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血栓好發症 Thrombophilia

內科部血液科 林建廷 Dec 29, 2008. 血栓好發症 Thrombophilia. 血栓好發症 Thrombophilia. 易血栓狀態 靜脈血栓、動脈血栓，但多數情形下以靜脈血栓為主 DVT (Deep vein thrombosis) PE (Pulmonary embolism) PVT (Portal vein thrombosis). Wintrobe’s Clinical Hematology, 11 th edition, 2004. Clinical Chemistry 47:9 1597~1606, 2001.

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血栓好發症 Thrombophilia

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  1. 內科部血液科 林建廷 Dec 29, 2008 血栓好發症 Thrombophilia

  2. 血栓好發症 Thrombophilia • 易血栓狀態 • 靜脈血栓、動脈血栓，但多數情形下以靜脈血栓為主 • DVT (Deep vein thrombosis) • PE (Pulmonary embolism) • PVT (Portal vein thrombosis) Wintrobe’s Clinical Hematology, 11th edition, 2004 Clinical Chemistry 47:9 1597~1606, 2001

  3. 抗凝血因子與凝血因子的平衡 Platelet Fibrinolytic factor Fibrinolytic inhibitor Anticoagulant Coagulation factor

  4. 抗凝血因子與凝血因子的平衡被打破 Fibrinolytic factor Platelet Fibrinolytic inhibitor Anticoagulant Coagulation factor 血栓

  5. Initiation Propagation Thrombin generation Termination

  6. Deep Vein Thrombosis

  7. Wells Score of DVT 總分 ≦0: 低風險 (下肢深部靜脈血栓可能性 3%) 總分1~2: 中等風險(下肢深部靜脈血栓可能性 17%)總分 ≧3: 高風險(下肢深部靜脈血栓可能性 75%)

  8. Exam of DVT • 下肢深部靜脈栓塞： • Duplex echo（含括B-mode和color-flow Doppler） • Impedance plethysmography • 核醫Isotope venography • MRI • Contrast venography • 肺動脈栓塞： • CXR/ Spiral CT • Perfusion/ Ventilation scan

  9. Duplex Echo • 方便, 非侵入性 • 靈敏 • 對骨盆內的血栓敏感度較低

  10. Impedance Plethysmography

  11. Contrast venography • 黃金標準 • 侵入性 • 可能會痛, ~10%病人無法完成檢查

  12. D-dimer的意義? • Dimer是fibrin的分解產物, 敏感度比FDP高 • D-dimer (-): 可排除血栓疾病(can rule out) • D-dimer (+): 需做進一步確認(cannot rule in)

  13. Differential diagnosis of thrombophilia

  14. Etiology of DVT

  15. Prevalence in Western & Taiwan 西方國家 東方國家 Unclear APC-R PT G20210A • No factor V Leiden mutation (APC resistance) • No prothrombin G20210A mutation Vacular Medicine 2003; 8:33-46 Thromb Res 2000; 99, 447~452

  16. Inherited Factors of VTE • AT-III deficiency Factor VIII 與血型的關係 AT III PC PS Arterioscler Thromb Vasc Biol 2001;21:731-8

  17. 抗磷脂症候群Antiphospholipid syndrome(APS) • 動脈血栓、靜脈血栓 • 因胎盤血栓之習慣性流產 • 何時考慮APS? • 明明病人產生血栓, PTT卻明顯延長 • PTT mixing test : prolong PTT not corrected

  18. 抗磷脂症候群Antiphospholipid syndrome(APS) • Screening test: • Lupus anticoagulant (ex. PTT, dRVVT…) • Anti-cardiolipin antibody, IgG or IgM • Anti-ß2 glycoprotein I antibody, IgG or IgM • Confirmation test: • Platelet phospholipid neutralization test

  19. Evaluationof CongenitalVTE 誰應該接受篩檢? • Unusual sites • IVC • Renal vein • Portal vein or mesentery • Brain sinus • Recurrent VTE • Young age (< 45 y/o) • FHx • Unexplained recurrent feral loss (APS) • 好處有哪些? • Duration of therapy • Prognosis • Family screening Vascular Medicine 2003; 8:33-46 Clinical Chemistry 47:9 1597~1606, 2001

