ANTICOAGULATION AND HAEMOSTASIS DURING CARDIOPULMONARY BYPASS

Dr. Basant DindorModerator - 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 units100 units = 1 mg1 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 Lower molecular weight More cross linked structure Longer lasting Higher content of binding

sites for ATIII Higher doses needed for

CPB 25-30% less protamine

needed Higher incidence of delayed

hemorrhage Lower incidence of Heparin

indused thrombocytopenia

Bovine Higher molecular weight Less cross linking Shorter Lower content of ATIII

binding sites Lower doses needed May need more

protamine to neutralize Lower incidence of

heparin rebound Bovine spongiform

encephalopathy transmission (mad cow disease)

Heparin

Half life of heparin is dose dependent.

And Highly variable between patients

Dose Half life

Minutes

400 u/kg 126 +- 24

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 Hemotec

Blood required

2ml 0.4 ml

Activator Celite Kaolin

Automated Hemochron Automated Hemotec

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 protocol

1. 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 heparin

5. 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 HIT

1. Thrombocytopenia during heparin therapy

2. Absence of other cause of thrombocytopenia

3. Resolution of thrombocytopenia, after discontinuation of heparin

4. 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.

Heparin dose response curve

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 25 to 50 mg is given.

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.

Pt with know food allergy to fish avoid protamine.

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

whole blood clotting time

ACT Protamine

titration test PT APPT

Platelet count Bleeding time Platelet aggregation

& adhesion Test for

fibrinolysis Fibrinogen & fibrin

degradation product Thromboelastograph

Test for coagulation mechanisms

Test for platlet function

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)

Thromboelastograph

Thromboelastograph

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