Optimizing diagnostic testing for venous thromboembolism

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Diagnostic algorithms for venous thromboembolism exist, but most do not provide detailed guidance as to which patients, if any, may benefit from screening for thrombophilia. This article provides an overview of the optimized diagnosis of venous thromboembolism, with a focus on the appropriate use of thrombophilia screening.


  • A pretest clinical prediction tool such as the Wells score can help in deciding whether a patient with suspected venous thromboembolism warrants further workup.
  • A clinical prediction tool should be used in concert with additional laboratory testing (eg, D-dimer) and imaging in patients at risk.
  • In many cases, screening for thrombophilia to determine the cause of a venous thromboembolic event may be unwarranted.
  • Testing for thrombophilia should be based on whether a venous thromboembolic event was provoked or unprovoked.



When a patient presents with suspected venous thromboembolism, ie, deep vein thrombosis or pulmonary embolism, what diagnostic tests are needed to confirm the diagnosis? The clinical signs and symptoms of venous thromboembolism are nonspecific and often difficult to interpret. Therefore, it is essential for clinicians to use a standardized, structured approach to diagnosis that incorporates clinical findings and laboratory testing, as well as judicious use of diagnostic imaging. But while information is important, clinicians must also strive to avoid unnecessary testing, not only to decrease costs, but also to avoid potential harm.

If the diagnosis is confirmed, does the patient need testing for an underlying thrombophilic disorder? Such screening is often considered after a thromboembolic event occurs. However, a growing body of evidence indicates that the results of thrombophilia testing can be misinterpreted and potentially harmful.1 We need to understand the utility of this testing as well as when and how it should be used. Patients and thrombosis specialists should be involved in deciding whether to perform these tests.

In this article, we provide practical information about how to diagnose venous thromboembolism, including strategies to optimize testing in suspected cases. We also offer guidance on how to decide whether further thrombophilia testing is warranted.


Venous thromboembolism is a major cause of morbidity and death. Approximately 900,000 cases of pulmonary embolism and deep vein thrombosis occur in the United States each year, causing 60,000 to 300,000 deaths,2 with the number of cases projected to double over the next 40 years.3


Given the morbidity and mortality associated with venous thromboembolism, prompt recognition and diagnosis are imperative. Clinical diagnosis alone is insufficient, with confirmed disease found in only 15% to 25% of patients suspected of having venous thromboembolism.4–8 Therefore, the pretest probability should be coupled with objective testing.

Wells criteria for deep vein thrombosis and pulmonary embolism
Of the several scoring systems available to determine the pretest probability, the one most commonly used is the Wells score (Table 1).7–14 This score stratifies a patient’s probability of truly having deep vein thrombosis or pulmonary embolism into 3 tiers (low, moderate, high), while a modified version yields 2 tiers (likely, unlikely).

The Wells score shows good discrimination in the outpatient and emergency department settings, but it has been invalidated in the inpatient setting, and thus it should not be used in inpatients.10


Employing an understanding of diagnostic testing is fundamental to identifying patients with venous thromboembolism.

D-dimer is a byproduct of fibrinolysis.

D-dimer testing has very high sensitivity for venous thromboembolism (> 90%) but low specificity (about 50%), and levels can be elevated in a variety of situations such as advanced age, acute inflammation, and cancer.15 The standard threshold is 500 μg/L, but because the D-dimer level increases with age, some clinicians advocate using an age-adjusted threshold for patients age 50 or older (age in years × 10 μg/L) to increase the diagnostic yield.16

Of the laboratory tests for D-dimer, the enzyme-linked immunosorbent assay has the highest sensitivity and highest negative predictive value (100%) and may be preferred over the other test methodologies.17

With its high sensitivity, D-dimer testing is clinically useful for ruling out venous thromboembolism, particularly when the pretest probability is low, but it lacks the specificity required for diagnosing and treating the disease if positive. Thus, it is not useful for ruling in venous thromboembolism. If the patient has a high pretest probability, we can omit D-dimer testing in favor of imaging studies.

Other laboratory tests such as arterial blood gas and brain natriuretic peptide levels have been proposed as markers of pulmonary embolism, but studies suggest they have limited utility in predicting the presence of disease.18,19



If the pretest probability of deep vein thrombosis is high or a D-dimer test is found to be positive, the next step in evaluation is compression ultrasonography.

While some guidelines recommend scanning only the proximal leg, many facilities in the United States scan the whole leg, which may reveal distal deep vein thrombosis.20 The clinical significance of isolated distal deep vein thrombosis is unknown, and a selective anticoagulation approach may be used if this condition is discovered. The 2012 and 2016 American College of Chest Physicians (ACCP) guidelines on diagnosis and management of venous thromboembolism address this topic.20,21

Deep vein thrombosis in the arm should be evaluated in the same manner as in the lower extremities.


Invasive and therefore no longer often used, venography is considered the gold standard for diagnosing deep vein thrombosis. Computed tomographic (CT) or magnetic resonance (MR) venography is most useful if the patient has aberrant anatomy such as a deformity of the leg, or in situations where the use of ultrasonography is difficult or unreliable, such as in the setting of severe obesity. CT or MR venography may be considered when looking for thrombosis in noncompressible veins of the thorax and abdomen (eg, the subclavian vein, iliac vein, and inferior vena cava) if ultrasonography is negative but clinical suspicion is high. Venous-phase CT angiography is particularly useful in diagnosing deep vein thrombosis in the inferior vena cava and iliac vein when deep vein thrombosis is clinically suspected but cannot be visualized on duplex ultrasonography.


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