British Journal of Anaesthesia, 117 (S3): iii18–iii30 (2016)

doi: 10.1093/bja/aew358
Review Article

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Perioperative management of the bleeding patient
K. Ghadimi1, J. H. Levy1, and I. J. Welsby1,*
1
Divisions of Cardiothoracic Anesthesiology & Critical Care Medicine, Duke University Medical Center,
Durham, NC, USA

*Corresponding author. E-mail: [email protected]

Abstract
Perioperative bleeding remains a major complication during and after surgery, resulting in increased morbidity and mortality.
The principal causes of non-vascular sources of haemostatic perioperative bleeding are a preexisting undetected bleeding dis-
order, the nature of the operation itself, or acquired coagulation abnormalities secondary to haemorrhage, haemodilution, or
haemostatic factor consumption. In the bleeding patient, standard therapeutic approaches include allogeneic blood product
administration, concomitant pharmacologic agents, and increasing application of purified and recombinant haemostatic fac-
tors. Multiple haemostatic changes occur perioperatively after trauma and complex surgical procedures including cardiac sur-
gery and liver transplantation. Novel strategies for both prophylaxis and therapy of perioperative bleeding include tranexamic
acid, desmopressin, fibrinogen and prothrombin complex concentrates. Point-of-care patient testing using thromboelastogra-
phy, rotational thromboelastometry, and platelet function assays has allowed for more detailed assessment of specific tar-
geted therapy for haemostasis. Strategic multimodal management is needed to improve management, reduce allogeneic blood
product administration, and minimize associated risks related to transfusion.

Key words: coagulopathy; direct oral anticoagulants (DOACs); hemostasis & thrombosis; point-of-care testing; thromboembo-
lism; transfusion algorithm

Multiple factors contribute to the complex causes of bleeding Surgical bleeding is usually characterized by a site of bleed-
in surgical patients that include blood loss, haemodilution, ing and confined exclusively to the operative site. Meticulous
acquired platelet dysfunction, coagulation factor consumption in surgical technique, patience, and good patient selection all con-
extracorporeal circuits, activation of fibrinolytic, fibrinogenolytic tribute significantly to minimizing surgical bleeding in the high-
and inflammatory pathways, and hypothermia.1,2 Acquired hae- risk patient. The spectrum of available topical haemostatic
mostatic defects often present in surgical patients as a result of agents and devices are beyond the scope of this review.4 The
prescribed oral anticoagulants (warfarin, dabigatran, rivaroxaban, focus of this review is microvascular or coagulopathic bleeding
apixaban, edoxaban) and platelet inhibitors (P2Y12 receptor as a consequence of abnormal haemostatic mechanisms. While
inhibitors-clopidogrel, prasugrel, or ticagrelor). Thus, bleeding typically manifested as generalizing bleeding within the opera-
after surgery includes both preexisting and/or acquired defects in tive site, this can extend to percutaneous cannulation sites,
haemostasis. Congenital bleeding disorders are less common nasogastric tubes, and urinary catheters.
and, hopefully already addressed if a patient presents for surgery. Management of perioperative bleeding consists of identify-
From a preoperative evaluation standpoint, the ISTH bleeding ing patients at risk, understanding the impact of the operation
questionnaire is as effective as multiple, laboratory tests for iden- on haemostasis, institution of allogeneic blood and factor
tifying perioperative bleeding risk.3 concentrate based therapies, utilizing point-of-care laboratory

C The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia.
V
All rights reserved. For Permissions, please email: [email protected]

iii18
 Perioperative coagulopathy | iii19

Fibrinolysis
Editor’s key points
Activation of the fibrinolytic system is an important mecha-
• Perioperative bleeding can involve acquired coagulation nism of vascular homeostasis (Figure 1). Mechanistically, plas-
abnormalities secondary to haemorrhage, haemodilu- min generation is the enzymatic serine protease responsible for
tion, or haemostatic factor consumption. fibrinolysis and is formed after the action of t-PA on plasmino-
• Novel approaches for prophylaxis and therapy of perio- gen. Plasmin cleaves key coagulation proteins such as fibrin
perative bleeding include use of tranexamic acid, and fibrinogen, but also causes proteolysis of other critical pro-
desmopressin, fibrinogen and prothrombin complex teins, including fibronectin and von Willebrand factor.15 In the
concentrate. urogenital tract, hyperfibrinolysis occurs as a result of libera-
• Point-of-care testing of haemostatic function using tion of the urokinase plasminogen activator system.16 After car-

