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Vte path and rx

Vte path and rx

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Vte path and rx

  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 Vs Superficial Veins http://www.worldwidewounds.com/2002/september/Johnson/Compression-Hosiery-Leg-Ulcers.html
  5. 5. 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.
  6. 6. Pulmonary Embolism  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.
  7. 7. Post-Thrombotic (Phlebitic) Syndrome  Venous incompetence (Varicose veins);  Recurrent thrombosis and pulmonary embolism.  This complicates ~50% (25-75%) of DVT.
  8. 8. Virchow’s Triad Risk Factors For Thrombosis  Altered Blood Flow/Venous stasis  Immobilization  Obesity  Heart disease  Vessel wall damage  Accidental trauma  Surgical trauma  Prior history of DVT  Advanced Age  Increase In Blood “Coagulability”  Increase in Tissue Factor  Presence of activated factors  Decrease in coagulation inhibitors  CancerKyrle & Eichinger. Blood, 2009
  9. 9. Thrombophilias
  10. 10. Endothelial Cell-Dependent Anticoagulant Processes  Heparan Sulfate: AT III  Thrombomodulin: Protein C: Protein S  ADPase (CD39)  Tissue Factor Pathway Inhibitor  Nitric Oxide
  11. 11. 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.
  12. 12. 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.
  13. 13. 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 (~3- 7%), with ~1% in Indian subcontinent and Arabs.  Heterozygotes (in isolation); ~3-4-fold increase risk in thrombosis.  Homozygotes; ~ 50 fold increase in thrombotic risk.
  14. 14. 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
  15. 15. Fibrinolytic Pathway  Plasminogen;  Activated to Plasmin (a serine proteinase)  Plasmin proteolyzes fibrin and fibrinogen  Plasminogen Activators;  t-PA (Tissue-Plasminogen Activator)  u-PA (Urokinase- Plasminogen Activator)  Released by endothelial cells.  Serpins  PAI-1, PAI-2; Plasminogen Activator Inhibitors  2-Antiplasmin. http://rarecoagulationdisorders.org/wp- content/uploads/2013/03/Journal-Figure- 6.15.00_Kohler.jpg
  16. 16. 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. http://what- when- how.com/acp- medicine/thro mbotic- disorders- part-2/
  17. 17. 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
  18. 18. Hemostatic Abnormalities Associated With Thrombophilia  Franchini et al, Thrombosis and Haemostasis, 2015
  19. 19. 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
  20. 20. 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 hereditary thrombophilia.
  21. 21. 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.
  22. 22. 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.
  23. 23. 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.
  24. 24. 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.
  25. 25. Prothrombin Time Titration of Vitamin K Antagonist. Target PT ratio 2-3 X Control
  26. 26. Results  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. Group Total Deaths From PE Non-Fatal recurrences Other Deaths Untreated 19 5 5 0 Treated 54 0 1 2
  27. 27. Vitamin K Pathway/Warfarin
  28. 28. 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.
  29. 29. Risk of Recurrence Dependent on Risk at Time of Intial Venous Thromboembolism. Baglin et al. The Lancet. 362: 523-526, 2003.  Post-operative thrombosis have very low recurrence rate. (Removal of risk)  Non-surgical triggers (Reduced risk)  Unprovoked: No reduction in risk factors, presumably hereditary. Post-operative Non-surgical triggers Unprovoked
  30. 30. How Long To Treat DVT?  Short-term treatment to help resolve initial VTE. Long- term treatment to reduce risk of recurrent VTE.  Recurrences more likely during the initial 3 weeks of treatment.  Idiopathic VTE vs. Secondary VTE: OR: 2.4  Cancer: OR 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.
