Venous Thromboembolism

Venous thromboembolism (VTE) is a potentially fatal disease that occurs when a blood clot forms in a vein and impedes blood flow. VTE includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). The clinical presentation of DVT and PE is often nonspecific and overlaps with other conditions, but a prompt and accurate diagnosis leads to early treatment, significantly reducing the high morbidity and mortality associated with the disease. Imaging is the gold standard for accurate diagnosis of VTE. However, in selected patients with low or moderate pretest probability of the disease, high-sensitivity D-dimer testing may be performed to rule out VTE and avoid unnecessary imaging studies. Imaging is performed if the D-dimer result does not exclude VTE. Laboratory testing may also be used to monitor anticoagulant treatment of DVT and PE; the monitoring selected depends on the treatment used but may include assessment of international normalized ratio (INR), activated partial thromboplastin time (aPTT), or specific drug concentrations.

Quick Answers for Clinicians

Should patients diagnosed with pulmonary embolism or deep vein thrombosis be assessed for hereditary thrombophilia?

Testing for hereditary thrombophilia is not recommended after a diagnosis of venous thromboembolism (VTE), except in the presence of major risk factors or provoking factors (eg, trauma, major surgery, prolonged immobility, cancer).

For more information about when and how to test for hereditary thrombophilia, see the ARUP Consult Hereditary Thrombophilia topic.

When should assessment for pulmonary embolism or deep vein thrombosis begin with D-dimer testing?

When evaluating a patient for venous thromboembolism (VTE), D-dimer testing can help avoid unnecessary imaging, and for many patients with low or intermediate pretest probability, D-dimer results can rule out VTE and enable other diagnoses to be explored in a timely manner. For patients with a high likelihood of VTE, imaging should be performed directly without assessing D-dimer concentrations. Additionally, even in patients with a lower likelihood of VTE, D-dimer should only be performed if the results will be available in a timely manner. If VTE is not excluded by D-dimer results, imaging should be performed.

A pretest probability assessment guides the diagnostic approach and determines whether testing should begin with D-dimer or proceed directly to imaging. A number of clinical decision rules are available to calculate the pretest probability.

For more information about when D-dimer is preferred and when imaging is preferred, see the Deep Vein Thrombosis Testing and the Pulmonary Embolism Testing algorithms.

In which patient populations does D-dimer have limited utility?

D-dimer has limited utility in the following patient populations because of the high percentage of positive results when using the standard threshold:

Patients who are pregnant
Patients who are hospitalized
Patients who have had a recent surgery

D-dimer also has limited utility for diagnosis of pulmonary embolism (PE) in patients with cancer due to its lower predictive value in this population. When there is clinical suspicion of VTE in patients with cancer, diagnosis is made based on a combination of clinical exam, other laboratory tests, and imaging.

Do testing recommendations for thrombosis vary in individuals with COVID-19?

SARS-CoV-2 infection is associated with an increased risk of thrombosis, with venous thromboembolism (VTE) occurring more often than arterial thrombosis. In individuals with COVID-19, the diagnostic workup for VTE is generally the same as in those without COVID-19. When VTE is suspected, the use of hemostatic markers for diagnosis is not recommended. In addition, routine screening for VTE based on elevated D-dimer results is not recommended. Laboratory monitoring of hemostatic markers may provide information about the prognosis and severity of coagulopathy in those with COVID-19.

Is therapeutic drug monitoring recommended in individuals being treated for venous thromboembolism with direct factor Xa inhibitors?

Treatment with direct factor Xa inhibitors (eg, apixaban, edoxaban, rivaroxaban) does not require routine laboratory monitoring. However, measurement of direct factor Xa inhibitor concentrations may be informative in contexts that would affect their safe and effective use, such as impaired absorption, drug interaction, treatment failure, obesity, or renal impairment. Concentrations should be measured using an anti-Xa activity assay calibrated for the specific drug a patient is taking, which can accurately quantitate a wide range of drug concentrations typically seen in patients taking direct factor Xa inhibitors. For more information, see the Direct Xa Inhibitor Levels Test Fact Sheet and ARUP Consult Therapeutic Drug Monitoring topic.

Does the administration of anticoagulants for treatment of deep vein thrombosis and pulmonary embolism interfere with coagulation testing?

Yes. The four classes of anticoagulants in regular use (heparins, vitamin K antagonists [VKAs], direct factor Xa inhibitors, and direct thrombin inhibitors) all have the potential to interfere with laboratory testing.

For detailed information on the effects of these drugs on specific coagulation tests, see the ARUP Consult Impacts of Common Anticoagulants on Coagulation Testing resource.

Indications for Testing

Testing for VTE may be considered in the presence of signs and symptoms of DVT or PE.

Signs and symptoms of DVT include unilateral leg pain, redness, swelling, warmth, tenderness, and edema.

Signs and symptoms of PE include chest pain, dyspnea, hemoptysis, tachycardia, syncope, and hypotension.

