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  • 1. VENOUS THROMBOEMBOLIC DISEASE R. Duncan Hite, MD Section on Pulmonary and Critical Care Medicine
  • 2. Venous Thromboembolic Disease
    • Venous thrombosis - ~ 5 million pts yearly
        • Most caused by inadequate prophylaxis in hospitalized pts
    • 10 % suffer pulmonary embolism ~ 500,000
    • ~ 1% of all hospitalized pts have PE
    • Contributes to 6 % of all hospital deaths
    • ~ 125,000 deaths annually from PE
        • 3rd most common cardiovascular cause of death (MI, CVA)
        • Most deaths occur early – PREVENTION IS KEY !!
    • Diagnosis of PE made in < 30% when contributes to death; < 10% if incidental
  • 3.  
  • 4. CASE 1
    • 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.
      • PMH: bronchitis/sinusitis, Multiple Sclerosis x 5 years (uses cane, + muscle spasms - Rx’d Baclofen), Smoker
      • Exam: HR 107, BP 124/82, SaO 2 93% (RA), Afeb, tenderness over R ribs, coarse breath sounds on R, normal LE’s.
      • Tests: Nml CBC, CXR w/ “vague” infiltrate in RUL
    • Dx: Costochondritis - Rx’d with NSAIDs
    • July 10 - F/U w/PCP - Dx’ed with pneumonia - Rx’d w/Biaxin
    • July 12 - returns to ED with presyncope, N/V - D/C’d home
      • - returns 2 hours later with PEA arrest and dies
      • - autopsy -- massive PE
  • 5. CASE 2
    • 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%.
    • 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.
    • Early July (5 days post d/c) - Seen in walk-in clinic for non-productive cough and SOB. CXR clear. Dx: bronchitis
    • Mid July - symptoms persist/worse. Repeat CXR reveals new LLL effusion. Dx’ed with CHF and given diuretics. + PPD.
    • Early August - referred to Pulmonary Clinic for persistent cough, SOB and effusion. ? CA v. TB.
  • 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.
  • 7. Venous Thromboembolic Disease Epidemiology
    • 85-90% of PE pts have DVT risk factors
    • 90-95% of PEs arise from lower ext. DVT
    • Defined DVT Risk Factors: (Virchow’s Triad)
      • Venous stasis - CHF, Immobility, Age > 70, Travel, Obesity, Recent surgery (4 weeks) or hospitalization (6 mos)
      • Venous Injury - Prior DVT/PE, LE Trauma/Surgery
          • LE trauma or surgery - Very high (50+%)
          • Major surgery - (5 - 8%)
      • Hypercoaguability - Cancer, Pregnancy, Nephrotic Syndrome, Hyperhomocysteinemia, Factor V Leyden mutation, Deficiency of Protein C/S or ATIII, Anti Phospholipid Ab, HITTS, Smoking
  • 8. Deep Venous Thrombosis Diagnosis
    • Venography - remains the “gold standard”
        • Pitfalls: Difficult to perform, expensive, contrast load, DVT
    • Compression Ultrasound ( Sonography, Duplex and Color Doppler )
        • Criteria: echogenicity, noncompressibility, distension, free floating thrombus, absence of Doppler waveform, Abnormal color image
        • Accuracy:
          • Symptomatic Patients: Sensitivity = 90-100%, Specificity = 95-100%
          • High Risk Asymptomatic: Sensitivity = 50-80%, Specificity = 95-100%
    • Impedance Plethysmography
    • Radionuclide Venography ( Indium-111 )
    • MRI - increasing popularity and utilization, includes deep pelvic veins
  • 9. Deep Venous Thrombosis Prevention
    • ACCP Consensus Guidelines
    • Chest , 2004, 126 (3), Sept Supplement
    • Includes:
    • Prevention of venous thromboembolism
    • Antithrombotic therapy for venous thrombo-embolic disease
    • Antithrombotic therapy for:
    • Afib, MI, CVA, Valvular Heart Do, PVD
    • Heparin-induced thrombocytopenia
    • Anticoagulants
  • 10. Deep Venous Thrombosis Prevention
    • Orthopedic Surgery
    • Other Surgery (General, Urologic, Vascular, Gyn)
    • Neurosurgery
    • Trauma, Spinal Cord Injury, Burns
    • Medical (General, Cancer, Critical Care)
    • Long Distance Travel
    ACCP Consensus Statement. Chest , 2004, 126 (3), Sept suppl.