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thromboelastography, thromboelastometry, and platelet diopulmonary bypass and/or tissue injury that occurs with
function assays allows specific targeted therapy of surgery or trauma, fibrinolysis is activated and represents an
coagulopathy. important cause of coagulopathy.17 In trauma, orthopaedic sur-
gery, and cardiac surgery, multiple studies support the role of
antifibrinolytic agent administration in order to decrease bleed-
ing and the need for allogeneic transfusions.17 These agents
can also be used as an adjunct to treating congenital bleeding
testing, and understanding the limitations of monitoring tech-
disorders.18
niques.5 Clinically important bleeding can paradoxically evolve
Since CRASH-2 was published in 2010,19 meta-analyses rec-
into pathologic thrombosis, with the transition of perioperative
ommend antifibrinolytic use (mostly tranexamic acid) in
coagulopathy to hypercoagulability related to the acute phase
abdominal bleeding20 and trauma, while on-going major stud-
response. This can be exacerbated by overzealous replacement
ies are being conducted for gastrointestinal bleeding (HALT-IT
of deficient procoagulant factors, inattention to deficient antico-
trial)21 and postpartum haemorrhage (WOMAN trial).22
agulant factors, and reluctance to initiate needed anticoagulant
The use of tranexamic acid (TXA) is increasing and additional
agents for venous thromboembolic prophylaxis after a recent
data are forthcoming. Despite initial concerns about aprotinin,
bleed. Navigating this complex, rapidly changing haemostatic
this agent is now being reintroduced in many European
balance exemplifies the value of the perioperative physician
markets.23
with detailed knowledge of haemostasis, anticoagulation, and
While we will not discuss postpartum haemorrhage in detail,
transfusion medicine. In this review, we address specific and
three major considerations are emerging for managing bleeding
general considerations for various pathophysiological states or
parturients: routine use uterotonics, aggressive fibrinogen
circumstances and haemostatic agents and provide algorithmic
replacement, and prevention of excessive fibrinolysis, as
approaches to bleeding management, in order to place the
recently reviewed.24,25
administration of agents in clinical context.
The following section represents general considerations of
haemostasis related to hypothermia and fibrinolysis, which can
occur in all patient populations undergoing invasive procedures Antifibrinolytic agents: lysine analogues
and require review before approaching the coagulation defects The two antifibrinolytic agents administered clinically include
particular to specific patient populations. epsilon aminocaproic acid (EACA) and TXA.26 While both medi-
cations competitively inhibit plasminogen conversion to the
active protease plasmin,27 only TXA has been shown to inhibit
higher plasma concentrations of plasmin.28,29 Although most of
General considerations: hypothermia the data for the antifibrinolytic lysine analogues are with TXA,
and fibrinolysis EACA continues to be extensively utilized in the USA.30
Temperature regulation and the coagulopathy Although multiple studies (primarily meta-analyses of
randomized-controlled trials) have shown that lysine analogues
of hypothermia
decrease bleeding in cardiac surgical patients, there are limited
In controlled circumstances, such as during cardiopulmonary prospective safety data regarding the use of antifibrinolytic
bypass or hypothermic circulatory arrest, hypothermia is used agents. Most dosing studies include total EACA doses of 20 to
as a neuroprotective mechanism.6 Inadvertent hypothermia 30 g per patient, or total TXA doses from 2 to 25 g, mainly from 2
seen with severe trauma, or poorly maintained intraoperative to 8 g.26
temperature regulation can be associated with worse outcomes. An increase in the incidence of seizures after cardiac surgery
For example, isolated hypothermia of 32.2 ! C is associated with from 1.3% to 3.8% has been temporally associated with higher-
a 23% mortality rate, while trauma-induced hypothermia below dose TXA use.31 The mean age of patients in this report was "70
32 ! C is associated with 100% mortality.7–8,9 The coagulopathy of yr, and open chamber surgery, with possible air entrainment,
hypothermic patients includes dysregulation of coagulation was a risk factor.31 Mechanistically, TXA enhances neuronal
enzyme processes, platelet function, activation of fibrinolysis, excitation by antagonizing inhibitory gamma-aminobutyric acid
and endothelial injury.10 Bleeding observed at reduced tempera- (GABA)32 and glycine33 neurotransmission at the receptor level,
tures (33 – 37 ! C) often occurs because of defects in platelet an established cause of seizures. This side-effect was not noted
adhesion, while at temperatures below 33 ! C, both reduced pla- in prospective trials, which were notably underpowered for this
telet function and coagulation enzyme activity contribute.11 outcome. Seizure activity has not been described in patients
Active warming should be applied perioperatively if exposed receiving EACA. For other indications such as orthopaedic,
surface area allows. Additionally, hypothermia and acidosis fre- trauma and obstetric indications, the data are mostly for
quently occur together requiring correction of metabolic abnor- patients receiving a total of 2 g of TXA, where seizures have
malities.11–14 rarely been reported.
 iii20 | Ghadimi et al.

Coagulation Anticoagulation Fibrinolysis Inhibition Activation

TFPI
D-
Activated platelet Dimers FDPs
TF
VIIa
Extrinsic

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tenase
ATIII
complex X Fibrin cross-linkage
FGN Fibrin
Fibrin
Fibrin Fibrin
II Fibrin

Thrombin
Xa Va (IIa)
XIIIa
Prothrombinase
complex
PS
X XIII
Plasmin
IXa VIIIa APC

Intrinsic tenase IIa

complex
TAFIa tPA

PC TM

TAFI
Thrombin-thrombomodulin Plasminogen
complex

Fig 1 Interplay between coagulation, anticoagulation, and the fibrinolytic systems. In a simplified model, coagulation factors are illustrated upon the activated
platelet surface. Through the activation of factor X (Xa) via intrinsic (Factor IXa, VIIIa) and extrinsic tenase (Xase) complexes, factors Xa and Va convert factor II
(prothrombin) to factor IIa (thrombin). Thrombin then cleaves fibrinogen into fibrin. Fibrin polymerization is facilitated by the activation of factor XIII that forms
cross links leading to clot stabilization. Factor II, VII (not pictured), IX (not pictured) and X are targeted for repletion with prothrombin complex concentrate (PCC)
administration. Factor VIIa is targeted for repletion with administration of recombinant factor VIIa (rFVIIa). Simultaneously, anticoagulants negatively modulate
clot formation. Antithrombin III (ATIII) modulates factor IIa (primarily) and factor Xa (secondarily), but ATIII-dependent inhibition of factor IXa, XIa, and VIIa-TF
complex occurs to a lesser extent (not pictured). Other important anticoagulants include TFPI-modulation of Tissue Factor and factor VIIa, and Activated Protein
C (APC) which, through activation of protein S, inhibits factor Va, weakening the prothrombinase complex and impairing thrombin generation. Upstream, APC
inhibits factor VIIIa of the intrinsic Xase complex. Factor IIa complexes with Thrombomodulin (TM) to activate PC. Of note, the thrombin-TM/PC/PS system is pri-
marily localized to the endothelium but can be expressed on platelets and monocytes. This complex initiates thrombin-activatable fibrinolysis inhibitor (TAFI),
which prevents plasmin production by inhibiting tissue-plasminogen activator and through direct inhibition of plasminogen (not pictured). Plasmin is a serine
protease and, as the primary driver of fibrinolysis, results in clot destabilization, degradation of fibrin cross linkage, and production of fibrin degradation prod-
ucts, which include D-dimers. Plasmin triggers platelet activation (not pictured) thereby competing with TAFI at the local level. TF, Tissue Factor; PC, Protein C;
PS, Protein S; TFPI(a), Tissue-Factor Pathway Inhibitor (activated); ATIII, Antithrombin III; FGN, Fibrinogen; TM, Thrombomodulin; FDPs, Fibrin Degradation
Products; tPA, tissue-Plasminogen Activator.

