COAGULOPATHY IN CARDIAC SURGERY

BY:Dr Hatem Mohd Altaher

Coagulation and bleeding assume particular importance when operations are performed on the heart using extracorporeal circulation.

The interaction of the platelets, endothelial cells, and proteins to either activate or deactivate coagulation is a highly buffered and controlled process.
Coagulation itself the injury/control leading to hemostasis is a four-part event
initiation
acceleration

lysis

control

Platelet activation by CPB

Activation

CPB negatively charged plastic surface

The central role of Thrombin (Thr) in hemostatic activation

Modulating effects of coagulation.

ATIII

Heparan & heparin thrombin

TFPI
heparin

Thrombin + ATIII

VIIa & Xa

II ,XIIa,XIa, and Xa; kallikrein; plasmin.

The fibrinolytic system

BLEEDING PATIENT
Following cardiac surgery, some patients bleed excessively. Prompt diagnostic and therapeutic action will avoid impaired hemodynamics, decreased oxygen-carrying capacity, and impaired hemostasis from depletion of endogenous hemostatic resources. creates the potential for hemorrhage, sometimes aided by preoperative attempts to lyse intracoronary thromboses. Beyond that, however, many factors govern whether a particular patient will experience excessive bleeding after cardiac surgery. Excessive bleeding, a chest tube drainage > 10 mLlkg in the first hour post op or a total of > 20 mLlkg over the first 3 hours post op any sudden increase of >300 mLlhr or greater following minimal initial drainage

I- Patient Factors
patient with a personal or family history of abnormal bleeding following surgery should be investigated.
Concurrent systemic disease affects hemostasis during surgery.

Uremia from RF results in platelet dysfunction. Severe hepatic compromise impairs every aspect of hemostasis: prekallikrein and most coagulation factors splenomegaly induces thrombocytopenia; maldistribution of vWF lead to impairs platelet adhesiveness and aggregation; impaired clearance of endogenous plasminogen activators accentuates fibrinolysis; and decreased levels of coagulation inhibitors induce a consumptive coagulopathy.

II- Medications
warfarin hold 2 to 5 days. urgent surgery parenteral vitamin K or FFP thrombolytic therapy as streptokinase should respond to antifibrinolytic therapy with (EACA) or tranexamic acid. ASA or other platelet-inhibiting drugs regularly cannot halt that therapy within 7 days of surgery. No antidote can correct the platelet defect. B-Lactam antibiotics coat the platelet membrane, while the cephalosporins are rather profound but short-term platelet inhibitors. Many cardiac surgeons may not realize that their standard drug regimen for antibiotics may be far more of a bleeding risk than aspirin

II- Anti-platelet
Drug Type Aspirin Composition Acetylsalicylic acid Multiple Multiple Thienopyridines Mechanism Irreversible COX inhibition Reversible COX inhibition Reversible COX inhibition Irreversible inhibition of ADP binding Indications CAD, AMI, PVD, PCI, ACS Pain VHD, PVD AMI, CVA, PVD, ACS, PCI Route Oral Halflife 10days 2 days 12 hr 5 days

NSAIDs Adhesion inhibitors (e.g., dipyridamole) ADP receptor antagonists (e.g., clopidogrel) GPllb/llla receptor inhibitors Abciximab (ReoPro)

Oral Oral Oral

Monoclonal antibody Peptide

Nonspecific-binds to other receptors Reversiblespecific to GPllb/llla Reversible specific to

PCI, ACS

IV

12 to 18 hr 2 to 4 hr 2 to 4 hr

Eptifibatide (Integrilin)

PCI, ACS

IV

TIrofiban (Aggrastat)

Nonpeptidetyrosine

PCI, ACS

IV

III- Insult of CPB

A- Fibrinolysis
Numerous investigations support the notion that CPB activates the fibrinolytic pathway. Why might this occur? Despite clinically adequate doses and blood concentrations of heparin, coagulation pathway activity persists. Formation of prothrombin and fibrinopeptide fragments and thrombin-antithrombin complexes continued. The site of thrombin activity probably resides in the ECC , which contains a large surface of thrombogenic material. Thrombin activation results in fibrinolytic activity. Activation of fibrinolysis

Plasminogen activator concentrations rise during CPB, while levels of its inhibitor PAl-I remain unchanged.
Does fibrin formation during CPB constitute a consumptive coagulopathy?

