In Brief

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Deep venous thrombosis (DVT) and pulmonary embolism (PE) remain serious health problems. Together, it has been estimated that there are more than 900,000 cases per year in this country alone. Acquired risk factors for thrombosis include age, malignancy, surgery and trauma, immobilization, oral contraceptive use, hormone replacement therapy, pregnancy and the puerperium, obesity, neurological disease, cardiac disease, and antiphospholipid antibodies. Genetic risk factors include deficiencies of antithrombin, proteins C and S, factor V Leiden, prothrombin 20210A gene variant, blood group non-O, hyperhomocystinemia, dysfibrinogenemia, dysplasminogenemia, reduced heparin cofactor II activity, elevated levels of clotting factors, and elevated plasminogen activator inhibitor-1 levels. For venous thrombosis, indications for screening for these genetic factors include thrombosis in unusual locations, idiopathic venous thrombosis, recurrent venous thrombosis, thrombosis on oral contraceptives, and episodes of aggressive superficial thrombophlebitis.

The pathogenesis of venous thrombosis involves a combination of stasis, endothelial perturbations, and hypercoagulabilities. Thrombus is amplified by inflammation, and it appears that the balance between pro-inflammatory and anti-inflammatory cytokines and chemokines determine the ultimate vein wall response to the thrombus. P-selectin and procoagulant microparticles appear to participate to a large extent in this process. Additionally, tissue factor released from the vein wall also contributes to this process.

The diagnosis of DVT includes clinical clues and duplex ultrasound imaging, which carries high sensitivity, specificity, and reproducibility. Magnetic resonance imaging (MRI) is helpful to diagnose central pelvic vein and inferior vena cava (IVC) thrombosis, and spiral computed tomography (CT) is used most often today when combined with chest imaging for examination for pulmonary embolism. Even at the calf level, a level in which duplex imaging is felt to be less accurate, duplex imaging is an acceptable technique in symptomatic patients. This test also identifies other potential causes of a patient's symptoms. Combining clinical characteristics with a D-dimer assay may also decrease the number of negative duplex ultrasound examinations performed in an individual laboratory. Importantly, a single complete technically adequate negative duplex scan is accurate enough to withhold anticoagulation with minimal long-term adverse thromboembolic complications. For the diagnosis of PE, the ventilation/perfusion scan (V/Q scan) gives excellent information when normal or interpreted as high probability in a patient of high clinical suspicion, but only a small portion of V/Q scans are in 1 of these 2 categories. Spiral CT imaging has demonstrated excellent sensitivity and specificity for the diagnosis of PE and if the clinical presentation and results of the spiral CT are concordant, therapies may proceed based on the results of the CT. On the other hand, when the CT and clinical presentation are discordant, other confirmatory testing is needed.

Patients with axillary-subclavian vein thrombosis often present with arm pain, edema, and cyanosis. Upper extremity duplex imaging is useful to establish the diagnosis, and phlebography and thrombolysis should be considered, especially when a patient presents with effort thrombosis, the Paget Schrotter syndrome. It is important in these patients to remember to perform positional phlebography and chest radiography looking for a cervical rib.

The standard therapy for venous thromboembolism (VTE) is systemic anticoagulation. This reduces the risk of PE, extension of thrombosis, and recurrence of thrombosis. It has been shown that becoming therapeutic in the first 24 hours will reduce VTE recurrence significantly. Traditionally, systemic intravenous heparin has been used. However, due to the need for intravenous administration, frequent monitoring, and bleeding risks, low molecular weight heparin (LMWH) has been advanced. LMWHs demonstrate less thrombin inhibition and more factor Xa inhibition, a significant improvement in bioavailability, less endothelial cell and protein binding, a lower risk of hemorrhage, and a superior thrombus recanalization rate. Their use does not require monitoring (except in certain situations such as renal failure and morbid obesity) and they are usually given subcutaneously, making outpatient treatment feasible. LMWHs may also decrease the incidence of the post-thrombotic syndrome. There is some indication that LMWHs are better than warfarin for long-term use in cancer patients, and the use of once daily dosing is equivalent to twice daily dosing in most situations. Remembering that LMWHs in most cases are the bridge to longer term oral anticoagulation, warfarin should be started after heparin or LMWH is therapeutic, usually on the first day of therapy. Criteria for the length of warfarin treatment include the patient's initial presentation along with the amount of scar tissue inside the venous circulation leading to stasis and the level of D-dimer obtained 1 month after warfarin therapy is complete. For idiopathic thrombosis, long-term treatment aiming for an international normalized ratio (INR) of 2 to 3 is desirable. In aggregate, criteria for discontinuation of oral anticoagulation include thrombosis risk, residual thrombus burden, and coagulation system activation.

