ANTICOAGULATION ANDHAEMOSTASIS DURINGCARDIOPULMONARYBYPASS Dr. Basant Dindor Moderator - Dr. S.P. Meena
Introduction The hemostatic management of patients undergoing cardiac surgery is a complex issue because there exists the need to maintain a delicate balance between Anticoagulation for cardiopulmonary bypass (CPB) Hemostasis after CPB. These two opposing goals must be managed carefully and modified with respect to the patient’s initial hematologic status, specific timing during cardiac surgery, and desired hemostatic outcome.
During CPB, optimal anticoagulation dictates that coagulation be antagonized and platelets be prevented from activating so that microvascular clots do not form on the extracorporeal circuit. After surgery, coagulation abnormalities, platelet dysfunction, and fibrinolysis can occur, creating a situation whereby hemostatic integrity must be restored.
Normal coagulation pathway The various coagulation factors participate in a series of activating reactions that end with the formation of an insoluble clot. The whole process of clot formation can be divided into Contact phase Intrinsic pathway Extrinsic pathway Common pathway
Contact phase The damaged vascular surface exposes the collegen matrix which initiates the surface activation of coagulation proteins Factor XII binds with negatively charged collagen material and is autoactivated to factor XIIa. High molecular weight kininogen ( HMWK) binds prekallikrein and factor XI to surface. Factor XIIa splits factor XI to form factor XIa and prekallikrein to form kallikrein.
Intrinsic pathway The net result of intrinsic pathway is formation of factor Xa from product of surface activation. Factor XIa converts factor IX to form factor IXa in presence of Ca++. Factor IXa then activates factor X in presence of Ca++ and factor VIIIa.
Extrinsic pathway Activation of factor X can also be achieved independently by substances extrinsic to the vasculature. Thromboplastin released from the tissues act as a cofactor to activate factor X by factor VII, Ca++ is also required for this process.
Common pathway Factor Xa split prothrombin to thrombin, Ca++ and factor Va are required for this process. Thrombin split the fibrinogen molecule to form soluble fibrin monomer. Factor XIII, activated thrombin, crosslinks these fibrin strands to form a clot.
Fibrinolysis Fibrinolysis is dissolution of fibrin. It occurs in the proximity of clot and dissolves it when endothelial healing occurs. It is mediated by the serine protease plasmin, which is prouced from the plasminogen with the help of tissue plasminogen activator ( t- PA). Fibrinolysis is normal response to clot formation and represent pathological condition, when it occures systemically.
Heparin Glucosaminoglycan (polysaccharide) Found most commonly in mast cells Strongest macromolecular acid in the body
Heparin • Heterogeneous mixture of molecules from 3,000 to 40,000 daltons (mean ~ 15,000) • Batch to batch heparin preparations may have different activity levels per milligram • standardized activity levels reported in units 100 units = 1 mg 1 unit will maintain anticoagulation of 1 ml of recalcified sheep serum for 1 hour
Sources of Heparin First isolated from liver extract (hepatic) Porcine intestinal mucosa Bovine lung
Heparin Porcine Bovine Lower molecular weight Higher molecular weight More cross linked structure Less cross linking Longer lasting Shorter Higher content of binding Lower content of ATIII sites for ATIII binding sites Higher doses needed for Lower doses needed CPB May need more protamine 25-30% less protamine to neutralize needed Lower incidence of heparin Higher incidence of delayed rebound hemorrhage Bovine spongiform Lower incidence of Heparin encephalopathy indused thrombocytopenia transmission (mad cow disease)
Heparin Half life of heparin Dose Half life is dose dependent. Minutes And Highly variable 400 u/kg 126 +- 24 between patients 200 u/kg 93 +-6 100 u/kg 61 +-9
Mechanism of action Heparin Acts as a catalyst for antithrombin III (ATIII) to accelerate the neutralization of Thrombin Xa IXa XIa XIIa VIIa/TF complex
Dosage during CPB Initial dose for 200 to 400 units/kg Maintenance dose 50 to 100 units/kg (administered any where b/w 30 min to 2hour) The extracorporeal circulation was primed with bank blood that was heparinised in the dose of 2500 to 5000 units/unit of blood.
Monitoring heparin effect The anticoagulant effect of heparin should be monitored functionally before instituting CPB. The administration of heparin does not guarantee that all patients will be adequately anticoagulated because there are differences in levels of circulating co-factors and inhibitors that can alter the pharmacokinetics and pharmacodynamics of the drug.
