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tributaries. The deep veins of the leg accompany the major arteries. Perforating veins connect the superficial and deep systems at multiple locations. Bicuspid valves are present throughout the venous system to direct the flow of venous blood centrally. VENOUS THROMBOSIS The presence of thrombus within a superficial or deep vein and the accompanying inflammatory response in the vessel wall is termed venous thrombosis or thrombophlebitis. Initially, the thrombus is composed principally of platelets and fibrin. Red cells become interspersed with fibrin, and the thrombus tends to propagate in the direction of blood flow. The inflammatory response in the vessel wall may be minimal or characterized by granulocyte infiltration, loss of endothelium, and edema. The factors that predispose to venous thrombosis were initially described by Virchow in 1856 and include stasis, vascular damage, and hypercoagulability. Accordingly, a variety of clinical situations are associated with increased risk of venous thrombosis (Table 232-2). Venous thrombosis may occur in >50% of patients having orthopedic surgical procedures, particularly those involving the hip or knee, and in 10 to 40% of patients who undergo abdominal or thoracic operations. The prevalence of venous thrombosis is particularly high in patients with cancer of the pancreas, lungs, genitourinary tract, stomach, and breast. Approximately 10 to 20% of patients with idiopathic deep vein thrombosis have or develop clinically overt cancer; there is no consensus on whether these individuals should be subjected to intensive diagnostic workup to search for occult malignancy. The risk of thrombosis is increased following trauma, such as fractures of the spine, pelvis, femur, and tibia. Immobilization, regardless of the underlying disease, is a major predisposing cause of venous thrombosis. This fact may account for the relatively high incidence in patients with acute myocardial infarction or congestive heart failure. The incidence of venous thrombosis is increased during pregnancy, particularly in the third trimester and in the first month postpartum, and in individuals who use oral contraceptives or receive postmenopausal hormone replacement therapy. A variety of clinical disorders that produce systemic hypercoagulability, including resistance to activated protein C (factor V Leiden); prothrombin G20210A gene mutation; antithrombin III, protein C, and protein S deficiencies; antiphospholipid syndrome; hyperhomocysteinemia; SLE5 ; myeloproliferative diseases; dysfibrinogenemia; and disseminated intravascular coagulation, are associated with venous thrombosis. Venulitis occurring in thromboangiitis obliterans, Behcet's disease, and homocysteinuria may also cause venous thrombosis. DEEP VENOUS THROMBOSIS (DVT) The most important consequences of this disorder are pulmonary embolism (Chap. 244) and the syndrome of chronic venous insufficiency. DVT6 of the iliac, femoral, or popliteal veins is suggested by unilateral leg swelling, warmth, and erythema. Tenderness may be present along the course of the involved veins, and a cord may be palpable. There may be increased tissue turgor, distention of superficial veins, and the appearance of
prominent venous collaterals. In some patients, deoxygenated hemoglobin in stagnant veins imparts a cyanotic hue to the limb, a condition called phlegmasia cerulea dolens. In markedly edematous legs, the interstitial tissue pressure may exceed the capillary perfusion pressure, causing pallor, a condition designated phlegmasia alba dolens. The diagnosis of DVT7 of the calf is often difficult to make at the bedside. This is so because only one of multiple veins may be involved, allowing adequate venous return through the remaining patent vessels. The most common complaint is calf pain. Examination may reveal posterior calf tenderness, warmth, increased tissue turgor or modest swelling, and, rarely, a cord. Increased resistance or pain during dorsiflexion of the foot (Homans' sign) is an unreliable diagnostic sign. DVT8 occurs less frequently in the upper extremity than in the lower extremity, but the incidence is increasing because of greater utilization of indwelling central venous catheters. The clinical features and complications are similar to those described for the leg. Diagnosis D-Dimer, a degradation product of cross-linked fibrin, is often elevated in patients with venous thrombosis. It is a