Disorders of Hemostasis: Thrombosis

1. Disorders of Hemostasis: Thrombosis John Lazarchick, M.D. Director, Hematopathology/Hemostasis August 30, 2001

3. Hypercoagulability • Definition: Alteration in the hemostatic balance between blood fluidity and clot formation. This is due to genetic and acquired disorders which shift this balance toward excessive or inappropriate platelet aggregation and fibrin formation and predispose to thrombosis.

4. Prethrombotic States • 10 - inherited abnormalities resulting from mutations affecting the function of coagulant proteins and natural inhibitors • 20 - acquired defects that either affect the endothelium, fluid flow or blood components. These defects are often superimposed on 10 defects

5. Hypercoagulability:Prethrombotic States • Virchow (1856) • Abnormalities of blood vessels • Abnormalities of fluid flow • Abnormalities of blood components

6. Blood Vessel Abnormalities • Endothelial cell antithrombotic properties- PGI2, NO2, TFPI, PAI-1, heparans, thrombomodulin • Genetic predisposition and acquired defects in these functions increase the risk of arterial and venous thrombosis • Role of dietary excesses, hypertension, diabetes mellitus, obesity, smoking, lipid abnormalities in atherosclerosis

7. Atherosclerosis • Endothelial injury and dysfunction • LDL cholesterol – oxidized LDL--- foam cells • Diabetes mellitus – glycated LDL cholesterol • Smoking – free radical production • Hypertension – smooth muscle proliferation • Genetic alterations – MTHFR mutations

8. R. Ross. Atherosclerosis. NEJM 340:115-126, 1999

9. Atherosclerosis • Site specific: • Bifurcations • Branching vessels • Curvatures • Decreased shear stress and increased turbulence • Plaque formation and rupture

10. Unstable plaque. R.Ross NEJM 340:115-126, 1999.

11. Blood Flow Abnormalities • Stasis is the underlying mechanism as the cause of venous or arterial thrombosis • Conditions - immobilization, surgery, congestive heart failure, pregnancy, obesity. • Increased blood viscosity • RBCs - polycythemias, sickle cells • WBCs – myeloproliferative disorders especially CML • Platelets - primary thrombocytosis • Paraproteins - Myeloma, Waldenstrom’s Macroglobulinemia

12. Factor V Leiden Prothrombin 20210 Protein C Protein S Anti-thrombin III Dysfibrinogenemia Hyperhomocysteinemia PAI-I Platelet glycoprotein IIb/IIIa Hypercoagualbility:Hereditary/Acquired

14. Factor V Leiden • Mutation at position 506 rendering FV insensitive to degradation by activated protein C. • Autosomal dominant; 5% Caucasian population. • Heterozygote - 7x increased risk for venous thrombosis • Homozygote - 80x increased risk • Often found in association with other risk factors - protein C and S deficiencies

15. Prothrombin 20210 Mutation • Mutation results in increased synthesis of prothrombin resulting in elevated plasma levels of biochemically normal prothrombin • Autosomal dominant; 1-2% of population • Increased risk of venous thrombosis - 2x

16. Protein C Deficiency • Autosomal dominant • Mutation results in mild to severe deficiency; increase risk for venous thrombosis homozygote = purpura fulminans • 0.2% of US population • Acquired - DIC, liver disease, oral contraceptives, oral anticoagulant use

17. Protein S Deficiency • Autosomal dominant • Increased risk of venous thrombosis • Acquired deficiencies - DIC, liver disease. coumarin therapy, pregnancy (2nd and 3rd trimesters), estrogen replacement therapy, L-asparginase chemotherapy

18. Hyperhomocysteinemia • Increased levels are associated with increased risk of arterial and venous thrombosis. • Multiple effects on endothelial cells - decreased thrombomodulin, increased TF activity, inhibition of NO and TPA

19. Hyperhomocysteinemia • Primary - mutation of MTHFR gene • Acquired - vitamin B12, B6 or folic acid deficiency, hypothyroidism, isoniazid, methotrexate, theophylline

20. Hereditary Thrombophilia • Consider if : • family history of thrombosis • history of recurrent thrombosis • thrombosis at a young age • no acquired predisposing factors for thrombosis

21. Malignancy • Risk for thrombosis is multifactorial. • Predominantly venous thrombosis - stasis, tumor invasion of vessels, chemotherapy effects superimposed on acquired or primary defects in hemostasis. • Distinct procoagulant (cysteine protease) found in many patients which can activate FX directly.

22. Antiphospholipid Antibody Syndrome • Autoimmune disorder, either primary or secondary, associated with an increased risk for arterial and venous thrombosis. • Antibody is to cardiolipin in APA (ELISA assay); antibody is to beta 2 glycoprotein 1 and platelet phospholipids in patients with lupus anticoagulants (aPTT and/or PT).

23. Thrombus • Size, shape and morphology Mural thrombus Infected thrombus – bacterial endocarditis Verrucous thrombus – Libman-Sacks endocarditis

27. Thrombus • Natural history: • Resolution • Propagation • Fragmentation/embolization • Organization

28. Resolution

29. Propagation – complete occlusion

30. Fragmentation and Embolization F

31. Organization – Fibroblast proliferation

32. Organization – Endothelial cell differentiation

33. Resolution

34. Organization - Rethrombosis

35. Thrombus • Clinical presentation: Arterial – coronary, carotid and femoral • Acute MI, Angina • CVA, TIA • Claudication Venous – superficial veins, deep veins Thrombophlebitis, swollen, painful extremity Pulmonary embolus