Coagulation abnormalities in different ongoing coagulation defects.37 Initial retrospective analyses from
patient populations military trauma reported repletion of intravascular volume using
predetermined ratios of fresh frozen plasma (FFP), platelet con-
Trauma centrate (PC), and red blood cells (RBCs) at 1:1:1 reduced mortality
in patients with major bleeding.38–42 To prospectively evaluate
The coagulopathy of trauma is a complex pathophysiologic state this strategy, Holcomb and colleagues43 reported that with severe
that results in diffuse, microvascular bleeding.34,35 Approximately trauma and major bleeding, early administration of FFP, PC, and
40% of trauma-related mortality is associated with profound coa- RBCs in a 1:1:1 ratio compared with a 1:1:2 ratio, did not signifi-
gulopathy.36 Management of major bleeding requires repair of cantly decrease mortality at 24 h or 30 days. They also reported
the underlying cause after surgery or trauma, volume resuscita- more patients in the 1:1:1 group achieved haemostasis and with
tion with blood products, and diagnosis and management of the less mortality from exsanguination at 24 h (9.2% vs 14.6%;
 Perioperative coagulopathy | iii21

** Balanced resuscitation if
Send type and screen x1 >4units of PRBCs**
LABS – EVERY 30 MINS Immediate resuscitation
Transfuse balanced ratio Round 1 Round 2 Round 3
PT/PTT, fibrinogen Start lab-based management once 4 RBC 8 RBC 8 RBC
CBC surgical bleeding being addressed
Arterial blood gas 4 FFP 8 FFP 8 FFP
call blood bank
ROTEM:Extem+FIBtem 1 Platelet
1 Cryo

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Note: RBCs and FFP will be issued
as above, additional platelets
and cryo may be ordered
Lab-based decisions

Hgb<7 g dL–1 Plt<50K PT/INR ratio>1.5x

Fibrinogen<200 Fibrinogen<150
or or
mg dL–1 mg dL–1
A10ex<45 mm CTex>80s
or or
and A10ex<45 mm A10ex<45 mm
RBC: 1-2 U A10fib≥13 mm and and
target A10fib<13 mm A10fib<10 mm
Hgb 8 g dL–1 FFP: 10-15 ml/kg

Platelet: 1 dose
Refractory bleed?
** If>4 units RBC given, CRYO: 1 bag (5U) CRYO: 2 bag (10U) Consider factor conc:
consider balanced transfusion or 2g fib conc or 4g fib conc PCC 10-20u/kg repeatx1
per Red box above** rFVlla 1-2mg repeatx1

Fig 2 Transfusion algorithm for intraoperative bleeding during noncardiac surgery. Focus on a laboratory-based, viscoelastic testing paradigm, with opportunities
for intervention based on clinical decision-making. Our protocol advocates antifibrinolytic therapy, correction of acidosis, and correction of acute hypocalcaemia.
Inside the redbox, our balanced ratio recommendations are presented if the patient has been transfused four units of blood and intraoperative haemorrhage is
ongoing. Consideration is given to low-dose factor concentrate usage (PCCs, rFVIIa) if bleeding is refractory to balanced resuscitation and algorithmic options.
Figure modified from a draft version of our local massive transfusion protocol. CBC, complete blood count; Cryo, cryoprecipitate; FFP, fresh frozen plasma; Hgb, haemo-
globin; RBC, red blood cell; PLT, platelet count; T & S, type and screen; PCC, prothrombin complex concentrates.

P ¼ 0.03). Although use of FFP and PC in the 1:1:1 group was separate sections in this review. Briefly, although haemoglobin
higher, transfusion related complications including multiorgan targets vary depending upon patient injuries and comorbidities, a
failure were similar.43 While evidence supports the 1:1:1 value of > 8 g dl $ 1 is targeted. Platelet concentrate, cryoprecipi-
approach, it is not conclusive, and the optimal ratio of tate (generally for hypofibrinogenaemia but occasionally admin-
FFP:PC:RBCs is still not clear.44–50 Extension of this principle into istered in patients with known von Willebrand factor or Factor
the arenas of civilian trauma and massive surgical blood loss has XIII deficiency), and FFP are also administered. Once 4 units of
been guided by local massive transfusion protocols, as illustrated packed RBCs have been transfused, attention is turned to the red
in Figure 2, but high-volume transfusions are associated with box insert within the algorithm, and balanced resuscitation is
complications. Without massive bleeding criteria, defined as <10 performed according to blood and blood products given (i.e.,
Units of packed RBCs within 12 h of admission, FFP transfusion is Round 1, 2, 3, etc.). Of note, PC and fibrinogen are administered
associated with acute lung injury (ALI).46,51–54 FFP is associated early in this algorithm based on laboratory data, as they are cru-
with a dose-dependent relationship with both transfusion associ- cial to haemostasis. Fibrinogen remains the first component to
ated circulatory overload (TACO) and transfusion-related acute reach critically low values during haemorrhage.58 If refractory
lung injury (TRALI).53,55 While 1:1:1 transfusion might be appro- bleeding is noted in our algorithm, consideration is given to
priate for out-of-hospital resuscitation, such complications sup- administration of factor concentrates. Viscoelastic testing has
port refining these protocols when gross exsanguination has been recently advocated in severely-injured trauma patients, in
been surgically or manually controlled. Use of viscoelastic coagu- order to help guide antifibrinolytic therapy in the setting of sys-
lation tests (e.g. ROTEMV C and TEGV C ) offers guided coagulopathy temic, post injury hyperfibrinolysis, physiologic/normal fibrinoly-
treatment that also includes antifibrinolytic agents, cryoprecipi- sis, or hypofibrinolysis/fibrinolytic shutdown.59 The European
tate and factor concentrates.5,56,57 In our transfusion algorithm Task Force for Advanced Bleeding in Trauma has provided a
for adult noncardiac surgery (Figure 2), initial steps include utiliza- guideline document in order to manoeuvre through the expan-
tion of laboratory data in parallel with packed RBCs. Discussion sive possibilities related to coagulopathic management in the
of specific components within this algorithm is described in trauma patient.60
 iii22 | Ghadimi et al.

