1. Pathology 430/826 Thrombosis David Lillicrap

2. Cardiovascular Disease 30% of all deaths in Canada 54% ischemic heart disease 20% stroke 23% heart attack

3. Arterial Thrombosis

4. Myocardial Infarction

5. Cerebral Infarction following Cerebrovascular Thrombosis

6. Peripheral Vascular Disease

7. Deep Vein Thrombosis

8. 30% Progression to Pulmonary Embolism

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

10. Hemophilia Single Gene Mutation Thrombosis Multigenic + Environmental Factors Pathogenetic Associations and Hemostasis Genetic diagnosis available Genetic therapy feasible Genetic pathogenesis still under investigation Multifactorial, Complex Pathogenesis Simple, Monogenic Pathology

11. 90% of Canadians have at least one risk factor for heart disease or stroke Smoking Alcohol Lack of physical activity Obesity Hypertension Hypercholesterolemia diabetes

12. Venous Thromboembolism Incidence 5 cases per 100,000 person/year (<15 years old) 5 cases per 1,000 person/year (80 years old)

13. Influence of Age on the Incidence of Venous Thromboembolism

14. 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

15. VWF collagen Blood flow Physiological Hemostatic Mechanism

16. Fibrin Insoluble end product Common pathway Extrinsic pathwayIntrinsic pathway 1 3 2

17. Coagulation System 1 3 2

18. collagen Blood Flow collagen

19. Blood Flow collagen VWF Subendothelial Tissue Factor Microparticle Tissue Factor (WBC/platelet derived)

20. VWF collagen Platelet adhesion GpIb/VWF Blood Flow

21. VWF collagen Platelet adhesion GpIb/VWF Blood Flow Platelet Rolling GpIb/VWF GpVI +  2  1/collagen

22. VWF collagen Platelet adhesion GpIb/VWF Blood Flow Platelet Rolling GpIb/VWF GpVI +  2  1/collagen Stable adhesion platelet activation aggregation GpIIb/IIIa – fibrinogen/VWF

23. VWF collagen Blood flow Physiological Hemostatic Mechanism

24. VWF collagen Occlusive Platelet Thrombus

25. Coagulation System 1 3 2

26. VWF collagen Occlusive Platelet Thrombus + Fibrin

27. Mechanisms to Control Thrombus Development 1. Endothelial Cell “protection”

28. Prostacyclin (PGI2) Vasodilatation Inhibits platelet aggregation Cell surface Heparin-like molecules Cell surface ADPase Endothelial Cell

29. Mechanisms to Control Thrombus Development 2. VWF degradation

30. Globular form of VWF Normal plasma conformation Growing thrombus = Vasoconstriction = Increased shear Extended form of VWF ADAMTS13 accessible (mechano-enzymatic cleavage)

31. Mechanisms to Control Thrombus Development 3. Anticoagulant plasma proteins - antithrombin - protein C - protein S - tissue factor pathway inhibitor (TFPI)

32. Thrombin IIa Thrombomodulin Endothelial Cell Protein C Activated Protein C FVIIIa FVa Protein S EPCR

33. +ve feedback Antithrombin Anticoagulation

34. +ve feedback TFPI Anticoagulation

35. Mechanisms to Control Thrombus Development 4. Fibrinolytic pathway – plasmin-mediated degradation of fibrin

36. Endothelial Cell Tissue Plasminogen Activator (tPA) Plasminogen Plasmin Fibrin Degradation

37. Thrombotic Risk Factors 1. Inherited a) Frequent - minor influence b) Rare – more significant effect 2. Acquired

38. Inherited Thrombotic Risk Factors - Thrombophilic Traits Prevalence:2-5% of Western Populations a) Factor V Leiden - inability to proteolytically inactivate FVa b) Prothrombin gene varaint – enhanced stability of prothrombin mRNA Enhanced thrombotic risk: 2 to 7-fold increase

39. Inherited Thrombotic Risk Factors - Thrombophilic Traits Prevalence:<1:1,000 a) Antithrombin deficiency b) Protein C deficiency c)Protein S deficiency Enhanced thrombotic risk: 5 to 20-fold increase

40. Acquired Thrombotic Risk Factors Smoking Lack of physical activity Obesity Hypertension Hypercholesterolemia Diabetes Cancer Inflammation/infection Pregnancy/estragenic states

41. Pathological Thrombotic Events – Very Often Multifactorial 1. 32 year old female long distance runner - DVT + PE Ruptured synovial cyst in knee + dehydration. 2. 43 year old female - large DVT chronic crohns disease + Factor V Leiden heterozygote 3. 35 year old female – large iliac vein thrombosis pregnancy + antithrombin deficiency

42. Break