B- Thrombocytopenia
Thrombocytopenia occurs during CPB as a result of

Hemodilution. Heparin. hypothermia-induced. splenic sequestration of platelets. platelet destruction from the blood-gas and blood-tissue interfaces created by cardiotomy suction, filters, and bubble oxygenators. Platelet count rarely drops below 50,000/mm3.

C- platelet dysfunction
Not only does the number of platelets decrease during CPB, but remaining platelets become impaired by partial activation.
Fibrinogen and fibrin, which adhere to artificial surfaces of the ECC, form a nidus for platelet adhesion and aggregation. reduced content of platelet granules constitutes the evidence for partial activation. Nearly one-third of circulating platelets undergo a-granular release during CPB. also depletes platelet glycoprotein receptors Ib and IIb/I1Ia. Use of frequent cardiotomy suction and bubble oxygenators aggravates the extent of platelet activation. Activation of the fibrinolytic system may contribute to platelet dysfunction.

Antifibrinolytic medications preserve platelet function and prevent some platelet abnormalities that occur during bypass

D- Clotting Factors
Denaturation of plasma proteins, including the coagulation factors, occurs at blood-air interfaces. Liberal use of cardiotomy suction and prolonged use of bubble oxygenators potentially impair coagulation by decreasing coagulation.

Hemodilution also decreases factor concentrations.

However, rarely do coagulation factor levels fall below the thresholds for adequate formation of fibrin in adult surgery.

In infants, however, the smallest achievable pump priming volumes can dilute factors to below 30% of normal levels.

IV- Hypothermia
First, the splanchnic circulation responds to hypothermia with sequestration of platelets. Second, transient platelet dysfunction occurs, evidenced by a platelet shape change, increased adhesiveness, inhibition of ADP-induced aggregation, and decreased synthesis of both thromboxane and prostacyclin. Third, hypothermia slows the enzymatic cleavage upon which activation of coagulation factors depends. Many biologic phenomena display a 7% attenuation of activity for each decrease of 1C in temperature. While coagulation factor structure remains unaltered, formation of fibrin may be sluggish when the patient is cold. Fourth, hypothermia accentuates fibrinolysis.

Prevention of Bleeding A- Preoperative Factors

Identified and treated existing disorders of hemostasis. The bleeding diathesis of uremia responds to hemodialysis, red blood cell transfusion, and administration of desmopressin. Impaired hemostasis from hepatic failure may respond to intravenous desmopressin. Correction of hematologic disorders Administration of platelet-inhibiting drugs should cease pre OR Aspirin 10 days NSAIDs 2 days ADP receptor antagonists (e.g., c1opidogrel)5 days GPllbllla receptor inhibitors Tirofiban (Aggrastat) 2 to 4hr

Prevention of Bleeding B- Physical Factors

Correction of Hypothermia Incomplete surgical hemostasis Limiting the intensity and frequency of use of the cardiotomy suction Selection. membrane Vs bubble-type oxygenator Centrifuge Vs Roller pump A small priming volum. ANH

B- Physical Factors

cont.

Speed of surgery Shorter CPB duration Preserves platelet function and limits the coagulant stimulus for subsequent fibrinolysis. limits tissue exposure to the hypothermia positive END-EXPIRATORY PRESSURE (5 to 10cm H20).

A tamponade effect in the mediastinum may explain this salutary effect.

Unfortunately, controlled studies have not confirmed this benefit. Also, excessive pressure impedes venous return, worsening hemodynamics in the hypoovolemic patient.

B- Physical Factors
-

cont

maiaintenance of systemic blood pressure in the low-normal range promotes tissue perfusion while limiting leakage around suture lines. Adequate depth of anesthesia during surgery and sufficient postoperative analgesia and sedation should be verified prior to initiating vasodilator therapy. Topical haemostatic agents Fibrin sealants are composed of human fibrinogen, human or bovine thrombin or human factor VIII and bovine aprotinin.

