Venous Thromboembolism

  • Diagnosis
  • Monitoring
  • Pharmacogenetics
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

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
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.

D-Dimer for Venous Thromboembolism

Partial Thromboplastin Time 0030235
Method: Electromagnetic Mechanical Clot Detection

Guidelines

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

Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Nov 2016]

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

Raja AS, Greenberg JO, Qaseem A, Denberg TD, Fitterman N, Schuur JD, Clinical Guidelines Committee of the American College of Physicians. Evaluation of Patients With Suspected Acute Pulmonary Embolism: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians Ann Intern Med. 2015; 163(9): 701-11. PubMed

General References

Adam SS, Key NS, Greenberg CS. 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 RA, Mos IC, Erkens PM, Nizet TA, Durian MF, Hovens MM, van Houten AA, Hofstee HM, Klok FA, Cate Ht, Ullmann EF, Büller HR, Kamphuisen PW, Huisman MV, 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 NJ, Danley DL, Van Maanen RJ. Recurrent venous thromboembolism. Am Fam Physician. 2011; 83(3): 293-300. PubMed

Hunt JM, Bull TM. 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

Righini M, Van Es J, Exter PL, Roy P, Verschuren F, Ghuysen A, Rutschmann OT, Sanchez O, Jaffrelot M, Trinh-Duc A, Le Gall C, Moustafa F, Principe A, van Houten AA, Wolde MT, Douma RA, Hazelaar G, Erkens PM, Van Kralingen KW, Grootenboers MJ, Durian MF, Cheung W, Meyer G, Bounameaux H, Huisman MV, Kamphuisen PW, Le Gal G. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study JAMA. 2014; 311(11): 1117-24. PubMed

Schouten HJ, Geersing GJ, Koek HL, Zuithoff NP, Janssen KJ, Douma RA, van Delden JJ, Moons KG, Reitsma JB. Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis BMJ. 2013; 346: f2492. PubMed

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

Stein PD, Woodard PK, Weg JG, Wakefield TW, Tapson VF, Sostman D, Sos TA, Quinn DA, Leeper KV, Hull RD, Hales CA, Gottschalk A, Goodman LR, Fowler SE, Buckley JD, 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 MV. 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 PS. 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 AH, Rodgers GM, Gilreath JA. 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 NM, Murphy KK, Crist RA, Wilson AR, Rodgers GM, Smock KJ. 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 BD, Lenzini PA, Wadelius M, Jorgensen AL, Kimmel SE, Ridker PM, Eriksson N, Anderson JL, Pirmohamed M, Limdi NA, Pendleton RC, McMillin GA, Burmester JK, Kurnik D, Stein M, Caldwell MD, Eby CS, Rane A, Lindh JD, Shin J, Kim H, Angchaisuksiri P, Glynn RJ, Kronquist KE, Carlquist JF, Grice GR, Barrack RL, Li J, Gage BF. 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 SL, Dominguez CM, Roberts WL. Performance characteristics of the AxSYM D-dimer assay. Clin Chim Acta. 2008; 390(1-2): 148-51. PubMed

Lehman CM, Rettmann JA, Wilson LW, Markewitz BA. 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 MT, Pendleton RC, Wheeler M, Rodgers GM. The treatment of venous thromboembolism in special populations. Thromb Res. 2007; 119(4): 391-402. PubMed

Shirts BH, Rodgers GM, Smock KJ. 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

Streiff MB, Holmstrom B, Ashrani A, Bockenstedt PL, Chesney C, Eby C, Fanikos J, Fenninger RB, Fogerty AE, Gao S, Goldhaber SZ, Hendrie P, Kuderer N, Lee A, Lee JT, Lovrincevic M, Millenson MM, Neff AT, Ortel TL, Paschal R, Shattil S, Siddiqi T, Smock KJ, Soff G, Wang T, Yee GC, Zakarija A, McMillian N, Engh AM. Cancer-Associated Venous Thromboembolic Disease, Version 1.2015 J Natl Compr Canc Netw. 2015; 13(9): 1079-95. PubMed

Win K, Rodgers GM. 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: November 2016