Venous Thromboembolism

Diagnosis

Indications for Testing

  • Risk factors for VTE with other symptoms such as shortness of breath, extremity swelling/pain/heaviness, swelling in face or neck
    • May mimic other conditions, so a high index of suspicion is necessary

Criteria for Diagnosis

  • DVT – use Wells Clinical Prediction Rule to establish pretest probability (not validated in pregnant women)
    • 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)
      • Previously documented DVT
    • Score negative 2 points for
      • Alternative diagnosis at least as likely as DVT
    • Total score for clinical probability – <2 = unlikely, >2 = likely
  • PE – use Wells Clinical Prediction Rule to establish pretest probability (not validated in pregnant women)
    • Score +3 points for
      • Clinical signs of DVT
      • Alternative diagnosis less likely than pulmonary embolism
    • Score +1.5 points for
      • Previous pulmonary embolism or DVT
      • 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

  • Initial testing – sensitive d-dimer testing in conjunction with duplex ultrasound for DVT (may also include ventilation/perfusion scanning to rule out PE)
    • Low probability by Wells – negative d-dimer plus low pretest probability virtually excludes DVT and PE
      • False-positives may occur (may have variable sensitivity and specificity depending on patient population)
      • Results must be interpreted in the context of clinical presentation
    • High probability by Wells and/or positive d-dimer – follow with ultrasound
      • 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
          • Use is limited in pregnancy
            • D-dimer rises in first trimester
            • ≥35 weeks, all d-dimers >500 μg/L
            • Low level combined with low probability virtually excludes DVT
      • Performance of d-dimer antigen test varies between labs; understanding the performance characteristics of the testing lab is essential
    • Follow up thrombophilia testing often not warranted unless patient has factors suggesting underlying thrombophilia (eg, recurrent DVT/PE, atypical site, recurrent pregnancy loss)

Imaging Studies

  • Suspected extremity thromboembolism
    • Duplex venous ultrasound has high sensitivity (89-100%) and specificity (86-100%) for proximal symptomatic DVT, poor sensitivity for calf-vein and pelvic DVT
      • Sensitivity and specificity decrease in third trimester of pregnancy
    • Gold standard testing – arteriography or helical CT/CT angiography for PE
      • Contrast venography, although gold standard, is rarely used and has been replaced by duplex venous ultrasound
    • Suspected pulmonary embolism 
      • Negative d-dimer, low pretest probability, and negative helical CT – associated with <1.5% subsequent fatal or nonfatal VTE
      • Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED II) offers algorithms for PE diagnosis in patients from low- and moderate- to high-probability categories
      • Ventilation/perfusion (V/Q) scan or CT scan in pregnant women if ultrasound is negative

Prognosis

  • Two- to eightfold increase in mortality in cancer patients

Differential Diagnosis

Monitoring

  • INR – standard monitoring for warfarin therapy
  • PTT – standard monitoring for unfractionated heparin therapy
  • Heparin anti-Xa tests – monitor low molecular weight heparin therapy when indicated

Pharmacogenetics and Therapeutic Drug Monitoring

  • Warfarin (Coumadin®) has potentially severe hemorrhagic or thrombotic consequences if dosed incorrectly
  • Warfarin inhibits production of vitamin K-dependent coagulation factors through inhibition of vitamin K epoxide reductase
    • Response to warfarin therapy is routinely assessed through prothrombin time/INR testing
  • Warfarin is metabolized in the liver by cytochrome P450 enzymes
    • S-warfarin, the more potent of the two enantiomers, is metabolized primarily by CYP2C9
    • Warfarin has a narrow therapeutic index that is influenced by a variety of drugs and illnesses
  • Pharmacogenetics affect dosing
    • CYP2C9 genotype accounts for up to 18% of the variability in warfarin dosing
      • Variant alleles reduce warfarin clearance, which affects the time required to reach steady state warfarin concentrations
    • VKORC1 genotype accounts for up to 29% of the variability in warfarin dosing
    • Combining genotypes with clinical factors may account for 50-70% of variability in warfarin dosing
  • Consider CYP2C9 and VKORC1 genotyping in warfarin-naïve patients and those with a history of previous difficulty in anticoagulation
  • Clinical dosing of warfarin – genotype-based dosing of warfarin; many algorithms and models for dosing are available