C- blood Products
The bleeding patient becomes subject to additional hemostatic derangements. The need to maintain intravascular blood volume arises in nearly all cases prior to identification of the cause of bleeding. However, red blood cells,platelets, and coagulation factors become diluted when continued bleeding is treated with such replacement. Also, PRBCs and banked whole blood do not provide platelets or sufficient factor V & VIII to maintain hemostasis. Although routine prophylactic administration of FFP or platelets plays no role in modern cardiac surgical care.

A platelet counr below 100,000/mm3 or prolongation of the PT or aPTT despite adequate heparin neutralization in a patient actively bleeding is an indication for platelet or plasma replacement in the absence of coagulation tests to

guide therapy

D- Pharmacological Intervention
HEPARIN AND PROTAMINE

Too little heparin invites active fibrin formation during CPB with consumption of clotting factors and platelets and excessive activation of the fibrinolytic system. Too much heparin risks postoperative heparin rebound. With too little protamine, the remaining unneutralized heparin impairs hemostasis by its anticoagulant action. Doses of protamine excessive enough to overwhelm the endogenous proteases may exert an anticoagulant effect, as well as induced lung injury and pulmonary vasoconstriction.

HEPARIN AND PROTAMINE

ACT nearly doubling following a protamine dose four times that needed to neutralize heparin. At a lO-fold dose, the ACT prolonged and thrombocytopenia developed The optimal approach utilizes coagulation testing to estimate the appropriate heparin and protamine doses, and confirm both adequate anticoagulation and its neutralization.

D- Pharmacological Intervention
DESMOPRESSIN

cont.

This analog of vasopressin desmopressin releases coagulation system mediators from vascular endothelium.

Factor VIII increases 2- to 20-fold. Factor XII levels Endothelium : releases of vWF. Specific applications of desmopressin's hemostatic benefit include :

uremia, Correction of prolonged bleeding times

Liver cirrhosis patients shortens prolonged bleeding times. corrected the aspirin-induced prolongation in bleeding time

D- Pharmacological Intervention
SYNTHETIC ANTIFIBRINOlYTICS

cont

For decades, antifibrinolytics have been proposed as potential hemostatic agents during cardiac surgery. Prophylactic antifibrinolytics may spare platelet function by inhibiting the deleterious effects of plasmin.

These simple molecules analogs of the amino acid lysine, bind to plasminogen and plasmin, thus inhibiting binding of plasminogen at the lysine residues of fibrinogen.
Antifibrinolytics undergo renal concentration and excretion with a plasma half-life of about 80 minutes. The loading dose of 10mg/kg for TA followed by 1mg/kg/hr or 50 mg/kg of EACA then 25 mg/kg/hr

Pharmacokinetic studies demonstrate a need to readminister a bolus of EACA upon institution of CPB.

Several investigations, using prophylactic antifibrinolytics; document a savings in blood loss, as well as in blood transfused in a general population of cardiac surgery
chest tube drainage in the first 12 hours following operation decreased by 30%, The likelihood of receiving banked blood within 5 days of operation decreased from 41% to 22%:48 Administration of very large doses of antifibrinolytics appears to offer no greater savings.

D- Pharmacological Intervention
Recombinant Factor Seven

cont

Factor VII is synthesized in the liver has the shortest half-life of all procoagulant factors (3-6 h). Novel indications for rFVIIa (based on case reports & clinical trials)

Patients with liver disease, Thrombocytopenia, or Qualitative platelet dysfunction Patients with no coagulation disorders who are bleeding as a result of extensive surgery or major trauma

Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non-coronary cardiac surgery: randomized double-blind placebo-controlled pilot study British Journal of Anaesthesia 95 (5): 596602 (2005)

2006 Effective Management of Refractory Postcardiotomy Bleeding With the Use of Recombinant Activated Factor VII Farzan Filsoufi, MD, Javier G. Castillo, MD, Parwis B. Rahmanian, MD,Corey Scurlock, MD, Gregory Fischer, MD, and David H. Adams, MD Departments of Cardiothoracic Surgery and Anesthesiology, Mount Sinai Hospital, New York, New York

Crit. Care Med. 2005; 33(10)

Von Heymann C ;et al, Department of Anesthesiology and Intensive Care Medicine, St. Mary's Medical Center, San Francisco, CA, USA

STUDIES
Blood loss and transfusion requirements were significantly reduced in the period after the administration of rFVIIa. Early Mortality and 6-month survival rates were not different between the groups. No thromboembolic complications were observed in the rFVIIa group CONCLUSIONS: When used as a last resort, rFVIIa was safe , efficacious over conventional hemostatic therapy n=24

2007 Recombinant Activated Factor VII in CardiacSurgery: A Systematic Review Oliver Warren, MRCS, et al, Department of BioSurgery and Surgical Technology, St.