  • 11. Deep Venous Thrombosis Prevention Samama, etal NEJM , 1999, 341, 793.
  • 12. Deep Venous Thrombosis Prevention Samama, etal NEJM , 1999, 341, 793.
  • 13. Deep Venous Thrombosis Prevention Samama, etal NEJM , 1999, 341, 793.
  • 14. PE SIGNS AND SYMPTOMS
    • Symptoms
    • Dyspnea - 80%
    • Chest pain - 70%
    • Cough - 50%
    • Apprehension - 50%
    • Hemoptysis - 30%
    • Signs
    • Tachycardia - 60%
    • Tachypnea - 70%
    • Fever - 60%
    • Clinical DVT - 30%
  • 15. Pulmonary Embolism Diagnosis
    • Chest x-ray - nonspecific abnormalities in most; normal early
        • Westermark's sign and Hampton's hump uncommon
    • Arterial blood gas – hypoxemia is common
        • 15 - 20% will not manifest hypoxemia (i.e. normal A-a gradient)
    • ECG – nonspecific changes typically
        • S 1 Q 3 T 3 pattern in massive PE with RV strain
        • helpful in evaluating other causes of chest pain
  • 16. PE – V/Q LUNG SCAN
    • Radiolabeled Xenon inhaled for ventilation and radiolabeled Technetium for perfusion
    • Safe
    • Not very specific
    • Not very useful if pre-existing lung disease
  • 17. Pulmonary Embolism Diagnosis - V/Q Scan PIOPED. JAMA , 1990, 263, 2753.
  • 18. Pulmonary Embolism Clinical Presentation: D-dimer Ginsberg, Ann Int Med , 1998, 129, 1006.
  • 19. Pulmonary Embolism Clinical Presentation: D-dimer Ginsberg, Ann Int Med , 1998, 129, 1006.
  • 20. Pulmonary Embolism Probability Assessment Ginsberg, Ann Int Med , 1998, 129, 1006.
  • 21. Pulmonary Embolism Probability Assessment Anand, Wells, etal. JAMA , 1998, 279, 1094.
  • 22. Pulmonary Embolism Probability Assessment Anand, Wells, etal. Ann Int Med , 2005, 143, 129.
  • 23. Pulmonary Embolism Diagnosis - Chest CT
  • 24.
    • Accurate for segmental or larger PE
        • Sensitivity 85 - 95% (Overall 50-60%)
        • Specificity 90 - 100%
    • Accuracy depends on interpreter
        • Large Inter-interpreter variability
        • Reduced accuracy with less experience
    • Significant contrast load ~ 65% of PA gram
    • Similar expense to Pulmonary Arteriogram
    • Can identify other pulmonary etiologies
    Pulmonary Embolism Diagnosis - Chest CT
  • 25. Pulmonary Embolism Diagnosis - Pulmonary Arteriogram
    • Remains “gold standard” for Dx of PE
    • Expensive
    • Low morbidity and mortality
      • Mortality < 0.1%
      • Major morbidity < 0.5%
      • Pulmonary Hypertension not a contraindication
  • 26. Pulmonary Embolism Diagnosis - Pulmonary Arteriogram Lobar Defect Normal Segmental Defect
  • 27. Pulmonary Emboli Diagnosis - MRA Oudkerk, etal. Lancet , 2002, 359, 1643.
  • 28. Venous Thromboembolism Treatment
    • Continuous IV Heparin:
      • Begin when PE suspected - bolus dose
      • Continue for 7 - 10 days overlap with warfarin
      • Permits fibrinolytic system (plasmin) to lyse clot
      • Inhibits further clot formation / propagation
      • Give adequate dose!
