1. Disorders of Coagulation and Thrombosis Courtney Bunevich, D.O. October 24, 2007

2. ProthrombinThrombin Factor Xa Factor X Tissue Factor Factor VIIa Secondary Hemostasis Initiation Phase

3. Secondary Hemostasis Amplification Phase Thrombin Factor VIIIaFactor VIII Factor VaFactor V Thrombin Factor XIFactor XIa Thrombin

4. Secondary Hemostasis Final Pathway Prothrombin Factor Xa Factor Va Factor X Factor IXa Factor VIIIa Ca 2+, PL Factor IX Factor XIa

5. Inherited hypercoagulable states Inherited hypercoagulable states Acquired hypercoagulable states Acquired hypercoagulable states Thrombosis

6. Antithrombin III Serine proteinase inactivation ProthrombinThrombin Factor Xa Factor Va Factor X Factor IXa Factor VIIIa Ca 2+, PL Antithrombin III (Heparin)

7. Fibrinolysis Fibrinogen Plasmin Thrombin Fibrin Plasminogen t-PA, Urokinase Fibrin Degradation Products

8. Protein C deficiency Prevalence in the normal population ~0.2-0.4% Prevalence in the normal population ~0.2-0.4% Present in ~3-4% of patients with venous thromboembolism. Present in ~3-4% of patients with venous thromboembolism. Homozygosity is associated with neonatal purpura fulminans and neonatal DIC. Homozygosity is associated with neonatal purpura fulminans and neonatal DIC. These patients require periodic plasma transfusion and not oral warfarin to prevent thrombosis. These patients require periodic plasma transfusion and not oral warfarin to prevent thrombosis. 50% of patients with protein C deficiency will have a thrombosis by age 36 years. 50% of patients with protein C deficiency will have a thrombosis by age 36 years. Proteoloyze Factor Va and VIIIa. Proteoloyze Factor Va and VIIIa. These patients are at risk for warfarin skin necrosis. These patients are at risk for warfarin skin necrosis.

9. Protein S deficiency Prevalence in the normal population ~0.003% Prevalence in the normal population ~0.003% Present in ~2-3% of patients with venous thromboembolism. Present in ~2-3% of patients with venous thromboembolism. Homozygosity is associated with neonatal purpura fulminans and DIC. Homozygosity is associated with neonatal purpura fulminans and DIC. 50% of patients with protein S deficiency will have a thrombosis by age 36 years. 50% of patients with protein S deficiency will have a thrombosis by age 36 years.

10. Activated Protein C Resistance Factor V Leiden

11. APC Resistance Amino acid substitution abolishes the cleavage site for APC. Amino acid substitution abolishes the cleavage site for APC. Approximately 3% of the population is heterozygous for this mutation. Approximately 3% of the population is heterozygous for this mutation. Absent is Asians, African Americans, and Native Americans. Absent is Asians, African Americans, and Native Americans. Can account for up to 25% of VTE disease. Can account for up to 25% of VTE disease. Homozygotes have 20 times increased risk of VTE Homozygotes have 20 times increased risk of VTE Heterzygotes on OCP or pregnant have a 15 times higher risk of VTE. Heterzygotes on OCP or pregnant have a 15 times higher risk of VTE.

12. Factor V Leiden and venous thromboembolism

13. Hyperhomocysteimenia Prevalence of 10-20% in the general population. Prevalence of 10-20% in the general population. Can be associated with increased VTE disease and arterial thrombosis. Can be associated with increased VTE disease and arterial thrombosis. Can be associated with early onset of CVA and CAD. Can be associated with early onset of CVA and CAD.