  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. Other (recurrent, active cancer, etc.) Long term.
  32. 32. Risks for Recurrent VTE After Initial Unprovoked VTE:  Post-Thrombotic Syndrome  Obesity, BMI > 30  Older Age, Different studies, > 50 yr, >65 Yr.,  Male  Past Hormone Use (lower risk of recurrent VTE)  D-Dimer (?)  Residual Thrombus (?)
  33. 33. “Indefinite” Anticoagulation After Initial Unprovoked VTE?  Elevated D-Dimer after completion of anticoagulation.  Data weak  Residual Thrombus  Data weak  Post-Thrombotic Syndrome
  34. 34. Annualized Risk of Recurrent VTE: First Unprovoked VTE By D-Dimer Levels. Levels done several weeks after completion of anticoagulation.  Bauer, K, ASH Education Book, 2010.
  35. 35. D-Dimer and Risk of Recurrent VTE  “The risk for recurrence in patients with a first unprovoked VTE who have negative D-dimer results is not low enough to justify stopping anticoagulant therapy in men but may be low enough to justify stopping therapy in women.  Kearon et al. Ann Intern Med. 2015;162:27-34. doi:10.7326/M14-1275
  36. 36. Association Between Residual Vein Obstruction And Recurrent VTE After First Episode of DVT (Provoked or Unprovoked) Following At Least 3 Months Of Anticoagulation.  Carrier et al, Journal of Thrombosis and Haemostasis, 9: 1119–1125, 2011.
  37. 37. Thrombolysis In Pulmonary Embolism For massive Pulmonary Embolism: Shock Right heart strain  Thrombolytics indicated for reduction in short- term mortality. For submassive PE: Improved rate of resolution with thrombolytics, but benefit does not persist after one month.
  38. 38. PEITHO Study: Pulmonary Embolism Thrombolysis  Evaluation of thrombolysis in PE patients who are hemodynamically stable, but have: A. RV dysfunction or B. Myocardial Injury Meyer et al. NEJM 370:15, 2014
  39. 39. PEITHO Study: Pulmonary Embolism Thrombolysis 7 Day Endpoints Tenecteplase (n=506) Placebo (n=499) P All‐cause mortality 1.2% 1.8% 0.42 Hemodynamic Collapse 1.6% 5.0% 0.002 PE Recurrence 0.2% 1.0% 0.13 Non-intracranial major bleeding 6.3% 1.2% <0.001 All Stroke 2.4% 0.2% 0.003 Hemorrhagic stroke 2.0% 0.2% Serious adverse events 10.9% 11.8% 0.63 Meyer et al. NEJM 370:15, 2014
  40. 40. 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.
  41. 41. 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%)
  42. 42. Cumulative Incidence of Post-Thrombotic Syndrome With Compression Hose  Active versus placebo ECS.  30-40 mm Hg vs < 5 mm Hg.  Kahn et al, Lancet, 2014
  43. 43. 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 et al, Lancet, 2014
  44. 44. New Oral Anticoagulants To Be Fully Discussed in Upcoming Talk
  45. 45. Adapted from Soff, Arteriosclerosis, Thrombosis, and Vascular Biology 2012, 32:569-574.
  46. 46. FDA Approved Direct Anticoagulants Dabigatran. Pradaxa ® Rivaroxaban. Xarelto ® Apixaban. Eliquis ® Edoxaban Savaysa ® Non-Valvular Atrial Fibrillation + + + +* VTE Prophylaxis after knee and hip replacement surgery Failed + + Treatment of DVT/PE +** + + +** • * Less effective in AF patients with CrCl >95 mL/min. • ** Not validated as initial anticoagulation.
  47. 47. NOAC For DVT/PE  Rivaroxaban May start as initial anticoagulant. Non-inferior to enoxaparin-warfarin for safety and efficacy  Apixaban May start as initial anticoagulant Non-inferior to enoxaparin-warfarin for efficacy Superior to enoxaparin-warfarin for safety  Dabigatran Requires parenteral anticoagulant for 5-10 days. Non-inferior to warfarin for safety and efficacy.
  48. 48. 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.
  49. 49. Did Not Cover  Prophylaxis  HITT  Cancer-Associated Thrombosis

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