DEFINITION AND NATURAL HISTORY
Venous thromboembolism includes both deep-vein thrombosis (DVT) and pulmonary thromboembolism (PE). DVT results from blood clot formation within large veins, usually in the legs. PE results from DVTs that have broken off and traveled to the pulmonary arterial circulation. About one-half of pts with pelvic vein or proximal leg DVT develop PE, which is often asymptomatic. Isolated calf vein thrombi have much lower risk of PE. Although DVTs are typically related to thrombus formation in the legs and/or pelvis, indwelling venous catheters have increased the occurrence of upper extremity DVT. In the absence of PE, the major complication of DVT is postphlebitic syndrome, which causes chronic leg swelling and discomfort due to damage to the venous valves of the affected leg. In its most severe form, postphlebitic syndrome causes skin ulceration. PE is often fatal, usually due to progressive right ventricular failure. Chronic thromboembolic pulmonary hypertension is another long-term complication of PE. Some genetic risk factors, including factor V Leiden and the prothrombin G20210A mutation, have been identified, but they account for only a minority of venous thromboembolic disease. A variety of other risk factors have been identified, including immobilization during prolonged travel, cancer, obesity, smoking, surgery, trauma, pregnancy, oral contraceptives, and postmenopausal hormone replacement. Medical conditions that increase the risk of venous thromboembolism include cancer and antiphospholipid antibody syndrome.
CLINICAL EVALUATION
History
DVTs often present with progressive lower calf discomfort. For PE, dyspnea is the most common presenting symptom. Chest pain, cough, or hemoptysis can indicate pulmonary infarction with pleural irritation. Syncope can occur with massive PE.
Physical Examination
Tachypnea and tachycardia are common in PE. Low-grade fever, neck vein distention, and a loud P2 on cardiac examination can be seen. Hypotension and cyanosis suggest massive PE. Physical examination with DVT may be notable only for mild calf tenderness. However, with massive DVT, marked thigh swelling and inguinal tenderness can be observed.
Laboratory Tests
Normal d-dimer level (<500 μg/mL by enzyme-linked immunosorbent assay) essentially rules out PE in pts with low-to-moderate likelihood of PE, although hospitalized pts often have elevated d-dimer levels due to other disease processes. Although hypoxemia and an increased alveolar-arterial O2 gradient may be observed in PE, arterial blood gases are rarely useful in diagnosing PE. Elevated serum troponin, plasma heart-type fatty acidbinding protein, and brain natriuretic peptide levels are associated with increased risk of complications and mortality in PE. The electrocardiogram can show an S1Q3T3 sign in PE, but that finding is not frequently observed.
Imaging Studies
Venous ultrasonography can detect DVT by demonstrating loss of normal venous compressibility. When combined with Doppler imaging of venous flow, the detection of DVT by ultrasonography is excellent. For pts with nondiagnostic venous ultrasound studies, CT or MRI can be used to assess for DVT. Contrast phlebography is very rarely required. About one-half of pts with PE have no imaging evidence for DVT. In PE, a normal chest x-ray (CXR) is common. Although not commonly observed, focal oligemia and peripheral wedge-shaped densities on CXR are well-established findings in PE. Chest CT with IV contrast has become the primary diagnostic imaging test for PE. Ventilation-perfusion lung scanning is primarily used for subjects unable to tolerate IV contrast. Transthoracic echocardiography is valuable to assess for right ventricular hypokinesis with moderate to large PE, but it is not typically useful for diagnosing the presence of a PE. Transesophageal echocardiography can be used to identify large central PE when IV contrast chest CT scans are not appropriate (e.g., renal failure or severe contrast allergy). With the advent of contrast chest CT scans for PE diagnosis, pulmonary angiography studies are rarely performed.
Integrated Diagnostic Approach
An integrated diagnostic approach that considers the clinical suspicion for DVT and PE is required. For individuals with a low clinical likelihood of DVT or with a low to moderate clinical likelihood of PE, the d-dimer level can be used to determine if further imaging studies are required. An algorithm for imaging studies in both DVT and PE is shown in . The differential diagnosis of DVT includes a ruptured Baker’s cyst and cellulitis. The differential diagnosis of PE is broad and includes pneumonia, acute myocardial infarction, and aortic dissection.