Activated clotting time Functional tests of heparin activity are related to the whole blood clotting time. The whole blood clotting time required that whole blood placed in a glass tube, maintained at 37ºC, and manually tilted until blood fluidity was no longer detected. Glass tube containing diatomaceous earth (celite), kaolin, or a combination of activators. The presence of an activator augments the contact activation phase of coagulation, which stimulates the intrinsic coagulation pathway.
Detection of ACT values can be performed manually but is more commonly by automated method, as in Hemochron and Hemotec systems. Hemochron HemotecBlood required 2ml 0.4 mlActivator Celite Kaolin
ACT monitoring Bull et al (1975) recommended structured approach using ACT monitoring. They adopted ACT of 480 sec as safe value, ACT below 180 sec - life threatening b/w 180 to 300 sec - questionable ≥ 600 - unwise
Current practice Gravlee et al have selected following CPB heparin management protocol1. Administer heparine 300 units/kg IV2. Draw an arterial sample for ACT in 3 to 5 min.3. Give additional heparin to achieve ACT>300 sec during normothermic CPB & >400 sec for hypothermic <30ºC.4. Prime extracorporial circuit with 3 units/ml heparin5. Monitor ACT every 30 min. during CPB.6. If ACT decreses below desired min. value, doses of 50 to 100 units/kg given.
Limitation of ACT ACT values may prolongsd by following factors Hypothermia Haemodilutation Apotinin : a serine protease inhibitor, is used for blood conservation during open heart surgery. Maintain ACT value >750 when apotinin is used.
Heparin concentration During CPB, the sensitivity of the ACT to heparin is increased. The ACT is prolonged even in conjunction with unchanged or decreasing heparin levels. For this reason, the functional measure of heparin anticoagulation may be supplemented with the quantitative measure of the whole blood heparin concentration. Protamine titration test: 1ml of blood is added to several glass tubes at 37ºC containing a known conc. Of protamine. First tube to clot determine the concentration of heparine. Hepcon is an automated protamine titration test.
Heparin resistance Heparin resistance is documented by an inability to raise the ACT to expected levels despite an adequate dose and plasma concentration of heparin. Clinical conditions associated with heparin resistance,• Familial AT-III deficiency• Ongoing heparin therapy• Extreme thrombocytosis ( >7,00,00/mm³)• Septicaemia
Adverse effect of heparin Bleeding Deep vein thrombosis Heparin indused hyperkalaemia Heparin indused thrombocytopenia : it develops 7 to 14 days after initiation of heparin, but may develop within 1 or 2 day in pt with previous exposure to heparin. It is likely to be immune mediated (antibody formed against PF 4/ heparin complex)
Diagnosis of HIT Chong has suggested criteria for diagnosis of HIT1. Thrombocytopenia during heparin therapy2. Absence of other cause of thrombocytopenia3. Resolution of thrombocytopenia, after discontinuation of heparin4. Confirmation of heparin dependent antibody by in vitro testing
Management of HIT Discontinuation of heparin for 4 to 8 wk Changing tissue source of heparin LMWH can be used Plasmapheresis Use of heparin substitutes Supplementing heparin administration with pharmacological platelet inhibitor using prostacyclin, aspirin, dipyridamol have been repoted with favorable outcome.
Alternatives to heparin Low molecular weight heparin(LMWH) : Less capable of inhibiting thrombin, but potent inhibitors of factor Xa. Inhibition of factor Xa prevents thrombos formation without impairing haemostasis. Thus prophylaxis against deep vein thrombosis can occur with lower incidence of bleeding complication.
Alternatives to heparin Dematan sulfate : It accelerates the inhibtion of thrombosis by heparin cofactor II. Hirudin : isolated from medicinal leeches & inhibits thrombin without requring AT III. Used in pt with HIT Defibrinogenating agents Ancrod : It lyses fibrinogen thus preventing formation of fibrin polymers. Streptokinase and Urokinase : these thrombolytic agents are capable of producing defibrinogenation, increased plasmin formation can lead to hyperfibrinolysis.
Heparin coated surfaces Binding of heparin to the internal surface of CPB circuit, the need for systemic heparinisation during CPB may be reduced. The use of heparin coated circuit in combination with full systemic heparinisation has been shown to better then uncoated circuit in terms of platelet preservation and postoperative bleeding.
