Venous Thromboembolism

Clinical Background

Deep venous thrombosis (DVT) is the presence of thrombus in a vein with accompanying inflammation.

Epidemiology

Incidence
- 1/1,000 for venous thromboembolic disease (VTE)
- Estimated 5,000,000 DVT patients annually
- 500,000 pulmonary emboli (PE) develop from these DVTs
Sex – M>F (minimal)
- M<F during childbearing years
Ethnicity
- More common in Asians and Pacific Islanders
- Less common in Hispanics (2 to 4 times lower risk than Caucasians and African Americans)

Risk Factors

Surgery – highest risk with orthopedic operations
Neoplasms – highest risk with pancreas, ovary, lung, urinary tract, breast and stomach cancers
- Odds ratio of 7.0
Trauma – highest risk with fractures of the spine and lower extremities
Pregnancy – highest risk in 1st and 3rd trimesters
Hormone use – postmenopausal replacement, oral contraceptives, tamoxifen citrate
- Odds ratio of 2.0-4.0
Immobilization – highest risk with acute myocardial infarction (MI), congestive heart failure (CHF) and stroke
Hypercoagulable states – anti-phospholipid antibodies, activated protein C resistance/factor V Leiden mutation, prothrombin G20210A mutation, deficiencies of protein C, protein S, or antithrombin, elevated homocysteine
Previous DVT or PE
- Odds ratio as high as 15.6
Indwelling catheters – most common source of upper-extremity DVT
Age – risk increases incrementally with age

Pathophysiology

Factors that predispose to DVT were first described by Virchow in 1856
- Virchow triad – stasis, vascular damage and hypercoagulability
- Individual risk is the complex interaction of acquired risk factors and congenital (inherited) factors

Clinical Presentation

DVT
- Extremity pain and swelling, warmth and erythema, pain in the calf with foot dorsiflexion (Homans sign)
  - Usually unilateral
- Pulmonary embolism
  - Dyspnea, pleuritic chest pain, hemoptysis, low-grade fever, tachycardia, split S2 heart sound on cardiac auscultation

Treatment

Therapy is necessary for proximal DVT
Acute therapy:
- Low molecular weight heparin or unfractionated heparin
  - Fondaparinux in certain cases
  - More aggressive therapy is recommended for patients with large PE/DVT
  - Monitor therapy with partial thromboplastin time (PTT) (unfractionated heparin) and heparin anti-Xa test (low molecular weight heparin)
  - Outpatient therapy typically includes oral warfarin (length of treatment depends on clinical factors)
  - Monitor with International Normalized Ratio (INR) to ensure therapeutic range
Prophylaxis
- Depending on risk factors and risk of bleeding, consider use of anticoagulants, graduated compression stockings, or intermittent pneumatic compression

Diagnosis

Indications for testing – risk factors for VTE with other symptoms such as shortness of breath, leg swelling/pain
- May mimic other conditions, so a high index of suspicion is necessary
DVT – use Wells Clinical Prediction Rule to establish pretest probability
- Score +1 point for
  - Active cancer (treatment ongoing, within previous 6 months, or palliative)
  - Paralysis, paresis, or recent plaster immobilization of the lower extremities
  - Recently bedridden >3 days or major surgery within 12 weeks requiring general or regional anesthesia
  - Localized tenderness along the distribution of the deep venous system
  - Entire leg swollen
  - Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below tibial tuberosity)
  - Pitting edema confined to the symptomatic leg
  - Collateral superficial veins (nonvaricose)
  - Previous documented DVT
- Score negative 2 points for
  - Alternative diagnosis at least as likely as deep venous thrombosis
- Total score for clinical probability: <2 = unlikely, >2 = likely
PE – use Wells Clinical Prediction Rule to establish pretest probability
- Score +3 points for
  - Clinical signs of deep vein thrombosis
  - Alternative diagnosis less likely than pulmonary embolism
- Score +1.5 points for
  - Previous pulmonary embolism or deep vein thrombosis
  - Heart rate >100 beats per minute
  - Recent surgery or immobilization
- Score +1 point for
  - Hemoptysis
  - Cancer
- Total score for clinical probability: 0-1 = low, 2-6 = intermediate, ≥7 = high
Other clinical prediction rules include Charlotte and Geneva/modified Geneva
- Laboratory testing
  - Sensitive d-dimer testing in conjunction with duplex ultrasound for DVT (may also include ventilation/perfusion scanning to rule out PE)
    - Use for excluding diagnosis (negative d-dimer plus low pretest probability virtually excludes DVT and PE)
      - False-positives may occur
      - Results must be interpreted in the context of clinical presentation
    - D-dimer is sensitive but not specific for DVT and PE; do not use to exclude VTE in patient with high pretest probability
      - Certain patients may have elevated d-dimer values not due to thromboembolic disease
        D-dimer testing to exclude DVT/PE is less useful in hospitalized, pregnant, elderly (>80 years), and cancer patients
      - Performance of d-dimer antigen test varies between labs; understanding the performance characteristics of the testing lab is essential.
Imaging studies
- Suspected extremity thromboembolism
  - Doppler ultrasound has high sensitivity (89-100%) and specificity (86-100%) for proximal symptomatic DVT
- Suspected extremity thromboembolism
  - Gold standard testing is venography for DVT, arteriography or helical CT/CT angiography for PE
    - Negative d-dimer, low pretest probability and negative helical CT are associated with <1.5% subsequent fatal or nonfatal VTE
  - PIOPED II offers algorithms for PE diagnosis in patients from low-, moderate- and high-probability categories

Differential Diagnosis

Shortness of breath
- Pneumonia
- Congestive heart failure
- Acute coronary syndrome
- Sepsis
Swollen leg
- Cellulitis
- Lymphedema
- Venous stasis

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations
Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Recommended Use	Limitations	Follow Up
Venous Thromboembolism (VTE), Qualitative 0030070 Method: Enzyme Immunoassay	Use to rule out VTE in an outpatient setting Test is EIA for d-dimer; serves as one component of a clinical algorithm determining the likelihood VTE	Not recommended for inpatient testing due to poor specificity in that population Due to the relatively high prevalence of VTE in patients diagnosed with cancer, false-negative results may occur more frequently in this population Due to a poor positive predictive value, positive results are not clinically useful	Positive result necessitates further investigation to rule out DVT or PE, including any of the following – Doppler ultrasound, venography, helical CT scan or angiography
Heparin Anti-Xa, Low Molecular Weight Heparin 0030144 Method: Chromogenic/Inhibition of Xa	Monitor low molecular weight heparin therapy in pediatric patients or any patient with renal disease	Antithrombin III deficiency or platelet factor 4 release may lead to underestimation of the heparin level
Heparin Anti-Xa, Unfractionated 0030143 Method: Chromogenic Assay/Inhibition of Xa	Monitor heparin anticoagulation in patients with an abnormal baseline PTT	Antithrombin III deficiency or platelet factor 4 release may lead to underestimation of the heparin level
Prothrombin Time/International Normalized Ratio 0030224 Method: Electromagnetic Mechanical Clot Detection	Monitor oral anticoagulation (Warfarin, Coumadin)
Prothrombin Time 0030215 Method: Electromagnetic Mechanical Clot Detection	Screen for hemostasis
Partial Thromboplastin Time 0030235 Method: Electromagnetic Mechanical Clot Detection	Monitor heparin therapy

Additional Tests Available

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Thrombotic Risk (Acquired) Reflexive Panel 0030268 Method: Refer to individual components
D-Dimer 0030057 Method: Immunoturbidimetric	Should not be used to rule out VTE