Deep Venous Thrombosis (DVT) Workup

Updated: Jul 06, 2017
  • Author: Kaushal (Kevin) Patel, MD; Chief Editor: Barry E Brenner, MD, PhD, FACEP  more...
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Workup

Approach Considerations

Routine blood tests that have the potential to help clinicians stratify patients with the risk for deep venous thrombosis (DVT) include D-dimer assay; levels of antithrombin III (ATIII), N-terminal pro-brain natriuretic peptide (NT-proBNP), and C-reactive protein (CRP); and erythrocyte sedimentation rate (ESR). [99]

A clinical practice guideline from the American Academy of Family Physicians (AAFP) and the American College of Physicians (ACP) provides four recommendations for the workup of patients with probable DVT). [5] First, validated clinical prediction rules should be used to estimate the pretest probability of venous thromboembolism (VTE) and interpret test results. The Wells prediction rules for DVT and for pulmonary embolism meet this standard, although the rule performs better in younger patients without comorbidities or a history of VTE than it does in other patients.

Second, in appropriately selected patients with low pretest probability of DVT or pulmonary embolism, it is reasonable to obtain a high-sensitivity D-dimer. A negative result indicates a low likelihood of VTE. Third, in patients with intermediate to high pretest probability of lower-extremity DVT, ultrasonography is recommended.

Fourth, patients with intermediate or high pretest probability of pulmonary embolism require diagnostic imaging studies. Options include a ventilation-perfusion (V/Q) scan, multidetector helical computed axial tomography (CT), and pulmonary angiography; however, CT alone may not be sufficiently sensitive to exclude pulmonary embolism in patients who have a high pretest probability of pulmonary embolism.

VTE remains an underdiagnosed disease, and most cases of pulmonary embolism (PE) are diagnosed at autopsy. Diagnosis depends on a high level of clinical suspicion and the presence of risk factors that prompt diagnostic study. Because the presentation is nonspecific and because the consequence of missing the diagnosis is serious, it must be excluded whenever it is a feasible differential diagnosis. Because the prevalence of the disease is 15-30% in the population at clinical risk, a widely applicable (inexpensive and simple) screening test is required.

Conclusive diagnosis historically required invasive and expensive venography, which is still considered the criterion standard. Since 1990, the diagnosis has been obtained noninvasively by means of (still expensive) sonographic examination. The validation of the simpler and cheaper D-dimer test as an initial screening test permits a rapid, widely applicable screening that may reduce the rate of missed diagnoses. Algorithms are based on pretest probabilities and D-dimer results. As many of 40% of patients with a low clinical suspicion and a negative D-dimer result require no further evaluation. [100, 101]

Kleinjan et al have proposed a diagnostic algorithm that uses a combination of a clinical decision probability, D-dimer testing, and ultrasonographic findings to exclude upper extremity DVT (UEDVT). [102]  The algorithm was feasible and completed in 390 of 406 patients (96%), excluded UEDVT from 87 patients (21%) with an unlikely clinical score and normal D-dimer levels, and identified superficial venous thrombosis in 54 (13%) and UEDVT in 103 (25%) patients. [102]

Laboratory analysis has also been used in aiding the diagnosis of venous thrombosis. Protein S, protein C, ATIII, factor V Leiden, prothrombin 20210A mutation, antiphospholipid antibodies, and homocysteine levels can be measured. Deficiencies of these factors or the presence of these abnormalities all produce a hypercoagulable state. These are rare causes of DVT. Laboratory investigations for these abnormalities are primarily indicated when DVT is diagnosed in patients younger than 50 years, when there is a confirmed family history of a hypercoagulable state or a familial deficiency, when venous thrombosis is detected in unusual sites, and in the clinical setting of warfarin-induced skin necrosis.

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D-Dimer Testing

D-dimers are degradation products of cross-linked fibrin by plasmin that are detected by diagnostic assays. D-dimer level may be elevated in any medical condition where clots form. D-dimer level is elevated in trauma, recent surgery, hemorrhage, cancer, and sepsis. [103] Many of these conditions are associated with higher risk for deep venous thrombosis (DVT).

D-dimer levels remain elevated in DVT for about 7 days. Patients presenting late in the course, after clot organization and adherence have occurred, may have low levels of D-dimer. Similarly, patients with isolated calf vein DVT may have a small clot burden and low levels of D-dimer that are below the analytic cutoff value of the assay. This accounts for the reduced sensitivity of the D-dimer assay in the setting of confirmed DVT.

Current evidence strongly supports the use of a D-dimer assay in the setting of suspected DVT. Most studies have confirmed the clinical utility of D-dimer testing, and most clinical algorithms incorporate its use. The D-dimer assay has a high sensitivity (up to 97%); however, it has a relatively poor specificity (as low as 35%) [104] and therefore should only be used to rule out DVT, not to confirm the diagnosis of DVT.

A negative D-dimer assay result rules out DVT in patients with low-to-moderate risk (Wells DVT score <2). (See Risk Stratification.) A negative result also obviates surveillance and serial testing in patients with moderate-to-high risk and negative ultrasonographic findings. All patients with a positive D-dimer assay result and all patients with a moderate-to-high risk of DVT (Wells DVT score >2) require a diagnostic study (duplex ultrasonography).