Chronic liver disease and orthotopic anticoagulant concentrations are further depleted and procoagu-
liver transplantation lant constituents predominate. Portal vein thrombosis can occur
in cirrhotics with specific prothrombotic coagulation factor muta-
Haemostatic changes seen with end-stage liver disease are
tions that include factor V Leiden and prothrombin G20210A,85
complex, resulting from reduced concentrations of pro- and
especially with commonly elevated concentrations of vWF and
anti-coagulant proteins, plasmin-related qualitative platelet
factor VIII.86 Antithrombin concentrate can restore the balance
dysfunction from defective thromboxane A2 synthesis, storage
between pro- and anti-coagulants through direct modulation of
pool deficiency, platelet glycoprotein Ib abnormalities,61–63
clot formation (Figure 1).87 In a retrospective, observational study
and platelet sequestration.64 Platelet function defects, however,
of laparoscopic splenectomy, 4% of cirrhotics receiving antith-
are attenuated by the exaggerated concentrations of von
rombin III (ATIII) suffered portal vein thrombosis compared with
Willebrand Factor (vWF), resulting from deficiency of the hep-

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36% who did not.88 ATIII supplementation is also considered after
atically synthesized protease ADAMTS 13.65 Relative plasmino-
liver transplant, to minimize allograft thrombosis, but high qual-
gen activator inhibitor (PAI-1 and 2) deficiency reduces t-PA
ity data are limited.
clearance increasing fibrinolytic potential. Reduced thrombin
activatable fibrinolysis inhibitor (TAFI) and alpha-2 antiplasmin
further exacerbate this. Cardiopulmonary bypass and cardiac surgery
During surgery, with reperfusion of the donor liver, hyperfi- Coagulation abnormalities encountered during cardiac surgery
brinolysis can occur as a result of extensive release of t-PA into are multifactorial and include preoperative antiplatelet agents,
the circulation. As a result, these patients can benefit from heparin reversal with protamine, acquired platelet dysfunction
treatment with antifibrinolytic agents, while taking care to after cardiopulmonary bypass (CPB), haemodilution, and loss of
avoid hypercoagulation.66–69 As previously discussed, viscoelas- clotting factors and platelets. Although off-pump cardiac sur-
tic testing has been utilized in severely-injured trauma patients gery avoids the effects of CPB discussed below, other causes of
in order to help guide antifibrinolytic therapy.59 With that said, coagulopathy still apply. CPB induces a complex pathophysio-
the rationale for utilizing viscoelastic testing might not be the logic state, with pathophysiologic changes that are potentially
best approach guide to antifibrinolytic use in hepatic failure similar to sepsis and a systemic inflammatory response.89,90 In
patients undergoing orthotopic liver transplantation.70 The bal- a more severe form, coagulopathy after prolonged CPB can pro-
ance between bleeding and clotting varies, with the potential duce a consumptive coagulopathy, leading to clinically signifi-
for hepatic artery or portal vein thrombosis upon reperfusion cant bleeding and/or thrombosis with factor consumption.91
and postoperatively coexisting with severe coagulopathic bleed- Excessive thrombin generation and activation of tissue factor
ing, especially in the dissection phase of liver transplantation. causes endothelial dysfunction (predisposing to microvascular
Cirrhosis impairs synthesis of all procoagulant factors thrombosis), with concomitant coagulopathy developing as a
(except factor VIII produced by endothelium) and often co-exists result of consumption of both pro- and anti-coagulant proteins
with vitamin K deficiency,71 as reflected by prolongation of the (especially fibrinogen and antithrombin), deposition and loss of
prothrombin time (PT), which is highly sensitive to concen- platelets, and potent activation of fibrinolysis.92,93 Laboratory
trations of factor VII. Although PT and activated partial throm- findings pathognomonic for diffuse intravascular coagulation
boplastin time (aPTT) are widely used as a monitor in cirrhotic (DIC), characterized by decreased platelet counts, low fibrino-
patients, they do not reflect the overall status of pro- and anti- gen, increased PT, PTT, and D-dimer concentrations, also com-
coagulant deficiency or excessive fibrinolysis. More current monly occur in patients after CPB.92,93 One important difference
efforts to identify relevant biomarkers, focus on pro- is that D-dimer concentrations might not be elevated after car-
inflammatory cytokines such as monocyte chemoattractant diac surgery because of routine administration of antifibrino-
protein-1.72 Neither PT or aPTT correlate well with bleeding after lytics.94 Acquired ATIII deficiency can occur in cardiac surgical
surgery, liver biopsy or other potentially haemorrhagic proce- patients as a result of multiple causes that include preoperative
dures in patients with cirrhosis,73–76 which are better evaluated heparin administration, haemodilution, and consumption. Low
by more global tests, such as viscoelastic testing or the endoge- concentrations of ATIII that range from 20% to 50% commonly
nous thrombin potential (ETP).77,78 Decreased concentrations of occur in cardiac surgical patients associated with CPB.95,96
protein C, antithrombin and factor II result in only a 25% reduc- Ongoing studies are evaluating the role of ATIII supplementa-
tion in thrombin generation in cirrhotics, reflecting a steady tion during support with extracorporeal membrane oxygenation
state, with almost “matching” anticoagulant and procoagulant (ECMO) and in cardiac surgery.97,98
deficiencies.78 This precarious balance is lost after major stress Our group has developed a transfusion algorithm for cardiac
responses such as infection or blood loss, with haemodilution surgery (Figure 3), adopted from similar concepts related to
resulting in profound deficiencies and extreme coagulopathy. trauma-induced coagulopathy (Figure 2), while incorporating
Of note, viscoelastic testing commonly demonstrates normal the concepts highlighted above. In our algorithmic approach,
coagulation profiles in these settings.79 laboratory data, including viscoelastic testing with ROTEMV C

