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VENOUS THROMBOEMBOLIC DISEASE

R. Duncan Hite, MDSection 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• ~ 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

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

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.

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.

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

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

Deep Venous ThrombosisPrevention

• ACCP Consensus Guidelines Chest, 2004, 126 (3), Sept Supplement

Includes:Prevention of venous thromboembolismAntithrombotic therapy for venous

thrombo-embolic diseaseAntithrombotic therapy for:

Afib, MI, CVA, Valvular Heart Do, PVD

Heparin-induced thrombocytopenia

Anticoagulants

Deep Venous ThrombosisPrevention

• 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.

Deep Venous ThrombosisPrevention

Samama, etal Samama, etal NEJMNEJM, 1999, 341, , 1999, 341, 793.793.

Deep Venous ThrombosisPrevention

Samama, etal Samama, etal NEJMNEJM, 1999, 341, , 1999, 341, 793.793.

Deep Venous ThrombosisPrevention

Samama, etal Samama, etal NEJMNEJM, , 1999, 341, 793.1999, 341, 793.

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%

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• S1Q3T3 pattern in massive PE with RV strain

• helpful in evaluating other causes of chest pain

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

Pulmonary EmbolismDiagnosis - V/Q Scan

CLINICAL PROBABILITY Scan Prob High Intermed. Low

High 96%(28/29)

88%(70/80)

56%(5/9)

Int./Ind. 66%(27/41)

28%(66/236)

16%(11/68)

Low 40%(6/15)

16%(30/191)

4%(4/90)

Normal 0%(0/5)

6%(4/62)

2%(1/61)

PIOPED. JAMA, 1990, 263, 2753.

Pulmonary EmbolismClinical Presentation: D-dimer

Pts w/ PE Pts w/o PEPre-TestProbability

+ D-dimer - D-dimer + D-dimer - D-dimer

Low 19 5 163 516

Moderate 81 20 136 145

High 67 5 11 9

Ginsberg, Ann Int Med, 1998, 129, 1006.

Pulmonary EmbolismClinical Presentation: D-dimer

Pts w/ PE Pts w/o PELungScan + D-dimer - D-dimer + D-dimer - D-dimer

Normal 3 1 73 242

Indeterminate 40 12 227 419

High Prob 124 17 10 9

Ginsberg, Ann Int Med, 1998, 129, 1006.

Pulmonary EmbolismProbability Assessment

Ginsberg, Ann Int Med, 1998, 129, 1006.

Pulmonary EmbolismProbability Assessment

Anand, Wells, etal. JAMA, 1998, 279, 1094.

Pulmonary EmbolismProbability Assessment

Anand, Wells, etal. Ann Int Med, 2005, 143, 129.

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

Pulmonary EmbolismDiagnosis - Chest CT

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

Pulmonary EmbolismDiagnosis - Pulmonary Arteriogram

Lobar DefectNormal Segmental Defect

Pulmonary Emboli Diagnosis - MRA

AngiogramMRA

PE + PE - Total

PE + 27 2 29

PE - 8 81 89

Total 35 83 118

Oudkerk, etal. Lancet, 2002, 359, 1643.

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

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• Less immunogenic if used primarily

Molecular weight (daltons)

10,000 15,0005,000

5,400

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.

Venous ThromboembolismOutpatient LMWH

Enoxaparin sodium

Unfractionated heparin

$2,278

$5,323

To

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P 0.0001

95% CI $2,012 to $4,050

O’Brien et al. O’Brien et al. Arch Int MedArch Int Med. . 1999;159:2298-2304.1999;159:2298-2304.

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 (??)

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 3 months to lifetime

depending on # events and risk factors.

Venous ThromboembolismTreatment - 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

Pulmonary Hypertension Hemodynamic Effects

PAP PVR

RV/RA CO RVEDV

LVEDV CO HR

BP SVR

Pulmonary EmbolismTreatment - Thrombolytics

Konstantinides, etal. N Engl J Med, 2002, 347, 1143.

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.