1. General Review of Hemostasis Fibrinolysis and Thrombosis 高志平台北榮總血液腫瘤科

3. Von Willebrand Disease v vWF:  enhance production of FVIII protect FVIII  binding platelet (GPIb/IX) and collagen in subendothelium v vWD  FVIII: low, prolonged aPTT  BT: prolonged  RIPA, ristocetin cofactor  Mild bleeding tendency Blood, Hadin et al, eds, 2003

4. Hematology, Hoffman et al, eds,2005

5. Laboratory Assays for vWD v Diagnosis  vWF Ag  vWF activity: ristocetin cofactor  FVIII activity (moderate and severe vWD)  BT (moderate and severe vWD)  aPTT: too insensitive  Molecular diagnosis: type II, exon 28 v Classification  RIPA  vWF multimers

6. Management of vWD v Reassurance v Cryoprecipitate v DDAVP v FVIII v vWF product

7. Extrinsic pathway Prothrombin time: adding tissue factor, Ca ++

8. aPTT: activated partial thromboplastin time Partial thromboplastin: phospholipid, Ca ++, lacking tissue factor

9. TFPI: tissue factor pathway inhibitor Hemostasis and Thrombosis 2005

10. Coagulation v Tissue factor initiate blood coagulation  TF express in adventitial cells, vascular smooth muscle cells, epidermal cells, neuroglia  TF express in monocytes and endothelium after activation v Amplification of the initial stimulus  FVIIa activate FIX  FIIa (thrombin) can activate XI, V, VIII v Feedback inhibition of the procoagulant system  TFPI: tissue factor pathway inhibitor  AT, PC, PS, EPCR

11. Thrombin can activate v Fibrinogen v FXI v FV v FVIII v FXIII v Protein C (after binding thrombomodulin) v TAFI (thrombin-activatable fibrinolysis inhibitor)

12. Factors synthesized in endothelial cells v vWF v Thrombomodulin v EPCR (endothelial protein C receptor) v Protein S v TFPI v tPA v PAI-1 v PGI2 (prostacyclin), NO (EDRF), CD39, ET-1

13. Common Causes of Prolonged PT v Deficiencies of FVII, X, V, II, fibrinogen v Elevated FDP v Heparin of high conc. v Coumadin v Lupus anticoagulant occasionally v Inhibitors of clotting factors

14. Vitamin K-dependent coagulation factors and anticoagulants v Factors II, VII, IX, X v Protein C, S v Protein Z (anti-Xa v (Not AT, Not TFPI, Not TAFI)

15. Hematology, Hoffman et al, eds,2005

16. Superwarfarin v Long-acting v Need high dose vitamin K v Potentially lethal

17. Common Causes of Prolonged aPTT v Clotting factor deficiencies other than FVII v Lupus anticoagulant v Inhibitors of clotting factors v Elevated FDP v Heparin, coumadin

20. Interpretation of Mixed aPTT v Definition of “correctable”: mixed aPTT – C : < 3-5” v Inhibitior with time-dependence after incubation

21. Mixinf aPTT v P: 60.5 C: 28.5 Mixed: 31.0 (o hr) v P: 64.5 C: 32.5 Mixed: 34.0 (2 hr) v P: 60.5 C: 28.5 Mixed: 56.0 (o hr) v P: 64.5 C: 32.5 Mixed: 60.0 (2 hr) v P: 60.5 C: 28.5 Mixed: 31.0 (o hr) v P: 64.5 C: 32.5 Mixed: 63.0 (2 hr)

22. FVIII inhibitor v P: 60.5 C: 28.5 Mixed: 34.0(o hr) v P: 64.5 C: 32.5 Mixed: 60.0 (2 hr) v PNT : negative v FVIII inhibitor assay: 5 Bethesda unit v FVIII5 % v FIX90 % v FVII110 %

26. Lupus anticoagulant v P: 60.5 C: 28.5 Mixed: 54.0(o hr) v P: 64.5 C: 32.5 Mixed: 60.0 (2 hr) v PNT : + v FVIII inhibitor assay: negative v FVIII90 % v FIX90 % v FVII110 %

27. Antiphospholipid syndrome v Anticardiolipin antibodies v Lupus anticoagulant  Antigen specificity: majority  2-GPI, prothrombin  Protein cofactor  Syphilis: not dependent on protein cofactor v Mechanisms of thrombosis  Disruption of annexin A5 shield  Interference protein C pathway  Injury to endothelium  …………. ?

