Stroke Education Series - 2010

1. Stroke Education Series - 2010 Phaniraj Iyengar MD Director Hypercoaguable states & Stroke

2. Disclosure • I am on the speaker panel for Bristol Myers and Sanofi Aventis

3. Discussion Points • Introduction • Hemostasis • Thrombosis • Neurologist workup philosophy • Inherited hypercoaguable states • Acquired hypercoaguable states • Case presentations (Two) • Final summary

4. Hypercoaguable states & Stroke • Coagulation disorders that predispose to strokes remain POORLY DEFINED. • They may have been implicated in venous strokes (Cerebral venous thrombosis) rather than arterial strokes. • Known hematological abnormalities are estimated to account for about 4% of all strokes. This proportion may be higher for younger people.

5. Hypercoaguability and Stroke Hemostasis

6. Introduction • The ability of blood to coagulate is ESSENTIAL to the survival of the species. • In humans, when coagulation is TOO EFFICIENT, thrombosis becomes one of THE MOST COMMON CAUSES of morbidity and mortality in developed countries – specifically CAD & STROKE.

7. Hemostatic ProcessThe Three main Steps • Primary hemostasis • Local vasoconstriction & platelet plug formation. • Coagulation cascade. • Fibrinolysis

8. Hemostasis A very complex process!!!

9. Rube Goldberg MachinePencil Sharpener Open window (A) and fly kite (B).  String (C) lifts small door (D) allowing moths (E) to escape and eat red flannel shirt (F).   As weight of shirt becomes less, shoe (G) steps on switch (H) which heats electric iron (I) and burns hole in pants (J).   Smoke (K) enters hole in tree (L), smoking out opossum (M) which jumps into basket (N), pulling rope (O) and lifting cage (P), allowing woodpecker (Q) to chew wood from pencil (R), exposing lead.  Emergency knife (S) is always handy in case opossum or the woodpecker gets sick and can't work.

10. Platelet Activation & AggregationFirst Step Exposed endothelial surface Platelets exposed to collagen Platelets are activated Release contents of cytoplasmic granules Adenosine Diphosphate (ADP) Thromboxane (TxA2) Accelerates Platelet activation Platelet aggregation Vasoconstriction Increases ADP release from Platelets

11. Hemostatic ProcessCoagulation Cascade • To stabilize and reinforce the weak platelet plug • Fibrinogen → fibrin • Three main steps: • Formation of prothrombin activator • Conversion of prothrombin into thrombin • Conversion of fibrinogen to fibrin

12. Coagulation Cascade TF =tissue factor PK = prekallikrein HK=high molecular kininogen a = activated Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

13. Coagulation Pathways Intrinsic Pathway Extrinsic Pathway “Contact Activation” IX Tissue Factor + VII “TF Pathway” X XI TF-VIIa Common Pathway Prekallikrein HMW Kininogen PL Ca2+ XIIa Prothrombin XIa PL, Ca2+ (Tenase) IXa PL, Ca2+ VIIIa Xa XIII Anticoagulation proteins: Protein C, Protein S, Antithrombin III, TFPI Va (Prothrombinase) Thrombin XL- Fibrin Polymer XIIIa Fibrin Monomer Fibrinogen

14. CoagulationSome facts to consider… • Coagulation is a MULTIFACTORIAL PATHWAY of "accelerators". • Coagulation is TIGHTLY REGULATED and only a SMALL quantity of each coagulation enzyme is converted to its active form. • Regulation is important - there is enough clotting potential in 1 mL of blood to CLOT ALL THE FIBRINOGEN IN THE BODY in 10 to 15 seconds!

15. Hypercoaguability and Stroke Thrombosis

16. Thrombosis Is Clotting In the Wrong Place ThrombosisAn Eye Opener

17. Introduction • Thrombosis can be divided anatomically into VENOUS and ARTERIAL thrombosis. • Pathophysiology of these two types of clotting is quite different. • Clotting in the low flow venous system is generally associated with DEPOSITION OF FIBRIN, whereas in the arterial system, thrombosis is associated with PLATELET REACTIVITY AND VASCULAR WALL DAMAGE.

18. Arterial ThrombosisPathophysiology • Arterial thrombosis is the result of an Atheromatous plaque rupture that causes platelet activation and aggregation resulting in an obstructive lesion that subsequently leads to tissue damage.

