血栓好發症 thrombophilia

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內內內內內內 內內內 Dec 29, 2008

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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. - PowerPoint PPT Presentation

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Page 1: 血栓好發症  Thrombophilia

內科部血液科林建廷Dec 29, 2008

Page 2: 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, 11th edition, 2004Clinical Chemistry 47:9 1597~1606, 2001

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Anticoagulant

Fibrinolytic factor

Coagulation factor

Fibrinolytic inhibitor

Platelet

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抗凝血因子與凝血因子的平衡

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血栓

Anticoagulant

Fibrinolytic factor

Coagulation factor

Fibrinolytic inhibitor

Platelet

4

抗凝血因子與凝血因子的平衡被打破

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Initiation

Propagation

Thrombin generation

Termination

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Wells Score of DVT

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新診斷 (<6m) 或正在治療中的癌症 1 分下肢無力、癱瘓或無法移動 1 分近日絕對臥床超過 3 天或 1 個月內接受過重大手術 1 分深部靜脈處出現局部壓痛 1 分腿部腫脹 1 分在脛骨棘下 10 公分處測量小腿圍長,患側比對側大超過 3 公分 1 分凹陷性水腫 ( 患側較嚴重 ) 1 分出現側枝循環靜脈 ( 須排除靜脈曲張 ) 1 分可用其他非血栓疾病來解釋病人的症狀 -2 分

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%)

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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

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Duplex Echo

方便 , 非侵入性 靈敏 對骨盆內的血栓敏感度較低

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Impedance Plethysmography

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Contrast venography

黃金標準 侵入性 可能會痛 , ~10%病人無法完成檢查

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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)

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Page 14: 血栓好發症  Thrombophilia

Etiology of DVT

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後天性 先天性年老避孕藥懷孕手術後腎病症候群癌症 ( 尤其腸胃道癌症 )慢性骨髓增生性疾病抗磷脂質症候群

Protein S deficiencyProtein C deficiencyAntithrombin III deficiencyPlasminogen deficiencyDysfibrinogenemiaHomocysteinemiaFactor V Leiden mutation (APC resistance)Prothrombin G20210A mutation

Page 15: 血栓好發症  Thrombophilia

Prevalence in Western & Taiwan

Area No Proportion (%)AT PC PS

香港 52 9.6 17.4 19.2台灣 ,1997 85 3.5 18.8 32.9台灣 ,2000 116 5.2 17.2 33.6

APC-RPT G20210A

Thromb Res 2000; 99, 447~452 Vacular Medicine 2003; 8:33-46

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Unclear

西方國家 東方國家

•No factor V Leiden mutation (APC resistance)No factor V Leiden mutation (APC resistance)•No prothrombin G20210A mutation No prothrombin G20210A mutation

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Inherited Factors of VTE

AT-III deficiency Factor VIII 與血型的關係Blood O Blood A

vWF:Ag 65.4 % 96.7%

F VIII 105.6 % 136.2 %

Blood B Blood ABvWF:Ag 102.5 % 119.1 %

F VIII 149.2 % 219.2 %

Arterioscler Thromb Vasc Biol 2001;21:731-8

AT III

PC

PS

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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

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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

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Evaluation of Congenital VTE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

Clinical Chemistry 47:9 1597~1606, 2001 Vascular Medicine 2003; 8:33-46 19

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Evaluation of 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)

?20

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Targets of anticoagulants

Xa

IIa

TF/VIIa

X IX

IXaVIIIaVa

II

FibrinFibrinogenAdapted from Weitz & Bates, J Thromb Haemost 2005

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Targets of anticoagulants

ORAL PARENTERAL

Xa

IIa

TF/VIIa

X IX

IXaVIIIaVa

II

FibrinFibrinogenAdapted from Weitz & Bates, J Thromb Haemost 2005

Warfarin

HeparinLMWH

Pentasaccharide

XimelagatranDabigatran

LepirudinBivalirudinArgatroban

AT

AT

AT

RivaroxabanApixaban

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Heparin and LMWH

Xa: IIa inhibition ratio= 1:1

Xa: IIa inhibition ratio= 2-4:124

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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25

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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

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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)

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Rivaroxaban

口服 Direct Xa inhibitor

Roehrig et al., J Med Chem 2005; Perzborn et al., J Thromb Haemost 2005

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Targets of anticoagulants

ORAL PARENTERAL

Xa

IIa

TF/VIIa

X IX

IXaVIIIaVa

II

FibrinFibrinogenAdapted from Weitz & Bates, J Thromb Haemost 2005

Warfarin

HeparinLMWH

Pentasaccharide

XimelagatranDabigatran

LepirudinBivalirudinArgatroban

AT

AT

AT

RivaroxabanApixaban

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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

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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

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Vit K dependent Factor Depletion with Warfarin Initiation

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33Lancet 2005; 365: 1163–74

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Conventional Dosage of Warfarin in VTE

Indications INR•Tx of VTE•Prevention of systemic embolism

- Atrial fibrillation - VHD- Tissue heart valve

2 – 3

•Prosthetic mechanical valve 2.5 – 3.534

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Duration of Warfarin in VTE

Condition DurationSituational DVTFirst idiopathic DVTPERecurrent idiopathic DVTDVT with ongoing risk factorsMassive PE

6 week -- 3 m≧6 m≧6 m≧12 mlong-termlong-term

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Warfarin overdose 的處理

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INR < 6 INR 6-10 INR > 10

No or Minor bleeding

停藥 1~3 日 停藥 2~3 日,Vit K 1-2mg

停藥 2~4 日,Vit K 3~5mg

Major bleeding

Vit K 10mg ,必要時每 12小時重複FFP 4-5U or PCC

同左 同左

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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

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Targets of anticoagulants

ORAL PARENTERAL

Xa

IIa

TF/VIIa

X IX

IXaVIIIaVa

II

FibrinFibrinogenAdapted from Weitz & Bates, J Thromb Haemost 2005

Warfarin

HeparinLMWH

Pentasaccharide

XimelagatranDabigatran

LepirudinBivalirudinArgatroban

AT

AT

AT

RivaroxabanApixaban

Page 39: 血栓好發症  Thrombophilia

Direct Thrombin Inhibitor (DTI)Drug Profile Lepirudin Argatroban Bivalirudin

Derivate Recombinant Hirudin

L-arginine derivative

Semisynthetic Hirudin-based peptide

DTI effect Irreversible Reversible ReversibleRoute iv or sc iv iv or scHalf-life 1.5 hr 40 min 25 minMonitor aPTT aPTT aPTT or ACTHeparin cross-rxn None None NoneApproved for HIT Yes, 1998 Yes, 2000 Unknown, primary

used during PCIClearance Kidney Liver (Ccr not

affected)Kidney

Antidote No, may try VIIa, DDAVP

No No

Wintrobe’s Clinical Hematology, 2004, p1735

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Oral Direct Thrombin Inhibitor (DTI)--

Ximelagatran Fixed dosing No monitor needed Wide safe dosing range

Unacceptable hepatotoxicity

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NNNNHHOOOO NN

HHOONHNH22

OOCH3 -CH2

NN OHOH

Ximelagatran

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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 LMWH41