Because the clinical presentation of DVT and PE is often nonspecific and overlaps with other conditions, testing should only be performed after a pretest probability assessment has been performed.

Laboratory Testing

Diagnosis

High-sensitivity D-dimer testing, which can quantify very small amounts of D-dimer, is the primary laboratory test used in the diagnosis of VTE. D-dimer testing has a high sensitivity but low specificity for VTE. As such, a negative D-dimer result essentially rules out VTE, whereas a positive D-dimer result indicates that further testing, such as imaging, should be performed.

The validated D-dimer cutoff for exclusion of VTE is specific to each individual D-dimer assay due to different unit types used (eg, fibrinogen equivalent units [FEUs] or D-dimer units [DDUs]), and different units of measurement and other assay characteristics. In outpatients older than 50 years, an age-adjusted D-dimer cutoff may be used. However, because D-dimer testing and reporting are not standardized, age-adjusted cutoffs should only be used when supportive data have been generated using the specific D-dimer kit in use.

The initial diagnostic approach to VTE depends on the individual’s pretest probability, which may be assessed using clinical gestalt and/or a clinical prediction rule appropriate for the particular clinical situation:

Wells’ criteria for PE
Wells’ criteria for DVT
Geneva score (revised) for PE
Pulmonary embolism rule-out criteria (PERC)

Diagnostic Approaches to Initial Diagnosis of DVT and PE in Hemodynamically Stable Patients
Disorder	Pretest Probability	Diagnostic Approach
PE	Low or intermediate	Perform high-sensitivity D-dimer as initial test^a If D-dimer is positive, proceed to imaging^b
PE	High	Perform imaging^a as initial test
Lower-extremity DVT	Low	Perform high-sensitivity D-dimer as initial test^a If D-dimer is positive, proceed to imaging^b
	Intermediate	Perform imaging^b as initial test; high-sensitivity D-dimer^a may be considered for some intermediate-risk patients if prevalence is estimated at ≤15% If D-dimer is performed and positive, proceed to imaging^b
	High	Perform imaging^a as initial test
Upper-extremity DVT	Unlikely	Perform high-sensitivity D-dimer as initial test^a If D-dimer is positive, proceed to imaging^b
Upper-extremity DVT	Likely	Perform either D-dimer^a or imaging^b as initial test If D-dimer is performed and positive, proceed to imaging^b
^aD-dimer should only be performed as an initial test if the results will be available in a timely manner and if patients do not have other underlying conditions that would cause a baseline elevation of D-dimer. ^bFor the specific types of imaging recommended in each scenario, see the American Society of Hematology 2018 Guidelines for Management of Venous Thromboembolism: Diagnosis of Venous Thromboembolism. Source: ASH, 2018

Monitoring

Vitamin K Antagonists

Treatment with vitamin K antagonists (VKAs) such as warfarin requires regular monitoring with the INR.

Timing of INR measurements in patients receiving VKA therapy relies on multiple factors evaluated by the treating physician to optimize the exact timing of laboratory measurements for an individual patient.

Direct Oral Anticoagulants

Direct oral anticoagulants (DOACs), such as oral direct thrombin inhibitors and direct factor Xa inhibitors, do not require routine laboratory monitoring. However, measurement of DOAC concentrations may be indicated in contexts that would affect their safe and effective use, such as impaired absorption, drug interaction, treatment failure, or renal impairment. Oral direct thrombin inhibitor concentration is generally measured using diluted thrombin time (dTT) or ecarin-based assays, whereas direct factor Xa inhibitor concentration is measured using an anti-Xa activity assay calibrated for the specific drug the patient is taking.

Regular monitoring of renal function (eg, creatinine clearance) may be useful in some individuals receiving DOAC therapy, but monitoring decisions should be informed by clinical discretion.

Heparins

Heparins include low molecular-weight heparin (LMWH) and unfractionated heparin (UFH). UFH therapy may be monitored by either aPTT or anti-factor Xa chromogenic assays, whereas LMWH can only be monitored via anti-factor Xa assays. Decision-making regarding use of anti-factor Xa activity in the setting of LMWH therapy relies on many variables and should be individualized for each patient.

In certain cases, heparin therapy may lead to heparin-induced thrombocytopenia (HIT). For information on when and how to monitor for HIT, see the ARUP Consult Heparin-Induced Thrombocytopenia topic.

Pharmacogenetics

Certain genetic variants result in warfarin sensitivity. Genetic testing of relevant genes (CYP2C9, CYP2C, CYP4F2, and VKORC1) may be indicated for patients who are warfarin naïve before starting therapy, for individuals with a personal or family history of difficulty managing warfarin therapy, and for patients taking warfarin as prescribed who are not responding as expected. Variants in these genes may affect the medication dosage or the medication type for a patient. Genetic information can be used in combination with nongenetic factors to help determine warfarin dosing through the use of calculators, such as that found on WarfarinDosing.org.

For more information, see the ARUP Consult Germline Pharmacogenetics topic and the Warfarin Sensitivity Genotyping Test Fact Sheet.