19. Hypercoaguability • Factors that ACCELERATE the hemostatic mechanism or INHIBIT mechanisms that counteract hemostasis CONTRIBUTE to an INCREASED state of THROMBOGENICITY or HYPERCOAGUABILITY, and thereby play an etiological role in strokes.

20. Hypercoaguable Workup in StrokeIs Challenging because of • The relative LOW PREVALENCE of these disorders in stroke patients • Their UNCERTAIN SIGNIFICANCE • Their POTENTIAL INTERACTION with traditional stroke risk factors • The HIGH COST of testing • The LACK OF diagnostic gold standards • The DIFFICULTY WITH INTERPRETATION of some tests in the setting of acute thrombosis.* Brigden ML. The hypercoagulable state: who, how, and when to test and treat. Postgrad Med.1997; 101: 249–267. Bushnell CD, Goldstein LB. Diagnostic testing for coagulopathies in patients with ischemic stroke. Stroke. 2000; 31: 3067–3078. Bushnell CD, Siddiqi Z, Morgenlander JC, Goldstein LB. Use of specialized coagulation testing in the evaluation of patients with acute ischemic stroke. Neurology. 2001; 56: 624–627.

21. Before ordering please……… • Attempt to connect the dots by asking the right questions especially in the context of • History • Presentation • Imaging Because these tests are expensive!!!

22. Cost of Hypercoaguabilty workup * Duke Coagulation Laboratory

23. Hypercoaguability and Stroke Neurologists Hypercoaguability Workup philosophy

24. Workup of a suspected Hypercoaguable state causing Stroke • Fifty-nine (75%) surveys were completed. • Specialized coagulation tests were reported to INFREQUENTLY influence stroke patient management (<25% of the time or NEVER for 95% of respondents). • Factors reported to INCREASE test-ordering included young patient age (76%), history of thrombosis (46%), history of miscarriages (36%), and HAVING FEW traditional stroke risk factors (35%).

25. Workup of a suspected Hypercoaguable state causing Stroke • MOST (88%) indicated they would order specialized coagulation tests for a hypothetical young patient with NO known stroke risk factors. • In contrast, ONLY A FEW (14%) would obtain the tests for a patient having traditional stroke risk factors, and • NONE would order the tests for a stroke patient with Atrial fibrillation.

26. Laboratory Evaluation

27. Hypercoaguability and Stroke Evaluation for Causes of a Hypercoaguable State is Complicated What the Mind Does Not Know, The Eye Does Not See

28. Inherited Risk Factors APC resistance-Factor V Leiden Anti-Thrombin deficiency Protein C deficiency Protein S deficiency Prothrombin Mutation Fibrinogen Mutations Platelet protein polymorphisms Sickle cell disease Acquired Risk Factors Age Malignancy Immobilization Trauma, Post-op Pregnancy Estrogen use Antiphospholipid Antibodies Long distance flights Hematologic Diseases TTP Factors leading to Thrombosis Inherited or Acquired Risk Factors • Hyperhomocystenemia • Elevated levels of Factor VIII, IX,XI

29. Hypercoaguability and Stroke Inherited Hypercoaguable States

30. MUTATIONS RARE Antithrombin III deficiency. Protein C deficiency. Protein S deficiency POLYMORPHISMS COMMON Factor V Leiden. Prothrombin gene polymorphism. Thermolabile MTHFR variant. Inherited Hypercoaguable States

31. Inherited Hypercoaguable States

32. Inherited Hypercoaguable StatesPolymorphisms of coagulation proteins • The MOST common cause of venous thrombosis is Activated Protein C resistance (APC Resistance) which is MOST OFTEN associated with a single mutation causing substitution of arginine by glutamine at residue 506 of Factor V gene (Factor V Leiden).

33. Inherited Hypercoaguable StatesFactor V Leiden • Most common inherited cause of thrombosis in Caucasians • 3-8% Caucasians carry the mutation and 0.1% are homozygotes • Homozygotes have 80 fold increased risk of thrombosis

34. Inherited Hypercoaguable StatesFactor V Leiden • Occurs in 5-7% of the population • Occurs in 20% of patients with DVT. • Occurs in 60% of patients with recurrent DVT’s. • Incidence of Factor V Leiden with stroke is UNKNOWN.