sensitive, but not specific, test for venous thrombosis. The noninvasive test used most often to diagnose DVT9 is duplex venous ultrasonography (B-mode, i.e., two-dimensional, imaging, and pulse-wave Doppler interrogation). By imaging the deep veins, thrombus can be detected either by direct visualization or by inference when the vein does not collapse on compressive maneuvers. The Doppler ultrasound measures the velocity of blood flow in veins. This velocity is normally affected by respiration and by manual compression of the foot or calf. Flow abnormalities occur when deep venous obstruction is present. The sensitivity of duplex venous ultrasonography approaches 95% for proximal DVT and 75% for symptomatic calf vein thrombosis. Magnetic resonance imaging (MRI) is another noninvasive means to detect DVT10. Its diagnostic accuracy for assessing proximal DVT is similar to that of duplex ultrasonography. It is useful in patients with suspected thrombosis of the superior and inferior venae cavae or pelvic veins. DVT11 can also be diagnosed by venography. Contrast medium is injected into a superficial vein of the foot and directed to the deep system by the application of tourniquets. The presence of a filling defect or absence of filling of the deep veins is required to make the diagnosis. DVT12 must be differentiated from a variety of disorders that cause unilateral leg pain or swelling, including muscle rupture, trauma, or hemorrhage; a ruptured popliteal cyst; and lymphedema. It may be difficult to distinguish swelling caused by the postphlebitic syndrome from that due to acute recurrent DVT. Leg pain may also result from nerve compression, arthritis, tendinitis, fractures, and arterial occlusive disorders. A careful history and physical examination can usually determine the cause of these symptoms. TREATMENT
Anticoagulants (See also Chap. 244) Prevention of pulmonary embolism is the most important reason for treating patients with DVT13, since in the early stages the thrombus may be loose and poorly adherent to the vessel wall. Patients should be placed in bed, and the affected extremity should be elevated above the level of the heart until the edema and tenderness subside. Anticoagulants prevent thrombus propagation and allow the endogenous lytic system to operate. Initial therapy should include either unfractionated heparin or low-molecular-weight heparin. Unfractionated heparin should be administered intravenously as an initial bolus of 7500 to 10,000 IU, followed by a continuous infusion of 1000 to 1500 IU/h. The rate of the heparin infusion should be adjusted so that the activated partial thromboplastin time (aPTT) is approximately twice the control value. Subcutaneous injection of heparin has been used as an alternative form of therapy. In <5% of patients, heparin therapy may cause thrombocytopenia (heparin-induced thrombocytopenia, HIT). Infrequently, these patients develop arterial thrombosis and ischemia. Low-molecular-weight (4000 to 6000 Da) heparins are as effective as or better than conventional, unfractionated heparin in preventing extension or recurrence of venous thrombosis. Depending on the specific preparation, low-molecular-weight heparin is administered subcutaneously, in fixed doses, once or twice daily; for example, the dose of enoxaparin is 1 mg/kg subcutaneously bid. The incidence of thrombocytopenia is less with low-molecular-weight heparin than with conventional preparations. A direct thrombin inhibitor, such as lepirudin or argatroban, may be used as initial anticoagulant therapy for patients in whom heparin is contraindicated because of HIT. Warfarin is administered during the first week of treatment with heparin and may be started as early as the first day of heparin treatment if the aPTT is therapeutic. It is important to overlap heparin treatment with oral anticoagulant therapy for at least 4 to 5 days because the full anticoagulant effect of warfarin is delayed. The dose of warfarin should be adjusted to maintain the prothrombin time at an international normalized ratio (INR) of 2.0 to 3.0. Anticoagulant treatment is indicated for patients with proximal DVT14, since pulmonary embolism may occur in ~50% of untreated individuals. The use of anticoagulants for isolated DVT of the calf is controversial. However, approximately 20 to 30% of calf thrombi propagate to the thigh, thereby increasing the risk of pulmonary embolism. The overall incidence of pulmonary embolism in patients