  20. Evaluationof Congenital VTE ? APC-R test • PLT • PT/ PTT • PS function • PC function • AT-III function • F VIII:c • Fibrinogen • Homocysteine • DRVVT, APA, ACA, lupus anti-coagulant • (Plasminogen function)

  21. Treatment of VTE

  22. Targets of anticoagulants TF/VIIa X IX IXa VIIIa Va Xa II IIa Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005

  23. Targets of anticoagulants ORAL PARENTERAL TF/VIIa X IX Pentasaccharide IXa VIIIa AT Va Rivaroxaban Apixaban Xa AT Heparin LMWH Warfarin II AT IIa Lepirudin Bivalirudin Argatroban Ximelagatran Dabigatran Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005

  24. Heparin and LMWH Xa: IIainhibition ratio= 1:1 Xa: IIa inhibition ratio= 2-4:1

  25. Heparin Disadvantage & Advantage • iv/ sc route • aPTT monitoring needed • “Heparin resistance”— 按經驗國人一日所需最大劑量很少超過35000 U • HITT(heparin-induced thrombocytopenia and thromobosis)is rare, but severe • Antidote：protamine sulfate • 停藥後大約6小時即可恢復正常凝血功能

  26. LMWH • More predictable pharmocokinetics • 可較專一性抑制factor Xa：IIa =2-4：1 • Low interaction • 依BW計算劑量, 老人, Ccr＜30 mL/min要減量 • 使用方便，不需抽血監測（若以PTT監測，PTT不會延長） • LMW heparin過量時，注射protamine僅能中和60% • HITT : • Infrequently • Still contraindicated

  27. Pentasaccharide--Fondaparinux • 人工合成, 專一性 indirect inhibit Xa • 不需以PTT作監測 • No antidote • No cross-rxn to Heparin (Tx for HITT is OK)

  28. Rivaroxaban • 口服 • Direct Xa inhibitor Roehrig et al., J Med Chem 2005; Perzborn et al., J Thromb Haemost 2005

  29. Targets of anticoagulants ORAL PARENTERAL TF/VIIa X IX Pentasaccharide IXa VIIIa AT Va Rivaroxaban Apixaban Xa AT Heparin LMWH Warfarin II AT IIa Lepirudin Bivalirudin Argatroban Ximelagatran Dabigatran Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005

  30. Warfarin • 不同個體差異很大 • Absorption: ~ 100% • 99.4% bind to albumin • Liver metabolism, CYP-450 dependent • 機轉: Vit-K dependent factors: • II (T1/2= 96 hrs) • VII (T1/2= 6 hrs) • IX, X • protein C (T1/2= 6 hrs) • protein S

  31. PC deficiency應特別小心 • 接受warfarin第一周，可能發生 warfarin-induced skin necrosis及加重DVT，須同時併用heparin或LMWH • 不給loading dose • 低劑量開始

  32. Vit K dependent Factor Depletion with Warfarin Initiation

  33. Lancet 2005; 365: 1163–74

  34. Conventional Dosage of Warfarin in VTE

  35. Duration of Warfarin in VTE

  36. Warfarin overdose的處理

  37. Mx of DVT • 彈性襪, 穿到膝部 • Post-thrombotic syndrome(PTS):~1/3病人患部仍有酸痛感，久站後易發生

  38. Targets of anticoagulants ORAL PARENTERAL TF/VIIa X IX Pentasaccharide IXa VIIIa AT Va Rivaroxaban Apixaban Xa AT Heparin LMWH Warfarin II AT IIa Lepirudin Bivalirudin Argatroban Ximelagatran Dabigatran Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005

  39. Direct Thrombin Inhibitor (DTI) Wintrobe’s Clinical Hematology, 2004, p1735

  40. OH N H O O N O NH2 H N O CH3 -CH2 N Oral Direct Thrombin Inhibitor (DTI)-- Ximelagatran • Fixed dosing • No monitor needed • Wide safe dosing range • Unacceptable hepatotoxicity Ximelagatran

  41. Oral Direct Thrombin Inhibitor (DTI)-- Dabigatran • Rapid onset of action • Once-daily dosing • Predictable activity • Monitoring is not required • For DVT prophylaxis—Efficacy is equivalent to LMWH • Hepatotoxicity is similar to LMWH

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