Pathogenesis and Clinical Management of Thrombotic Disease

1. Pathogenesis and Clinical Management of Thrombotic Disease

2. Arterial Thrombosis

3. Abnormal Blood Flow Abnormal Vessel Wall Abnormal Blood The Hypercoagulable State (thrombophilia) Dr. Rudolph Virchow 1821-1902

4. Pathogenetic Associations and Hemostasis Hemophilia Single Gene Mutation Thrombosis Multigenic + Environmental Factors Genetic diagnosis available Genetic pathogenesis still under investigation Genetic therapy feasible Far More Complex

5. Mechanisms of Thrombosis Clinical associations with thrombotic disease Immobility Obesity Smoking Cancer Pregnancy Estrogen therapy

6. Types of Thrombosis Arterial: platelet-based (white) thrombus Platelet-VWF interactions critical Associated with end-stage atherosclerosis Venous: Fibrin-based (red) thrombus Coagulation factors critical Venous stasis

7. Loss of Function Mutations Natural Anticoagulant Proteins Antithrombin Protein C Protein S Rare - 0.02 – 0.2% of General Population 1-3% prevalence in Thrombosis Population Stronger Risk Factors For VTE ~ 10 to 25-fold

8. Gain of Function Mutations Pro-coagulant Proteins Factor V Leiden Prothrombin 20210 Mutation Common - 2 – 10% in Western Populations 6% (prothrombin) to 20% (FV Leiden) in Thrombosis Weaker Risk Factors For VTE 2 to 7-fold

9. Factor V Leiden Factor Va Arg 506 Arg 306 Arg 1765 Arginine CGA Glutamine CAA Factor Va resistant to APC cleavage

10. Leiden Study Group Data Relative Risk for Venous Thrombosis Factor V Leiden Heterozygote x 7 Factor V Leiden Homozygote x 80 Oral Contraceptives x 3 Oral Contraceptives + Factor V Leiden x 35

11. Quantitative Traits Homocysteine FVIII FIX FXI 2 to 4-fold increased relative risk Unknown genetic mechanisms

12. CLINICAL CASE #1 • 72 year old male seen in the ER • Three day history of swollen, painful right leg up to mid-thigh • Hypertension for 10 years. Treated with a diuretic • 10 pound weight loss over past four months • Smoked 20 cigarette/day for 50 years

13. Clinical Examination Circumference of right leg 3 cm bigger than left at mid point of calf Right leg warm, tender and erythematous

14. Differential Diagnosis Venous thrombosis Cellulitis Knee pathology ie ruptured synovial cyst Calf muscle strain Calf muscle hematoma

15. Objective imaging test to confirm DVT Invasive - radiocontrast venogram (gold standard) Non-invasive Doppler ultrasound studies Less sensitive to thrombi distal to the popliteal vein

16. Flow of clinical management Clinical history and examination Imaging assessment Day 1 Positive Test Begin treatment Negative Test Need to retest ~25% of initial negatives will progress (ie extend proximal to the popliteal vein)

17. Reasons to Treat Venous Thromboembolic Disease Threat of embolization Much greater with large proximal vein thrombosis

18. Pulmonary Embolism

19. Reasons to Treat Venous Thromboembolic Disease Local Effects Acute pain/swelling Long-term: Post-phlebitic Limb

20. Treatment Options Standard anticoagulant therapy Thrombolytic therapy Vena caval interruption In >95% of cases Standard anticoagulants In 2008 - Low Mol Wt. Heparin

21. Relative or absolute contraindications to anticoagulant treatment History of peptic ulcer disease Recent surgery

22. Heparin • Highly sulphated glycosaminoglycan • Functions with Antithrombin as a cofactor • Unfractionated MW. 5-30,000 Daltons • Low Molecular Weight Heparins • MW 5,000 • More predictable pharmacokinetics • Less cell binding, less protein binding • Laboratory monitoring not required

23. +ve feedback Heparin Action through antithrombin

24. Low Molecular Weight Heparins Several Types eg. Tinzaparin (Innohep) Daltaparin (Fragmin) • Dosage calculated by body weight • Q daily or Q12Hrly SC administration • No Laboratory monitoring necessary Exceptions - children, obesity, renal failure

25. Oral Anticoagulants Coumadin/Warfarin Vitamin K antagonists Interfere with gamma carboxylation Peak effect reached in ~4/5 days Monitor with the PT (International Normalized Ratio - INR)

26. + Protein C and Protein S Procoagulant Vit K dependent proteins

27. Start Coumadin Daily INR Days 1 2 3 4 5 6 7 Stop LMWH When INR>2 Begin therapy with SC LMWH Start of Coumadin effect

28. Anticoagulant Complications Coumadin Bleeding 2-5% per year Embryopathy - skeletal abnormalities Allergies - skin rashes Low Molecular Weight Heparin Bleeding 2-5% per year Thrombocytopenia Osteoporosis

29. Novel anticoagulant Targets Anti-Xa Anti-IIa

30. New Anticoagulant Drugs Possible standard therapy within 2-5 years • Anti-Xa Rivaroxaban Synthetic pentasaccharide • Thrombin inhibitors Lepirudin Dabigatran No laboratory monitoring required No specific antidotes to treat bleeding

31. Unresolved Anticoagulant Issues 1. Optimal Duration of Treatment 3 months - several years Optimal Intensity of Anticoagulation Less Thromboembolic Recurrences Less Bleeding Events Target INR 2-3

32. Heterozygosity for Factor V Leiden is associated with which one of the following? • An increased risk of arterial thrombosis. • A prevalence of 15% in Western populations. • Autosomal recessive inheritance. • An increased risk of venous thrombosis.

33. FV Leiden Heterozygosity • 5% in Western populations • Increased risk for venous thrombosis (~7-fold) • Autosomal co-dominant inheritance • risk with homozygous FV Leiden 70-fold

34. Heparin treatment is NOT associated with which one of the following? • Inhibition of FIXa. • Prolongation of the thrombin clotting time. • Inhibition of FVIIIa. • Prolongation of the aPTT.

35. +ve feedback Heparin Action through antithrombin

36. Coumadin anticoagulation is associated with which one of the following? • Prolongation of the thrombin clotting time. • Laboratory test abnormalities consistent with vitamin K deficiency. • A low plasma FXI level. • Inability to correct the PT with a 50:50 mix.

38. Antithrombin deficiency is NOT associated with which one of the following? • Increased risk of venous thrombosis. • Autosomal dominant inheritance. • Resistance to heparin therapy. • Increased levels of FX.

39. +ve feedback Heparin Action through antithrombin