THROMBOPHILIA

2. THROMBOPHILIA Abdulkareem Almomen, MD, FRCPC KSU-MED 341 March, 2010

3. THROMBOPHILIA Pre-Thrombotic States, Thrombogenic States, Hypercoagulable States

4. Hemostasis • Blood must be fluid • Must coagulate (clot) at appropriate time • Rapid • Localized • Reversible Thrombosis…inappropriate coagulation

5. 3 Major systems involved • Vessel wall • Endothelium • Platelets • Coagulation factors

6. Vessel injury Prothrombotic Antithrombotic (Favors fluid blood) (Favorsclotting)

7. Antithrombotic Properties of the Endothelium • Anti-platelet properties • Healthy endothelium does not bind platelets • Produce PGI-2 (prostacyclin) and NO (Nitric Oxide) which inhibit platelet binding • Produce ADPase which counters the platelet aggregating effects of ADP

8. Antithrombotic Properties of the EndotheliumAnticoagulant propertiesProduce Heparin-like proteoglycans which activate anti-thrombin Produce Thrombomodulin which make a complix with thrombin and activates protein C ,Produce tPA which activates fibrinolysisby activating plasminogento plasmin

9. Prothrombotic Properties of the Endothelium • Synthesis of von Willebrand factor • Release of tissue factor • Production of plasminogen activator inhibitors (PAI) • Membrane phospholipids bind and facilitate activation of clotting factors via Ca++ bridges

10. Procoagulant Anticoagulant

11. Procoagulant Anticoagulant

12. Virchow’s Triad • Pathogenesis of a Thrombus Endothelial injury Abnormal blood flow Hypercoagulability • Primary (genetic) • Secondary (acquired)

13. ENDOTHELIAL INJURY THROMBOSIS ABNORMAL BLOOD FLOW HYPERCOAGULABILITY

14. Signs & Symptoms • DVT: • Painful, swollen, warm, and Plethoric extremity with reduced pulse volume • PE: • Cough, SOB, Hemoptysis • Tachycardia

17. 1. Initiation phase Injury of vessels wallleads to contact between blood and subendothelial cells Tissue factor (TF) isexposed and binds toFVIIa or FVII which is subsequently converted to FVIIa The complex between TF and FVIIa activates FIX and FX FXa binds to FVa on thecell surface

18. Intrinsic pathway XIIa Extrinsic Pathway XIa TF Prothrombin IXa VIIa VIII VIIIa Xa V Va Soft clot Thrombin Fibrinogen Fibrin XIIIa Hard clot Fibrin

20. The FXa/FVa complexconverts small amountsof prothrombin into thrombin The small amount ofthrombin generatedactivates FVIII, FV, FXI and platelets locally. FXIa converts FIX to FIXa 2. Amplification phase Activated platelets bind FVa, FVIIIa and FIXa

22. Physiologic Inhibitors of coagulation • Antithrombin • Activated Protein C + protein S • Inactivates Va and VIIIa (via proteolysis) • Thrombomodulin • Binds to thrombin • activate Protein C

23. Non-physiologic inhibitors of coagulation • Vitamin K antagonists (in vivo only) • Ca chelators (in vitro only) • EDTA • Citrate • Oxalate * Heparin (in vivo and in vitro)

24. Clot removal

25. Fibrinolysis Plasminogen tPA Plasmin Fibrin Fibrin Split Products (FSP)

26. Inhibitors of fibrinolysis • Plasminogen activator inhibitors (PAIs) • a2-antiplasmin (serpin)

27. Fate of a Thrombus Diagram from Robbins Pathologic Basis of Diseases

28. Hereditary Thrombophilias • Protein C pathway • Factor V Leiden • Protein C deficiency • Protein S deficiency • Prothrombin G20210A mutation • Antithrombin deficiency • Hyperhomocystinemia • C677T MTHFR mutation

29. Factor V Leiden Mutation • Mutation in Factor V • Protein C/S complex • Impaired anticoagulation • 5-11% of white Europeans • Heterozygous • Autosomal dominant • Homozygous rare

30. PAIi PAIa Platelet surface APC VIIIi VIIIa S active C4BP S inactive PC Thrombin Vi Va Thrombomodulin Endothelial surface Protein C Pathway

