Pathophysiology of thromobosis and mana


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Pathophysiology of thromobosis and mana

  1. 1. Venous Thromboembolism: Pathophysiology and Management Gerald A. Soff M.D.
  2. 2. Thrombosis    A thrombosis is a pathological clot that forms within the lumen of a blood vessel or the heart. Thromboses may form on the arterial or venous sides of the circulation. Deep Vein Thrombosis – May embolize to form a pulmonary embolism.  Arterial Thrombosis – May cause ischemia or necrosis of the affected tissues. – Myocardial infarction and cerebral infarctions (ischemic stroke) result from arterial thrombosis.  We will focus on venous thrombosis
  3. 3. Normal Vein Function   Veins move blood against gravity by use of a series of valves and compression of the vein by surrounding muscles, especially in the legs. There are superficial and deep veins that tend to run in parallel and are connected by perforating veins. Deep are of much larger capacity.
  4. 4. Deep Vein Thrombosis   Thrombus typically forms at venous valves. Legs may be swollen, painful, warm, and erythematous. But often the signs are much more subtle, or case may be asymptomatic.
  5. 5. Pulmonary Embolism     Part of thrombus breaks off (usually from leg, pelvic, or inferior vena cava), travels through the right heart, and lodges in pulmonary artery. Direct obstruction of pulmonary circulation and vaso-spasm cause decreased pulmonary blood flow. Associated with pain, decreased oxygen delivery, and in severe cases vascular collapse and death. Calf DVT are much less likely to embolize.
  6. 6. Post-Thrombotic (Phlebitic) Syndrome    Venous incompetence (Varicose veins); Recurrent thrombosis and pulmonary embolism. This complicates ~50% (25-75%) of DVT.
  7. 7. Virchow’s Triad Risk Factors For Thrombosis  Altered Blood Flow/Venous stasis – – –  Vessel wall damage – – – –  Accidental trauma Surgical trauma Prior history of DVT Advanced Age Increase In Blood “Coagulability” – – – Kyrle & Eichinger. Blood, 2009 Immobilization Obesity Heart disease Increase in tissue factor Presence of activated factors Decrease in coagulation inhibitors
  8. 8. Thrombophilias
  9. 9. Endothelial Cell-Dependent Anticoagulant Processes      Heparan Sulfate: AT III Thrombomodulin: Protein C: Protein S ADPase (CD39) Tissue Factor Pathway Inhibitor Nitric Oxide
  10. 10. Heparan:Antithrombin III  Deficiency first described in 1965. – (Egeberg O. Inherited antithrombin III deficiency causing thrombophilia. Thromb Diath Haemorrh 13:516-30, 1965)   AT III neutralizes the active enzymes in the coagulation system. Dominant Inheritance.
  11. 11. Protein C/Protein S System  Constituents; – Protein C – Protein S – Thrombomodulin  Activated Protein C (With cofactor Protein S) inactivates Va and VIIIa, the cofactors of the cascade – (Probable role in augmenting fibrinolysis.)   Deficiencies are dominant (Usually). Homozygous individuals have purpura fulminans.
  12. 12. Factor V:Leiden/ Activated Protein C Resistance      Reduced neutralization of Factor Va by Activated Protein C. Genetically a balanced Polymorphism. Found predominantly in European populations (~37%), with ~1% in Indian subcontinent and Arabs. Heterozygotes (in isolation); ~3-4-fold increase risk in thrombosis. Homozygotes; ~ 50 fold increase in thrombotic risk.
