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  1. 1. VENOUS THROMBOEMBOLIC DISEASE R. Duncan Hite, MD Section on Pulmonary and Critical Care Medicine
  2. 2. Venous Thromboembolic Disease <ul><li>Venous thrombosis - ~ 5 million pts yearly </li></ul><ul><ul><ul><li>Most caused by inadequate prophylaxis in hospitalized pts </li></ul></ul></ul><ul><li>10 % suffer pulmonary embolism ~ 500,000 </li></ul><ul><li>~ 1% of all hospitalized pts have PE </li></ul><ul><li>Contributes to 6 % of all hospital deaths </li></ul><ul><li>~ 125,000 deaths annually from PE </li></ul><ul><ul><ul><li>3rd most common cardiovascular cause of death (MI, CVA) </li></ul></ul></ul><ul><ul><ul><li>Most deaths occur early – PREVENTION IS KEY !! </li></ul></ul></ul><ul><li>Diagnosis of PE made in < 30% when contributes to death; < 10% if incidental </li></ul>
  3. 4. CASE 1 <ul><li>July 8 - 37 yo WM presents to the ED with right sided pleuritic chest pain x 24 hours. No fever or cough. Minimal SOB. Denies chest trauma. </li></ul><ul><ul><li>PMH: bronchitis/sinusitis, Multiple Sclerosis x 5 years (uses cane, + muscle spasms - Rx’d Baclofen), Smoker </li></ul></ul><ul><ul><li>Exam: HR 107, BP 124/82, SaO 2 93% (RA), Afeb, tenderness over R ribs, coarse breath sounds on R, normal LE’s. </li></ul></ul><ul><ul><li>Tests: Nml CBC, CXR w/ “vague” infiltrate in RUL </li></ul></ul><ul><li>Dx: Costochondritis - Rx’d with NSAIDs </li></ul><ul><li>July 10 - F/U w/PCP - Dx’ed with pneumonia - Rx’d w/Biaxin </li></ul><ul><li>July 12 - returns to ED with presyncope, N/V - D/C’d home </li></ul><ul><ul><li>- returns 2 hours later with PEA arrest and dies </li></ul></ul><ul><ul><li>- autopsy -- massive PE </li></ul></ul>
  4. 5. CASE 2 <ul><li>Early June - 52 yo BM admitted for acute AMI requiring cardiac cath and PTCA of LAD. Requires mechanical ventilation x 5 days, ICU x 7 days and in hospital x 10 days. ECHO prior to d/c reveals EF of approx 25%. </li></ul><ul><li>Late June - pt readmitted for W/U of persistent leukocytosis noted on earlier admission. Undergoes BM Bx with findings consistent with CML. Discharged to home after 3 days. </li></ul><ul><li>Early July (5 days post d/c) - Seen in walk-in clinic for non-productive cough and SOB. CXR clear. Dx: bronchitis </li></ul><ul><li>Mid July - symptoms persist/worse. Repeat CXR reveals new LLL effusion. Dx’ed with CHF and given diuretics. + PPD. </li></ul><ul><li>Early August - referred to Pulmonary Clinic for persistent cough, SOB and effusion. ? CA v. TB. </li></ul>
  5. 6. CASE 3 - 43 yo AA male truck driver who has bilateral knee injuries while playing basketball. Requires bilateral knee repairs requiring fixation of both lower extremities for 6 - 8 weeks. Received appropriate DVT prophylaxis during hospital stay. - Returns to the ED 4 weeks later with chest pain, SOB and hypoxemia. Has massive PE by CT angiogram and pulmonary hypertension/RV dilation by echocardiogram. - Given TPA with good clinical response.