Studies indicate that the D-dimer test can be used as a rapid screening measure in cases where leg swelling exists in the face of equivocal or negative clinical or radiologic findings. Forty percent of patients with a negative clinical examination and negative D-dimer test require no further clinical evaluation. Similarly, subjects with an elevated D-dimer test at 1 month following anticoagulant cessation have a significantly higher risk of recurrent venous thromboembolism (VTE). [105]

A randomized, multicenter, controlled trial involving 1723 patients found that selective testing of D-dimer levels lowered the proportion of patients who underwent ultrasonography and decreased the percentage of patients who needed D-dimer testing by 21.8%. [106, 107] This suggests that a selective D-dimer testing strategy based on clinical pretest probability (C-PTP), as opposed to testing all patients presenting with symptoms of a first DVT episode, can exclude DVT in more patients without increasing the rate of missed diagnoses.

Characteristics of different D-dimer assays

Many different D-dimer assays are available, with varying sensitivities and specificities. These assays are not standardized. They incorporate different monoclonal antibodies to the D-dimer fragment. Results may be reported quantitatively or qualitatively. Different units may be used; some assay results are reported as fibrinogen equivalent units (FEU) and others in nanograms per milliliter (ng/mL). The results of one assay cannot be extrapolated to another. Accordingly, physicians should know their hospital’s D-dimer assay.

All D-dimer assays have been evaluated in various validation studies that determine the assay’s sensitivity, specificity, and negative predictive value (NPV). Unfortunately, fewer management studies have been conducted to determine the safety of withholding anticoagulant therapy on the basis of a negative test result. Furthermore, the NPV of a specific assay falls as the pretest probability of the study population at risk for DVT increases. An assay with a sensitivity of 80% has an NPV of 97.6% in a low-risk patient. However, the NPV of the same assay is only 33% in high-risk patients with a pretest probability of 90% for DVT.

Traditional enzyme-linked immunosorbent assays (ELISAs), although accurate, are time-consuming and not practical for use in the emergency department. A rapid ELISA assay (VIDAS) with high sensitivity was validated in a large European trial. In that study a negative VIDAS D-dimer assay essentially ruled out DVT. All patients with a negative D-dimer result did not require further diagnostic testing with ultrasonography. [108]

The older qualitative latex agglutination assay is not accurate and should not be used for making treatment decisions in patients with suspected DVT. Newer latex-enhanced immunoturbidimetric and immunofiltration assays have high sensitivity and are available.

A rapid qualitative red blood cell agglutination assay (SimpliRED) is available. It is sensitive for proximal vein DVT but less so for calf vein DVT. A large study confirmed that, in low-risk patients with low pretest probability for DVT, a negative SimpliRED D-dimer result rules out DVT. Ultrasonography was not required in these patients. [109]

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Coagulation Profile

Additional blood work should include coagulation studies to evaluate for a hypercoagulable state, if clinically indicated. A prolonged prothrombin time or activated partial thromboplastin time does not imply a lower risk of new thrombosis. Progression of deep venous thrombosis and pulmonary embolism can occur despite full therapeutic anticoagulation in 13% of patients.

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Imaging in Deep Venous Thrombosis

Imaging studies used in deep venous thrombosis (DVT) include ultrasonography, venography, impedance plethysmography, MRI, and nuclear imaging. Ultrasonography is the current first-line imaging examination for DVT because of its relative ease of use, absence of irradiation or contrast material, and high sensitivity and specificity in institutions with experienced sonographers.

The criterion standard to diagnostic imaging for DVT remains venography with pedal vein cannulation, intravenous contrast injection, and serial limb radiographs. However, the invasive nature and significant consumption of resources are only 2 of its many limitations.

In some countries, impedance plethysmography (IPG) has been the initial noninvasive diagnostic test of choice and has been shown to be sensitive and specific for proximal vein thrombosis. However, IPG also has several other limitations; among them are insensitivity for calf vein thrombosis, nonoccluding proximal vein thrombus, and iliofemoral vein thrombosis above the inguinal ligament.

MRI has increasingly been investigated for evaluation of suspected DVT. Limited studies suggest the accuracy approaches that of contrast venography. MRI is the diagnostic test of choice for suspected iliac vein or inferior vena caval thrombosis when CT venography is contraindicated or technically inadequate. Radiolabeled peptides that bind to various components of a thrombus have been investigated. The cost of the tests and the inability to visualize the anatomy of the area of involvement (which many clinicians prefer) has lead to the underuse of scintigraphy.

For more information, see Imaging in Deep Venous Thrombosis.

Additionally, note that imaging modalities, techniques, and findings may be specific to the upper extremities and lower extremities.

For more information, see Imaging in Deep Venous Thrombosis, Lower Extremity.

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Risk Stratification

The Wells clinical prediction guide quantifies the pretest probability of deep venous thrombosis (DVT). The model enables physicians to reliably stratify their patients into high-risk, moderate-risk, or low-risk categories. Combining this with the results of objective testing greatly simplifies the clinical workup of patients with suspected DVT. The Wells clinical prediction guide incorporates risk factors, clinical signs, and the presence or absence of alternative diagnoses.

Predictors of venous thromboembolism (VTE) in a Japanese study comprising data from 3,578 patients diagnosed with VTE over 6 years (2008-2013) included the presence of malignancies and the use of antipsychotic agents and/or nonsteroidal anti-inflammatory agents. [110]

Please go to the main article on Deep Venous Thrombosis Risk Stratification to see complete information on this topic.

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