  13. 13. Prothrombin Gene Mutation: (Prothrombin G20210A)   Genetic polymorphism associated with increased expression of the prothrombin mRNA, increased levels of prothrombin (Factor II), and a 2-3-fold increased risk of thrombosis. ~1.7-3% % of population in Europe and European ancestry. – Rosendaal, F. R. et al. Thromb. Haemost. 79: 706-708, 1998.  Arose approximately 24,000 years ago. – Zivelin et al. Blood 107: 4666-4668, 2006
  14. 14. Fibrinolytic Pathway  – Plasmin proteolyzes fibrin and fibrinogen  – u-PA (Urokinase-Plasminogen Activator) – Released by endothelial cells. Plasminogen; – Activated to Plasmin (a serine proteinase) Plasminogen Activators; – t-PA (Tissue-Plasminogen Activator)  Serpins – PAI-1, PAI-2; Plasminogen Activator Inhibitors – 2-Antiplasmin.
  15. 15. Homocysteine Metabolism  Elevated Homocysteine levels associated with increased incidence of both arterial and venous thrombosis.  Homocysteine (tHcy) levels decreased with folic acid or combination vitamin therapy.  den Heijer et al. Arterioscler Thromb Vasc Biol. 18:356, 1998.
  16. 16. Clinical and Diagnostic Laboratory Criteria for Antiphospholipid Syndrome (aPL)   Sydney Criteria (Revised Sapporo Criteria) Clinical — The presence of either vascular thrombosis or pregnancy morbidity, defined as follows: – Venous, arterial, or small vessel thrombosis (>1 Episode) – Pregnancy morbidity: • Unexplained fetal death at ≥10 weeks gestation of a morphologically normal fetus, or • >1 premature births before 34 weeks of gestation because of eclampsia, preeclampsia, or placental insufficiency, or • >3 embryonic (<10 week gestation) pregnancy losses unexplained by maternal or paternal chromosomal abnormalities or by maternal anatomic or hormonal causes.  Laboratory criteria: The presence of aPL, on two or more occasions at least 12 weeks apart – IgG and/or IgM aCL in moderate or high titer (>40 units GPL or MPL or >99th percentile). – Antibodies to ß2-glycoprotein I (anti-β2GPI) of IgG or IgM isotype at a titer >99th percentile. – Lupus anticoagulant (LA) activity detected according to published guidelines
  17. 17. Molecular/Biochemical Risk Factors Of Thromboembolic Disease  Common – G1691A mutation in the factor V gene (factor V Leiden) – G20210A mutation in the prothrombin (factor II) gene – Homocysteinemia  Rare – Antithrombin III deficiency – Protein C deficiency – Protein S deficiency  Very rare – Dysfibrinogenemia – Homozygous homocystinuria – Alterations in fibrinolysis.  Probably inherited – Increased levels of factors VIII, IX, XI, or fibrinogen.
  18. 18. Synergy of “Risk” Factors For Thrombosis    Most patients with a hereditary or other underlying risk for thrombosis do not experience a thrombosis. Thrombosis usually develops when there are multiple risk factors at the same time. Therefore need to consider a series of inherited and acquired risk factors. Risk Ratio of Thrombosis Estrogen Containing Contraceptives ~3-4-fold risk Factor V:Leiden ~3-4-fold risk Estrogen Containing Contraceptives Plus Factor V:Leiden ~40-Fold risk
  19. 19. Hypercoagulable Work-up  Why work-up? – Avoidance of oral contraceptives – Family knowledge   Consensus in Hematologic Community growing to not routinely do hypercoagulable workup. Studies fail to show recurrent VTE rates associated with thrombophilia
  20. 20. Risk of Recurrence Dependent on Underlying Thrombophilia. Baglin et al. The Lancet. 362: 523-526, 2003.   Presence of thrombophilia does predict risk of recurrence of thrombosis. Supports hypercoagulable testing for patients with an “unprovoked” initial thrombosis.
  21. 21. Hypercoagulable Work-Up (By Gerald A. Soff M.D.)  Thrombophilia Genetic polymorphism – Factor V:Leiden, Prothrombin G20210A Mutation – MTHFR (Not worth doing)       Protein C Protein S Antithrombin III Homocysteine Lupus Anticoagulant/Anticardiolipin Antibody Except for DNA analysis, do not work-up during acute event, pregnancy, oral contraceptives, acute medical/surgical illness.