31. Prothrombin G20210A mutation • Mutation in promotor • 150-200%  in prothrombin levels • 2-3% of Europeans • Heterozygous • autosomal dominant • Homozygous similar to Factor V

32. MTHFR and Thrombosis • Hyperhomocysteinemia implicated in both arterial and venous thrombosis • Why is homocysteine thrombogenic? Theories: • Direct toxicity to endothelial cells • Inhibits Protein C activation • Promotes endothelial tissue factor expression • Surpresses endothelial cell surface heparin sulfate

33. Hyperhomocysteinemia • Atherosclerosis, NTD, thromboembolism • Severe – homozygous • 1 in 200,000-355,000 • Cystathionine -synthase • Mild to moderate – • Heterozygotes for CS mutation • Homozygous for 667C-T MTHFR (11%)

34. Folate and Homocysteine Metabolic Pathways

35. Possible mechanism for role in atherogenesis, thrombogenesisLancet Vol 354, 1999

36. AT Deficiency • Multiple mutations • Most thrombogenic disorder • Type I • Levels and activity • Type II • Activity

37. Protein C / Protein S Deficiencies • Protein C deficiency • Type I –  number and activity • Type II –  activity • Protein S deficiency • Type I –  total and free forms • Type II –  cofactor activity • Type III -  free only • Autosomal dominant • 0.2-0.5, 0.8 prevalence

38. PAIi PAIa Platelet surface APC VIIIi VIIIa S active C4BP S inactive PC Thrombin Vi Va Thrombomodulin Endothelial surface Protein C Pathway

39. Antiphospholipid Antibody Syndrome • Autoimmune Acquired Prothrombotic Disorder • Very High Risk for recurrent thromboembolic disease • both venous and arterial • Indefinite duration anticoagulation recommended +/- immunosuppression • Strict Diagnostic Criteria

40. Antiphospholipid Syndrome • Clinical criteria (≥1 must be present): 1. Vascular thrombosis: - ≥ 1clinical episode of, objectively confirmed, arterial, venous, or small vessel thrombosis 2. Pregnancy morbidity: - ≥ 1 unexplained fetal death @ ≥ 10 weeks EGA - ≥ 1 premature birth (≤ 34th week of gestation) due to eclampsia, severe pre-eclampsia, or placental insufficiency - ≥ 3 unexplained consecutive spontaneous abortions @ <10 weeks EGA Revised Sapporo/Sydney Criteria. JTH 2006;4:295-306

41. Antiphospholipid Syndrome • Laboratory criteria (≥1 must be present): • LA (+) ≥ 2 occasions, at least 12 weeks apart, according to ISTH guidelines: • prolonged PL-based clotting assay, lack of correction with 1:1 mix, and correction with excess PL • ACLA and/or anti-β2 glycoprotein-I antibody: • medium or high IgG and/or IgM isotype titer ≥ 2 occasions, at least 12 weeks apart • Standardized ELISA assays Revised Sapporo/Sydney Criteria. JTH 2006;4:295-306

42. Risk Factors for Thrombosis Acquired thrombophilia Hereditary thrombophilia Atherosclerosis Thrombosis Surgery trauma Immobility Estrogens Inflammation Malignancy

43. Therapies/Heparin • Mechanism: catalysis of AT. • Neonates have lower AT levels. • Monitoring: aPTT • Problems • aPTT levels based on adult therapeutic studies. • Even in adults, therapeutic aPTT may not suggest clinically sufficient anti-coag.

44. Therapies/Heparin • Recommended dose 75U/kg loading. • Maintenance drip dose varies: • Infants <1yr of age 28U/kg/hr • Children > 1yr 20U/kg/hr • Side effects (besides bleeding): • Heparin induced thrombocytopenia • Osteoporosis

45. Therapies/ LMWH • Low Molecular Weight Heparin • Less monitoring needed, more predictable blood levels, less osteoporosis. • Increase dose needed for age <2mo (0.75mg Q12). >2mo (0.5mg) • Monitor anti-factor Xa levels. • In children you need to monitor , unlike adults. • Peak is 2-6hrs after injection SQ.

46. Therapies/Oral-anticoagulants • Impairs function of vitamin-K dependent proteins (II, VII, IX, X) plus Proteins C & S. • Newborns have reduced levels of vitamin-K dependent proteins. (Shot at birth helps.) • Vitamin K added to formulas. • Minimal in breastmilk.