Marys Hospital, London, UK

performed a meta-analysis of 5 clinical trials hemostatic properties of rFVIIa could reduce the rate of surgical reexploration after cardiac surgery even if an increase of hazardous side effects (eg, perioperative stroke) could not be excluded.

Recombinant Activated Factor VII in Cardiac Surgery: A Metaanalysis 2009

Journal of Cardiothoracic and Vascular Anesthesia,

Pediat. Crit Care Med. 2005

Wittenstein B ; Ng C ; Ravn H ; Goldman A Great Ormond Street Hospital for Children, London, UK

Thromboembolic adverse events after used of factor VIIa OConnell K JAMA 2006: 295:293

Retrospective review of factor VII use in 18 Canadian centres, 2003 2006 Data collected on 503 patients

Blood Coag Fibrinolysis 2006; 17:389

Factor VIIa in cardiac surgery: a systematic review

Warren O Ann Thorac Surg 2007; 83:707

Thromboembolic adverse events after used of factor VIIa

OConnell K JAMA 2006: 295:293

431 AE reports 168 patients had thrombotic events

WHAT TO DO

Coagulation monitoring
Test
Platelets Platelet count
150,000-400,0001IlL <8 min

Bleeding time

Coagulation system Whole blood clotting time 2.5-6 min Activated clotting time (ACT) 90-130 sa time (PT) 12-15 s; INR 1.0-1.5 Activated partial thromboplastin 35-45 s; compare to control time (aPTT) Thrombin time <14 s; compare to control Fibrinogen250-500 mg/dL Fibrinolytic system Fibrin(ogen) split products d-Dimer <10ug/mL <0.5Iug/mL

Coagulation monitoring

Coagulation monitoring ADP Test

Rule out surgical cause

More protamine0.5 to 1mglkg

No oozing at puncture sites; chest radiograph

ACT >150 sec or aPTT >1.5 times control Core" temperature <35C
Prolonged bleeding time Elevated D-dimer or teardrop shaped TEG tracing

Warm the patient Desmopressin O.3uglkg IV

Aminocaproic acid or Tranexamic acid

Platelet transfusion1 unit/10kg

Fresh froze plasma 15mL./kg Cryoprecipitate 1unit/4kg

Platelet count <100,OOO/mm3

THROMBOCYTOATHENIA

PT or aPTT >1.5 times control

Fibrinogen <1 gIL or 100mg/dL

There have been fewer randomized trials of tranexamic acid or aminocaproic acid. One trial [15] of 210 cardiac surgery patients randomized to receive tranexamic acid or placebo resulted in a significant reduction in the proportion of patients requiring any blood product in the tranexamic group (12.5%) compared with the placebo group (31.1%). A Cochrane review [8] of over 200 clinical trials (not limited to cardiac surgery) found that antifibrinolytic drugs used at the time of major surgery reduced bleeding, the need for transfusion and the need for repeat surgery because of bleeding. The authors [8] found that lysine analogues were probably as effective as aprotinin and were cheaper; the evidence for tranexamic acid is stronger than for aminocaproic acid. Large variations in dosages used between the published studies make it impossible to evaluate the relationship between dosage and efficacy. In the paediatric population, antifibrinolytics have been used for scoliosis surgery. A Cochrane review [16] showed that antifibrinolytics reduce blood loss, but their effect on

rFVIIa binds to tissue factor at the site of tissue injury and vascular wall disruption, generating thrombin and activating platelets. The activated platelet surface then forms a template, on which rFVIIa mediates further activation of coagulation. This in turn generates a thrombin burst, which leads to the conversion of fibrinogen to fibrin. Furthermore, rFVIIa-mediated activation of thrombin-activatable fibrinolysis inhibitor results in clot stabilization by inhibition of fibrinolysis [1].

