eMedicine Specialties > Emergency Medicine > Cardiovascular

Deep Venous Thrombosis and Thrombophlebitis: Differential Diagnoses & Workup

Author: Donald Schreiber, MD, CM, Associate Professor of Surgery (Emergency Medicine), Stanford University School of Medicine
Contributor Information and Disclosures

Updated: Aug 5, 2009

Differential Diagnoses

Cellulitis
Pulmonary Embolism
Thrombophlebitis, Septic
Thrombophlebitis, Superficial

Other Problems to Be Considered

In approximately 70% of patients with clinically suspected DVT, alternate diagnoses are ultimately found, as follows:

Achilles tendonitis
Arterial insufficiency
Arthritis
Asymmetric peripheral edema secondary to CHF, liver disease, renal failure, or nephrotic syndrome
Cellulitis, lymphangitis
Extrinsic compression of iliac vein secondary to tumor, hematoma, or abscess
Hematoma
Lymphedema
Muscle or soft tissue injury
Neurogenic pain
Postphlebitic syndrome
Prolonged immobilization or limb paralysis
Ruptured Baker cyst
Stress fractures or other bony lesions
Superficial thrombophlebitis
Varicose veins

Workup

Laboratory Studies

D-dimer testing

  • The D-dimer test has an important role in the diagnostic approach to deep venous thrombosis (DVT).5,6 D-dimer fibrin fragments are present in fresh fibrin clot and in fibrin degradation products of cross-linked fibrin. Monoclonal antibodies specific for the D-dimer fragment are used to differentiate fibrin-specific clot from non–cross-linked fibrin and from fibrinogen. These specific attributes of the D-dimer antibodies account for their high sensitivity for venous thromboembolism.
  • 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. Many of these conditions are associated with higher risk for DVT. The D-dimer assays have low specificity for DVT; therefore, they should only be used to rule out DVT, not to confirm the diagnosis of 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 cut-off value of the assay. This accounts for the reduced sensitivity of the D-dimer assay in the setting of confirmed DVT.
  • Many different D-dimer assays are available, with varying sensitivities and specificities. The 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.
  • Most studies have confirmed the clinical utility of D-dimer testing, and most clinical algorithms incorporate their use. 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 ED. 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.7
  • 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 RBC 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.8
  • Current evidence strongly supports the use of a D-dimer assay in the clinical algorithm of suspected DVT.5 A negative D-dimer assay result rules out DVT in patients with low-to-moderate risk (Wells DVT score <2). A negative result also obviates surveillance and serial testing in patients with moderate-to-high risk and negative ultrasonographic findings.
  • D-dimer results should be used as follows:
    • A negative D-dimer assay result rules out DVT in patients with low-to-moderate risk and a Wells DVT score less than 2.
    • 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).
Other blood tests
  • Protein S, protein C, antithrombin III, 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.

Imaging Studies

  • Because of the inherent inaccuracy of clinical diagnosis that is based on the history, the physical examination, and the assessment of risk factors, D-dimer testing and a determination of pretest probability (eg, Wells DVT score) should be used to identify those patients who require further objective diagnostic testing.
  • Diagnosing DVT and committing patients to the risks of anticoagulation therapy without confirmatory objective testing is unacceptable.
  • The criterion standard for evaluating patients with suspected DVT has been contrast venography. For many reasons, including allergic reactions, contrast-induced DVT, technical difficulties, inadequate studies, interobserver variability, and lack of availability, venography is either contraindicated or nondiagnostic in as many as 20-25% of patients. As a result, noninvasive studies have essentially replaced venography as the initial diagnostic test of choice.
  • Duplex ultrasonography
    • Technological advances in ultrasonography have permitted the combination of real-time ultrasonographic imaging with Doppler flow studies (duplex ultrasonography). The major ultrasonographic criterion for detecting venous thrombosis is failure to compress the vascular lumen, presumably because of the presence of occluding thrombus. The absence of the normal phasic Doppler signals arising from the changes to venous flow provides indirect evidence of venous occlusion.
    • Many studies have confirmed the diagnostic sensitivity and specificity of duplex ultrasonography for proximal vein thrombosis. Sensitivity of duplex ultrasonography for proximal vein DVT is 97% (95% confidence interval [CI], 96-98%) but only 73% for calf vein DVT (95% CI, 54-93%). The NPV for proximal vein DVT is 99%. Overall specificity is 95%.
    • Duplex ultrasonography is also helpful to differentiate venous thrombosis from hematoma, Baker cyst, abscess, and other causes of leg pain and edema.
    • The primary disadvantage of duplex ultrasonography is its inherent inaccuracy in the diagnosis of calf vein thrombosis. Venous thrombi proximal to the inguinal ligament are also difficult to visualize. Nonoccluding thrombi may be difficult to detect. In patients with suspected acute recurrent DVT, duplex ultrasonography may not be able to differentiate between old and new clots. Diagnostic accuracy varies depending on local expertise.
  • Impedance plethysmography
    • In some countries, impedance plethysmography (IPG) has been the initial noninvasive diagnostic test of choice. Plethysmography is derived from the Greek word meaning "to increase." This procedure is based on recording changes in blood volume of an extremity, which are directly related to venous outflow. Several different techniques can be used to measure these changes, including electrical impedance. In the setting of proximal vein thrombosis, venous outflow from the lower extremity is slowed and the blood volume or venous capacitance is increased. Standardized graphs are used to discriminate normal IPG study results from abnormal results.
    • In many studies, IPG has been shown to be sensitive and specific for proximal vein thrombosis. It is insensitive for calf vein thrombosis, nonoccluding proximal vein thrombus, and ileofemoral vein thrombosis above the inguinal ligament. IPG cannot distinguish between thrombotic occlusion and extravascular compression of the vein. False-positive results occur in the setting of significant CHF and raised central venous pressure as well as in severe arterial insufficiency.
  • MRI
    • MRI has increasingly been investigated for evaluation of suspected DVT. In limited studies, the accuracy approaches that of the criterion standard, 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.
    • In the second and third trimester of pregnancy, MRI is more accurate than duplex ultrasonography because the gravid uterus alters Doppler venous flow characteristics.
    • In suspected calf vein thrombosis, MRI is more sensitive than any other noninvasive study.
    • Expense, lack of general availability, and technical issues limit its use.
  • Nuclear medicine imaging studies
    • Nuclear medicine studies with I125 -labeled fibrinogen are no longer recommended for patients in the ED. They are relatively insensitive for proximal vein thrombosis and take longer than 24 hours to obtain results. I125 -labeled fibrinogen is no longer available in the United States.
  • CT venography
CT venography showing bilateral deep venous throm...