  22. 22. Acute Management of Venous Thromboembolic Disease:    Randomized, controlled study of anticoagulation versus no treatment. Med/Surg. patients with PE (based on history, physical exam, pulmonary infarction on CXR, and right heart strain on EKG. Treatment: – Heparin 10,000 units q 6 hours, for 6 doses without laboratory control. – Acenocoumarol (Nicoumalone) adjusted for Prothrombin Time  Barritt, D. W. and S. C. Jordan. Lancet 1(7138): 1309-1312, 1960.
  23. 23. Prothrombin Time Titration of Vitamin K Antagonist. Target PT ratio 2-3 X Control
  24. 24. Results Group Total Deaths From PE Non-Fatal recurrences Other Deaths Untreated 19 5 5 0 Treated 54 0 1 2   Interim analysis resulted in early termination of untreated group. Deaths in Treatment Arm: – 1 death from aspiration pneumonia – 1 death related to medication error. Patient received phenindione instead of Acenocoumarol and developed renal failure. – Barritt, D. W. and S. C. Jordan (1960). Lancet 1(7138): 1309-1312.
  25. 25. Vitamin K Pathway/Warfarin
  26. 26. How Long To Treat With Anticoagulation After VTE?   Balance risk of recurrent VTE with risk of bleeding. Not all “bad” outcomes are equally bad. – Mild-moderate recurrent DVT, requires continued/resumption of anticoagulation. – But hemorrhagic CVA leads to severe debility. – Do not keep on life-time anticoagulation to avoid need to go back on anticoagulation.
  27. 27. Risk of Recurrence Dependent on Risk at Time of Intial Venous Thromboembolism. Baglin et al. The Lancet. 362: 523-526, 2003. Unprovoked Non-surgical triggers Post-operative    Post-operative thrombosis have very low recurrence rate. (Removal of risk) Non-surgical triggers (Reduced risk) Unprovoked: No reduction in risk factors, presumably hereditary.
  28. 28. How Long To Treat DVT?   Short-term treatment to help resolve initial VTE. Longterm treatment to reduce risk of recurrent VTE. Recurrences more likely during the initial 3 weeks of treatment. – – – – Cancer (odds ratio 2.7), Chronic cardiovascular disease (OR 2.3), Chronic respiratory disease (OR 1.9) Other clinically significant medical disease (OR 1.8). – Bounameaux & Perrier. ASH Education Book, 2008.
  29. 29. Annualized risk of recurrent VTE: First unprovoked VTE By D-dimer levels  Bauer, K, ASH Education Book, 2010.
  30. 30. Risks for Recurrent VTE After Initial Unprovoked VTE:       Post-Thrombotic Syndrome Positive D-Dimer Obesity, BMI > 30 Older Age, Different studies, > 50 yr, >65 Yr., Male Past Hormone Use (less likely)
  31. 31. How Long To Treat DVT? Indication 8th ACCP Guideline First episode of VTE secondary to a transient risk factor 3 months First episode of idiopathic (unprovoked) VTE At 3 months, if favorable Risk:Benefit ratio, consider long-term treatment. Long term. Other (recurrent, active cancer, etc.)
  32. 32. Aspirin and VTE Extended Prevention Brighton TA, et al. N Engl J Med. 2012, 367:1979-87
  33. 33. Bleeding With Anticoagulants  Heparin: – Major bleeding: 0.8% per day – Fatality rate: 0.05% per day  Oral anticoagulants: – Major bleeding: 0.4% per month. – Bounameaux & Perrier. ASH Education Book, 2008
  34. 34. Thrombolysis In Pulmonary Embolism  For massive Pulmonary Embolism: – Shock – Right heart strain – Thrombolytics indicated for reduction in shortterm mortality.  For submassive PE: – Improved rate of resolution with thrombolytics, but benefit does not persist after one month.
