This document discusses anticoagulation and hemostasis during cardiopulmonary bypass. It covers normal coagulation pathways, the use of heparin for anticoagulation during bypass, and protamine for reversing the effects of heparin afterwards. Complications from heparin like heparin-induced thrombocytopenia and alternatives to heparin and protamine are also reviewed. Maintaining the delicate balance of anticoagulation during bypass and restoring hemostasis afterwards is an important consideration in cardiac surgery.

1. ANTICOAGULATION AND
HAEMOSTASIS DURING
CARDIOPULMONARY
BYPASS
Dr. Basant Dindor
Moderator - Dr. S.P.
Meena

2. 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.

3.  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.

4. 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

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. Heparin
 Glucosaminoglycan
(polysaccharide)
 Found most
commonly in mast
cells
 Strongest
macromolecular acid
in the body

12. 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

13. Sources of Heparin
 First isolated from liver extract (hepatic)
 Porcine intestinal mucosa
 Bovine lung

14. 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)

15. 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

16. 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

17. 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.

18. 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.

19. 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.

20.  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

21. Automated Automated
Hemochron Hemotec

22. 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

23. Current practice
 Gravlee et al have selected following CPB heparin
management protocol
1. Administer heparine 300 units/kg IV
2. 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.

24. 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.

25. 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.

26. 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

27. 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)

28. 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

29. 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.

30. 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.

31. 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.

32. 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.

33. 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.

34. 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.

35. 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.

36.  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.

37. Heparin dose response curve

38.  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

39. 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.

40.  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.

41. 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.

42. 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.

43. 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

44. 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

45. 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)

46. Thromboelastograph

47. Thromboelastograph

48. 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