factor II or factor X deficiencies. However, evidence
If rFVIIa is given to control perioperative bleeding in inherited supporting prophylactic use of PCCs in factor II707,708 or
factor VII deficiency, we suggest lower doses (e.g. 20 to factor X deficiency is scarce.709,710 For factor XI
25 mg kg1 every 4 to 6 h) than in haemophilia patients with deficiency, both factor XI concentrate and virally inacti-
inhibitors. 2C vated FFP are reasonable, although tranexamic acid
There is insufficient data to recommend rFVIIa in perioperative alone may suffice for minor procedures.556
bleeding for patients with other RBDs. Bleeding risk in RBD patients is largely assessed by
There is insufficient data to recommend peri-procedural referring to case reports and expert opinion.699701
DDAVP or antifibrinolytic drugs in patients with mild RBDs. Residual plasma levels of deficient factors do not always
predict the bleeding tendency. A European registry,
RBDs include inherited deficiencies of coagulation fac- based on data from 489 patients, documented that the
tors other than factors VIII and IX, for example
minimum level to ensure complete absence of clinical
deficiencies of fibrinogen, prothrombin, factor V, factor symptoms is different for each disorder.711 There is a
VII, factor X, factor XI, factor XIII, various combined
strong association between residual coagulant activity
factor disorders, as well as vitamin K-dependent clotting and clinical bleeding severity for deficiencies of fibrino-
factor deficiencies which include factor II, factor VII,
gen, factor X, factor XIII and combined factor V factor
factor IX and factor X.556,698 The prevalence of RBDs is VIII.712 There is a weak association between residual
low, between 1 : 500 000 and 1 : 2 000 000,699,700 account-
coagulant activity and clinical bleeding severity for iso-
ing for 3 to 5% of inherited coagulation disorders.701 lated factor V and factor VII deficiencies.712 Residual
Factor VII and XI deficiencies are the most common
factor XI activity did not predict clinical bleeding sever-
RBDs.698 ity.712 For example, among factor XI-deficient women
Clinical manifestations of the different RBDs are hetero- giving birth, 70% experienced no PPH, suggesting no
geneous and include mucocutaneous, joint and organ relationship between factor XI levels and the risk of

PPH.713 Similarly, no difference in PPH was seen in Registry data suggest that rFVIIa treatment may control or
deliveries with or without prophylaxis in women with prevent bleeding in other RBDs, with a favourable safety
factor VII deficiency.714 Perioperative bleeding in profile.733 Low-dose rFVIIa (33 to 47 mg kg1) also appears
patients with RBDs is treated by supplementing the to be well tolerated and effective for surgery in patients
deficient factor.706 However, the minimum required with severe factor XI deficiency and inhibitors.734 Co-
levels of coagulation factors levels have not been defined. administration of tranexamic acid has also proved effec-
The choice to use haemostatic regimens before surgery tive,735,736 although it may increase thrombotic risks. Else-
and the type of regimen is made according to the avail- where, effective haemostasis was reported in 100% of
ability of products, levels of deficient factor, type of factor XI deficient patients receiving prophylactic rFVIIa
surgery and anaesthesia, the tissue/organ involved, and before dental procedures, and minor or major surgery.678
the severity of the personal and family history of bleed- No alternative haemostatic agents or transfusions were
ing.715,716 For example, risk of bleeding after surgery in administered, except for tranexamic acid. An acute
patients with factor XI deficiency is particularly high if cerebrovascular accident was reported in a patient with
anatomical sites rich in fibrinolytic activity are a history of cardiovascular disease. The authors concluded
involved.713,716 Although deficiency in factor XI is not that rFVIIa was an effective alternative to plasma-derived
correlated with a haemorrhagic phenotype, a correct factor XI, but that rFVIIa may not be suitable for patients
diagnosis and appropriate management can dramatically with pre-existing thrombotic risk factors.
decrease the bleeding rate during surgery or peripar-
However, these data are insufficient to make a recom-
tum.716
mendation for using rFVIIa in other RBDs apart from
Surgical and peri-procedural experience in patients with factor VII deficiency.
specific RBDs is scarce, and the bleeding complication DDAVP has also been used in RBDs, especially in mild
rates are variable.716728 In some cases, surgery was cases. Limited data suggest a potential role for DDAVP
uneventful without supplementation of the deficient in the treatment of bleeding episodes or prevention of
factor.715,721 postoperative bleeding in mild factor XI defects.716,737
rFVIIa is the treatment of choice for factor VII Antifibrinolytic agents may be given to patients with
deficiency.706 The recommended dose of rFVIIa for RBDs, particularly for mucosal bleeding or bleeding
factor VII deficiency is 20 to 25 mg kg1 every 4 to 6 h, prevention following dental extractions.556,706,723,732
individualised according to bleeding phenotype698 and
supplemented until wound healing is established.706 Thrombosis is a major concern with coagulation factor
However, a wide rFVIIa dose range, dosing intervals supplementation. Afibrinogenaemia, factor VII or factor
and treatment durations have been reported in factor XI deficiencies may be associated with venous or arterial
VII deficiency.729,730 Continuous infusion of rFVIIa has thrombosis, spontaneously or after deficient factor
also been reported as well tolerated, effective and highly supplementation.699701,711,717,720,733,738740 Inherited or
cost-effective in factor VII deficiency.731,732 acquired thrombotic risk factors may coexist with the
underlying defect. However, there are no data on patients
In a prospective international web-based registry (STER, with RBDs pertaining to the use of prophylaxis to prevent
Seven Treatment Evaluation Registry) which includes 41 postoperative VTE, particularly after orthopaedic
surgical operations performed in 34 subjects with docu- surgery. Therefore, replacement therapy must be indi-
mented congenital factor VII deficiency, haemostatic vidualised and associated antithrombotic prophylaxis in
efficacy was observed in 88% of major surgical procedures mild factor deficiencies must be considered.741
safeguarded with rFVIIa.722 Bleeding occurred in three
cases in which rFVIIa was given at low doses. The
effective regimen was calculated as at least 13 mg kg1
Acknowledgements relating to this article
Assistance with the guidelines: we thank Irma Klerings, Depart-
per single dose with at least three doses per day, and the ment for Evidence-based Medicine and Clinical Epidemiology,
first dose given on the day of surgery. In the 29 minor Danube University Krems, Cochrane Austria, for performing the
surgical procedures, haemostatic efficacy with rFVIIa was systematic literature search.
100%.723 The mean daily doses ranged from 4.8 mg kg1
Financial support and sponsorship: the systematic search was
to 300 mg kg1. Factor VII antibody was observed in one
funded by the European Society of Anaesthesiology. Editorial
patient undergoing a multiple dental extraction. No assistance by Meridian HealthComms was funded by the Austrian
thromboses were reported. The same group published Society of Anaesthesiology, Resuscitation and Intensive Care.
two further studies confirming the efficacy of rFVIIa in
Conflicts of interest: AA received advisory fees from Masimo,
spontaneous or traumatic bleeds in factor VII deficiency
Metronic/Covidien, CSL Behring. CA received honoraria for lec-
patients.724,726 A regimen of rFVIIa (90 to 100 mg kg1 turing from Octapharma. PA received honoraria for lecturing from
weekly), split into three divided doses, proved to be both Abbott, Bayer, Boehringer Ingelheim, CSL Behring, Daiichi San-
efficacious and well tolerated in the long-term prophy- kyo, LFB, Fresenius and Pfizer-BMS. PA is on the advisory
laxis of bleeding in severe deficiency of factor VII.726 committees of Bayer, Boehringer Ingelheim and Pfizer-BMS. ER