        • Recurrence higher with lower doses
        • Weight based bolus with “protocol” for adjustments
      • Emphasis on PTT probably excessive
        • PTT not direct measure of antithrombotic effect
        • PTT does not correlate with bleeding complications
  • 29. Venous Thromboembolism Treatment
    • Low Molecular Weight Heparins:
      • Dosing: (Lovenox)
        • Prophylaxis: 30 mg BID
        • Treatment: 1 mg/kg twice daily or 1.5 mg/kg qday (max 150 mg)
      • Less monitoring (Factor Xa assay)
        • Two Exceptions:
          • Obesity
          • Renal Failure
      • Cross Reactive with Heparin Antibodies
        • Less immunogenic if used primarily
    Molecular weight (daltons) 10,000 15,000 5,000 5,400
  • 30. Heparin-Induced Antibodies HITTS
    • Clinicopathologic Syndrome :
        • Unexplained  50% decrease in platelets (even if absolute total > 150)
        • Positive test for Heparin antibodies
            • Activation assay (more relevant but more difficult)
            • Antigen assay
    • Types :
      • Type I
        • begins early (few hours) after starting heparin
        • typically benign with plts usually staying > 100K. No Rx needed.
      • Type II
        • begins several days into treatment (unless previously sensitized)
        • High risk for thrombotic complications. Requires Rx.
  • 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.
  • 32. Venous Thromboembolism Treatment
    • Synthetic Heparins:
    • Fondaparinux (Arixtra)
      • Trials:
        • DVT Prevention in Orthopedic Surgery
          • Lancet , 2002, 359, 1715-26
      • Dosing:
        • Prophylaxis: 2.5 mg qday
      • Less monitoring (Factor Xa assay)
        • Not recommended in renal failure
      • Does not cause Heparin Antibodies (??)
  • 33. Venous Thromboembolism Treatment
    • Oral anticoagulation (Coumadin):
      • Inhibits synthesis of Vitamin K dependent factors
        • PT sensitive to Factor VII - short half-life -correlates with bleeding risk
        • Thrombosis related to Factors II and X - longer half-life
      • Overlap with heparin or LMWH until PT therapeutic for 3 - 5 days
        • Coumadin decreases Protein C and S levels more quickly
      • Warfarin load (high dose) not useful
      • Target INR range = 2.0 - 3.0
      • Continue anticoagulation for 3 months to lifetime depending on # events and risk factors.
  • 34. Venous Thromboembolism Treatment - Thrombolytics
    • Massive Pulmonary Embolism
      • Significant hemodynamic compromise present
      • Evidence of RV failure on Echocardiogram (?)
    • Phlegmasia Cerulea Dolens
    • Agents studied
      • Streptokinase - 250,000 U load; 100,000 U/hr x 24hrs
      • Urokinase - 4,400 U load; 2,200 U/hr x 12 hrs
      • tPA - 100mg over 2 hrs
  • 35. Pulmonary Hypertension Hemodynamic Effects  PAP  PVR  RV/RA  CO  RVEDV  LVEDV  CO  HR  BP  SVR
  • 36. Pulmonary Embolism Treatment - Thrombolytics Konstantinides, etal. N Engl J Med , 2002, 347, 1143.
  • 37. Inferior Vena Cava Filter
    • Indications :
      • Intolerance to anticoagulation**
      • Recurrent PE despite adequate anticoagulation
      • Chronic PE with Pulm HTN
      • Surgical removal of acute or chronic PE
      • Massive PE (?)
    • Outcomes :
      •  PE rate,  DVT rate, Mortality unchanged
      • Decousos, etal. ( NEJM , 1998, 338, 409 ) - no benefit
        • Pts with contraindication/failure of anticoagulation excluded
    • CONTINUE ANTICOAGULATION! - if possible
    Ballew etal. Clin Chest Med , 1995, 16, 295.
  • 38.  

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