Venous Thromboembolism

  • Diagnosis
  • Monitoring
  • Pharmacogenetics
  • Background
  • Lab Tests
  • References
  • Related Content

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 – high sensitivity d-dimer testing
    • Enzyme immunoassay and immunoturbidimetric methods available
    • 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 in the absence of thromboembolic disease
        • Pregnant 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
        • Elderly patients (>80 years)
        • Hospitalized patients
      • Performance of d-dimer antigen test varies between labs; understanding the performance characteristics of the testing lab is essential
    • Follow up thrombophilia testing not warranted in first DVT with a risk factor or patient with factors suggesting underlying thrombophilia (eg, recurrent DVT/PE, atypical site, recurrent pregnancy loss) – ASCP's Pathology-Related Choosing Wisely Recommendations, 2015; Society for Vascular Medicine

Imaging Studies

  • Duplex venous ultrasound (DVT)
    • DVT 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
    • Contrast venography, although gold standard, is rarely used and has been replaced by duplex venous ultrasound
  • Pulmonary embolism (PE) angiography
    • Gold standard
    • 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

  • 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
  • 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

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
  • PE
    • Dyspnea, pleuritic chest pain, hemoptysis, low-grade fever, tachycardia, split S2 heart sound on cardiac auscultation, syncope, decreased oxygen saturation

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

Venous Thromboembolism (VTE), Qualitative 0030070
Method: Immunoassay

Limitations

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

Follow Up

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

Partial Thromboplastin Time 0030235
Method: Electromagnetic Mechanical Clot Detection

Additional Tests Available

Heparin Anti-Xa, Unfractionated 0030143
Method: Chromogenic Assay

Comments

Monitor heparin anticoagulation in patients with an abnormal baseline PTT

Prothrombin Time/International Normalized Ratio 0030224
Method: Electromagnetic Mechanical Clot Detection

Comments

Monitor oral anticoagulation therapy (warfarin/Coumadin)

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

Comments

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

Comments

Identify common inherited thrombotic risk factors

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

Comments

Identify less-common inherited thrombotic risk factors

Thrombotic Risk, DNA Panel 0056200
Method: Polymerase Chain Reaction

Comments

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

D-Dimer 0030057
Method: Immunoturbidimetry

Comments

Should not be used to rule out VTE

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

Comments

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

Warfarin Sensitivity, CYP2C9 and VKORC1, 3 Variants 2012772
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Comments

Identify individuals with inherited variants that affect metabolism and/or sensitivity to warfarin

Clinical sensitivity – ~90% in Caucasians when both CYP2C9 and VKORC1 are performed; less characterized in other populations

Analytical sensitivity and specificity – >99% for CYP2C9 and VKORC1 

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

Guidelines

American Society for Clinical Pathology. Choosing Wisely - Pathology-Related Choosing Wisely Recommendations. An initiative of the ABIM Foundation. [Initial posting Feb 2015; Accessed: Nov 2015]

Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines . American College of Chest Physicians - Medical Specialty Society. 2001 January (Revised 2012 February). NGC: 008932

British Thoracic Society Standards of Care Committee Pulmonary Embolism Guideline Development Group. British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax. 2003; 58(6): 470-83. PubMed

NCCN Clinical Practice Guidelines in Oncology, Cancer-Associated Venous Thromboembolic Disease. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jun 2015]

General References

Adam S, Key N, Greenberg C. D-dimer antigen: current concepts and future prospects. Blood. 2009; 113(13): 2878-87. PubMed

Baglin T. Using the laboratory to predict recurrent venous thrombosis. Int J Lab Hematol. 2011; 33(4): 333-42. PubMed

Douma R, Mos I, Erkens P, Nizet T, Durian M, Hovens M, van Houten A, Hofstee H, Klok F, Cate H, Ullmann E, Büller H, Kamphuisen P, Huisman M, Prometheus Study Group. Performance of 4 clinical decision rules in the diagnostic management of acute pulmonary embolism: a prospective cohort study. Ann Intern Med. 2011; 154(11): 709-18. PubMed

