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Risk Factors and the Role of Ultrasound in the Management of Extremity Venous Disease
Introduction
Duplex sonography can effectively diagnose the presence of acute and chronic venous thrombosis in the extremity veins. Most commonly, duplex sonography is used when acute deep vein thrombosis is suspected, but it is also a reliable means for determining the extent of chronic venous disease and the accompanying physiologic alterations in venous hemodynamics. Performance of the diagnostic venous ultrasound examination is also tailored to current approaches in patient management and the availability of various treatments. Both these aspects will be covered in the following pages.
Acute Deep Vein Thrombosis Etiology and Risk Factors
Venous thromboembolic (VTE) disease includes both deep vein thrombosis (DVT) and pulmonary embolism (PE) because they represent different aspects of the same disease process. Suspected VTE is the most common indication for the clinical evaluation of the extremity veins. Although a comprehensive review of VTE is beyond the scope of this chapter, a brief review of risk factors and conditions fostering the development of VTE is given. The annual incidence of VTE in the United States is estimated at over 2.5 million cases. Roughly 25% of untreated patients with DVT will sustain a nonfatal PE. Moreover, without treatment, PE is associated with mortality of approximately 30%. A myriad of clinical conditions increases the risk of incident venous thrombosis. This susceptibility to develop venous thrombosis was first described in 1865 as Virchow's triad: (1) venous stasis, (2) endothelial damage, and (3) hypercoagulability.
Venous stasis can occur in any situation of prolonged immobility. It may also be promoted by any situation where venous return to the heart is obstructed by compression of the vein lumen as can be seen in cases of pelvic tumors.
Endothelial damage includes direct trauma to the vein through puncture of the lumen. It can also occur in cases of trauma when shearing forces are applied to the vein wall and the endothelial layer is disrupted. This exposes the underlying collagen-rich tissues to blood.
Thrombus formation occurs through the activation of enzymatic reactions in the intrinsic and tissue factor coagulation pathways ( Fig. 20.1 ). This leads to thrombin formation via the prothrombin enzyme complex. The thrombomodulin-protein C system primarily limits coagulation, while the fibrinolytic system further limits fibrin deposition. This homeostatic system is continuously active and balances activation and inhibition of coagulation and fibrinolysis. The predisposition to thrombus formation results either from nonreversible (genetic factors, age) or reversible (acquired) prothrombotic conditions ( Table 20.1 ).
TABLE 20.1
Risk Factors for Venous Thromboembolic Disease.
| Genetic Risk Factors | Acquired Risk Factors | Environmental |
|---|---|---|
| Elevated factor VIII, IX, or XI | Age | Immobilization including travel |
| Factor V Leiden | Prior venous thrombosis or pulmonary embolism | Major surgery within 3 months |
| Primary hyperhomocysteinemia | Oral contraception and hormone replacement therapy | Oral contraception and hormone replacement therapy |
| Protein S deficiency | Malignancy | Central venous catheters |
| Antithrombin III deficiency | Obesity (BMI ≥30 kg/m 2 ) | Pregnancy and postpartum state |
| Protein C deficiency | Cigarette smoking | Trauma |
| Non-O ABO blood group | Hypertension | Chemotherapy |
| Dysfibrinogenemia | Secondary hyperhomocysteinemia | |
| Acquired antiphospholipid syndrome | ||
| Congestive heart failure | ||
| Myeloproliferative disorders | ||
| Nephrotic syndrome | ||
| Inflammatory bowel disease | ||
| Sickle cell anemia | ||
| Marked leukocytosis in acute leukemia | ||
| Infectious (e.g., sepsis, HIV) |
Inherited prothrombotic disease states have been described with increasing frequency over the past 30 years. This category of venous thrombosis is considered nonreversible and, as such, the patient keeps his/her increased risk of developing venous thromboembolic disease throughout life.
Antithrombin III deficiency was the first reported congenital thrombotic condition. It is transmitted as an autosomal dominant pattern with a prevalence of 1 : 5000. Isolated spontaneous thrombosis has been described with this condition. This deficiency lowers the threshold for the development of DVT in the presence of precipitating circumstances, such as trauma, pregnancy, and surgical procedures.
