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Hypercoagulation

Hypercoagulation. Thrombosis ~~ Virchow ’ s Triad. Congenital & Acquired hypercoagulable states. Racial difference. Asians &Africans: protein C deficiency, protein S deficiency predominant Whites: Factor V Leiden, prothrombin gene G20210A mutation predominant.

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Hypercoagulation

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  1. Hypercoagulation

  2. Thrombosis ~~ Virchow’s Triad

  3. Congenital & Acquired hypercoagulable states

  4. Racial difference • Asians &Africans: protein C deficiency, protein S deficiency predominant • Whites: Factor V Leiden, prothrombin gene G20210A mutation predominant

  5. Congenital & Acquired hypercoagulable states

  6. 1. Protein C deficiency • Synthesis in the liver; Vit-K dependent; Autosomal dominant • Inactivate factorⅤ and factorⅧ. It needs a cofactor: protein S • Deep vein thrombosis(DVT) 、pulmonary embolism(PE) 、superficial thrombophlebitis: most common manifestations • Arterial thrombosis are rare • Easy to occur warfarin-induced skin necrosis (1/3 warfarin-induced skin necrosis underlying protein C deficiency)

  7. 2. Protein S deficiency • Synthesis in hepatocytes & megakaryocytes; Vit-K dependent; Autosomal dominant • Cofactor of activated protein C(APC) • 74%: DVT ; 72%: superficial thrombophelbitis • Warfarin-induced skin necrosis may occur

  8. 3. Antithrombin Ⅲ deficiency • Synthesis in liver & endothelial cells • Activated by binding to heparin-like molecule • Inhibits thrombin, factor Ⅸa,Ⅹa, XIa, XIIa • DVT、PE、mesenteric vessels thrombosis • Resistant to unfractionated heparin • Must treat with low-molecular-weight heparin(LMWH)

  9. 4. Factor V Leiden(=activated protein C resistance) • Point mutation of facotr V gene • Results in impaired inactivation of factor V by activated protein C • Present in 5% of whites; virtually absent in Asians & Africans • Venous thrombosis & fetal wastage • Heterozygosity: 2x ~ 3x risk Homozygosity: 80x risk • Heterozygosity factor V Leiden is a relative mild risk factor of thrombosis, and appears not to affect life expectancy

  10. 5. Prothrombin gene G20210A mutation • Prothrombin gene mutation: nucleotide position 20210: G  A • Elevated prothrombin levels and activity • Increased risk of venous thrombosis • Rare in Asians & Africans

  11. 6. Hyperhomocysteinemia(1) • 1: methionine synthase • 2: methylenetetrahydrolate reductase(MTFHR) • 3: betaine-homocysteine methyltransferase • 4: cystathionine β –synthase(CBS)

  12. 6. Hyperhomocysteinemia(2) • Elevated homocysteine  (1) vascular endothelial injury (via free oxygen radicals) (2) decreased protein C activation (3) increased factor V activity (4) induction of endothelial cell tissue factor activity • Causes: (1) cystathionine β–synthase def. (most common) (2) Vit-B6, Vit-B12, folic acid deficiency • Cause premature arterial atherosclerosis and venous thromboembolism • Tx: standard fashion + vitamin supplementation

  13. 7. Dysfibrinolysis • 5 major forms: (1) congenital plasminogen deficiency (2) tissue plasminogen activator deficiency (3) increased plasminogen activator inhibitor (4) congenital dysfibrinogenemia (5) factor XII deficiency (factor XII involved in plasmin generation ~ kinin cascade)

  14. 1. Antiphospholipid antibody syndrome (1) • Most common of hypercoagulable disorder • Heterogenous autoantibody binds to phospholipid-protein complex • Include lupus anticoagulant syndrome & anticardiolipin antibody syndrome • Exact mechanism is unknown • Venous and arterial thrombosis, recurrent spontaneous abortion, stroke, TIA(transient ischemic attack)

