Etiology

Venous thrombosis may develop as a result of endothelial damage, hypercoagulability, and venous stasis (Virchow triad). Of these risk factors, relative hypercoagulability appears most important in most cases of spontaneous DVT, whereas stasis and endothelial damage play a greater role in secondary DVT following immobilization, surgery, or trauma. Identifiable risk factors for VTE may be classified as inherited, acquired, and those with a mixed etiology (Table 12-1).

 TABLE 12–1 Common Inherited and Acquired Risk Factors for Venous Thrombosis

When multiple inherited and acquired risk factors are present in the same patient, a synergistic effect may occur. Clinically manifest thrombosis most often occurs with the convergence of multiple genetic and acquired risk factors.⁴ Hospitalized patients have an average of 1.5 risk factors per patient, with 26% having three or more risk factors.⁵ Multiple risk factors often act synergistically to increase risk dramatically above the sum of individual risk factors. For example, patients who are heterozygous for factor V Leiden are at only moderately increased risk for VTE (4- to 8-fold). However, when combined with the additional risk of oral contraceptive use, the risk for VTE increases to approximately 35-fold, the same order of magnitude as for someone who is homozygous for factor V Leiden. The concomitant presence of obesity, advancing age, and factor V Leiden increases the thrombosis risk associated with hormone replacement therapy alone. In symptomatic outpatients, the odds ratio for an objectively documented DVT increases from 1.26 for one risk factor to 3.88 for three or more risk factors.⁶

Other factors associated with venous thrombosis include traditional cardiovascular risk factors (obesity, hypertension, diabetes), and there is a racial predilection among whites and African Americans compared with Asians and Native Americans. Certain gene variants (single nucleotide polymorphisms) are associated with a mild increased risk for DVT, and their presence may interact with other risk factors to increase the overall risk for venous thrombosis. However, testing for these polymorphisms is not common in clinical practice.

Natural History

Overt venous injury appears to be neither a necessary nor sufficient condition for thrombosis, although the role of biologic injury to the endothelium is increasingly apparent. Under conditions favoring thrombosis, the normally antithrombogenic endothelium may become prothrombotic, producing tissue factor, von Willebrand factor, and fibronectin. Stasis alone is probably also an inadequate stimulus in the absence of low levels of activated coagulation factors.⁷

The rate of VTE recurrence in patients with untreated isolated calf DVT is approximately 20% to 30%. In contrast, the rate of recurrence in patients with untreated proximal DVT is more difficult to determine, since the majority of patients with proximal DVT receive therapeutic anti-coagulation. Limited older data suggest that about 50% of patients with inadequately treated proximal DVT will develop symptomatic PE.

Therapeutic anticoagulation effectively stabilizes venous thrombus, prevents propagation, and promotes dissolution by endogenous plasmin and its mediators. However, there is a low rate of VTE recurrence, even with adequate dosages of heparin, low-molecular-weight heparin, pentasaccharides, and/or vitamin K antagonists. Most VTE recurrence takes place in the first few weeks after anticoagulant therapy is initiated, and it is dependent upon the location of the original DVT. Extension of isolated calf DVT is effectively attenuated by anticoagulation. However, even adequately treated proximal DVTs have a low rate of recurrence.

Laboratory Testing for Venous Thromboembolism

There are no laboratory tests that confirm or exclude the presence of DVT or superficial venous thrombosis (SVT).

D-dimer testing may be useful in two clinical settings. In the first of these situations, a negative D-dimer testing in combination with a low probability clinical scoring criteria in combination with D-dimer testing has a negative predictive value for excluding DVT. However, D-dimer testing is a poorer predictor for the presence of DVT or PE. In the setting of patients with established DVT who have received a course of anticoagulation, D-dimer testing may be used to help guide the duration of anticoagulation.

Imaging

The venous duplex scan is the most commonly performed test for the detection of infrainguinal DVT, both above and below the knee, with sensitivity and specificity of greater than 95% in symptomatic patients. In a venous duplex examination performed with the patient supine, spontaneous flow, variation of flow with respiration, and response of flow to the Valsalva maneuver, all are assessed. Continued improvements in ultrasound technology also have improved the ability to visualize color flow within the tibial veins. However, the primary method of detecting DVT with ultrasound is demonstration of the lack of compressibility of the vein with probe pressure on B-mode imaging. Normally, in transverse section, the vein walls should coapt with pressure (Figs. 12-1 and 12-2). Lack of coaptation indicates thrombus.

Fig 12–1 Common femoral vein without and with compression. Complete vein wall coaptation indicates absence of deep vein thrombosis.

Fig 12–2 Normal saphenofemoral junction.

Venography is the most definitive test for the diagnosis of DVT in both symptomatic and asymptomatic patients. Diagnostic venography involves placement of a small catheter in the dorsum of the foot, with injection of radiopaque contrast to produce projections in at least two views. Venography is not used routinely for the evaluation of lower extremity DVT because of associated complications. More commonly, it is used for imaging prior to operative venous reconstruction or catheter-based endovenous therapy.