Protein C and protein S are vitamin K–dependent cofactors that facilitate degradation of activated factor V. Deficiencies therefore predispose to thrombosis. Congenital deficiencies of these factors are well described. Because these proteins are synthesized in the liver, acquired deficiencies may also occur from variations in liver function as well as with dietary changes. Protein C or S deficiency confers a roughly sevenfold increased risk of developing venous thrombosis. Resistance to activated protein C is also known as factor V Leiden. This disorder results from a point mutation in the factor V gene, rendering activated factor V resistant to degradation by activated protein C. It is present in 12% to 33% of patients with spontaneous VTE, making it the most common inherited hypercoagulable condition.
Factor II (prothrombin) G20210A is a mutation seen in 2% to 3% of individuals, predominantly those of European descent. It can increase the risk of VTE by as much as 2.8 times compared with individuals without this mutation.
Primary hyperhomocysteinemia increases risk for VTE, along with the development of premature atherosclerosis. Serum elevation of coagulation factors VIII, IX, and XI have been shown to confer elevated risk for venous thrombosis in the Leiden thrombophilia study. Factor IX and XI levels greater than the 90th percentile, respectively, confer a 2.5-fold and 2.2-fold increased risk of VTE. Dysfibrogenemias and hypofibrinolysis impair the steps involved in the generation, cross-linkage, and breakdown of fibrin. Bleeding diathesis, as well as VTE, has been described with this condition.
Acquired prothrombotic states are more numerous than inherited states. Clinical conditions that predispose to VTE are listed in Table 20.1 . Several of these conditions are briefly considered. Pregnancy and the postpartum period increase VTE risk compared with the nonpregnant state. PE is a leading cause of maternal death after childbirth, with one fatal PE per 100,000 births. Oral contraceptives and hormone replacement therapy can increase the risk of VTE in premenopausal and postmenopausal women. Lidegaard and colleagues reported a prevalence of VTE in women receiving oral contraceptives of one to three in 10,000. Women receiving hormone replacement therapy have a twofold increased risk of VTE with rates depending on the type of contraceptive and a greater risk at the onset of therapy. Antiphospholipid antibody syndrome is an acquired condition due to the presence of either the lupus anticoagulant antibody or anticardiolipin antibodies. Overall, the syndrome can be identified in 1% to 5% of the population. Among those with positive titers for the lupus anticoagulant, the risk of developing VTE is 6% to 8%. Patients with anticardiolipin antibody titers greater than the 95th percentile have a 5.3-fold increased risk of developing VTE.
Other risk factors for VTE that are often ignored include age and elevated body mass index (BMI). VTE is uncommon in children but increases progressively with age after adolescence. Obesity, defined as an increased BMI ≥30 kg/m 2 is associated with a 2 to 3 times increased risk of DVT. Trauma and concurrent malignancy remain two major sources of provoked episodes of deep vein thrombosis.
Wells score and D-dimer levels
An important consideration for the triage of patients is the application of the Wells score ( Table 20.2 ). This clinical prediction rule is a useful guide for determining the need to perform a diagnostic imaging test, most often venous ultrasound, given an a priori likelihood that the patient has deep vein thrombosis. Once calculated, the Wells score can be used to estimate the likelihood of DVT: a low risk is a score of 0 or less, an intermediate probability is a score of 1 or 2, and a high probability is a score of 3 or more.
TABLE 20.2
The Wells Score for Deep Vein Thrombosis.
| Clinical Characteristics | Points |
|---|---|
| Active cancer (patient receiving treatment for cancer within the previous 6 months or currently receiving palliative treatment) | +1 |
| Paralysis, paresis, or recent plaster immobilization of the lower extremities | +1 |
| Recently bedridden for 3 days or more or major surgery within the previous 12 weeks requiring general or regional anesthesia | +1 |
| Localized tenderness along the distribution of the deep venous system | +1 |
| Entire leg is swollen | +1 |
| Calf swelling at least 3 cm larger than that on the asymptomatic side (measured 10 cm below tibial tuberosity) | +1 |
| Pitting edema confined to the symptomatic leg | +1 |
| Collateral superficial veins (nonvaricose) | +1 |
| Previously documented DVT | +1 |
| Alternative diagnosis at least as likely as DVT | –2 |
The points obtained are summed.
There are two ways to use the score. The first is as a two-level indicator of DVT : if the total is <2, then the probability of DVT is low at 5.5% (95% confidence intervals: 3.8% to 7.6%). If the score is ≥2, then the likelihood of DVT is relatively high at 27.9% (95% confidence interval: 23.9% to 31.8%). The second approach is to use a three level score : if the total is 0 or less, then the probability of DVT is low at 5.0% (95% confidence intervals: 4% to 8%); if the total is between 1 and 2, then the probability of DVT is intermediate at 17.0% (95% confidence intervals: 13% to 23%). If the score is >2, then the likelihood of DVT is high at 53% (95% confidence interval: 44% to 61%).
