Venous Thromboembolism

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

Indications for Testing

  • Evaluation for venous thromboembolism (VTE) should include assessment of deep vein thrombosis (DVT) and pulmonary embolism (PE), both of which present with non-specific symptoms
    • PE symptoms – shortness of breath, pleuritic chest pain, presyncope or syncope, and hemoptysis
    • DVT symptoms – unilateral extremity swelling and pain in the absence of trauma
      • Thrombus may also occur in other veins
        • Portal vein – causes symptoms of hepatic congestion
        • Mesenteric venous system – causes pain out of proportion to exam

Criteria for Diagnosis

Laboratory Testing

  • Initial testing
    • D-dimer test
      • For patients with intermediate or low pretest probability by CPR
      • Negative test rules out VTE
      • Cut-off >500 ng/mL FEU or age times 10 ng/mL if >50 years old (cut-offs in fibrinogen equivalent units [FEU] do not apply to results generated from assays in D-Dimer units [DDU])
      • Test is not specific – patients with positive test require imaging, usually Doppler or Compression ultrasound
  • Concurrent or follow-up testing
    • CBC – used for serial monitoring for patients on heparin to detect heparin-induced thrombocytopenia (HIT)
    • HIT antibody – in high pretest probability scenario (refer to clinical probability charts); strong positive ELISA confirms diagnosis of HIT
    • Testing for inherited thrombophilia is not warranted in first DVT but may be indicated in select patients
    • Testing for acquired thrombophilia should be considered for high risk patients

Imaging Studies

  • CT angiography (CTA) – initial imaging for patients with high pretest probability (D-dimer is not necessary)
  • Venous duplex ultrasound (DUS) – initial imaging for patients with positive D-Dimer
    • Positive scan confirms diagnosis; negative scan requires further imaging with CTA or ventilation/perfusion (V/Q) scan
  • V/Q scan
    • Imaging of choice to spare radiation or contrast exposure in patients with the following conditions
      • Young age, especially female
      • Pregnancy
      • History of contrast medium induced anaphylaxis
      • Severe kidney disease
      • Myeloma
      • Paraproteinemia
    • Also indicated for low clinical probability for PE with normal chest x-ray
  • Contrast venography and MRI are not recommended imaging, although MRI is being investigated for clinical use
  • Pulmonary angiography is rarely performed

Prognosis

  • Undetected clot carries a 30% risk of mortality, while the mortality for treated clot may be as low as 3%
  • 2-fold to 8-fold 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
  • CBC – monitor patients on heparin for heparin-induced thrombocytopenia (HIT)
  • Warfarin (Coumadin)
    • Metabolized in the liver by cytochrome P450 enzymes
  • Therapy
    • Response to warfarin therapy is routinely assessed through prothrombin time/INR testing
    • Cautions
      • Potentially severe hemorrhagic or thrombotic consequences if dosed incorrectly
      • Narrow therapeutic index influenced by many medications and illnesses
      • Inhibits production of vitamin K-dependent coagulation factors through inhibition of vitamin K epoxide reductase
        • Intake of food (eg, green leafy vegetables) must be carefully regulated during treatment
  • Warfarin 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

Venous thromboembolism (VTE)  is the presence of thrombus in a vein with accompanying inflammation.

Epidemiology

  • Incidence
    • 1-2/1,000 for 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, and lymphoma and myeloproliferative disorders
    • 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
  • 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
  • Indwelling catheters – most common source of upper-extremity DVT
  • Age – risk increases incrementally with age

Pathophysiology

  • Factors that predispose to VTE 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

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: Sep 2017]

Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JR, Wells P, Woller SC, Moores L. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report Chest. 2016; 149(2): 315-52. PubMed

Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, Gibbs SR, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Noordegraaf AV, Zamorano JL, Zompatori M, Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism Eur Heart J. 2014; 35(43): 3033-69, 3069a-3069k. PubMed

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

Crawford F, Andras A, Welch K, Sheares K, Keeling D, Chappell FM. D-dimer test for excluding the diagnosis of pulmonary embolism Cochrane Database Syst Rev. 2016; CD010864. 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

Stevens SM, Woller SC, Bauer KA, Kasthuri R, Cushman M, Streiff M, Lim W, Douketis JD. Guidance for the evaluation and treatment of hereditary and acquired thrombophilia J Thromb Thrombolysis. 2016; 41(1): 154-64. 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

van der Hulle T, Dronkers CE, Huisman MV, Klok FA. Current standings in diagnostic management of acute venous thromboembolism: Still rough around the edges Blood Rev. 2016; 30(1): 21-6. PubMed

van Es N, van der Hulle T, Van Es J, Exter PL, Douma RA, Goekoop RJ, Mos IC, Galipienzo J, Kamphuisen PW, Huisman MV, Klok FA, Büller HR, Bossuyt PM. Wells Rule and d-Dimer Testing to Rule Out Pulmonary Embolism: A Systematic Review and Individual-Patient Data Meta-analysis Ann Intern Med. 2016; 165(4): 253-61. 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

Content Reviewed: 
March 2017

Last Update: July 2017