CT venography showing bilateral deep venous thrombosis. Arrows indicate bilateral deep venous thrombosis.

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CT venography showing bilateral deep venous throm...

CT venography showing bilateral deep venous thrombosis. Arrows indicate bilateral deep venous thrombosis.


    • With the introduction of multidetector CT technology, CT venography has been incorporated into CT angiographic studies of the chest as part of the diagnostic evaluation for suspected PE. CT venography of the lower extremities is performed after scanning of the chest has been completed. Scanning usually begins at the level of the iliac crests and continues caudally down to the popliteal fossa.
    • In the Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) study reported by Stein et al, the addition of CT venography to CT angiography of the chest increased the diagnostic sensitivity for venous thromboembolic disease than CT angiography alone.9
    • A number of small studies have compared CT venography alone to duplex ultrasonography alone for the diagnosis of lower extremity DVT. Similar high sensitivities for ultrasonography and CT have been reported, but no large trials comparing the two have yet been performed.
    • The primary utility of CT venography is for the diagnosis of ileofemoral DVT. Ultrasonography is limited to the diagnosis of DVT in the venous system distal to the inguinal ligament. The iliac veins cannot usually be visualized by ultrasonography, and a different diagnostic modality must be used. Herein lies the value of CT venography where venous occlusion proximal to the inguinal ligament may be detected. The diagnosis of ileofemoral DVT should be considered if the ultrasonographic examination reveals thrombus extending into the superficial femoral vein at the inguinal ligament. A CT venogram should be obtained to assess for proximal thrombus and ileofemoral DVT.
    • The major problems with CT venography are technical issues with inadequately visualized veins, artifactual interference from metal implants such as hip and knee arthroplasties, and contraindications to the administration of contrast dye.
  • Summary - Which test is best?
    • When directly compared, duplex ultrasonography has superior sensitivity and specificity over IPG. Guidelines from the American College of Radiology recommend duplex Doppler compression ultrasonography as the most appropriate study in suspected lower extremity DVT. The guidelines note that, in addition to lower accuracy than compression ultrasonography, plethysmography requires meticulous technique and has a sensitivity of only 20-30% for calf vein thrombosis.6
    • Controversy still exists over the use of noninvasive studies such as duplex ultrasonography for the diagnosis of suspected calf vein DVT. Recognizing that duplex ultrasonography is relatively insensitive for calf vein thrombosis only matters if the clinician is inclined to place patients with calf vein DVT on anticoagulation therapy. If the clinical algorithm for calf vein thrombosis recommends clinical surveillance and serial studies to detect proximal extension, the lack of sensitivity of the noninvasive study for calf vein thrombosis is irrelevant.
    • Reports on the use of noninvasive studies for DVT in asymptomatic hospitalized patients should not be used to determine the optimal evaluation of ED patients with suspected DVT who are usually ambulatory and symptomatic. A number of authors have incorrectly recommended the routine use of contrast venography rather than a noninvasive study for suspected DVT on the basis of the low sensitivity that has been reported in studies of hospitalized patients after hip surgery.
    • In ambulatory outpatients with suspected DVT, the sensitivity of duplex ultrasonography for proximal vein thrombosis is 97%, and it remains the initial diagnostic test of choice.
    • CT venography is the best diagnostic modality for suspected ileofemoral DVT.
  • Simplified clinical management strategy for patients with suspected DVT
    • Using the pretest probability score calculated from the Wells DVT score, patients are stratified into 2 risk groups: DVT unlikely (DVT score <2) or DVT likely (DVT score >2).
    • Using a sensitive D-dimer assay such as the VIDAS rapid ELISA, the D-dimer results should be used as follows:
      • A negative D-dimer result rules out DVT in the unlikely group (low-to-moderate risk of DVT) with a Wells DVT score less than 2.
      • All patients with a positive D-dimer result and all patients in the likely group (moderate-to-high risk of DVT) with a Wells DVT score of 2 or greater require a diagnostic study (ie, duplex ultrasonography).
  • The results from duplex ultrasonography are incorporated as follows:
    • If the patient is scored as likely and the duplex ultrasonographic findings are positive, treat for DVT.
    • If the duplex study result is negative and the patient is scored as unlikely to have DVT, DVT is ruled out even if the D-dimer assay is positive.
    • When discordance exists between the pretest probability and the duplex ultrasonographic study result, further evaluation is required.
    • If the patient is scored as likely to have DVT (DVT score >2) but the ultrasonographic findings are negative, the patient still has a significant probability of DVT. Some authors recommend venography to rule out a calf vein DVT that ultrasonography did not detect. Most recommend surveillance with repeat clinical evaluation and ultrasonography in 1 week. Others use the results of the D-dimer assay to guide management. A negative D-dimer assay in combination with negative ultrasonographic findings rules out DVT. A positive D-dimer assay in this group mandates surveillance and repeat ultrasonography in 1 week.
    • If the patient is scored as unlikely to have DVT (DVT score <2) but the ultrasonographic findings are positive, some authors recommend a second confirmatory study such as venography before treating for DVT and committing the patient to the risks of anticoagulation. Most, however, treat the patient for DVT.
    • If the patient is scored as likely to have DVT (DVT score >2) but had a positive D-dimer assay result and the ultrasonographic findings are negative, repeat clinical evaluation and ultrasonography in 1 week is recommended.
  • The DVT score was developed in a specific subgroup of patients. Excluded from the model were patients with suspected coexistent PE and patients already taking anticoagulants. Therefore, the evaluation and subsequent treatment of these excluded subgroups must be individualized.