DVT , Deep vein thrombosis.
The D-dimer test detects the presence of breakdown products of linked fibrin, the main constituent of thrombus, due to in vivo thrombolysis. Although the test is very sensitive for the presence of thrombus, it is not specific. False positives can be due to trauma, malignancy, recent surgery, pregnancy, liver disease, or renal disease. In addition, the sensitivity of the test depends on the method used. The most sensitive is the ELISA (enzyme-linked immunosorbent assay) method, a test that is time-consuming, has an overall sensitivity of 95%, and is considered abnormal at a level above 500 µg/L. Other, more rapidly processed D-dimer tests show some heterogeneity in sensitivity and cut points.
The D-dimer test is often combined with the Wells score to help triage patients requiring compression ultrasound. For example, venous imaging may not be performed if a patient has both a low Wells score and a negative D-dimer test. This situation can occur in up to 40% of the outpatient population.
Anticoagulation and Thrombolysis in the Management of Venous Thrombosis
Overview
The management of patients with suspected DVT may affect the protocol implemented during ultrasound imaging of the extremity veins. Anticoagulation with an agent that offers a lower risk of bleeding than unfractionated heparin can justify postponing a venous ultrasound examination requested in the middle of the night to the next morning. The availability of new oral agents that permit effective treatment of calf vein DVT without excess risk of bleeding may help justify imaging of the calf veins. Low-risk anticoagulation being performed in the outpatient setting may necessitate a more quantitative evaluation of thrombus burden in order to help triage patients to outpatient or inpatient treatment.
Heparin
Anticoagulation with intravenous (unfractionated) heparin has been the gold standard for the initial management of DVT for decades (see Fig. 20.1 ). Heparin has an antifactor Xa effect. Heparin potentiates the action of antithrombin III, thereby preventing additional thrombus formation and permitting endogenous fibrinolysis. It also has an effect on inflammation (the “itis” in thrombophlebitis). Use of low molecular weight (fractionated) heparin compounds (enoxaparin [Lovenox] or dalteparin [Fragmin]) has decreased the risk of bleeding while keeping most of the benefits of unfractionated heparin. Low molecular weight heparins can be administered subcutaneously once or twice a day and do not require monitoring of the aPTT (activated partial thromboplastin time). They have permitted the empirical treatment of patients with suspected DVT while waiting for definite diagnostic testing ( Fig. 20.2 ).
In the absence of a contraindication to anticoagulation, prompt institution of heparin therapy is indicated for patients with either confirmed DVT (through imaging techniques) or for patients in whom a moderate or high clinical suspicion of DVT exists (see Fig. 20.2 ). Low molecular weight heparin is preferred if confirmatory venous ultrasound is not immediately available.
Vitamin K antagonists
Oral warfarin therapy is started while therapeutic heparin anticoagulation is being administered, usually over 5 days. Warfarin dosing is guided by measuring the International Normalized Ratio (INR), a reflection of the inhibition of vitamin K–dependent cofactors (see Fig. 20.1 ). Although the target INR will vary depending on the clinical circumstance, it is important to understand that early elevations in the INR (1 to 3 days after institution of warfarin therapy (with an INR target of 2 to 3) usually result from inhibition of factor VII because of its short half-life. Effective anticoagulation depends on the depletion of factor II (thrombin) and typically requires about 3 to 4 days of warfarin therapy to achieve a stable INR. This leads to a transition period of approximately 5 days. Therapy with oral warfarin in the absence of heparin anticoagulation should be avoided, as days will pass before anticoagulation is adequate, leaving the patient unprotected against PE; moreover, warfarin therapy in the absence of heparin anticoagulation may paradoxically intensify hypercoagulability and predispose to recurrent DVT.
The duration of anticoagulation varies with the clinical scenario. In general, for initial cases of uncomplicated DVT, 3 months of anticoagulation is recommended. Inherited and acquired procoagulant states, and cases of recurrent DVT may require longer anticoagulation therapy, typically 6 months. In some cases of recurrent VTE and irreversible risk factors, lifelong anticoagulation may be recommended.
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