Coagulation and Hemostasis

1. Coagulation and Hemostasis Joy Loy, M.D. MetroHealth Medical Center December 2006

2. Hemostatic process • Coagulation cascade • Fibrinolysis • Laboratory studies • Medications • Coagulation disorders

3. HemostasisPurpose • Ensure that coagulation mechanisms are • activated when there is injury • not unnecessarily activated • Restore tissue blood flow after repair of injury (fibrinolysis)

4. Hemostatic Process 3 main steps • Primary hemostasis: local vasoconstriction & platelet plug formation • Coagulation cascade • Fibrinolysis

5. Hemostatic ProcessPlatelet Plug Formation • vascular injury • release and binding of vWF to exposed blood vessel collagen • glycoprotein IB on platelet surface membrane binds to vWF • TxA2 → vasoconstriction & platelet adhesion • platelet factor 3 (PF3) phospholipid layer (procoagulant)

6. Platelet Activation & Aggregation exposed endothelial surface platelets exposed to collagen “activated” release contents of cytoplasmic granules adenosine diphosphate (ADP) thromboxane (Tx A2) accelerates platelet vasoconstriction aggregation/activation ↑ ADP release from platelets

7. Hemostatic ProcessCoagulation Cascade • to stabilize and reinforce the weak platelet plug • fibrinogen → fibrin • 3 main steps: • formation of prothrombin activator • conversion of prothrombin into thrombin • conversion of fibrinogen to fibrin

8. Coagulation Cascade TF =tissue factor PK = prekallikrein HK=high molecular kininogen a = activated Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

9. Coagulation Mechanism • activation of clotting factors • requires a phospholipid surface • tissue factor (TF) extrinsic to the blood • activated platelet (platelet factor 3 phospholipid) intrinsic to blood • vitamin-K dependent factors (II, VII, IX, X) • formation of reaction complex • labile factors : factors V and VIII

10. Factor VIII • extrahepatic origin • 2 components (separate genetic control) • VIII R : Ag VIII antigen + vWF • VIII : C coagulant activity *absence →hemophilia A • von Willebrand factor (vWF) •mediates adhesion of platelets to surface collagen • carrier of VIII:C • vWD: appears to have defect in primary hemostasis & hemophilia A

11. Factor VIII

12. Coagulation Cascade TF =tissue factor PK = prekallikrein HK=high molecular kininogen a = activated Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

13. Newer Concepts of Coagulation Reactions 2 main functions of tissue factor (TF) 1) to activate factor X to Xa 2) to activate factor IX to IXa

15. Control Mechanisms APC: activated protein C AT : antithrombin GAG: glycoaminoglycans T : thrombin PC : protein C S : protein S TF : tissue factor TM : thrombomodulin 1) TF pathway inhibitor 2) Protein C system 3) Antithrombin (e.g. AT III) 4) Glycoaminoglycans

16. Antithrombin III (AT III) • naturally-occuring anticoagulant • binds to factors IXa, Xa, XIa, XIIa (slow) • accelerated by heparin manyfold Implication: Heparin has almost NO anticoagulant action without AT III

17. Coagulation Factors Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

18. Fibrinolysis • Plasminogen →plasmin • Release of tPA by the endothelium • Lysis of clot→ FDPs or FSPs • Reopening of blood vessel

19. Laboratory MonitoringProthrombin Time (PT) • test of extrinsic pathway activity • measures vitamin K - dependent factors activity (factors II, VII, IX, X) • thromboplastin + Ca+2 to plasma = clotting time • normal values: 12-14 seconds • International Normalized Ratio (INR) ▪ standardizes PT reporting • normal values: 0.8 -1.2 seconds

20. Laboratory MonitoringProthrombin Time (PT) • monitors coumadin therapy • most sensitive to alteration in F VII levels • prolonged: 55 % ↓ of normal F VII activity • antithrombotic activity: reduction of factor II and factor X activity (after several days)

21. Laboratory MonitoringActivated Partial Prothrombin Time (aPTT) • test for intrinsic and common pathways • dependent on activity of all coagulation factors, except VII and XIII • normal values: 25 -35 seconds • monitors heparin tx & screen for hemophilia

22. Laboratory MonitoringActivated Prothrombin Time (aPTT) • prolonged: heparin, thrombin inhibitors, fibrin degradation products (FDP) • citrated plasma + surface activators + phospholipid • prolonged only if coagulation factors reduced to < 30 % of normal

23. Laboratory MonitoringActivated Clotting Time (ACT) • monitors heparin anticoagulation in the OR (cardiac and vascular surgeries) • normal values: 90 - 120 seconds

24. Laboratory MonitoringThrombin Clotting Time (TCT) • reflects abnormalities in fibrinogen → fibrin • plasma + excessive amount of thrombin • prolonged: heparin, thrombin inhibitors, low fibrinogen, dysfibrinogenemia • monitors hirudin, bivalirudin, LMWH tx • INR & PT may be normal or ↑ • TCT prolonged with adequate therapeutic levels