14. Prothrombin Gene Mutation Point mutation in prothrombin gene mutation with conversion of G to A at position 20210 Point mutation in prothrombin gene mutation with conversion of G to A at position 20210 Results in 30% increase in plasma prothrombin levels. Results in 30% increase in plasma prothrombin levels. Heterozygotes account for about 18% of cases of VTE disease in patients who have a family history of VTE disease Heterozygotes account for about 18% of cases of VTE disease in patients who have a family history of VTE disease

15. Dysfibrinogenemia Familial defects in fibrinogen, plasminogen, or decrease synthesis or release of t-PA. Familial defects in fibrinogen, plasminogen, or decrease synthesis or release of t-PA. Most dysfibrinogemeias cause bleeding but some can cause VTE. Most dysfibrinogemeias cause bleeding but some can cause VTE. Treated usually with heparin and warfarin. Treated usually with heparin and warfarin.

16. Antithrombin III Deficiency Antithrombin III combines with activated coagulation proteins and blocks biological activity. Antithrombin III combines with activated coagulation proteins and blocks biological activity. Heparin enhance this activity. Heparin enhance this activity. Treat VTE disease with heparin and life long warfarin therapy. Treat VTE disease with heparin and life long warfarin therapy. Plasma content is 5-15 mg/L, levels slightly below normal promote thrombosis Plasma content is 5-15 mg/L, levels slightly below normal promote thrombosis

17. Inherited Prothrombotic State DefectPrevalence Site of Thrombosis Factor V Leiden 12-40%Venous Prothrombin Gene Mutation 6-18%Venous Protein C deficiency, Protein S deficiency, and Antithrombin III deficiency 5-15%Venous Antiphospholipid antibody Syndrome 10/20% Venous and Arterial DysfibrinogenemiarareVenous

18. Inherited Hypercoagulable States Mutations:Rare Mutations:Rare Antithrombin III deficiency. Antithrombin III deficiency. Protein C deficiency. Protein C deficiency. Protein S deficiency. Protein S deficiency. Polymorphisms:Common Polymorphisms:Common Factor V Leiden. Factor V Leiden. Prothrombin gene polymorphism. Prothrombin gene polymorphism. Hyperhomocysteinemia. Hyperhomocysteinemia.

19. Who should get a thrombophilia (Inherited Hypercoagulable State) workup? Single episode of idiopathic venous thromboembolism and one or more of the following: Single episode of idiopathic venous thromboembolism and one or more of the following: Positive family history. Positive family history. Young age (less than 50 years). Young age (less than 50 years). Thrombosis at an unusual site. Thrombosis at an unusual site. Massive thrombosis. Massive thrombosis. Recurrent episodes of venous thromboembolism. Recurrent episodes of venous thromboembolism.

20. Inherited Thrombophilia Activated protein C resistance with factor V genotype confirmation for resistant results. Activated protein C resistance with factor V genotype confirmation for resistant results. Homocysteine analysis with MTHFR genotype evaluation for elevated results. Homocysteine analysis with MTHFR genotype evaluation for elevated results. Antiphospholipid antibody analysis by lupus anticoagulant and anticardiolipin antibody testing. Antiphospholipid antibody analysis by lupus anticoagulant and anticardiolipin antibody testing.

21. Inherited Thrombophilia Prothrombin gene analysis by PCR. Prothrombin gene analysis by PCR. Functional assays for protein C, antithrombin III, plasminogen, and fibrinogen. Functional assays for protein C, antithrombin III, plasminogen, and fibrinogen. Functional protein S analysis with free and total antigen analysis if activity decreased. Functional protein S analysis with free and total antigen analysis if activity decreased. Factor VIII level and CRP. Factor VIII level and CRP.

22. Acquired Hypercoagulable States Antiphospholipid antibody syndromes Antiphospholipid antibody syndromes Malignancy Malignancy Pregnancy Pregnancy Therapy-related hypercoagulable states Therapy-related hypercoagulable states Nephrotic syndrome Nephrotic syndrome Inflammatory bowel syndrome Inflammatory bowel syndrome Stasis Stasis PNH and myeloproliferative syndromes PNH and myeloproliferative syndromes

23. Antiphospholipid Antibody Syndrome Acquires state Acquires state Can be associated with Lupus. Can be associated with Lupus. Cause arterial and venous thrombosis. Cause arterial and venous thrombosis. Cause recurrent fetal loss. (Similar to Factor V Leiden) Cause recurrent fetal loss. (Similar to Factor V Leiden) Lab testing shows a failure to correct prolonged APTT and PT with mixing studies. Lab testing shows a failure to correct prolonged APTT and PT with mixing studies. Russell Viper Venom Test. Russell Viper Venom Test.