Complications of anticoagulation include bleeding and heparin-induced thrombocytopenia (HIT). Heparin-induced thrombocytopenia usually begins 3 to 14 days after heparin is begun, and is caused by a heparin-dependent antibody immunoglobulin that binds to platelets and leads to their activation. This diagnosis is suspected with a 50% or greater drop in platelet count or when the platelet count falls below 100,000, or in the presence of thrombosis on heparin. The direct thrombin inhibitors lepirudin and argatroban are FDA approved, and fondaparinux has also been found useful for treatment of this syndrome.

Two new classes of agents for venous thrombosis treatment include direct thrombin inhibitors and factor Xa inhibitors. Examples of these agents include dabigatran (thrombin inhibitor), fondaparinux (factor Xa inhibitor), and oral agents rivaroxaban and apixaban (both factor Xa inhibitors). These and other agents are in active stages of development.

Inferior vena cava filters are indicated for patients with complications of anticoagulation, contraindication to anticoagulation, or failure of anticoagulation. The success of filters has expanded their indications to include prophylaxis. Filters are usually placed in the infrarenal location, and they may be placed under radiographic or ultrasound guidance. Filters can be either permanent or optional (retrievable) devices. Nonpharmacological treatments for DVT include the use of compression stockings and a good program of ambulation, once anticoagulation is therapeutic. These measures have been found to significantly decrease the long-term morbidity of the post-thrombotic syndrome, pain, and leg swelling after DVT.

Prophylaxis for VTE should focus on preventing the many faces of the problem and not just preventing clinical and fatal events. Risk assessment for the individual patient is necessary because there are a variety of risk factors, but the relative risk of these factors is not the same. Evidence-based guidelines are applicable only for patients who fit the criteria of the clinical trials; the unique risk pattern of an individual may be such that the prophylaxis appropriate for a particular group may not be appropriate for an individual patient. A risk assessment tool that takes factors and gives them a weighted score based on the aggregate literature provides the basis for individual risk assessment. Despite these tools, the utilization of VTE prophylaxis is poor and until prophylaxis is mandated, the percentage of patients that receive appropriate protection will remain suboptimal. In the “real world,” VTE prophylaxis is being used approximately 40% to 60% of the time. However, even when prophylaxis is being used, it is conforming to Chest guidelines in only approximately one half of the cases.

Thrombosis prophylaxis must begin with a complete risk assessment of the patient looking for historical or physical findings that might represent an increased tendency for developing VTE. The degree of patient risk should dictate the selection of prophylaxis. Mechanical methods may be appropriate for those with few risk factors while anticoagulant prophylaxis should be selected for higher risk patients. Those individuals with a very high risk for developing VTE should receive a combination of physical and pharmacologic prophylaxis. The culture in the United States is to start anticoagulants postoperatively to minimize the fear of bleeding. Finally, reassessment of the patient should be performed at discharge and those with continuing risk should receive prophylaxis with anticoagulants after discharge.

Aggressive treatment for VTE is defined as adopting a strategy of thrombus removal before long-term anticoagulation, rather than accepting the existing venous thrombosis or embolic pulmonary occlusion and treating the patient with anticoagulation alone, thus accepting all of the post-thrombotic or embolic morbidity that accompanies this situation. There is a spectrum of evidence supporting a strategy of thrombus removal in patients with acute VTE. Patients with extensive DVT, especially those with iliofemoral thrombosis, will have severe post-thrombotic morbidity if treated with anticoagulation alone. Data are available from experimental observations in animal models, long-term follow-up studies in patients with acute DVT treated with anticoagulants alone, clinical reports of large patient series, and randomized trials. The aggregate data demonstrate that patency can be restored, vein wall and valvular function can be maintained, and post-thrombotic morbidity can be reduced if thrombus is eliminated successfully. Strategies for thrombus removal include catheter-based thrombolytic therapies and/or venous thrombectomy. Catheter-directed thrombolysis is the preferred treatment option for most patients who have no contraindication to thrombolytic therapy. Adjunctive mechanical techniques are becoming increasingly popular and tend to shorten treatment time and reduce the dose of plasminogen activator needed. In addition to improving venous patency, quality of life scales have demonstrated that when patients with iliofemoral venous thrombosis have the thrombus removed, their quality of life improves. Today, percutaneous techniques alone or in combination with thrombolysis have been developed to more rapidly clear the venous system. Examples of mechanical systems include rheolytic thrombectomy, ultrasound-accelerated thrombolysis, and the mechanical action of a dual balloon catheter.

For PE, aggressive therapy is indicated not only in situations associated with hemodynamic instability but also in situations in which there is evidence of right heart abnormalities. Patients with PE that raises pulmonary artery pressures to the point of affecting right ventricular function have a markedly increased early and long-term mortality rate, increased risk of recurrence, and increased risk of chronic thromboembolic pulmonary hypertension. All patients with PE should undergo cardiac echocardiography to assess pulmonary artery pressure and right heart function. Patients with abnormalities of right heart function should be considered for systemic thrombolytic therapy, catheter-based fragmentation or operative thrombectomy, if necessary.