Recombinant FVIIa is an expensive therapy; a single adult dose of 90mgkg1 costs approximately 6000 Euros. Its use is difficult to justify on economic grounds alone, given the cost of one unit of red blood cells (175 Euros). There is evidence that the clinical efficacy varies at different doses; in a meta-analysis, a subgroup analysis determined that at least 50mgkg1 was required for a significant benefit [18]. Therefore, the role of this drug has yet to be established, and further research is required.

Topical haemostatic agents Fibrin sealants are composed of human fibrinogen, human or bovine thrombin or human factor VIII and bovine aprotinin. They are topically applied and are used quite commonly in cardiothoracic, vascular, liver and spleen surgery to aid haemostasis at sites of cannulation, laceration and along suture lines [1]. A systematic review [26] of the use of fibrin sealants to minimize perioperative allogeneic blood transfusion suggested that they are efficacious, although large methodologically rigorous trials are still needed. In addition, such sealants are very expensive, and costbenefit analysis has yet to be performed, despite aggressive marketing from the manufacturers.

Autologous blood transfusion There are three types of autologous blood transfusion: preoperative blood donation, acute normovolaemic haemodilution (ANH) and red blood cell salvage (intraoperative and postoperative) [27]. A systematic review [28] of randomized controlled trials found that all three autologous transfusion techniques consistently reduced the frequency of allogeneic transfusions; the greatest relative risk reduction occurring with preoperative blood donation Carless PA, Moxey A, OConnell D, Henry D. Autologous transfusion techniques: a systematic review of their efficacy. Transfus Med 2004; 14:123144.

Acute normovolaemic haemodilution ANH is an autologous blood collection technique that involves the removal of whole blood from the patient immediately before surgery, along with simultaneous replacement with an intravenous fluid (crystalloid or colloid) in order to maintain normovolaemia. The blood is collected in standard blood bags containing citrate anticoagulant; it remains in the operating room and is reinfused at an appropriate time during surgery, or at the end of surgery, usually after major blood loss has ceased.

The efficacy of ANH in reducing allogeneic transfusion is dubious. Several prospective randomized trials [4043] have demonstrated that ANH reduces allogeneic blood transfusions in patients undergoing elective total knee replacement, liver resection and cardiac surgery; however, others [44,45] have failed to document any benefit. A meta-analysis of 42 trials [46] comparing ANH with alternative blood conservation methods or usual care suggested that the efficacy of ANH was likely to be small. It appears to modestly reduce bleeding and the volume of allogeneic blood required, but its efficacy with regard to avoidance of allogeneic transfusion is unproven.

Red blood cell salvage Red blood cell salvage has become popular over the past 10 years and is now used extensively in the surgical setting. Cell salvage is a term that covers a range of techniques that scavenge blood from operative fields or wound sites and reinfuse the blood back into the patient. Cell salvage can be performed during intraoperative or postoperative periods or during both. To remove noncellular matter prior to reinfusion, some of the devices use centrifugal washing of the salvaged blood [48], whereas others use a countercurrent system similar to haemofiltration [49]. The processing of blood, however, necessarily

removes platelets and plasma proteins, which may contribute to a dilutional coagulopathy. The washing process can also lead to haemolysis, especially if suction pressures are not carefully regulated or the washing process is accelerated. In addition, retained plateletleukocyte deposits may produce procoagulant leukotactic substances, increasing the risk of disseminated intravascular coagulation [50]. Relative contraindications include the potential for aspiration of malignant cells, the presence of infection, gross bacterial contamination of the surgical field and the presence of other contaminants such as amniotic fluid [51].

The effect of acute autologous blood transfusion on coagulation dysfunction after cardiopulmonary bypass Anaesthesiol 26:868873 Q 2009 European Society of Anaesthesiology.

elective cardiac surgery with cardiopulmonary bypass. The patients in group A underwent acute autologous blood transfusion with acute normovolemic haemodilution and those in group H received homologous blood, if needed, and served as controls.

Autologous blood transfusion of 15% estimated blood volume did not affect postcardiopulmonary bypass coagulopathy, nor did it decrease blood loss or homologous blood and its products transfusion in the early postoperative period. TEG is a valuable measure for detecting coagulation dysfunction with a potential role in the postoperative management of cardiac patients