Diagnosis and Management of Acute Lower-extremity Deep Venous Thrombosis
Timothy Liem
Gregory L. Moneta
Risk Factors for Deep Venous Thrombosis
Assessment of risk factors for deep venous thrombosis (DVT) has become important in both the development of algorithms for diagnosis of DVT and guiding duration of therapy for acute DVT. Risk factors for DVT include thrombophilia, age >40, malignancy (especially adenocarcinomas), trauma, surgery (especially hip and knee replacement), paralysis, periods of immobility, long-haul air travel, and to a lesser extent, obesity. Hypercoagulable conditions are also important risk factors for DVT. The presence of genetic and acquired thrombophilias, such as factor V Leiden, prothrombin 20210A mutation, and antiphospholipid antibodies, significantly increases the risk of DVT. The relative risk in factor V Leiden heterozygotes is fivefold to sevenfold higher than in the general population. The increased risk of thrombosis in homozygotes is 50- to 80-fold greater than in the general population. The combination of a Leiden and a prothrombin defect raises the risk of thrombosis to over 50%. Other markers, such as cysteinemia and antithrombin, protein C, and protein S deficiency, when combined with the previous mutations, will increase the risk of a thrombotic event 70% to 90%.
The most important risk factor for recurrence of lower-extremity DVT is a previous episode of lower-extremity DVT. Risk of recurrence is increased by residual thrombosis (10.5% per patient year), a permanent risk factor for DVT such as cancer (odds ratio, 8.76), and thrombophilia (8% per patient year). Elevated D-dimer levels, reflecting ongoing thrombosis and fibrinolysis, are additive to other risk factors in predicting recurrence of DVT.
Diagnosis
Ultrasound
Venous ultrasonography is the most widely used diagnostic modality for evaluation of possible acute DVT. Venous ultrasonography includes compression ultrasound (B-mode imaging only), duplex ultrasound (B-mode imaging and Doppler waveform analysis), and color Doppler alone. These types of venous ultrasonography are referred to interchangeably, but they actually have differing sensitivities and specificities for detecting acute DVT. Compression ultrasound is best used for evaluation of the proximal deep veins above the knee. A combination of color flow Doppler and compression works best below the knee, while iliac veins are often examined with color flow alone, as these veins cannot reliably be compressed transcutaneously.
A single, complete venous duplex and color Doppler examination is now employed in most hospitals for assessment of possible lower-extremity DVT. Whenever possible, a venous duplex examination is recommended to evaluate for possible DVT; it consists of examination of proximal and calf veins. Venous ultrasonography examinations, however, are not uniformly standardized. Protocols vary among laboratories, ranging from compression of as few as two deep veins to a complete duplex and color Doppler evaluation of the entire lower extremity. Many patient-specific factors will also influence which venous segments can be evaluated in an individual patient. These include obesity, edema, leg sensitivity to compression with the ultrasound transducer, and lower-extremity bandages, casts, and other immobilization devices. The clinician should be aware of any limitations to obtaining a full lower-extremity ultrasound evaluation for possible DVT, and the reporting laboratory should note any significant limitations to the study in the final report of the examination. Suboptimal studies in patients highly suspicious for DVT should lead the clinician to consider alternative forms of lower-extremity venous imaging. This is discussed in more detail later in the chapter.
Accuracy
Weighted mean sensitivities and specificities for venous ultrasonography (including all types), in comparison to venography, for diagnosis of symptomatic proximal (aboveknee) DVT, are 97% and 94%, respectively. When there are no constraining factors to the examination, the high specificity permits treatment for DVT to be initiated without other confirmatory tests, and the high sensitivity makes it possible to withhold treatment when the examination is negative. When the examination is suboptimal, serial studies or alternative imaging modalities should be strongly considered. Repeat or serial venous ultrasonography is advisable for negative examinations in symptomatic patients who are highly suspicious for DVT and for patients in whom an alternative form of imaging is contraindicated or not available. The study should also be repeated even if the initial exam was adequate but there is a significant change in patient symptoms.
Calf veins can now be imaged in 80% to 98% of patients using a combination of B-mode, Doppler waveform analysis, and color Doppler. In technically adequate studies, the sensitivity and specificity of color Doppler for detecting isolated calf vein thrombosis exceed 90%. Therefore, a negative examination that includes both
proximal and calf veins should be sufficient to withhold anticoagulation and preclude the need for routine follow-up studies in patients without clinical suspicion of pulmonary embolism. This is discussed in more detail later in the chapter. Serial examinations should be performed to evaluate for propagation or extension of calf vein thrombi that for some reason the clinician has elected not to treat with anticoagulation. Isolated calf vein thrombosis accounts for 20% of symptomatic DVT, and, in some studies, approximately one-quarter of untreated symptomatic calf vein thrombi will extend proximally within 1 to 2 weeks.
proximal and calf veins should be sufficient to withhold anticoagulation and preclude the need for routine follow-up studies in patients without clinical suspicion of pulmonary embolism. This is discussed in more detail later in the chapter. Serial examinations should be performed to evaluate for propagation or extension of calf vein thrombi that for some reason the clinician has elected not to treat with anticoagulation. Isolated calf vein thrombosis accounts for 20% of symptomatic DVT, and, in some studies, approximately one-quarter of untreated symptomatic calf vein thrombi will extend proximally within 1 to 2 weeks.