24. Acquired Hypercoagulable States OCP: lower Antithrombin III levels OCP: lower Antithrombin III levels L-asparginase: inhibit production of factors L-asparginase: inhibit production of factors Tamoxifen: unknown mechanism Tamoxifen: unknown mechanism Bechet’s syndrome and Kawaski disease: Disrupt endothelial cells Bechet’s syndrome and Kawaski disease: Disrupt endothelial cells

25. Acquired Hypercoagulable Diagnostic workup History and physical examination. History and physical examination. Review of medications (e.g., OCP, HRT). Review of medications (e.g., OCP, HRT). Complete blood count with review of blood film. Complete blood count with review of blood film. Baseline PT and aPTT (prior to starting anticoagulant therapy). Baseline PT and aPTT (prior to starting anticoagulant therapy). Malignancy screening appropriate for age. Malignancy screening appropriate for age.

26. Therapeutic options for venous thromboembolism Anticoagulant therapy. Anticoagulant therapy. Fibrinolytic therapy. Fibrinolytic therapy. Inferior vena cava filter. Inferior vena cava filter.

27. How do heparin and warfarin work?

28. Heparin Accelerates antithrombin III activity ProthrombinThrombin Factor Xa Factor Va Factor X Factor IXa Factor VIIIa Ca 2+, PL Antithrombin III (Heparin)

29. Low molecular weight heparins Preferential inactivation of factor Xa ProthrombinThrombin Factor Xa Factor Va Factor X Factor IXa Factor VIIIa Ca 2+, PL Antithrombin III (LMWH)

30. Heparin Natural anticoagulant Natural anticoagulant Binds to AT III Binds to AT III Inactivates factors IIa, Xa, IXa, XIIa. Inactivates factors IIa, Xa, IXa, XIIa. Binds to platelets Binds to platelets

31. Heparin Side Effects Bleeding Bleeding Osteoporosis: inhibits osteoblasts, activates osteoclasts Osteoporosis: inhibits osteoblasts, activates osteoclasts If treated for > 3 months or > 20,000 units daily dose If treated for > 3 months or > 20,000 units daily dose Thrombocytopenia Thrombocytopenia HIT HIT Skins lesions- urticaria, papules, necrosis Skins lesions- urticaria, papules, necrosis Hypoaldosteronism and hyperkalemia Hypoaldosteronism and hyperkalemia Bleeding reversible with protamine Bleeding reversible with protamine

32. Heparin Weight Adjusted Normogram Number of published normograms Number of published normograms Bolus 80 U/kg Bolus 80 U/kg Drip 18 U/kg/hour Drip 18 U/kg/hour Shorter time to therapeutic APTT Shorter time to therapeutic APTT No increase in bleeding No increase in bleeding

33. LMWH Increased bioavailability Increased bioavailability More predictable anticoagulant response More predictable anticoagulant response Once daily or twice daily, subcutaneous injection Once daily or twice daily, subcutaneous injection Outpatient management Outpatient management Not teratogenic Not teratogenic Decreased incidence of HIT (but cross reacts with antibody when present) Decreased incidence of HIT (but cross reacts with antibody when present)

34. LMWH and Bleeding Bleeding Bleeding Only partially reversible with protamine Only partially reversible with protamine 30% -60% 30% -60% Longer half life Longer half life Equivalent rates to UFH Equivalent rates to UFH

35. Direct thrombin inhibitors Antithrombin III-independent inhibition ProthrombinThrombin Factor Xa Factor Va Factor X Factor IXa Factor VIIIa Ca 2+, PL Hirudin Bivalirudin Argatroban

36. Oral anticoagulants Warfarin (Coumadin) Warfarin (Coumadin) Antagonizes the vitamin K-dependent  - carboxylation of factors II, VII, IX, and X (as well as protein C and protein S). Antagonizes the vitamin K-dependent  - carboxylation of factors II, VII, IX, and X (as well as protein C and protein S). A narrow-therapeutic-index drug that must be monitored by the prothrombin time (PT). A narrow-therapeutic-index drug that must be monitored by the prothrombin time (PT).