  15. 1. Antiphospholipid antibody syndrome (2) • Idiopathic(primary) or associated with SLE, infection, drug reactions(secondary) • Livedo reticularis, thrombocytopenia • PT,PTT prolonged • Diagnosis: specific assay to detect antiphospholipid antibody(lupus anticoagulants, anticardiolipin antibodies) in the serum; false-positive VDRL

  16. 2. Malignancy • 15% patients with cancer have clinical thrombosis • Esp. mucin-secreting adenocarcinoma(GI or lung), pancreatic cancer, acute promyelocytic leukemia • Mechanisms: hypercoagulability, endothelial injury, venous stasis • DVT, PE, Trousseau’s syndrome(migratory superficial thrombophlebitis), non-bacterial thrombotic endocarditis(NBTE) : fibrin-platelet vegetations on heart valvessystemic embolization • Occurrence of Trousseau’s syndrome or without known cancer  vigorous search for occult malignancy

  17. 3. Surgery / Trauma • Mechanisms: (1) release of tissue factor from injured tissue (2) decreased plasma level of anticoagulants • Particularly common in orthopedic surgery • Hip and knee surgery without anticoagulant prophylaxis  45~70% DVT

  18. 4. Pregnancy / Oral contraceptives 1. Placenta: placental plasminogen activator inhibitor type 2 2. Enlarged uterus venous stasis in the leg 3. Pelvic vein injury 4. Trauma of cesarian section • Oral contraceptives promote liver synthesis of coagulation factors

  19. When to suspect hypercoagulability? • Thrombosis < 50 years • Family history • Thrombosis in an unusual site(e.g. mesenteric v. or cerebral v.) • Idiopathic or recurrent thrombosis • Unexplained spontaneous abortions • Massive thrombosis

  20. Clinical features • DVT: unilateral leg pain & swelling, tenderness on compression calf muscle, Homan’s sign(pain during dorsiflexion of the foot), increased circumference at least 1 cm • PE: dyspnea, tachypnea, tachycardia, chest pain, decreased breathing sounds, hemoptysis

  21. Diagnosis ~ DVT Standard, accurate, but invasive Positive predictive value > 90%

  22. Diagnosis ~ PE >50% patients Normal result can not rule out PE Pulmonary angiography is standard test

  23. Diagnosis for congenital hypercoagulable state • Functional, antigenic, DNA-based assays • Avoid test when: (1) active thrombosis (2) anticoagulants treatment (3) pregnancy, estrogen use (4) liver disease (5) DIC

  24. Treatment ~ initial management Keep PTT 1.5~2.5

  25. Long term treatment ~ oral anticoagulant(Warfarin) • Vit-K antagonist • Should be adjusted according to PT(INR) • Inhibition of protein C first(6~8 hr), then inhibits other clotting factors(24~48 hr)  transient hypercoagulable state  Warfarin-induced skin necrosis • Warfarin started within 24 hr after initiation of heparin. Heparin should be given for at least 4 days and not discontinued until the INR in the therapeutic range(2.0 to 3.0) for 2 consecutive days

  26. Complications of treatment • Bleeding • Heparin-induced thrombocytopenia • Heparin-induced osteoporosis • Warfarin-induced skin necrosis • Post-thrombotic syndrome (venous hypertension caused by valvular incompetence) : pain, swelling, ulceration

  27. New oral anticoagulant Drugs • Oral • Less bleeding • No monitoring. • Good choice if we use it in the right way .

  28. References • Hypercoagulability syndromes: Arch intern med/Vol 161, Nov 12, 2001 • Genetic susceptibility to venous thrombosis: N Engl J Med, Vol 344, No. 16, April 19, 2001 • Management of venous thromboembolism: N Engl J Med, December 12, 1996 • Goldman: Cecil textbook of medicine, 21st ed. Chapter 187 • Robbins pathologic basis of disease, sixth ed. Chapter 5

  29. ~ END ~ Thank you

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