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VENOUS THROMBOEMBOLIC DISEASE

VENOUS THROMBOEMBOLIC DISEASE. R. Duncan Hite, MD Section on Pulmonary and Critical Care Medicine. Venous Thromboembolic Disease. Venous thrombosis - ~ 5 million pts yearly Most caused by inadequate prophylaxis in hospitalized pts 10 % suffer pulmonary embolism ~ 500,000

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VENOUS THROMBOEMBOLIC DISEASE

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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. 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, SaO2 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

  4. 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.

  5. 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. - 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. Venous Thromboembolic DiseaseEpidemiology • 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

  7.  PAP  PVR  RV/RA  CO  RVEDV  LVEDV  CO  HR  BP  SVR Pulmonary Hypertension Hemodynamic Effects

  8. Pulmonary Hypertension Hemodynamic Effects

  9. Deep Venous ThrombosisDiagnosis • 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

  10. Deep Venous ThrombosisPrevention • Orthopedic Surgery • LMWH or Coumadin (INR 2.0 - 3.0) beginning preoperatively or immediately postoperatively. Adjusted dose SQ Heparin is an acceptable alternative but more complex. • Adjuvant use of mechanical devices may add additional benefit. May be sufficient as primary prophylaxis for TKR if used optimally. • Low dose SQ Hep, Aspirin, IPC alone are not recommended (less effective). • Duration: • minimum of 7-10 days • Post Discharge Prophylaxis: 4-6 weeks for high risk patients ACCP Consensus Statement. Chest, 2001, 199 (Supp 1)

  11. Deep Venous ThrombosisPrevention • General Surgery (including Urologic) • Prophylaxis with SQHep, LMWH, ES or IPC • Moderate Risk - minor procedure with a risk factor or 40-60 yo, major procedures and <40 • High Risk - minor procedure with risk factors or >60, major procedures with risk factors or age >40. • Increased Risk of Bleeding - use ES or IPC • Combination therapy: very high risk - multiple risk factors • Postdischarge Prophylaxis: selected very high risk pts ACCP Consensus Statement. Chest, 2001, 199 (Supp 1)

  12. Deep Venous ThrombosisPrevention • Gynecologic Surgery • Major surgery for benign disease • SQ Hep BID, LMWH, IPC, continue for several days post op • Major surgery for malignancy • SQ Hep TID, Combination AC/Mech, high dose LMWH • Neurosurgery • Intracranial Surgery • IPC or ES, Low dose SQHep or LMWH may be acceptable • Combination IPC or ES with SQHep or LMWH in high risk ACCP Consensus Statement. Chest, 2001, 199 (Supp 1)

  13. Deep Venous ThrombosisPrevention • Trauma • LMWH as soon as possible • IPC or ES until LMWH started • Acute Spinal Cord Injury • LMWH recommended • Low dose SQHep, ES or IPC are less effective • Combination Mechanical/anticoagulant may be acceptable • Continue throughout rehabilatation • Medical(Cancer, CHF, Bedrest, MI, CVA…) • Low dose SQ Hep or LMWH • IPC if anticoagulation contraindicated ACCP Consensus Statement. Chest, 2001, 199 (Supp 1)

  14. Deep Venous ThrombosisPrevention Samama, etal NEJM, 1999, 341, 793.

  15. Deep Venous ThrombosisPrevention Samama, etal NEJM, 1999, 341, 793.

  16. Deep Venous ThrombosisPrevention Samama, etal NEJM, 1999, 341, 793.

  17. Deep Venous ThrombosisPrevention Samama, etal NEJM, 1999, 341, 793.

  18. 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%

  19. Pulmonary EmbolismDiagnosis • 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 • S1Q3T3 pattern in massive PE with RV strain • helpful in evaluating other causes of chest pain

  20. 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

  21. Pulmonary EmbolismDiagnosis - V/Q Scan PIOPED. JAMA, 1990, 263, 2753.

  22. Pulmonary EmbolismClinical Presentation: D-dimer Ginsberg, Ann Int Med, 1998, 129, 1006.

  23. Pulmonary EmbolismClinical Presentation: D-dimer Ginsberg, Ann Int Med, 1998, 129, 1006.

  24. Pulmonary EmbolismClinical Presentation: D-dimer Ginsberg, Ann Int Med, 1998, 129, 1006.

  25. Pulmonary EmbolismDiagnosis - 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 EmbolismDiagnosis - Pulmonary Arteriogram Normal Lobar Defect Segmental Defect

  27. Pulmonary EmbolismDiagnosis - Chest CT

  28. Pulmonary EmbolismDiagnosis - Chest CT • 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

  29. Oudkerk, etal. Lancet, 2002, 359, 1643. Pulmonary Emboli Diagnosis - MRA

  30. Venous ThromboembolismTreatment 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

  31. Heparin-Induced AntibodiesHITTS • 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.

  32. 5,400 10,000 5,000 15,000 Molecular weight (daltons) Venous ThromboembolismTreatment 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 • Possibly less immunogenic if used primarily

  33. Venous ThromboembolismOutpatient LMWH $5,323 Total mean costs per patient (CAN) P < 0.0001 95% CI $2,012 to $4,050 $2,278 Enoxaparin sodium Unfractionated heparin O’Brien et al. Arch Int Med. 1999;159:2298-2304.

  34. Venous ThromboembolismTreatment 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 (??)

  35. Venous ThromboembolismTreatment 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 4 - 6 months

  36. Venous ThromboembolismTreatment Oral anticoagulation (Ximelagatran): • Direct Thrombin inhibitor • BID oral therapy • Does not require dose monitoring Francis, etal. Ann Int Med,, 2002, 137, 648.

  37. Venous ThromboembolismTreatment - Thrombolytics • Massive Pulmonary Embolism • Significant hemodynamic compromise present • Evidence of RV failure on Echocardiogram • Controversial • 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

  38. Pulmonary EmbolismTreatment - Thrombolytics Konstantinides, etal. N Engl J Med, 2002, 347, 1143.

  39. 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 anticoagualtion excluded • CONTINUE ANTICOAGULATION! - if possible Ballew etal. Clin Chest Med, 1995, 16, 295.

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