Hemostasis Hemostasis is the body’s response to vascular injury. The three major components of hemostasis include Vascular endothelium Platelets, which determine primary hemostasis, and The coagulation cascade glycoproteins, which determine secondary hemostasis.
Protamine Protamine has been mainstay of heparin neutralization for more then 3 decades. It is derived from the sperms of salmon fish A polycationic protein Bind with heparin to produce stable precipitate which has no anticoagulant property. It has mild anticoagulant effect independent of heparin.
Dosage At the end of CPB, the remaining heparin in circulation should be neutralized in order to restore normal coagulation. 1 to 1.3 mg of protamine is administered for each 100 units of heparin. The amount of heparin neutralized is taken as the total dose of heparin administered during CPB or initial dose of heparin. Simple & no need of ACT measurment. Disadvantage - excessive or under neutralization of heparin.
Bull et al suggest calculations of protamine dose, based on heparin dose response curve. The ACT measured at the end of CPB is utilized to calculate the amount of residual heparin on the basis of DRC. The calculated amount of heparin is neutralized by protamine 1.3 mg/100 units of heparin. Advantage Accurate dose calculation Redused dose of protamine Possibly decreased infusion of blood,FFP & platelets. Disadvantage – ACT affected by many factors and has no correlation with heparin levels.
Protamine titration test has also been utilized for the purpose of calculating protamine doses. Decreased protamine doses are likely to be required as compared to ACT/dose response curve. In clinical practice : administer protamine in the ratio of 1:3 mg for each 100 units of heparin. Following this, ACT is measured & if found to be more then baseline, additional bolus dose
Protamine reaction Haemodynamic compromise following protamine administration during cardiac surgery is well known & documented. Characterised by Increase in PA & CVP Decrease in left atrial & systemic arterial pressure. Possible causes are Pharmacologial histamin release Anaphylactoid reaction True anaphylaxis mediated by specific antiprotamine Ig.
Protamine should not administered faster then 5 mg/min. Or average dose not >200mg in 40 min. Most anaesthesiologists prefer to give a bolus of 25 to 50mg & then carefully observe haemodynamics for short period of time. If no change is observed, another bolus is administered. The site of administration should be left side of circulation (LA,aorta) or peripheral vein with subsequent dilution.
Other agents Platelet factor 4 : neutralized heparin’s inhibition of factor Xa & thrombin. Recombinant PF4 has effectively neutralise heparin effect & useful alternative to protanime. Aprotinin : serine protease & kallikrein inhibitor with ability to preserve platelet function & inhibit fibrinolysis.
Other agents Desmopressin acetate : releases coagulation system mediators from vascular endothelium ( eg factor VIII,factor XII,prostacyclin & t-PA). Dose of 0.3 µg/kg by IV, IM or subcutaneous route. Epsillon aninocapnoic acid & tranexamic acid: these are antifibrinolytic agent. EACA is used to treat excessive bleeding after CPB. TA has also show reduced chest drainage & blood transfusion requirment.
Evaluation of coagulation abnormalities Test for coagulation Test for platlet mechanisms function Platelet count whole blood clotting Bleeding time time Platelet aggregation ACT & adhesion Protamine titration Test for test fibrinolysis PT Fibrinogen & fibrin APPT degradation product Thromboelastograp h
Thromboelastograph TEG provides a measure of global coagulation function & measures the haemostatic process in the whole blood from the start of clotting to clot lysis. Improve the management of bleeding & transfusion of blood products in postoperative period by doing TEG either during CPB or 10 & 60 min. after protamine administration. TEG based coagulation monitoring effective in Reducing re-exploration rate Diagnosis of fibrinolysis
Thromboelastograph Parameter measured by TEG include Reaction time (R valve) : time for initial fibrin formation, normal value 6-8 min Coagulation time ( K value): measure speed of clot formation, normal value 3-6min α angle: measure speed of clot formation, normal range 45 to 55 degrees. Maximal amplitude (MA): (50-60mm) index of clot strength determined by platelets function, cross linkage of fibrin, Amplitude 60 min. after MA (A60) Clot lyses indices at 30 & 60 min. after MA (LY30 & LY60)
Reference Kaplan’s cardiac anaesthesia 5th edition Clinical practice of cardiac anaesthesia- Deepak k. Tempe Management of coagulation during cardiopulmonary bypass -Continuing Education in Anaesthesia, Critical Care & Pain Volume 7 Number 6 2007 Monitoring anticoagulation and hemostasis in cardiac surgery- Anesthesiology Clin N Am21 (2003) 511 – 526