28. Blood 1999;93:2153

31. Hematology Hoffman et al, eds, 2005

32. Causes of bleeding in APS v Hypoprothrombinemia v Severe thrombocytopenia v Acquired platelet dysfunction v Acquired inhibitor to specific coagulation factor, e.g. anti-FVIII

33. Lupus anticoagulant with low levels of cogaulation factor activity v P: 60.5 C: 28.5 Mixed: 56.0(o hr) v P: 64.5 C: 32.5 Mixed: 60.0 (2 hr) v PNT: negative v FVIII inhibitor : negative v FVIII10 % v FIX16 % v FVII50 %

34. Lupus anticoagulant with low level of cogaulation factor activity v P: 60.5 C: 28.5 Mixed: 56.0(o hr) v P: 64.5 C: 32.5 Mixed: 60.0 (2 hr) v PNT: negative v FVIII inhibitor : negative v FVIII4 % v FIX60% v FVII80 %

35. FVIII activities in serial dilutions v 1:103.5% v 1:407.6%(1.9% x 4) v 1:80 17.6%(2.2% x 8) v 1:160 48% (3.0% x 16)

36. Therapy v No therapy for laboratory abnormality with clinical disorder v Anticoagulation for recurrent thrombosis v Low dose ASA and heparin for > = 3X pregnancy losses v Steroid for refractory cases

37. Thrombosis and Antithrombotic Therapy

38. Blood, Handin et al, eds, 2003

39. TTP v Thrombotic Thrombocytopenic Purpura v Mealloprotease (ADAMTS 13)  ultralarge multimers of vWF  platelet thrombi

40. TTP v Pentad:  thrombocytopenia  microangiopathic hemolytic anemia  fever  renal failure  fluctuating neurological symptoms v Management  Plasma exchange  Immunomodulation

41. NEJM 2002;347:596

42. Postgraduate Hematology 2005

43. Blood, Handin et al, eds, 2003

44. Serine protease v Canonical catalytic triad  His 57, Asp 102, Ser 195 by chymotrypsin number v FII, VII, IX, X, XI (NOT FV, FVIII, FXIII, fibrinogen, vWF) v Protein C (NOT protein S, AT) v Plaminogen, tPA (NOT PAI-I, TAFI)

45. Serpins v Serine protease inhibitor v Antithrombin v PAI-1, PAI-2 v PCI v Heparin cofactor II v  2-antiplasmin

47. FV Leiden and FV HongKong v FV Leiden: Arg506Gln APC resistance: APC sensitivity ratio v FV HongKong: Arg306Gla no increased risk of venous thrombosis v FV Cambridge: Arg306Thr

48. Hemostasis and Thrombosis, 5 th ed, 2006

49. Postgraduate Hematology 2005

51. Diagnosis of DVT/PE v D-dimer v Venogram: less used v Doppler, compression ultrasonography v Spiral CT scan v Radionucleotide lung scan v MRI

53. Management of DVT v Underlying etiologies (provoked or unprovoked) v Screening for thrombophilia genetics v Heparin/LMWH v Coumadin  Contraindication in pregnancy  Delayed effect  Variation in dosage v Thrombolytic agents?

54. Hemostasis and Thrombosis, 5 th ed, 2006

55. Postgraduate Hematology 2005

56. Hematology Hoffman et al, eds, 2005

58. Postgraduate Hematology 2005

59. Management of Coumarin Overdose v Risk of bleeding vs risk of thrombosis v INR < 6 lower dose v INR 6-10vit K 1-2 mg, PO or SQ v INR > 10vit K 2-4 mg, PO or SQ v Serious bleedingvit K 5-10 mg IV FFPPCC Williams Hematology 7th ed, 2006

60. Fibrinolysis v Lysine binding sites in tPA and PLG (plasminogen)  Cofactor activity of fibrin v tPA vs uPA: need of fibrin v uPAR v Glu-PLG  Lys-PLG v Antifibrinolytic agents: blocking LBS in PLG v Antiplasmin synthesized in liver

61. Blood, Handin et al, eds, 2003

62. TAFI v Thrombin-activatable fibrinolysis inhibitor Procarboxypeptidase B v Removing the carboxy-terminal lysine residue of fibrin, which are the binding sites for PLG and tPA v Reducing cofactor activity of fibrin in PLG activation

63. Blood, Handin et al, eds, 2003