Other Tests

Mahmoodi et al found that microalbuminuria is independently associated with an increased risk for venous thromboembolism (VTE). In a community-based prospective cohort study of 8574 subjects, the risk of VTE rose in tandem with the rate of urinary albumin excretion: the annual incidence of VTE was 0.12% among participants with <15 mg albumin per 24-hour urine collection compared with 0.40% among those with 30-300 mg albumin per 24 hours. Adjusted hazard ratio for microalbuminuria versus normoalbuminuria (ie, <30 mg/24 h) was 2.00 (P <0.001).10

More on Deep Venous Thrombosis and Thrombophlebitis

Overview: Deep Venous Thrombosis and Thrombophlebitis
Differential Diagnoses & Workup: Deep Venous Thrombosis and Thrombophlebitis
Treatment & Medication: Deep Venous Thrombosis and Thrombophlebitis
Follow-up: Deep Venous Thrombosis and Thrombophlebitis
Multimedia: Deep Venous Thrombosis and Thrombophlebitis
References
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[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Donald Schreiber, MD, CM, Associate Professor of Surgery (Emergency Medicine), Stanford University School of Medicine
Donald Schreiber, MD, CM is a member of the following medical societies: American College of Emergency Physicians
Disclosure: Abbott Point of Care Inc Research Grant and Speaker''''''''''''''''s Bureau Speaking and teaching; Bristol-Myers Squibb Inc Honoraria Speaking and teaching; Sanofi-Aventis, Inc Honoraria Speaking and teaching; Nanosphere Inc Grant/research funds Research; Singulex Inc Grant/research funds Research

Medical Editor

Francis Counselman, MD, Program Director, Chair, Professor, Department of Emergency Medicine, Eastern Virginia Medical School
Francis Counselman, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, Association of Academic Chairs of Emergency Medicine (AACEM), Norfolk Academy of Medicine, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Gary Setnik, MD, Chair, Department of Emergency Medicine, Mount Auburn Hospital; Assistant Professor, Division of Emergency Medicine, Harvard Medical School
Gary Setnik, MD is a member of the following medical societies: American College of Emergency Physicians, National Association of EMS Physicians, and Society for Academic Emergency Medicine
Disclosure: SironaHealth Salary Management position; South Middlesex EMS Consortium Salary Management position

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Barry E Brenner, MD, PhD, FACEP, Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, University Hospitals, Case Medical Center
Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

 
 
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