  6. 7. Venous Thromboembolic Disease Epidemiology <ul><li>85-90% of PE pts have DVT risk factors </li></ul><ul><li>90-95% of PEs arise from lower ext. DVT </li></ul><ul><li>Defined DVT Risk Factors: (Virchow’s Triad) </li></ul><ul><ul><li>Venous stasis - CHF, Immobility, Age > 70, Travel, Obesity, Recent surgery (4 weeks) or hospitalization (6 mos) </li></ul></ul><ul><ul><li>Venous Injury - Prior DVT/PE, LE Trauma/Surgery </li></ul></ul><ul><ul><ul><ul><li>LE trauma or surgery - Very high (50+%) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Major surgery - (5 - 8%) </li></ul></ul></ul></ul><ul><ul><li>Hypercoaguability - Cancer, Pregnancy, Nephrotic Syndrome, Hyperhomocysteinemia, Factor V Leyden mutation, Deficiency of Protein C/S or ATIII, Anti Phospholipid Ab, HITTS, Smoking </li></ul></ul>
  7. 8. Deep Venous Thrombosis Diagnosis <ul><li>Venography - remains the “gold standard” </li></ul><ul><ul><ul><li>Pitfalls: Difficult to perform, expensive, contrast load, DVT </li></ul></ul></ul><ul><li>Compression Ultrasound ( Sonography, Duplex and Color Doppler ) </li></ul><ul><ul><ul><li>Criteria: echogenicity, noncompressibility, distension, free floating thrombus, absence of Doppler waveform, Abnormal color image </li></ul></ul></ul><ul><ul><ul><li>Accuracy: </li></ul></ul></ul><ul><ul><ul><ul><li>Symptomatic Patients: Sensitivity = 90-100%, Specificity = 95-100% </li></ul></ul></ul></ul><ul><ul><ul><ul><li>High Risk Asymptomatic: Sensitivity = 50-80%, Specificity = 95-100% </li></ul></ul></ul></ul><ul><li>Impedance Plethysmography </li></ul><ul><li>Radionuclide Venography ( Indium-111 ) </li></ul><ul><li>MRI - increasing popularity and utilization, includes deep pelvic veins </li></ul>
  8. 9. Deep Venous Thrombosis Prevention <ul><li>ACCP Consensus Guidelines </li></ul><ul><li> Chest , 2004, 126 (3), Sept Supplement </li></ul><ul><li>Includes: </li></ul><ul><li>Prevention of venous thromboembolism </li></ul><ul><li>Antithrombotic therapy for venous thrombo-embolic disease </li></ul><ul><li>Antithrombotic therapy for: </li></ul><ul><li>Afib, MI, CVA, Valvular Heart Do, PVD </li></ul><ul><li>Heparin-induced thrombocytopenia </li></ul><ul><li>Anticoagulants </li></ul>
  9. 10. Deep Venous Thrombosis Prevention <ul><li>Orthopedic Surgery </li></ul><ul><li>Other Surgery (General, Urologic, Vascular, Gyn) </li></ul><ul><li>Neurosurgery </li></ul><ul><li>Trauma, Spinal Cord Injury, Burns </li></ul><ul><li>Medical (General, Cancer, Critical Care) </li></ul><ul><li>Long Distance Travel </li></ul>ACCP Consensus Statement. Chest , 2004, 126 (3), Sept suppl.
  10. 11. Deep Venous Thrombosis Prevention Samama, etal NEJM , 1999, 341, 793.
  11. 12. Deep Venous Thrombosis Prevention Samama, etal NEJM , 1999, 341, 793.
  12. 13. Deep Venous Thrombosis Prevention Samama, etal NEJM , 1999, 341, 793.
  13. 14. PE SIGNS AND SYMPTOMS <ul><li>Symptoms </li></ul><ul><li>Dyspnea - 80% </li></ul><ul><li>Chest pain - 70% </li></ul><ul><li>Cough - 50% </li></ul><ul><li>Apprehension - 50% </li></ul><ul><li>Hemoptysis - 30% </li></ul><ul><li>Signs </li></ul><ul><li>Tachycardia - 60% </li></ul><ul><li>Tachypnea - 70% </li></ul><ul><li>Fever - 60% </li></ul><ul><li>Clinical DVT - 30% </li></ul>
  14. 15. Pulmonary Embolism Diagnosis <ul><li>Chest x-ray - nonspecific abnormalities in most; normal early </li></ul><ul><ul><ul><li>Westermark's sign and Hampton's hump uncommon </li></ul></ul></ul><ul><li>Arterial blood gas – hypoxemia is common </li></ul><ul><ul><ul><li>15 - 20% will not manifest hypoxemia (i.e. normal A-a gradient) </li></ul></ul></ul><ul><li>ECG – nonspecific changes typically </li></ul><ul><ul><ul><li>S 1 Q 3 T 3 pattern in massive PE with RV strain </li></ul></ul></ul><ul><ul><ul><li>helpful in evaluating other causes of chest pain </li></ul></ul></ul>
  15. 16. PE – V/Q LUNG SCAN <ul><li>Radiolabeled Xenon inhaled for ventilation and radiolabeled Technetium for perfusion </li></ul><ul><li>Safe </li></ul><ul><li>Not very specific </li></ul><ul><li>Not very useful if pre-existing lung disease </li></ul>
  16. 17. Pulmonary Embolism Diagnosis - V/Q Scan PIOPED. JAMA , 1990, 263, 2753.
  17. 18. Pulmonary Embolism Clinical Presentation: D-dimer Ginsberg, Ann Int Med , 1998, 129, 1006.