These findings question the usefulness and safety of target- (assays for determination of extrinsic pathway coagulation defi-
ing PT correction with procoagulants such as plasma, rFVIIa or ciencies – EXTEMV C , and determination of fibrinogen-platelet

prothrombin complex concentrate (PCC).80–82 An ongoing multi- interaction - FIBTEMV C ), platelet count, and fibrinogen values,

centre, randomized, controlled trial is studying the utility of are obtained once rewarming is initiated on CPB. If hypofibrino-
PCCs with respect to reducing allogeneic RBC transfusion, dur- genaemia is noted and the EXTEMV C Clotting Time is > 80 s, con-

ing orthotopic liver transplantation in cirrhotic patients with sideration is given to administration of four units of FFP during
INR % 1.5 (PROTON Trial; Netherlands Trial Register: 3174).83 In CPB, followed by administration of cryoprecipitate upon separa-
our opinion, focusing on fibrinogen and platelet supplementa- tion from CPB. Other management modalities are illustrated,
tion makes more sense in this setting. and clinically important bleeding is determined along the way,
Cirrhotics are twice as likely to suffer venous thromboembo- in order to determine further laboratory investigation and focus
lism than the general population,84 presumably when administration of deficient coagulation components.
 Perioperative coagulopathy | iii23

Start: ROTEM #1, platelet count, fibrinogen at rewarming

*PCC note, use Kcentra Fibrinogen≤200mg/dL

for coumadin reversal (on- or CT EXTEM>80s+
label) and profilnine for CT HEPTEM>240s
refractory bleeding
Off CPB, post protamine, pack
chest for 5 min

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Discuss 4uFFP on
CPB, cryo, PCCs
Bleeding ? and/or
10 mg vit K i.v
Haemoglobin≤7 or
8g dl–1 Correct fibrinogen first
PLT PLT INR>1.3
<100 <50 or DHCA FIB≤200 mg/dL FIB≤150 mg/dL aPTT or PT>1.3 x
FibTEM A10 FibTEM A10 CT EXTEM>80s
1-2 U RBC 0.3mcg/kg DDAVP ≤13mm ≤10mm
suggest Hb 8-9 (not if cryo given)
g dl–1 DISCUSS!!
5 U cryo 10 U cryo *Profilnine 10-15u/kg
1U 2U
PLTs PLTs or FFP 10-15ml/kg
-repeat x 1
If >2- 4 units Retest
RBC used ? ?
?
post – CPB
consider 1:1 1U 1U
FFP:RBC PLTs PLTs rFVIIa 1mg-repeat x 1

retest Retest and request assistance

Fig 3 Transfusion Algorithm for intraoperative bleeding during cardiac surgery. In this laboratory, viscoelastic testing (ROTEMV
C ) paradigm, samples are sent upon body

temperature rewarming during CPB. Our algorithm directs the correction of hypofibrinogenaemia (using the Klaus Fibrinogen assay or FibTEMV
C A10 values and thrombocy-

topenia. Patients whom have undergone hypothermic circulatory arrest and the ensuing platelet dysfunction of hypothermia, receive platelet concentrate transfusion
depending on platelet value during on-CPB rewarming values, when temperatures are >33 ! C. Notably, because of established institutional practices, a first set of haemo-
stasis blood samples are sent to the laboratory on CPB, and in order to account for heparin effect, HEPTEMV
C is sent in addition to EXTEMV
C . Thus, if HEPTEMV
C is >240 s,

then it is presumed the added prolonged clotting time is as a result of additional factor deficiencies and requires FFP administration. A HEPTEMV
C CT <240 s indicates man-

ufacture-established values after heparin antagonism. This value aids the practitioner in deciding on FFP administration while on CPB, in order to avoid delayed initiation
of coagulation management after separation from CPB. Consideration is also made to post-CPB PCC administration, as PCC usage on CPB might be less useful owing to the
larger volume of distribution and potential deposition of PCC factors onto CPB filters. With opportunities for clinical observation and laboratory values for deciding further
clinical intervention, various deficiencies are managed through such blood, plasma, and factor concentrate administration. Antifibrinolytic therapy is standard practice for
our cardiac surgical patients that require CPB. Notably, we have internally tested our 5U-pack of cryoprecipitate and have found fibrinogen concentration to range between
1.5-2.5 grams. We recommend a similar assessment locally within each hospital to help with best practice. Figure modified from a draft version of our local cardiac surgery trans-
fusion protocol. AT III ¼ Antithrombin III; CT ¼ Clotting time; CPB ¼ cardiopulmonary bypass; Cryo ¼ Cryoprecipitate; FFP ¼ fresh frozen plasma; FIB ¼ Fibrinogen concentra-
tion; Hb ¼ Haemoglobin; PCCs ¼ Prothrombin complex concentrate; PLT ¼ platelet count; RBC ¼ Red blood cell; rFVIIa ¼ Recombinant activated factor VIIa; U ¼ unit.