25. Laboratory MonitoringThromboelastography (TEG) • continuous profiles during all phases of clot formation • provides more accurate picture of in vivo coagulation process • to evaluate: • hypo / hypercoagulable state • hemophilia • dilutional coagulopathy • rare coagulation disorders anticoagulation tx • coagulation problems with liver transplantation

26. Thromboelastogram (TEG)

27. Bleeding time • monitors platelet function • not specific indicator of platelet function • not very reliable • very operator - dependent • variable from each institution

28. Bleeding time • other factors: degree of venostasis, depth and direction of incision • no evidence as • a predictor of risk of hemorrhage • useful indicator of efficacy of antiplatelet therapy • insensitive to mild platelet defects

29. Laboratory MonitoringPlatelet Function Analyzer (PFA) - 100 • relatively new global test of platelet adhesion and aggregation • advantages • noninvasive, simple, easy to perform • very sensitive in detecting platelet defects associated with vWD • sensitive to dx of acquired platelet defects (ASA, NSAID, dietary factors: excessive cocoa intake) • monitors pro-hemostatic treatment • DDAVP & platelet transfusions

30. Laboratory MonitoringPFA-100 Limitations ■ inflexibility ■ results should be interpreted in the context of either a simultaneously or recently drawn full blood count ■ platelet count < 80,000 or Hct < 30% will prolonged CT even if no platelet abnormal

32. Implications for Therapy • Congenital & acquired factor deficiencies • history • medications • congenital factors: vWD, hemophilia, platelet disorders • acquired disorders: multifactor-renal, hepatic, DIC • Antiplatelet medications • Anticoagulants

33. Drugs affecting Coagulation

34. Prostaglandin Synthesis arachidonic acid cyclooxygenase prostaglandin G2 peroxidase prostaglandin H2 prostacyclinthromboxane synthetase synthetase prostacyclin thromboxane A2 PG F1a thromboxane B2

35. Mechanism of ActionASPIRIN arachidonic acidASPIRIN cyclooxygenase prostaglandin G2 peroxidase prostaglandin H2 prostacyclinthromboxane synthetase synthetase prostacyclin thromboxane A2 PG F1a thromboxane B2

36. Mechanism of ActionASPIRIN and NSAIDS arachidonic acidASPIRIN cyclooxygenase prostaglandin G2NSAIDS peroxidase prostaglandin H2 prostacyclinthromboxane synthetase synthetase prostacyclin thromboxane A2 PG F1a thromboxane B2

37. Antiplatelet Medications Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

38. Non-steroidal Anti-inflammatory Medications Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

39. Anticoagulants & Thrombolytics Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

40. Other Anticoagulants Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

41. Oral AnticoagulantsWarfarin • inhibits synthesis of vitamin - k dependent factors II, VII, IX, X and protein C & S • reversal: • stopping medication and waiting for ~4 days for PT normalization • vitamin K PO or IV (1-2mg) • immediate: rFVIIa, FFP (1-2 units), prothrombin complex concentrate • check PT prior to surgery

42. Oral AnticoagulantsWarfarin • biphasic effect on PT and INR • initial ↑: ↓F VII (shortest t ½) to 55 % of normal • subsequent ↑: ↓ F II and X – therapeutic anticoagulant • discontinuation • return to normal: F VII followed by F II & X • caution: INR =/< 1.4 no assurance of normal coagulation

43. Unfractionated Heparin • negatively charged, water - soluble glycosaminoglycan • extracted from porcine gut or bovine lung • binds and ↑ anti - thrombin III (AT III) activity to 1,000 fold →binds & inactivates factors IIa and factor Xa • degree of inhibition: F Xa = IIa * LMWH inhibition of Xa > IIa • lesser inhibition on F XIa, XIa and F XIIa

44. Unfractionated HeparinLow-dose or “minidose” • 5,000 U SC q 12 hrs for thromboprophylaxis • peak action: 40 - 50 minutes • duration 4 - 6 hrs • low risk for hemorrhage during anesthesia or surgery • 4 reported cases of SEH with CNB

45. Unfractionated HeparinStandard Dose • regular doses for therapeutic anticoagulation • high risk of bleeding during & after surgery • stop at least 6 hrs before surgery • restarted ~ 12 hrs postop if needed with close monitoring • immediate reversal: protamine

46. Low Molecular Weight Heparin (LMWH) • 4,000-6,500 daltons (vs. standard heparin 3,000 -30,000 daltons • retains anti-Xa activity • less anti -IIa than standard heparin • enhances AT-III interaction with F IIa & F Xa • degree of inhibition: F Xa > IIa

47. LMWH in the U.S.

48. Standard Heparin vs. LMWH

49. Standard Heparin vs. LMWH

50. Recombinant Factor VIIa(NovoSeven) • FDA approved for use in hemophilia & patients with inhibitors • enhances the TF pathway • binds loosely to platelets and directly activates F X →↑thrombin generation with F Va present • never completely normalizes thrombin generation but enhances hemostasis • dose: 90-120 mcg/kg q 2 hrs x 1st 24 hrs