TREATMENT
ANTICOAGULATION Although anticoagulants do not dissolve existing clots in DVT or PE directly, they limit further thrombus formation and allow fibrinolysis to occur. In order to provide effective anticoagulation rapidly, parenteral anticoagulation is used for the initial treatment of venous thromboembolism. Traditionally, unfractionated heparin (UFH) has been used, with a target activated partial thromboplastin time (aPTT) of 2–3 times the upper limit of the normal laboratory value. UFH is typically administered with a bolus of 5000–10,000 U followed by a continuous infusion of approximately 1000 U/h. Frequent dosage adjustments are often required to achieve and maintain a therapeutic aPTT with UFH. Heparin-induced thrombocytopenia can occur with UFH. However, the short half-life of UFH remains a significant advantage. Alternatives to UFH for acute anticoagulation include low-molecularweight heparins (LMWHs) such as enoxaparin and dalteparin. Laboratory monitoring is not required, but doses are adjusted for renal impairment or obesity. Fondaparinux, a pentasaccharide, is another parenteral alternative to UFH that does not require laboratory monitoring but does require dose adjustment for body weight and renal insufficiency. In pts with heparininduced thrombocytopenia, direct thrombin inhibitors (e.g., argatroban, lepirudin, or bivalirudin) should be used. After initiating treatment with a parenteral agent, warfarin is typically used for long-term oral anticoagulation. Warfarin can be initiated soon after a parenteral agent is given; however, 5–7 days are required for warfarin to achieve therapeutic anticoagulation. Warfarin is given to achieve a therapeutic international normalized ratio (INR) of the prothrombin time, which is typically an INR of 2.0–3.0. Pts vary widely in their required warfarin doses; dosing often begins at 5 mg/d, with adjustment based on the INR. The most troublesome adverse event from anticoagulation treatment is hemorrhage. For severe hemorrhage while undergoing treatment with UFH or LMWH, protamine can be given to reverse anticoagulation. Severe bleeding while anticoagulated with warfarin can be treated with fresh frozen plasma or cryoprecipitate; milder hemorrhage or markedly elevated INR values can be treated with vitamin K. Recombinant human coagulation factor VIIa provides an off-label option to manage catastrophic bleeding from warfarin. Warfarin should be avoided in pregnant pts. The duration of anticoagulation for an initial DVT or PE is at least 3–6 months. Pts with DVT or PE in the setting of trauma, surgery, or high estrogen states have a low recurrence rate after 3–6 months of anticoagulation. However, recurrence rate is high in pts with cancer or with idiopathic, unprovoked DVT or PE, and prolonged anticoagulation should be considered. Recurrent DVT or PE typically requires lifelong anticoagulation.
OTHER TREATMENT MODALITIES
Although anticoagulation is the mainstay of therapy for venous thromboembolism, additional therapeutic modalities also can be employed, based on risk stratification. Inferior vena cava filters can be used if thrombosis recurs despite adequate anticoagulation or if active bleeding precludes anticoagulation. Fibrinolytic therapy (often with tissue plasminogen activator) should be considered for PE causing right heart failure, although the risk of hemorrhage is significant. Surgical or catheter embolectomy also can be considered for massive PE. If PE pts develop chronic thromboembolic pulmonary hypertension, surgical intervention (pulmonary thromboendarterectomy) can be performed. There is no effective therapy for postphlebitic syndrome.
OTHER TREATMENT MODALITIES
Although anticoagulation is the mainstay of therapy for venous thromboembolism, additional therapeutic modalities also can be employed, based on risk stratification. Inferior vena cava filters can be used if thrombosis recurs despite adequate anticoagulation or if active bleeding precludes anticoagulation. Fibrinolytic therapy (often with tissue plasminogen activator) should be considered for PE causing right heart failure, although the risk of hemorrhage is significant. Surgical or catheter embolectomy also can be considered for massive PE. If PE pts develop chronic thromboembolic pulmonary hypertension, surgical intervention (pulmonary thromboendarterectomy) can be performed. There is no effective therapy for postphlebitic syndrome.
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