1. Hypercoagulation

2. Thrombosis ~~ Virchow’s Triad

6. Congenital & Acquired hypercoagulable states
Protein C deficiency
Protein S deficiency
Antithrombin Ⅲ deficiency
Factor V Leiden
Prothrombin gene G20210A mutation
Hyper-homocysteinemia
Dysfibrinolysis
Antiphospholipid antibody syndrome
Malignancy
Surgery / Trauma
Pregnancy / Oral contraceptives
Prolonged immobilization
Older age

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

8. Congenital & Acquired hypercoagulable states
Protein C deficiency
Protein S deficiency
Antithrombin Ⅲ deficiency
Factor V Leiden
Prothrombin gene G20210A mutation
Hyper-homocysteinemia
Dysfibrinolysis
Antiphospholipid antibody syndrome
Malignancy
Surgery / Trauma
Pregnancy / Oral contraceptive
Prolonged immobilization
Older age

9. 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)

10. 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

11. 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)

12. 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

13. 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

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

15. 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

16. 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)

17. 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)

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

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

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

26. 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

27. Treatment ~ initial management
Keep PTT 1.5~2.5

28. 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

29. 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

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

31. 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

32. ~ END ~
Thank you