Thrombophilia Wanwaroon Pumchumpol

Thrombophilia Thrombosis : formation, from constituents of the blood, of an abnormal mass within the vascular system of a living animal Rudolph Virchow : Virchow triad 1859

Virchow triad Blood stasis Vessel wall Hypercoagulability Hereditary -age -obesity -pregnancy -paralysis -Rt side heart failure -venous compression -long haul flight -Vasculitis -Endothelial injury -intravascular catheter -trauma -surgery Hereditary Acquired

Coagulation pathway Intrinsic Extrinsic PK , HMWK Antithrombin V XII XIIa XI XIa IX IXa VIIa-Tissue factor VIII VIIIa X Xa -ve Va XIII -ve -ve Thrombin XIIIa Fibrin monomer Polymer Cross-linked fibrin polymer APC Plasminogen Plasmin Thrombomodulin -ve plasminogen activator inhibitor X,Y,D,E -ve FDP D-Dimer Antithrombin V Prothrombin Protein S Fibrinogen Protein C

Thrombophilia Hereditary Acquired Mixed or unknown -APC resistance due to Fc V Leiden mutation -Antithrombin def. -Protein C def. -Protein S def. -Prothrombin G20210A mutation -Dysfibrinogenemia -Ass. with physiologic/ thrombogenic stimuli pregnancy immobilization trauma postoperative state advancing age estrogen use prolonged air travel -Antiphospholipid syndrome -Malignancy -NS -HIT -TTP -PNH -Myeloproliferative disorders -Hyperhomocysteinemia -APC resistance : other -Elevated Fc VIII, XI, IX -Elevated TAFI

Clinical Venous system Arterial system -DVT -Stroke -PE ขาบวมปวด Homans sign -PE sudden dyspnea,chest pain,hypoxia,hemopthysis -Superficial thrombophlebitis ( Trousseau’s syndrome) proteinC, proteinS, CA metastasis -Cerebral vein thrombosis ปวดศีรษะรุนแรง,localizing sign,ชัก,papilledema,CN6palsy -Hepatic vein thrombosis (Budd Chiari Syndrome) ปวดท้อง ตับม้ามโต เหลือง N/V ascites ,varice -Portal vein thrombosis ม้ามโต esophageal varices bleed -Mesenteric vein thrombosis acute/subacute colicky pain ถ่ายเป็นเลือด peritonitis -SVC thrombosis หน้า คอ แขน บวม UAO เส้นเลือดโป่งที่คอ และหน้าอก -IVC thrombosis ปวดหลัง ขาบวม2ข้าง เส้นเลือดโป่งที่ท้องและหลัง -Stroke -Coronary artery thrombosis -Peripheral arterial insufficiency -Ocular involvement

Short note Hereditary : AD , age <45 , FH ,uncommon site of thrombpsis APC resistance due to Fc V Leiden mutation most common of hereditary G1961A Arg506Gln , AD Antithrombin deficiency antithrombin จับกับ active site ของ thrombin, AD, 1st thrombosis 10-25 ปี Protein C deficiency AD trait/acquire,1st thrombosis ก่อน 30 ปี, warfarin-induce skin necrosis Homozygote-purpura fulminans neonatalis ; nonthrombocytopenic purpura ไข้ ซีด เลือดออกตามผิวหนัง ความดันต่ำ Heterozygous : DVT, PE, thrombophlebitis

Protein S deficiency AD, 1st thrombosis 18-19 ปี , act as AT & protein C Prothrombin G20210A mutation prothrombin มี mutation G A at 20210 Dysfibrinogenemia AD, bleed/thrombosis , a/v thrombin จับกับ fibrin ที่ผิดปกติไม่ได้ thrombin เพิ่ม fibrin ที่ผิดปกติ ไม่สามารถกระตุ้น t-PA – plasmin จึงย่อยสลายลิ่มเลือดไม่ได้

Hyperhomocysteinemia AR : homocystein รบกวน cross-linking ของ collagen : ตา กระดูก หลอดเลือด lens หลุดง่าย, osteoporosis, arterial/venous thrombosis,ปัญญาอ่อน heterozygous : thrombosis Antiphospholipid syndrome Antiphospholipid Ab – lupus anticoagulant , anticardiolipin ,PTT ยาว clinical triad : arterial/venous thrombosis : recurrent abortion : thrombocytopenia mechanism : phospholipid membrane – platelet aggretion : phospholipid membrane – emdothelium- B2 glycoprotein : inhibit protein C/S acquire APC resistance