Clinical Background

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

Epidemiology

  • Incidence
    • 1-2/1,000 for venous thromboembolic disease (VTE)
    • Estimated 5 million DVT patients annually
      • 20% have cancer etiology
    • 500,000 develop pulmonary emboli (PE) 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 cancers of pancreas, ovary, lung, urinary tract, breast, brain, stomach
    • Odds ratio of 7.0
    • Neutropenia associated with even higher risks
  • 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, congestive heart failure, and stroke
  • Hypercoagulable statesanti-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, syncope, decreased oxygen saturation

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 the following
        • Partial thromboplastin time (PTT) – unfractionated heparin
        • Heparin anti-Xa test – low molecular weight heparin (if monitoring is indicated)
      • 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

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

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 occur more frequently in this population

Due to a poor positive predictive value, positive results cannot be used alone for determination of DVT/PE

Positive result necessitates further investigation to rule out DVT or PE, including any of the following – duplex venous ultrasound, venography, ventilation/perfusion, helical CT scan, or angiography

Heparin Anti-Xa, Unfractionated 0030143
Method: Chromogenic Assay

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 therapy (warfarin/Coumadin)

   
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 NumberComments
Thrombotic Risk (Acquired) Reflexive Panel 0030268
Method: Electromagnetic Clot Detection/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Immunoturbidimetry/Quantitative Enzymatic

Identify acquired thrombotic risk factors, including lupus anticoagulant

If PTT and dRVVT are normal, then no further testing is performed; if PTT is abnormal, Thrombin Time is added; if Thrombin Time is normal, PTT 1:1 mix is added;  if Thrombin time is abnormal, Reptilase Time and PTT Heparin Neutralization is added; if PTT Heparin Neutralization is abnormal, PTT 1:1 mix is added; if PTT 1:1 mix is abnormal, Platelet Neutralization procedure is added; if dRVVT is abnormal, dRVVT 1:1 mix is added; if dRVVT 1:1 mix is abnormal, dRVVT confirmation is added; if Platelet Neutralization procedure and dRVVT confirmation are normal or if one is normal and the other not done, Hexagonal Phospholipid Neutralization is added

Thrombotic Risk, Inherited Etiologies (Most Common) with Reflex to Factor V Leiden 0030133
Method: Electromagnetic Clot Detection/Quantitative Enzymatic/Polymerase Chain Reaction/Fluorescence Monitoring

Identify common inherited thrombotic risk factors

Thrombotic Risk, Inherited Etiologies (Uncommon) 0030177
Method: Electromagnetic Clot Detection/Microlatex Particle-Mediated Immunoassay/Chromogenic Assay

Identify less-common inherited thrombotic risk factors

Thrombotic Risk, DNA Panel 0056200
Method: Polymerase Chain Reaction

Includes Factor V Leiden (F5) R506Q, MTHFR 2 mutations (c.665C>T and c.1286A>C), and prothrombin (F2) G20210A mutations

D-Dimer 0030057
Method: Immunoturbidimetry

Should not be used to rule out VTE

Heparin Anti-Xa, Low Molecular Weight Heparin 0030144
Method: Chromogenic Assay

Antithrombin III deficiency or platelet factor 4 release may lead to underestimation of the heparin level

Warfarin Sensitivity (CYP2C9 and VKORC1 ) 3 Mutations 0051370
Method: Polymerase Chain Reaction/DNA Hybridization/Electrochemical Detection

Confirm genotype affecting warfarin metabolism

Clinical sensitivity – 90% in Caucasians; detection rate in other ethnicities is reduced

Counseling and informed consent are recommended for genetic testing

Factor V Leiden (F5) R506Q Mutation 0097720
Method: Polymerase Chain Reaction/Fluorescence Monitoring