Pharmacological haemostatic agents damaged vascular subendothelium. DDAVP decreases bleeding

times in mild haemophilia A or von Willebrand disease, but beyond
A review of allogeneic blood products and dosing is beyond the
these indications, and despite widespread perioperative use, effi-
scope of this article. Outside of the massive trauma setting, their
cacy is limited.100 DDAVP is administered intravenously at doses of
use is guided by laboratory testing. In average adults, one unit
0.3 mcg kg $ 1, and should be infused over 15-30 min to avoid
of RBCs increases haemoglobin concentrations by "1g dl $ 1, one
changes in bp or cardiac chronotropy.101 Despite 18 trials of desmo-
adult dose of platelets increases platelet count by "25-35x109
pressin in 1295 patients undergoing cardiac surgery, only minimal
l $ 1, and a typical dose of 10-20 ml kg $ 1 plasma raises factor lev-
reduction of perioperative blood loss ("115 ml) was reported.102,103
els by "10%. Cryoprecipitate is discussed separately below.
The benefit of administering DDAVP in these patients is unclear,
especially with concomitant use of vasopressin.
Desmopressin
Desmopressin (DDAVP) is the V2 analog of arginine vasopressin
that releases vWF multimers from endothelial stores.99 vWF is a
Coagulation factor concentrates
critical protein that facilitates platelet adherence, by acting as a Although allogeneic blood products are the basis of coagulop-
protein bridge between platelet glycoprotein Ib receptors and athy management, they require cross matching, have well
 iii24 | Ghadimi et al.

documented transfusion reactions and other risks, require Recombinant activated factor VIIa. Recombinant FVIIa (rFVIIa,
blood bank management, and can be limited by availability and NovosevenV R , Novo Nordisk, Denmark) is approved in most

need for transport from the blood bank. Factor concentrates, countries for treating bleeding episodes in patients with haemo-
including fibrinogen concentrates and PCCs, are evolving as a philia A or B with inhibitors, congenital Factor VII deficiency,
way to replace or reduce allogeneic blood product administra- and Glanzmann’s thrombasthenia who are refractory to platelet
tion.104–106 Several factor concentrate based algorithms have transfusions, with or without antibodies to platelets; and for
been described favourably.107,108 treating bleeding for perioperative management in adults with
acquired haemophilia. In these examples, rFVIIa is effectively
Fibrinogen used as a bypassing agent at doses of 90-120 mcg kg $ 1 and infu-
Fibrinogen is a critical haemostatic factor for the development sions. Conversely, off-label dosing is unknown, with lower

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of effective local clot in surgical patients, and for managing peri- doses ("20 mcg kg $ 1) increasingly favored,123,124 and rFVIIa is
operative bleeding in cardiac surgical patients.106,109–111 Normal still included in guidelines for refractory bleeding.125,126* 127,128 It
fibrinogen concentrations are 200-400 mg dl $ 1 in the non- is important to have other coagulation substrates present for
parturient, but can be > 400 mg dl $ 1 during the third trimester optimal efficacy of generated FXa; predictors of rFVIIa-
of pregnancy. While the target fibrinogen concentration in a treatment failure include evidence of coagulation substrate defi-
bleeding patient is not known, bleeding increases for each ciency, haemodilution, or consumption, leading to altered labo-
100 mg dl $ 1 decrease in fibrinogen concentration in parturi- ratory measurements (INR > 2.0, platelet count < 80 x 109 L $ 1,
ents,112 and fibrinogen concentrations decrease in proportion to fibrinogen < 100 mg dl $ 1).128 High thromboembolism rate
increased blood loss after cardiac surgery.113,114 Many society (> 20%),129 a complication rate of 44%,128 and a mortality of
guidelines suggest a transfusion trigger of 100 mg dl $ 1 of fibri- 32%128 are also described in retrospective evaluations of regis-
nogen, based on the threshold of 80-100 mg dl $ 1 that begins to tries for refractory bleeding patients. Prospective trials report a
affect the PT or aPTT, despite the absence of in vivo clinical evi- lower incidence of thrombosis, but high rFVIIa doses increase
dence for this recommendation. European guidelines have rec- the risk of arterial, but not venous, thromboembolic events,
ommended targeting low normal concentrations ("200 mg dl $ 1) especially among the elderly.130 Recent large reviews of nonsur-
since at least 2010.60,115 To achieve this, 3-4 g fibrinogen concen- gical, noncardiac and cardiac surgical patients, demonstrated
trate or 15-20 single donor units of cryoprecipitate have been effectiveness.131 A modest increase in thromboembolic risk was
recommended in the bleeding patient, ideally targeted by labo- seen with both therapeutic (RR 1.21; 95% C.I. 0.93 – 1.58) and pro-
ratory data. phylactic use (RR 1.32; 95% CI 0.84 – 2.06).132
While the exact fibrinogen content of each unit of cryopreci- The overenthusiastic initial adoption of rFVIIa was subse-
pitate is unknown, in a 70 kg adult, a 5-unit bag of cryoprecipi- quently tempered by thromboembolism complications.130,132,133
tate increases fibrinogen by approximately 25-35 mg dl $ 1.116 We can apply this knowledge to PCC use in refractory bleeding
This approximate incremental increase might be reduced in the by addressing substrate repletion and minimizing dosage (10-
event of ongoing haemorrhage. In mainland Europe, fibrinogen 15 IU kg $ 1; Figures 2 and 3). Failure to address platelet, fibrino-
concentrates are used for fibrinogen repletion as cryoprecipitate gen, Factors II, VIII, IX or X deficiencies in patients with severe
is not readily available. Fibrinogen concentrates lack other com- haemorrhage can limit the effectiveness of rFVIIa or PCC to
ponents of cryoprecipitate such as vWF and factors VIII and restore thrombin generation and fibrin clot formation.5
XIII.106 In a prospective study, patients randomized to fibrino-
gen concentrate as a first line therapy had a significantly lower
Protamine
rate of any allogeneic blood product transfusions, including
packed RBCs and FFP.117 Conversely, fibrinogen concentrate was Protamine, isolated from salmon sperm, is a highly basic
not effective after aortic reconstruction surgery, possibly attest- nuclear histone, that binds DNA to provide structural integrity.
ing to the multifactorial nature of this coagulopathy and a com- Its molecular weight is "5000 Da with "70% arginine residues
plexity that confounds a single agent panacea.118 that result in its highly basic nature. Protamine binds to the
acidic heparin molecule via a simple acid-base interaction,134
Prothrombin complex concentrates. Prothrombin complex concen- but only partially antagonizes low-molecular-weight heparin
trates (PCCs) are purified coagulation factors that include pro- (LMWH) activity. Excess protamine should be avoided when
coagulant factors II, VII, IX and X and anticoagulant proteins C, antagonizing heparin as it can contribute to coagulopathy135 by
S and Z in variable concentrations; minimal antithrombin and inhibiting factor V activation and platelet activity.136 To better
heparin are present in some preparations, as recently match the pharmacokinetic profile of heparin slowly released
reviewed.5 The use of PCCs for the emergent or urgent vitamin from poorly perfused tissues, such as adipose tissue after CPB
K antagonist anticoagulants reversal is extensively reported in (heparin rebound), a protamine infusion of 25-50 mg h $ 1 can
guidelines.105,119 Currently, there is extensive and increased use significantly reduce blood loss after cardiac surgery.137 Heparin
for off-label applications, include reversing direct oral anticoa- concentrations during rebound usually range from 0.1 to 0.3 IU
gulants (DOACs) such as apixiban, dabigatran, rivaroxaban, and mL $ 1, which is at the low end of the therapeutic range. The
edoxaban, and for treating refractory bleeding in surgical activated clotting time (ACT) is poorly sensitive as a measure of
patients.108,120–122 Initially developed as a source of factor IX in heparin at such low concentrations.
haemophilia B,5 PCCs were used in activated form as a bypass-
ing agent for haemophiliacs, with alloantibodies or inhibitors to
purified or recombinant factor VIII (haemophilia A) or factor IX
Direct oral anticoagulants
(haemophilia B). Factors VIII and IX are bypassed with activated Direct oral anticoagulants (DOACs) represent a class of orally
PCCs, which enhance factor Xa production through the extrinsic administered factor inhibitors approved for anticoagulation in
tenase complex, which feeds into the prothrombinase complex patients with venous thromboembolic disease and stroke pre-
and restores downstream thrombin generation (Figure 1). Of vention in patients with nonvalvular atrial fibrillation. As the
note factor VIIa was developed from activated PCCs.5 prevalence of patients taking DOACs continues to increase, so
 Perioperative coagulopathy | iii25