presenting initially with deep calf vein thrombosis is 5 to 20%. Also, isolated calf vein thrombosis has been identified as a cause of embolic stroke via a patent foramen ovale. Therefore, patients with calf vein thrombosis should either receive anticoagulants or be followed with serial noninvasive tests to determine whether proximal propagation has occurred. Anticoagulant treatment should be continued for at least 3 to 6 months for patients with acute idiopathic DVT and for those with a temporary risk factor for venous thrombosis to decrease the chance of recurrence. In a recent study of patients with idiopathic venous thromboembolism, long-term management with low-intensity warfarin using a targeted INR15 of 1.5 to 2.0, following at least 3 months of therapy with full-dose anticoagulation, reduced the risk of recurrent DVT and pulmonary embolism. The duration of treatment is indefinite for patients with recurrent DVT and for those in whom associated causes, such as malignancy or hypercoagulability, have not been eliminated. If treatment with anticoagulants is contraindicated because of a bleeding diathesis or risk of hemorrhage, protection from pulmonary embolism can be achieved by
mechanically interrupting the flow of blood through the inferior vena cava. Inferior vena cava plication generally has been replaced by percutaneous insertion of a filter. Thrombolytics Thrombolytic drugs such as streptokinase, urokinase, and tPA4 may also be used, but there is no evidence that thrombolytic therapy is more effective than anticoagulants in preventing pulmonary embolism. However, early administration of thrombolytic drugs may accelerate clot lysis, preserve venous valves, and decrease the potential for developing postphlebitic syndrome. Prophylaxis Prophylaxis should be considered in clinical situations where the risk of DVT16 is high. Low-dose unfractionated heparin (5000 units 2 h prior to surgery and then 5000 units every 8 to 12 h postoperatively), warfarin, and external pneumatic compression are all useful. Low-dose heparin reduces the risk of DVT associated with thoracic and abdominal surgery and with prolonged bed rest. Low-molecular-weight heparins have been shown to prevent DVT in patients undergoing general or orthopedic surgery and in acutely ill medical patients. They are said to be more effective than conventional heparin and to cause an equal or lower incidence of bleeding. Danaparoid, a low-molecular-weight heparinoid, may be used for prophylaxis in patients undergoing hip surgery. Fondaparinux, a synthetic pentasaccharide capable of catalysing antithrombin-mediated inhibition of factor Xa, may be used for prophylaxis in patients undergoing major orthopedic surgery. Warfarin in a dose that yields a prothrombin time equivalent to an INR17 of 2.0 to 3.0 is effective in preventing DVT associated with bone fractures and orthopedic surgery. Warfarin is started the night before surgery and continued throughout the convalescent period. External pneumatic compression devices applied to the legs are used to prevent DVT when even low doses of heparin or warfarin might cause serious bleeding, as during neurosurgery or transurethral resection of the prostate. SUPERFICIAL VEIN THROMBOSIS Thrombosis of the greater or lesser saphenous veins or their tributaries — i.e., superficial vein thrombosis — does not result in pulmonary embolism. It is associated with intravenous catheters and infusions, occurs in varicose veins, and may develop in association with DVT18. Migrating superficial vein thrombosis is often a marker for a carcinoma and may also occur in patients with vasculitides, such as thromboangiitis obliterans. The clinical features of superficial vein thrombosis are easily distinguished from those of DVT. Patients complain of pain localized to the site of the thrombus. Examination reveals a reddened, warm, and tender cord extending along a superficial vein. The surrounding area may be red and edematous. TREATMENT Treatment is primarily supportive. Initially, patients can be placed at bed rest with leg elevation and application of warm compresses. Nonsteroidal anti-inflammatory drugs may provide analgesia but may also obscure clinical evidence of thrombus propagation. If a thrombosis of the greater saphenous vein develops in the thigh and extends toward the saphenofemoral vein junction, it is reasonable to consider anticoagulant therapy to prevent extension of the thrombus into the deep system and a possible pulmonary