  18. 19. Pulmonary Embolism Clinical Presentation: D-dimer Ginsberg, Ann Int Med , 1998, 129, 1006.
  19. 20. Pulmonary Embolism Probability Assessment Ginsberg, Ann Int Med , 1998, 129, 1006.
  20. 21. Pulmonary Embolism Probability Assessment Anand, Wells, etal. JAMA , 1998, 279, 1094.
  21. 22. Pulmonary Embolism Probability Assessment Anand, Wells, etal. Ann Int Med , 2005, 143, 129.
  22. 23. Pulmonary Embolism Diagnosis - Chest CT
  23. 24. <ul><li>Accurate for segmental or larger PE </li></ul><ul><ul><ul><li>Sensitivity 85 - 95% (Overall 50-60%) </li></ul></ul></ul><ul><ul><ul><li>Specificity 90 - 100% </li></ul></ul></ul><ul><li>Accuracy depends on interpreter </li></ul><ul><ul><ul><li>Large Inter-interpreter variability </li></ul></ul></ul><ul><ul><ul><li>Reduced accuracy with less experience </li></ul></ul></ul><ul><li>Significant contrast load ~ 65% of PA gram </li></ul><ul><li>Similar expense to Pulmonary Arteriogram </li></ul><ul><li>Can identify other pulmonary etiologies </li></ul>Pulmonary Embolism Diagnosis - Chest CT
  24. 25. Pulmonary Embolism Diagnosis - Pulmonary Arteriogram <ul><li>Remains “gold standard” for Dx of PE </li></ul><ul><li>Expensive </li></ul><ul><li>Low morbidity and mortality </li></ul><ul><ul><li>Mortality < 0.1% </li></ul></ul><ul><ul><li>Major morbidity < 0.5% </li></ul></ul><ul><ul><li>Pulmonary Hypertension not a contraindication </li></ul></ul>
  25. 26. Pulmonary Embolism Diagnosis - Pulmonary Arteriogram Lobar Defect Normal Segmental Defect
  26. 27. Pulmonary Emboli Diagnosis - MRA Oudkerk, etal. Lancet , 2002, 359, 1643.
  27. 28. Venous Thromboembolism Treatment <ul><li>Continuous IV Heparin: </li></ul><ul><ul><li>Begin when PE suspected - bolus dose </li></ul></ul><ul><ul><li>Continue for 7 - 10 days overlap with warfarin </li></ul></ul><ul><ul><li>Permits fibrinolytic system (plasmin) to lyse clot </li></ul></ul><ul><ul><li>Inhibits further clot formation / propagation </li></ul></ul><ul><ul><li>Give adequate dose! </li></ul></ul><ul><ul><ul><li>Recurrence higher with lower doses </li></ul></ul></ul><ul><ul><ul><li>Weight based bolus with “protocol” for adjustments </li></ul></ul></ul><ul><ul><li>Emphasis on PTT probably excessive </li></ul></ul><ul><ul><ul><li>PTT not direct measure of antithrombotic effect </li></ul></ul></ul><ul><ul><ul><li>PTT does not correlate with bleeding complications </li></ul></ul></ul>
  28. 29. Venous Thromboembolism Treatment <ul><li>Low Molecular Weight Heparins: </li></ul><ul><ul><li>Dosing: (Lovenox) </li></ul></ul><ul><ul><ul><li>Prophylaxis: 30 mg BID </li></ul></ul></ul><ul><ul><ul><li>Treatment: 1 mg/kg twice daily or 1.5 mg/kg qday (max 150 mg) </li></ul></ul></ul><ul><ul><li>Less monitoring (Factor Xa assay) </li></ul></ul><ul><ul><ul><li>Two Exceptions: </li></ul></ul></ul><ul><ul><ul><ul><li>Obesity </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Renal Failure </li></ul></ul></ul></ul><ul><ul><li>Cross Reactive with Heparin Antibodies </li></ul></ul><ul><ul><ul><li>Less immunogenic if used primarily </li></ul></ul></ul>Molecular weight (daltons) 10,000 15,000 5,000 5,400
  29. 30. Heparin-Induced Antibodies HITTS <ul><li>Clinicopathologic Syndrome : </li></ul><ul><ul><ul><li>Unexplained  50% decrease in platelets (even if absolute total > 150) </li></ul></ul></ul><ul><ul><ul><li>Positive test for Heparin antibodies </li></ul></ul></ul><ul><ul><ul><ul><ul><li>Activation assay (more relevant but more difficult) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Antigen assay </li></ul></ul></ul></ul></ul><ul><li>Types : </li></ul><ul><ul><li>Type I </li></ul></ul><ul><ul><ul><li>begins early (few hours) after starting heparin </li></ul></ul></ul><ul><ul><ul><li>typically benign with plts usually staying > 100K. No Rx needed. </li></ul></ul></ul><ul><ul><li>Type II </li></ul></ul><ul><ul><ul><li>begins several days into treatment (unless previously sensitized) </li></ul></ul></ul><ul><ul><ul><li>High risk for thrombotic complications. Requires Rx. </li></ul></ul></ul>
  30. 31. Venous Thromboembolism Outpatient LMWH Enoxaparin sodium Unfractionated heparin $2,278 $5,323 Total mean costs per patient (CAN) P  0.0001 95% CI $2,012 to $4,050 O’Brien et al. Arch Int Med . 1999;159:2298-2304.