Combined Ultrasound and Clinical and/or Laboratory Assessment
It is estimated that more than 1 million ultrasound examinations are performed per year in the United States for suspected DVT. Only 12% to 25% are positive. Because of the cost associated with negative examinations, and the burden that afterhours examinations place on vascular technologists, strategies are being developed to decrease negative ultrasound studies. Algorithmic approaches using ultrasound in combination with clinical assessment and D-dimer testing are under evaluation. Unfortunately, there are no large, randomized, multicenter studies comparing the outcomes of branching pathways that include adequate sample sizes at the end of each pathway. However, there are some well-designed cohort studies.
While signs and symptoms alone are well known to be inadequate for the evaluation of possible DVT, some clinical presentations are in fact more likely to be associated with DVT. Based upon the presence of thrombotic risk factors, clinical signs and symptoms, and the possibility of alternative diagnoses, patients can be stratified into three risk categories—low, moderate, and high. Patients who present with at least one DVT risk factor and unilateral pain and swelling have an 85% probability of DVT. Outpatients who present with no identifiable risk factors and with features not typically associated with DVT have about a 5% probability of DVT. An evaluation of pretest probability assessment prior to compression ultrasound was performed in 593 patients with possible DVT. Patients with low pretest probability of DVT underwent a single ultrasound test of the proximal veins. A negative ultrasound was felt to exclude acute DVT. Positive studies were confirmed with venography. More than half of the patients were classified as “low” probability of DVT. One-third were “moderate” pretest probability, while 14% were assessed as having “high” pretest probability for DVT. The incidence of positive venous ultrasound studies in these three groups (low, moderate, and high) was 3%, 17%, and 75%, respectively.
The evaluation of a pretest probability model in conjunction with D-dimer testing has also been performed. D-dimer is a fibrin-specific degradation product that detects cross-linked fibrin resulting from endogenous fibrinolysis. Therefore, it is an indirect marker of DVT. However, the precise role of D-dimer assays, as an adjunct to ultrasound examination for DVT, has not been definitively established. D-dimer measurements have a lower sensitivity for isolated calf vein thrombi. D-dimer negative predictive values vary with pretest probability of disease. Negative predictive values are exceptionally good in low-risk patients but are unacceptable in high-risk patients. There are many different assays for D-dimer, and they vary in their sensitivity and specificity. Data using D-dimer assays therefore cannot be extrapolated to predict anticipated results with other assays.
Several studies have evaluated D-dimer in combination with clinical assessment in the evaluation of outpatients with suspected DVT. In a recent study, 1,096 consecutive outpatients suspected of DVT were stratified according to the clinical likelihood of DVT. Patients were then randomized to undergo ultrasound imaging alone or to undergo D-dimer testing and then ultrasound imaging. If the D-dimer was negative and the patient was considered unlikely to have a DVT, ultrasound testing was withheld. Only 0.4% of patients in whom DVT was excluded developed DVT. The authors concluded that DVT could be excluded when DVT was clinically unlikely and the D-dimer test was negative. They also concluded that ultrasound could be safely omitted in patients with a negative D-dimer and a low clinical likelihood of DVT.
Despite such encouraging results, algorithms to limit ultrasound examinations are not currently well accepted, and they are infrequently used in routine clinical practice. Reasons include the complexity of the algorithms, medical-legal considerations, and the practical fact that a negative ultrasound examination allows the evaluating physician to immediately consider alternative diagnoses. It is likely that algorithms, which incorporate D-dimer testing, will become more widely used in ongoing attempts to limit costs and improve diagnostic processes for DVT.
Alternative Diagnostic Tests
Some alternative examinations to venous ultrasound for diagnosis of DVT, such as plethysmography and fibrinogen labeling, are of historic interest only. When venous duplex scanning cannot be performed or is of questionable accuracy, the current alternative choices for diagnosis of lower-extremity DVT are magnetic resonance venography (MRV), computed tomography, or contrast catheter-based venography.
Magnetic Resonance Venography (MRV)
MRV can be performed without contrast using phase-contrast or time-of-flight techniques. Gadolinium can also be given intravenously as a contrast agent. The contrast-enhanced technique allows faster acquisition times and better accuracy in areas of slow flow or vessel tortuosity. MRV is most useful as an alternative to contrast venography in evaluating the iliac veins and the vena cava; these vessels are often difficult to examine with ultrasound. MRV can be quite accurate for evaluating proximal veins with sensitivities of 100% and specificities of 98% reported for pelvic and common femoral veins. It is not useful for evaluating possible calf vein thrombosis. The technique is currently limited by high costs, limited availability, and logistical constraints.
Computed Tomography Venography (CTV)