received honoraria for lecturing from Fresenius Kabi. He was chair 2 Kozek-Langenecker SA, Afshari A, Albaladejo P, et al. Management of
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of the ESA Guideline Committee during most of the period over
Anaesthesiology. Eur J Anaesthesiol 2013; 30:270382.
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ium and travel funding for preparation of the 2013 guidelines on Western Australia Patient Blood Management Program (WA PBMP),
trauma bleeding supported by CSL Behring Germany and LFB World Health Assembly (WHA) and Advisory Committee on Blood Safety
Biomedicaments France. The honorarium for preparation of the and Availability (ACBSA). Best Pract Res Clin Anaesthesiol 2013;
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Merck/MSD. NRM is a member of advisory boards for CSL in 110 patients. PLoS ONE 2015; 10:e0126692.
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from CSL Behring, Pulsion, Sorin Group, TEVA, Mitsubishi Thromboelastometry (ROTEM(R)) during major surgery with hemorrhage.
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parameters. Lab Med 2013; 44:319323.
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grants, and advisory fees from Abbott, Aesculap Akademie, Astellas laboratory evaluation. Scand J Clin Lab Invest 2013; 73:214220.
Pharma, Aventis Pharma, Baxter Biotest, CSL Behring, Drager 18 Acedillo RR, Shah M, Devereaux PJ, et al. The risk of perioperative
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Medical, Fresenius Kabi, Heinen-Lowenstein, Masimo, Medi- meta-analysis. Ann Surg 2013; 258:901913.
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Deutschland, AQAI, Astra Zeneca, B. Braun, Biosyn, BMS, Dr F. 2015; 24:30463062.
20 Levy JH, Szlam F, Wolberg AS, Winkler A. Clinical use of the activated
Kohler Chenie, Essex Pharma, Fresenius Medical Care, Gilead,
partial thromboplastin time and prothrombin time for screening: a review
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MSD, Novo Nordisk Pharma, Pfizer Pharma, Salvia, Teva, Vera- 34:453477.
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declared any conflict of interest. prothrombin time screening in elective neurosurgical procedures.
Neurosurg Focus 2012; 33:E9.
This guideline update was undertaken by the European Society of 22 Townsend JC, Heard R, Powers ER, Reuben A. Usefulness of
international normalized ratio to predict bleeding complications in patients
Anaesthesiology [ESA] in collaboration with representatives from
with end-stage liver disease who undergo cardiac catheterisation. Am J
the European Board of Anaesthesiology [EBA] (EDR), the Euro- Cardiol 2012; 110:10621065.
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(DFa), the Network for Advancement of Transfusion Alternatives patients requiring massive blood transfusion during living donor liver
[NATA] (JS), and European Digestive Surgery (GB). SAKL was the transplantation. Ann Transplant 2013; 18:443447.
24 Cywinski JB, Alster JM, Miller C, et al. Prediction of intraoperative
chair of the guidelines committee. transfusion requirements during orthotopic liver transplantation and the
influence on postoperative patient survival. Anesth Analg 2014;
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Eur J Anaesthesiol 2017; 34:332395

Management of severe perioperative bleeding: guidelines

Copyright European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.

Eur J Anaesthesiol 2017; 34:332395

1. Summary: recommendations, suggestions 1.1.1. Evaluation of platelet function

Clarity of risk/benefit Quality of supporting evidence Implications

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1.6.1. Storage lesions We recommend treatment of hypofibrinogenaemia in

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In patients chronically treated with aspirin for secondary 1.9.2. Heparin

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1.11.4. Platelet defects 2. Introduction

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3. Methods recommendations are still valid and should be considered

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6.2. Evidence-based medicine and Recommendation

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9.6.6. Acute upper gastrointestinal bleeding

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11.2. Patients with congenital bleeding

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