does the importance of understanding how to best antagonize this combination is associated with an increased bleeding
the anticoagulant effect of these agents. Although the reader is risk.148 Prasugrel and ticagrelor have stronger antiplatelet effect
directed elsewhere for review of approaches to management of than clopidogrel because of more effective metabolism and less
bleeding in these patients,138 general efforts using PCCs or dependence on cytochrome P450 enzymes subject to genetic
aPCCs remain unproved with unknown dosing regimens. polymorphisms.149
Additionally, specific antidotes are currently available or under The decision whether or not the interrupt or even antago-
development, as follows. nize antithrombotic therapy with dual platelet inhibition
requires careful thrombotic risk and haemostatic benefit evalu-
ation, especially in patients with recent drug-eluting stent
Specific antidotes for direct oral anticoagulants
rather than bare-metal stent implantation. Administration of

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Recently, idarucizumab (PraxbindTM, Boerhinger Ingelheim, platelet concentrates ("2 units) can correct the haemostatic
Germany) was approved for antagonism of dabigatran, a direct defect after antiplatelet drugs have been stopped for 12–24 h
thrombin inhibitor (DTI) within the class of the direct oral anti- (free drug can inhibit transfused platelets).150,151 Ideally, aspirin
coagulants (DOACs). Concentrations of unbound dabigatran is restarted 6 h and P2Y12 receptor blockade is restarted 12–48 h
remained low at 24 h in 79% of the patients, and for most opera- after surgery. When continued P2Y12 receptor blockade is desir-
tive normal haemostasis was restored. One thrombotic event able, cangrelor infusion can serve as a bridge to surgery.152 In
occurred within 72 h after idarucizumab administration in a the actively bleeding patient, testing for platelet dysfunction
patient in whom anticoagulants had not been reinitiated.139 has been thought to be unreliable as most tests require a rela-
Factor Xa inhibitors are another subclass of DOACs without tively normal platelet count and most of the platelet function
an approved antagonism agent. Andexanet alfa (Portola testing might not work well after the dilutional changes and
Pharmaceuticals, South San Francisco, California, USA) is a activation after CPB.12 However, a recent prospective observatio-
modified, recombinant derivative of Factor Xa with the serine nal study, illustrated that preoperative ADP-induced platelet
on the FXa-active site mutated to alanine, inactivating the ser- aggregability predicted the risk for severe bleeding in cardiac
ine protease activity and thus removing its ability to cleave pro- surgical patients treated with preoperative ticagrelor.153
thrombin to thrombin.140,141 The membrane-binding domain of
plasma-derived Factor X has also been deleted, precluding
Transfusion algorithms and bleeding
inclusion of andexanet into the prothrombinase complex. This
“decoy molecule” sequesters FXa inhibitors, rapidly reducing Transfusion algorithms represent one of the most important
free plasma concentration and neutralization anticoagulant strategies to reduce excess transfusion, and all components of
effect. Andexanet alfa binds to antithrombin complexed with coagulation management outlined in our review have been
LMWH, fondaparinux, rivaroxaban, apixaban and edoxaban. included in the algorithms presented. Developing a specific
The short half-life of andexanet alfa relative to FXa inhibitors therapeutic plan through use of transfusion algorithms has
can be insufficient to correct coagulopathy, particularly in the been shown to consistently reduce allogeneic blood administra-
setting of renal dysfunction or older age,142 although interim tion.107 It is important to realize that any laboratory testing that
reports from a clinical trial are encouraging.143 Other antago- discourages empirical blood product administration, is impor-
nism agents in development include PER977.144 But antagonism tant as part of a multimodal approach to blood conservation
of anticoagulation incurs a thrombosis risk that will have to be and reduction of allogeneic blood product use, while realizing
balanced with bleeding and will likely need to be addressed that laboratory values can lag behind the clinical scenario, if
once haemostasis is achieved.141 Despite the potential for these blood loss remains rapid.37,154 Transfusion algorithms generally
specific antagonism agents, a multimodal approach to coagula- recommend administration of plasma when bleeding is accom-
tion management is needed during management of bleeding panied by PT or aPTT > 1.5 times normal, platelet transfusions
related to DOACs, which might necessitate coagulation factor for thrombocytopenia with a platelet count <50,000–100,000, or
concentrate administration. cryoprecipitate or fibrinogen concentrate when fibrinogen con-
centrations are < 200 mg dl $ 1 (2 g l $ 1).155 The critical role of
fibrinogen continues to evolve with most data suggesting the
Antiplatelet agents: aspirin and importance of normalizing fibrinogen in bleeding patients. With
thienopyridine derivatives critical bleeds, and turn over time in standard laboratory test-
Aspirin is used extensively for the secondary prevention of ing, point-of-care testing, including rotational thromboelastom-
atherothrombotic disease that includes occlusive coronary etry (ROTEMV C ), thromboelastography (TEGV C ) and/or platelet