  35. 35. PEITHO Study: Pulmonary Embolism Thrombolysis  Evaluation of thrombolysis in PE patients who are hemodynamically stable, but have: – A. RV dysfunction or – B. Myocardial Injury
  36. 36. PEITHO Study: Pulmonary Embolism Thrombolysis 7 Day Endpoints Tenecteplase Placebo (n=506) (n=499) P All‐cause mortality 1.2% 1.8% 0.43 Hemodynamic Collapse 1.6% 5.0% 0.002 PE recurrence 0.2% 1.0% 0.13 Non-intracranial major bleeding 6.3% 1.5% <0.01 All Stroke 2.4% 0.2% 0.003 Serious adverse events 5.7% 7.8% 0.19
  37. 37. Low Molecular Weight Heparin in Obese or Mildly Renal Impairment     The literature is not clear on dosing in obese (i.e. over >120 Kg), or those with mild renal impairment. One should monitor and adjust therapy, in these patients with anti-Xa assays. Anti-Xa:Treatment Dose: 0.7-1.1 units/mL Anti-Xa: Prophylactic Dose: 0.2-0.3 units/mL.
  38. 38. Compression Hose Reduces Development of Post-Thrombotic Syndrome Prandoni et al. Ann. Intern. Med. 141:249-245, 2004.      Anticoagulation was continued for those with underlying/persistent risks. Hose used for two years, and reevaluation done at 5 years. Control: 40% PTS Hose: 21% PTS (OR 52%)
  39. 39. Elastic Compression Stockings (ECS) To Prevent PTS    Active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in Centers in Canada and the USA. The primary outcome was PTS diagnosed at 6 months or later. The cumulative incidence of PTS was 14.2% in active ECS versus 12.7% in placebo ECS. – Kahn S et al. The Lancet, 6 December 2013.
  40. 40. New Oral Anticoagulants: (Direct) , © 2011 American Chemical Society
  41. 41. EINSTEIN: Rivaroxaban For Venous Thrombosis Treatment  EINSTEIN-DVT and EINSTEIN-PE: – Rivaroxaban 15 mg bid for 3 weeks followed by 20 mg once-daily – Enoxaparin 1 mg/kg twice-daily (> 5 days), plus vitamin K antagonist (INR 2.0-3.0) – (Allowed up to 48 hours of IV heparin, LMWH, Fondaparinux before enrollment.)  EINSTEIN Extension: – Rivaroxaban 20 mg once-daily versus placebo in patients who have already completed 6 or 12 months of Rivaroxaban or a vitamin K antagonist.   Primary Endpoint: Symptomatic, recurrent VTE Principle Safety Endpoint: Major bleeding and clinically relevant non-major bleeding. – Active cancer: Rivaroxaban, n=118 (6.8%), Control, n=89 (5.2%)
  42. 42. Cumulative Event Rates for the Primary Efficacy Outcome in the DVT and PE Studies. Acute Treatment Extended Treatment The EINSTEIN Investigators. NEJM 2010;363:2499-2510. P<0.001 for noninferiority P<0.001 for superiority
  43. 43. Cumulative Event Rates for the Principal Safety Outcome in the Acute DVT Study. The EINSTEIN Investigators. NEJM 2010;363:2499-2510.
  44. 44. Rivaroxaban (Xarelto®)       15 mg twice daily with food for the first 3 weeks after an acute DVT or PE, 20 mg once daily with food after those first 3 weeks and for the long-term prevention of another clot. No need for acute treatment with LMWH or heparin when treating acute VTE. The half-life of 5-9 hrs (given normal renal function). No established monitoring tool No reversal agent.
  45. 45. Inferior Vena Cava Filters     Mechanical device inserted into the IVC to “catch” emboli, and prevent life-threatening pulmonary emboli. Short-term protection from Pulmonary Embolism, Long-term increased risk of thrombosis. New generation of removable filters.
  46. 46. Did Not Cover    Prophylaxis HITT Cancer-Associated Thrombosis