VENOUS THROMBOEMBOLIC DISEASE

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VENOUS THROMBOEMBOLIC DISEASE

• R. Duncan Hite, MD
• Section on Pulmonary and Critical Care Medicine

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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 death

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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 - Rxd
  Baclofen), Smoker
• Exam HR 107, BP 124/82, SaO2 93 (RA), Afeb,
  tenderness over R ribs, coarse breath sounds on
  R, normal LEs.
• Tests Nml CBC, CXR w/ vague infiltrate in
  RUL
• Dx Costochondritis - Rxd with NSAIDs
• July 10 - F/U w/PCP - Dxed with pneumonia -
  Rxd w/Biaxin
• July 12 - returns to ED with presyncope, N/V -
  D/Cd home
• - returns 2 hours later with PEA arrest
  and dies
• - autopsy -- massive PE

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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. Dxed with CHF and
  given diuretics. PPD.
• Early August - referred to Pulmonary Clinic for
  persistent cough, SOB and effusion. ? CA v. TB.

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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.
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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 (Virchows 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

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Pulmonary Hypertension Hemodynamic Effects
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Pulmonary Hypertension Hemodynamic Effects
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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

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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)
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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
• 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)
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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)
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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)
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Deep Venous ThrombosisPrevention
Samama, etal NEJM, 1999, 341, 793.
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Deep Venous ThrombosisPrevention
Samama, etal NEJM, 1999, 341, 793.
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Deep Venous ThrombosisPrevention
Samama, etal NEJM, 1999, 341, 793.
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Deep Venous ThrombosisPrevention
Samama, etal NEJM, 1999, 341, 793.
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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

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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

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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

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Pulmonary EmbolismDiagnosis - V/Q Scan
PIOPED. JAMA, 1990, 263, 2753.
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Pulmonary EmbolismClinical Presentation D-dimer
Ginsberg, Ann Int Med, 1998, 129, 1006.
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Pulmonary EmbolismClinical Presentation D-dimer
Ginsberg, Ann Int Med, 1998, 129, 1006.
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Pulmonary EmbolismClinical Presentation D-dimer
Ginsberg, Ann Int Med, 1998, 129, 1006.
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Pulmonary EmbolismDiagnosis - Pulmonary
Arteriogram

• Remains gold standard for Dx of PE
• Expensive
• Low morbidity and mortality
• Mortality
• Major morbidity
• Pulmonary Hypertension not a contraindication

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Pulmonary EmbolismDiagnosis - Pulmonary
Arteriogram
Lobar Defect
Normal
Segmental Defect
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Pulmonary EmbolismDiagnosis - Chest CT
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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

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Pulmonary Emboli Diagnosis - MRA
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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

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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.

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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

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Venous ThromboembolismOutpatient LMWH
5,323
Total mean costs per patient (CAN)
P 2,278
Enoxaparin sodium
Unfractionated heparin
OBrien et al. Arch Int Med. 19991592298-2304.
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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 (??)

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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

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Venous ThromboembolismTreatment

• Oral anticoagulation (Ximelagatran)
• Direct Thrombin inhibitor
• BID oral therapy
• Does not require dose monitoring

Francis, etal. Ann Int Med,, 2002, 137, 648.
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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

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