Galioto N, Danley D, Van Maanen R. Recurrent venous thromboembolism. Am Fam Physician. 2011; 83(3): 293-300. PubMed

Hunt J, Bull T. Clinical review of pulmonary embolism: diagnosis, prognosis, and treatment. Med Clin North Am. 2011; 95(6): 1203-22. PubMed

Le Gal G, Carrier M, Rodger M. Clinical decision rules in venous thromboembolism. Best Pract Res Clin Haematol. 2012; 25(3): 303-17. PubMed

Magaña M, Bercovitch R, Fedullo P. Diagnostic approach to deep venous thrombosis and pulmonary embolism in the critical care setting. Crit Care Clin. 2011; 27(4): 841-67, vi. PubMed

Somarouthu B, Abbara S, Kalva S. Diagnosing deep vein thrombosis. Postgrad Med. 2010; 122(2): 66-73. PubMed

Stein P, Woodard P, Weg J, Wakefield T, Tapson V, Sostman D, Sos T, Quinn D, Leeper K, Hull R, Hales C, Gottschalk A, Goodman L, Fowler S, Buckley J, PIOPED II investigators. Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II investigators. Am J Med. 2006; 119(12): 1048-55. PubMed

Tan M, Huisman M. The diagnostic management of acute venous thromboembolism during pregnancy: recent advancements and unresolved issues. Thromb Res. 2011; 127 Suppl 3: S13-6. PubMed

Tripodi A. D-dimer testing in laboratory practice. Clin Chem. 2011; 57(9): 1256-62. PubMed

Wells P. Integrated strategies for the diagnosis of venous thromboembolism. J Thromb Haemost. 2007; 5 Suppl 1: 41-50. PubMed

Wilbur J, Shian B. Diagnosis of deep venous thrombosis and pulmonary embolism. Am Fam Physician. 2012; 86(10): 913-9. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Diaz A, Rodgers G, Gilreath J. Enoxaparin once daily vs. twice daily dosing for the treatment of venous thromboembolism in cancer patients: a literature summary. J Oncol Pharm Pract. 2012; 18(2): 264-70. PubMed

Heikal N, Murphy K, Crist R, Wilson A, Rodgers G, Smock K. Elevated factor IX activity is associated with an increased odds ratio for both arterial and venous thrombotic events. Am J Clin Pathol. 2013; 140(5): 680-5. PubMed

Horne B, Lenzini P, Wadelius M, Jorgensen A, Kimmel S, Ridker P, Eriksson N, Anderson J, Pirmohamed M, Limdi N, Pendleton R, McMillin G, Burmester J, Kurnik D, Stein M, Caldwell M, Eby C, Rane A, Lindh J, Shin J, Kim H, Angchaisuksiri P, Glynn R, Kronquist K, Carlquist J, Grice G, Barrack R, Li J, Gage B. Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb Haemost. 2012; 107(2): 232-40. PubMed

La'ulu S, Dominguez C, Roberts W. Performance characteristics of the AxSYM D-dimer assay. Clin Chim Acta. 2008; 390(1-2): 148-51. PubMed

Lehman C, Rettmann J, Wilson L, Markewitz B. Comparative performance of three anti-factor Xa heparin assays in patients in a medical intensive care unit receiving intravenous, unfractionated heparin. Am J Clin Pathol. 2006; 126(3): 416-21. PubMed

Rondina M, Pendleton R, Wheeler M, Rodgers G. The treatment of venous thromboembolism in special populations. Thromb Res. 2007; 119(4): 391-402. PubMed

Shirts B, Rodgers G, Smock K. Prothrombin time, activated partial thromboplastin time and dilute Russell's Viper Venom times are not shorter in patients with the prothrombin G20210A mutation, and dilute Russell's Viper Venom time may be longer. Thromb Res. 2012; 130(3): e134-8. PubMed

Win K, Rodgers G. New oral anticoagulants may not be effective to prevent venous thromboembolism in patients with antiphospholipid syndrome. Am J Hematol. 2014; 89(10): 1017. PubMed

Medical Reviewers

Last Update: January 2016