THROMBOPHILIA

2. THROMBOPHILIA Abdulkareem Almomen, MD, FRCPC KSU-MED 341 17-04- 2011 (13-05-1432)

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 (anti-thrombotic) • Platelets • Coagulation system coagulation factors, natural anticoagulants & fibrinolysis

6. Vessel injury Thrombogenic 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 ADP-ase which counters the platelet aggregating effects of ADP

8. Antithrombotic Properties of the Endothelium (cont.)Anticoagulant propertiesProduce Heparin-like proteoglycans which activate anti-thrombin Produce Thrombomodulin which make a complex with thrombin (TM.T complex ) and activates protein C ,Produce tPA which activates fibrinolysis by activating plasminogen to 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 • Genetic • acquired

13. ENDOTHELIAL INJURY THROMBOSIS ABNORMAL BLOOD FLOW HYPERCOAGULABILITY

14. Signs & Symptoms • DVT: • 50% with no clinical signs • ?Edematous extremity • Plethoric,Warm,Painful extremity • PE: • Cough, SOB, Hemoptysis • Tachycardia

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

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

17. 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)

18. Clot removal

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

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

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

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

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

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

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

26. 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

27. 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%)

28. Folate and Homocysteine Metabolic Pathways

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

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

31. 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

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

33. 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

34. 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

35. 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

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

37. 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.

38. 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

39. 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.

40. Antithrombin Thrombin Antithrombin Factor Xa Unfractionated Heparin LMW Heparin Pentasaccharide Pentasaccharide Low Molecular Weight Heparin

41. 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 breast milk. • New anti-coagulants: Direct anti-thrombin (Daqbigatran) Anti-Xa (Rivaroxaban)

42. Monitoring • PTT • PT/INR • TT (thrombin time) • Heparin level • Xa activity • No monitoring

43. Anti dotes (overdose) • Stop the anti-thrombotic/anti-coagulant agent, • Protamin sulfate (heparin) • Plasma/ vitamin K (warfarin) • Tranexamic acid (thrombolytic therapy, fibrinolysis) • DDAVP (anti-platelets) • rFVIIa ( universal anti hemorrhagic) ( dose= 4000-20000 SR )