Malignancy blood stasis : นอนพักนาน, tumor กดทับ vessel, เลือดหนืด, สร้างหลอดเลือดผิดปกติ coag. : หลั่ง tissue factor และ cancer procoagulant(vitK): factorX กระตุ้น mononuclear cell ให้หลั่งสาร coagulant fibrinolysis : activity platelet : turnover เพิ่ม, survival time ลด, consumptive-low grade DIC nonbacterial thrombotic endocarditis : arterial emboli HIT/HATT (heparin-associated thrombocytopenia and thrombosis) type 1 : early onset 2-5 d type 2 : late onset >6d – more severe, arterial thrombosis IgG/IgM Ab heparin-PF4 cpx. TXA2 plt.aggregate platelet may arterial embolism, skin necrosis

unclear : CD55, CD59 plt-surface + compliment & platelet PNH unclear : CD55, CD59 plt-surface + compliment & platelet CD87 fibrinolysis NS Protein loss : Antithrombin Estrogen use factor VII, X, XII, XIII ; protein S, antithrombin fibrinolytic activity but down regulation

Approach PH of thromboembolism location : venous/arterial/microvascular diagnostic study : venography , scans predisposing factor : surgery, trauma, pregnancy therapy : duration , efficacy, complications Disease associated with thrombois FH Medication Estrogen , chemotherapy, tobacco, alcohol, illicit drugs

Investigation Venous Arterial Microvascular CBC CBC CBC, PBS APC-resistance assay Prothrombin gene mutation Factor VIII activity Antithrombin activity Protein C Protein S Homocysteine Fibrinogen Thrombin time Lupus anticoagulant Anticardiolipin CBC Lupus anticoagulant Anticardiolipin Homocysteine(R to L shunt) Colony assays Lipid profile High-sensitivity CRP CBC, PBS DIC screen Lupus anticoagulant Anticardiolipin Protein C Protein S HIT assay

Timing : 2-3 wk after off oral anticoagulant Acute thrombosis : AT , Protein C & S Heparin : AT Warfarin : Protein C & S activity FH : Hereditary : plan for FH

Indication BUT ALL CASE Recurrent thrombosis FH of thrombosis Thrombosis : other site ,except DVT Multiple site of thrombosis Thrombosis without atherosclerosis Both arterial & venous thrombosis BUT ALL CASE

Clinical Risk factor Acquire risk Acquire risk Hereditary risk

Treatment Heparin 80 u/kg iv bolus, then 18 u/k/hr PTT q 6 hr : 1.5-2.5 x Warfarin : INR >2 *2d then off heparin LMWH Antithrombin concentrate AT deficiency with high dose heparin/recurrent thrombosis 50 u/kg then 60% of first dose q 24 hr keep >80%

Protein C deficiency : warfarin induce skin necrosis Rx : off warfarin : Vit K & Heparin : FFP , protein C concentration ---- before warfarin Lupus anticoagulant : PTT prolong --- FcX or thrombin LMWH Other -Elastic stocking prevent post thrombotic syndrome -Thrombolytic agent - massive PE , Phlegmasiacerulia dolens -IVC filter : contraindication of anticoagulant

Post thrombotic syndrome Venous valve incompetence venous reflux venous HT Leg pain & swelling , chronic skin ulcer Recurrent DVT : risk 6 time Dx : doppler U/S : reflux in popliteal vein : descending venogram

Prevention : Elastic compression stocking 2 yr Rx : หลีกเลี่ยงการยืนหรือนั่งนานๆ : graduated compression stocking : intermittent compressive pump , pressure 40 mmHg : venous ulcer : dressing & debridement & unna boot : Pentoxifylline : Sx : ligation, stripping, valve reconstruction Prevention : Elastic compression stocking 2 yr : prevent recurrent DVT

Long term management Aim : prevent early recurrent thrombosis High recurrent in unknown risk factor Evaluate : site & severity : risk factor : clot formation : เพศ อาชีพ

Idiopathic Thrombophilia Risk factor Thrombosis Idiopathic Thrombophilia Risk factor Heterozygous FV Leiden Homozygous FV Leiden , AT Protein C&S def. APA ชั่วคราว ยังมีต่อ 1st : > 6 mo 2nd long life >12 mo or long life Long life Or >6mo ถ้า risk หาย 3 mo or risk หาย

FH : 1st degree relation 50% - female : no pill : no hormone replacement - prophylaxis anticoagulant/AT, Protein C conc. :-Antithrombin deficiency : Protein C & S deficiency : Lupus anicoagulant : Sx , pregnancy , post-partum - Hyperhomocysteinemia : B6,12 , folic acid On warfarin : plan of pregnancy---stop warfarin