37. Factors Affecting Warfarin Effect Drug Interactions Drug Interactions Hereditary Resistance and Hypersensitivity Hereditary Resistance and Hypersensitivity cytochrome P450 (CYP2C9 mutation) cytochrome P450 (CYP2C9 mutation) Altered liver function Altered liver function Hypermetabolic state (fever, thyroid disease) Hypermetabolic state (fever, thyroid disease) Co-morbid conditions (chemotherapy, albumin) Co-morbid conditions (chemotherapy, albumin)

38. Caval Filter A single randomized trial has defined advantages and drawbacks of caval filters. The results indicate that inferior venacaval filters: A single randomized trial has defined advantages and drawbacks of caval filters. The results indicate that inferior venacaval filters: a)Prevent recurrent PE in short term b)Increase the risk of recurrent deep venous thrombosis (DVT) in the long term

39. Thrombolytic Therapy Not often indicated in venous thrombosis Not often indicated in venous thrombosis Useful in major PE Useful in major PE Possible new indication in submassive PE Possible new indication in submassive PE

40. Hemophilia A: Factor VIII Deficiency Regulated activation of Factor X. Regulated activation of Factor X. Circulates bound with vWF. Circulates bound with vWF. 1:10,000 males 1:10,000 males Bleeding in soft tissues, muscles, and weight bearing joints. Bleeding in soft tissues, muscles, and weight bearing joints. Patients with 5% of mild disease. Patients with 5% of mild disease. Femoral neuropathy can develop with unrecognized retroperitoneal hematomas, compartment syndrome, hemarthrosis. Femoral neuropathy can develop with unrecognized retroperitoneal hematomas, compartment syndrome, hemarthrosis. Each unit of Factor VIII replaced with increase plasma level by 2% per kg. Each unit of Factor VIII replaced with increase plasma level by 2% per kg. Extensive bleeding: 50% Extensive bleeding: 50% Less severe bleeding: 15-20% Less severe bleeding: 15-20% Half-life of 8-12 hours. Half-life of 8-12 hours. Dental procedures: factor VIII infusion and aminocaproic acid mouthwash Dental procedures: factor VIII infusion and aminocaproic acid mouthwash 50% hemophiliacs are HIV positive 50% hemophiliacs are HIV positive Develop inhibitors to Factor VIII after multiple transfusions. Develop inhibitors to Factor VIII after multiple transfusions.

41. Hemophilia B: Factor IX Deficiency Factor IXa activates Factor V in conjunction with activated Factor VIII. Factor IXa activates Factor V in conjunction with activated Factor VIII. 1:100,000 male births 1:100,000 male births Purified Factor IX preparations available. Purified Factor IX preparations available.

42. Factor XI Deficiency Autosomal recessive trait in Askenazi Jews Autosomal recessive trait in Askenazi Jews Correlation between factor level and propensity to bleed in not precise. Correlation between factor level and propensity to bleed in not precise. Present with prolonged post surgical bleeding or menorrhagia. Present with prolonged post surgical bleeding or menorrhagia.

43. HIT Associate with heparin therapy. Associate with heparin therapy. Decrease in platelets and new thrombosis. Decrease in platelets and new thrombosis. Perform a platelet-Factor 4 antibody assay. Perform a platelet-Factor 4 antibody assay. Confirm with a serotonin release assay. Confirm with a serotonin release assay. Stop heparin, lovenox, heparin coated lines and flushes. Stop heparin, lovenox, heparin coated lines and flushes. Start argatroban (or lepuridin) immediately and overlap with warfarin until INR >4 for 2 days. Argatroban with also increase INR. Monitor for thrombosis. Start argatroban (or lepuridin) immediately and overlap with warfarin until INR >4 for 2 days. Argatroban with also increase INR. Monitor for thrombosis.