  31. 32. Venous Thromboembolism Treatment <ul><li>Synthetic Heparins: </li></ul><ul><li>Fondaparinux (Arixtra) </li></ul><ul><ul><li>Trials: </li></ul></ul><ul><ul><ul><li>DVT Prevention in Orthopedic Surgery </li></ul></ul></ul><ul><ul><ul><ul><li> Lancet , 2002, 359, 1715-26 </li></ul></ul></ul></ul><ul><ul><li>Dosing: </li></ul></ul><ul><ul><ul><li>Prophylaxis: 2.5 mg qday </li></ul></ul></ul><ul><ul><li>Less monitoring (Factor Xa assay) </li></ul></ul><ul><ul><ul><li>Not recommended in renal failure </li></ul></ul></ul><ul><ul><li>Does not cause Heparin Antibodies (??) </li></ul></ul>
  32. 33. Venous Thromboembolism Treatment <ul><li>Oral anticoagulation (Coumadin): </li></ul><ul><ul><li>Inhibits synthesis of Vitamin K dependent factors </li></ul></ul><ul><ul><ul><li>PT sensitive to Factor VII - short half-life -correlates with bleeding risk </li></ul></ul></ul><ul><ul><ul><li>Thrombosis related to Factors II and X - longer half-life </li></ul></ul></ul><ul><ul><li>Overlap with heparin or LMWH until PT therapeutic for 3 - 5 days </li></ul></ul><ul><ul><ul><li>Coumadin decreases Protein C and S levels more quickly </li></ul></ul></ul><ul><ul><li>Warfarin load (high dose) not useful </li></ul></ul><ul><ul><li>Target INR range = 2.0 - 3.0 </li></ul></ul><ul><ul><li>Continue anticoagulation for 3 months to lifetime depending on # events and risk factors. </li></ul></ul>
  33. 34. Venous Thromboembolism Treatment - Thrombolytics <ul><li>Massive Pulmonary Embolism </li></ul><ul><ul><li>Significant hemodynamic compromise present </li></ul></ul><ul><ul><li>Evidence of RV failure on Echocardiogram (?) </li></ul></ul><ul><li>Phlegmasia Cerulea Dolens </li></ul><ul><li>Agents studied </li></ul><ul><ul><li>Streptokinase - 250,000 U load; 100,000 U/hr x 24hrs </li></ul></ul><ul><ul><li>Urokinase - 4,400 U load; 2,200 U/hr x 12 hrs </li></ul></ul><ul><ul><li>tPA - 100mg over 2 hrs </li></ul></ul>
  34. 35. Pulmonary Hypertension Hemodynamic Effects  PAP  PVR  RV/RA  CO  RVEDV  LVEDV  CO  HR  BP  SVR
  35. 36. Pulmonary Embolism Treatment - Thrombolytics Konstantinides, etal. N Engl J Med , 2002, 347, 1143.
  36. 37. Inferior Vena Cava Filter <ul><li>Indications : </li></ul><ul><ul><li>Intolerance to anticoagulation** </li></ul></ul><ul><ul><li>Recurrent PE despite adequate anticoagulation </li></ul></ul><ul><ul><li>Chronic PE with Pulm HTN </li></ul></ul><ul><ul><li>Surgical removal of acute or chronic PE </li></ul></ul><ul><ul><li>Massive PE (?) </li></ul></ul><ul><li>Outcomes : </li></ul><ul><ul><li> PE rate,  DVT rate, Mortality unchanged </li></ul></ul><ul><ul><li>Decousos, etal. ( NEJM , 1998, 338, 409 ) - no benefit </li></ul></ul><ul><ul><ul><li>Pts with contraindication/failure of anticoagulation excluded </li></ul></ul></ul><ul><li>CONTINUE ANTICOAGULATION! - if possible </li></ul>Ballew etal. Clin Chest Med , 1995, 16, 295.

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