35. Inherited Hypercoaguable StatesFactor V Leiden • Factor V Leiden is suspected to be associated with paradoxical emboli or with venous sinus thrombosis. • At this time, the data available DO NOT suggest any role between factor V Leiden and arterial thrombosis (stroke, heart attack).

36. Inherited Hypercoaguable States Factor V Leiden • Treatment • Warfarin x 6 months or until thrombosis free for 2 months • LMWH x 2 wks after Warfarin • then retested • Long term anticoagulation if persist or recurrent thrombotic event

37. Inherited Hypercoaguable StatesAntithrombin deficiency • 1965 - First inherited trait associated with thrombophilia. • Although called anti-thrombin, it actually serves to inhibit virtually ALL of the coagulation enzymes to at least some extent.

38. Inherited Hypercoaguable StatesAntithrombin deficiency • Although isolated reports exist of arterial disease in patients with heterozygous antithrombin deficiency, there is NO clear evidence of increased arterial disease in antithrombin deficiency.

39. Inherited Hypercoaguable StatesProthrombin Gene Mutation • Genetic defect at nucleotide position 20210A in prothrombin gene • results in high prothrombin levels which causes increased thrombin generation • 2-3% in Caucasians, 4-5% in Mediterranean • Less severe clinical manifestation

40. Inherited Hypercoaguable StatesProthrombin Gene Mutation • At this time, there is CONTRADICTING evidence regarding the role of the Prothrombin Gene mutation and arterial thrombosis (stroke, heart attack).

41. Inherited Hypercoaguable StatesProthrombin Gene Mutation and Stroke • Based on these data, for persons with the prothrombin gene mutation, the MOST IMPORTANT preventive steps for the purposes of arterial disease are controlling other risk factors including: Smoking, Hypertension, Hyperlipidemia, Obesity and a sedentary lifestyle (limited activity).

42. Inherited Hypercoaguable StatesProtein C • Vitamin K dependent plasma glycoprotein • Functions by inactivating factors Va and VIIIa • Protein C activity is enhanced by Protein S • Autosomal dominant inheritance

43. Inherited Hypercoaguable StatesProtein C deficiency • Prevalence in normal population ~0.2-0.4% • Present in ~3-4% of patients with venous thromboembolism. • Homozygosity is associated with neonatal purpura fulminans. • 50% of patients with protein C deficiency WILL have a thrombosis by age 36 years.

44. Inherited Hypercoaguable StatesProtein C deficiency • At this time, the data available DO NOT suggest any role between protein C deficiency and arterial thrombosis (stroke, heart attack).

45. Inherited Hypercoaguable StatesProtein S • Vitamin K dependent anticoagulant • Cofactor to protein C and enhances its activity against factors Va and VIIIa.

46. Inherited Hypercoaguable StatesProtein S Deficiency • Prevalence in the normal population ~0.003% • Present in ~2-3% of patients with venous thromboembolism. • Homozygosity is associated with neonatal purpura fulminans. • 50% of patients with protein S deficiency WILL have a thrombosis by age 36 years.

47. Inherited Hypercoaguable StatesProtein S Deficiency and Stroke • A prospective study did find free Protein S deficiency in 23% of young patients with Stroke of Uncertain Cause, but this finding could be associated with higher levels of C4b (an acute phase reactant that decreases free Protein S Levels).

48. Inherited Hypercoaguable States Protein S Deficiency and Stroke • At this time, the data available DO NOT suggest any role between protein S deficiency and arterial thrombosis (stroke, heart attack).

49. Inherited Hypercoaguable StatesFibrinogen • Elevated Fibrinogen levels are a common and consistent finding in patients with Stroke • Serum fibrinogen levels are variable and can increase in response to infectious or inflammatory conditions as part of the acute phase response. • Polymorphisms within the Fibrinogen gene have been associated with Stroke.

50. Inherited Hypercoaguable StatesFibrinogen Polymorphisms and Stroke • Results from the Austrian Stroke Study showed an association between a polymorphism in the beta chain of fibrinogen at position 148 and Carotid atherosclerosis. • Results from a Japanese study showed an association between a polymorphism at position 455 with cerebrovascular disease.