artery and peripheral arterial disease, and cerebrovascular function testing, are important.155 In the actively bleeding
thromboembolism.145 Although aspirin has the potential to patient, testing for platelet dysfunction is unreliable, as most
increase blood loss after major surgery, this probably does not tests need a relatively normal platelet count.12 With these capa-
result in increased needs for transfusions and should always be bilities and limitations in mind, we have developed transfusion
considered for risk vs benefit effects.146 As such aspirin should algorithms for both noncardiac (Figure 2) and cardiac (Figure 3)
not be discontinued preoperatively except before neurosurgery surgical patients in order to guide perioperative management of
procedures. Antagonism of aspirin is rarely necessary 48 h after coagulopathy.
the last dose and can be achieved by DDAVP147 or platelet
transfusion.
Clopidogrel (Plavix), prasugrel (Efient, Effient), ticagrelor
Conclusions
(Brilinta), and cangrelor (Kengreal) belong to the class of thieno- The potential for haemorrhage in trauma and surgical
pyridine derivatives that act by blocking the adenosine diphos- patients represents an ongoing concern for management.
phate (ADP) P2Y12 receptor on platelets. Dual antiplatelet Anticoagulation monitoring using point-of-care testing, optimal
therapy with aspirin and clopidogrel is a current standard of use of transfusion therapies, adjunct administration of antifibri-
care after percutaneous coronary intervention (PCI), however nolytics and purified and recombinant concentrates, provide
 iii26 | Ghadimi et al.

clinicians with the ability to administer vital coagulation thera- 9. Peng RY, Bongard FS. Hypothermia in trauma patients. J Am
pies to treat haemorrhage. Other key considerations include Coll Surg 1999; 188: 685–96
management of hypofibrinogenaemia, thrombocytopenia and 10. Martini WZ. Coagulopathy by hypothermia and acidosis:
platelet disorders, topical haemostasis, excluding surgical sour- mechanisms of thrombin generation and fibrinogen avail-
ces of bleeding, and temperature regulation. The integration of ability. J Trauma 2009; 67: 202–8. discussion 8-9
the optimal use of pharmacologic agents, allogeneic transfu- 11. Wolberg AS, Meng ZH, Monroe DM, 3rd, Hoffman M. A sys-
sion, and factor concentrates into a comprehensive periopera- tematic evaluation of the effect of temperature on coagula-
tive coagulation treatment algorithm for bleeding, is an tion enzyme activity and platelet function. J Trauma 2004;
important therapeutic approach for the management of bleed- 56: 1221–8
ing in surgical patients. 12. Le Quellec S, Bordet JC, Negrier C, Dargaud Y. Comparison

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of current platelet functional tests for the assessment of
aspirin and clopidogrel response. A review of the literature.
Authors’ contributions Thromb Haemost 2016; 116: 638–50
13. Ghadimi K, Gutsche JT, Ramakrishna H, et al. Sodium bicar-
Study conduct: K.G., I.J.W.
bonate use and the risk of hypernatremia in thoracic aortic
Data analysis: K.G., J.H.L., I.J.W.
surgical patients with metabolic acidosis following deep
Writing paper: K.G., J.H.L., I.J.W.
hypothermic circulatory arrest. Ann Card Anaesth 2016; 19:
Revising paper: all authors
454–62
14. Ghadimi K, Gutsche JT, Setegne SL, et al. Severity and
Declaration of interest Duration of Metabolic Acidosis After Deep Hypothermic
Circulatory Arrest for Thoracic Aortic Surgery. J Cardiothorac
K.G. is a co-investigator in a prospective, open-label study of Vasc Anesth 2015; 29: 1432–40
Andexanet-Alfa in patients receiving Factor Xa inhibitors with 15. Cesarman-Maus G, Hajjar KA. Molecular mechanisms of
acute major bleeding, sponsored by Portola Pharmaceuticals. fibrinolysis. Br J Haematol 2005; 129: 307–21
J.H.L. serves on steering committees for Boehringer- 16. Wada Y, Uchiba M, Kawano Y, et al. Severe bleeding ten-
Ingelheim, CSL Behring, Grifols, and Janssen; consultant to dency caused by a rare complication of excessive fibrinoly-
Instrumentation Laboratories and Pfizer. sis with disseminated intravascular coagulation in a
I.J.W. is the Principal Investigator in a prospective, open- 51-year-old Japanese man with prostate cancer: a case
label study of Andexanet Alfa in patients receiving Factor Xa report. J Med Case Rep 2012; 6: 378
inhibitors with acute major bleeding, sponsored by Portola 17. Levy JH. Antifibrinolytic therapy: new data and new con-
Pharmaceuticals and has recently received grant support from cepts. Lancet 2010; 376: 3–4
CSL Behring and Terumo BCT. 18. Tran HT, Sorensen B, Rea CJ, et al. Tranexamic acid as
adjunct therapy to bypassing agents in haemophilia A
patients with inhibitors. Haemophilia 2014; 20: 369–75
Funding 19. Collaborators C-T, Shakur H, Roberts I, et al. Effects of tra-
NIH R01HL121232-01 (I.J.W.), Departmental funding (K.G., J.H.L.) nexamic acid on death, vascular occlusive events, and
blood transfusion in trauma patients with significant hae-
morrhage (CRASH-2): a randomised, placebo-controlled
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