Introduction

Essentials of Diagnosis

• Pain in the calf or thigh, often associated with edema. Fifty percent of patients are asymptomatic.
• History of congestive heart failure, recent surgery, trauma, neoplasia, oral contraceptive use, or prolonged inactivity.
• Physical signs unreliable.
• Duplex ultrasound is diagnostic.

General Considerations

Acute Deep venous thrombosis (DVT) affects as many as 800,000 new patients per year. Treatment of this disease is estimated to cost $1-2.5 billion per year, not including costs associated with long-term sequelae.

Although the cause is often multifactorial, Virchow’s triad (stasis, vascular injury, and hypercoagulability) defines the events that predispose a vein to the development of thrombophlebitis. Trauma to the endothelium of the vein wall results in exposure of subendothelial tissues to platelets. With venous stasis, platelet aggregates form on the vein wall and deposition of fibrin, leukocytes, and erythrocytes results in a free-floating thrombus. Within 7-10 days, this thrombus becomes adherent to the vein wall and secondary inflammatory changes develop, though a free-floating tail may persist. The thrombus is ultimately invaded by fibroblasts, resulting in neovascularization and scarring of the vein wall and destruction of the valves. Central recanalization usually follows, with restoration of flow through the vein; however, because the valves are damaged irreparably, chronic venous insufficiency with postphlebitis syndrome occurs in approximately 35% of patients. In 80% of cases, the thrombosis begins in the deep veins of the calf. Propagation into the popliteal and femoral veins takes place in approximately 25% of these cases.

About 3% of patients undergoing major general surgical procedures will develop clinical manifestations of thrombophlebitis, and up to 30% develop asymptomatic DVT. Certain operations, such as total hip replacement, are associated with appreciably higher incidences of thromboembolic complications. Prolonged bed rest or immobility caused by cardiac failure, stroke, ventilatory support, pelvic bone or limb fracture, paralysis, extended air travel, or a lengthy operative procedure is one contributing factor. A hypercoagulable state resulting from malignancy, nephrotic syndrome, inherited deficiency in protein C or S or antithrombin III, homocystinuria, factor V Leiden mutation, or paroxysmal nocturnal hemoglobinuria may also play a role. Other risk factors for DVT include advanced age, type A blood group, obesity, previous thrombosis, multiparity, use of oral contraceptives, inflammatory bowel disease, and lupus erythematosus. Oral contraceptives should be avoided in women who smoke or who have a history of phlebitis because of the high associated risk of thrombotic disease.

Clinical Findings

A. Symptoms and Signs
Fifty percent of patients with thrombophlebitis and 60-70% with acute Pulmonary embolism have no symptoms or signs in the involved extremity. Symptomatic patients with Deep venous thrombosis may complain of a dull ache, tightness, or pain in the calf or leg, especially when walking. Physical examination may disclose slight edema of the involved calf, a palpable cord, distention of the superficial venous collaterals, or low-grade fever and tachycardia. Homans’ sign (pain on passive dorsiflexion of the ankle) is positive in only 50% of cases. Iliofemoral venous thrombosis can result in cyanosis of the skin (phlegmasia cerulea dolens) or a pale, cool extremity if reflex arterial spasm is superimposed (phlegmasia alba dolens).

B. Diagnostic Techniques
Because of the difficulty in making a precise diagnosis by history and physical examination and because of the morbidity associated with treatment, diagnostic studies should be used liberally.

1. Duplex ultrasonography
Duplex ultrasonography, because of its high sensitivity, specificity, and reproducibility, has supplanted venography as the most widely used diagnostic test in the initial evaluation of patients suspected of having this disorder. The examination includes both a B mode image and Doppler flow analysis. Each venous segment is assessed for the presence of thrombosis, indicated by venous dilation and incompressibility during light probe pressure. Doppler findings suggestive of acute thrombosis are absence of spontaneous flow, loss of flow variation with respiration, and failure to increase flow velocity with distal augmentation. The criteria for the presence of chronic venous thrombosis are less well established. The chronically occluded vein is often narrowed, and there are prominent nearby collaterals. Chronic thrombi are highly echogenic, whereas acute thrombi are anechoic (and therefore not visible) on the B mode image.

2. Ascending contrast venography
This study is used rarely because it is invasive and exposes the patient to ionizing radiation and the risks of contrast allergy, contrast-induced nephropathy, and phlebitis. Patients in whom DVT is strongly suspected but ultrasound is equivocal are now being referred for gadolinium-enhanced magnetic resonance venography. In experienced hands, this examination has a sensitivity of 100% and a specificity of 96% and may provide some information about the age of the thrombus.

3. D-dimer test
Recent evidence suggests that a negative D-dimer test in a patient suspected of having DVT is sufficient to omit ultrasound testing.

Differential Diagnosis

Localized muscle strain or contusion or Achilles tendon rupture can often mimic thrombophlebitis. Cellulitis can have a similar clinical presentation: edema, localized pain, and erythema. Other causes of unilateral leg edema (lymphedema, rupture of a Baker cyst, obstruction of the popliteal vein by a Baker cyst, obstruction of the iliac vein by tumor or fibrosis, or external compression of the left iliac vein by the right common iliac artery, known as May-Thurner syndrome) and bilateral leg edema (heart, liver, or kidney failure, or vena caval obstruction by tumor, retroperitoneal fibrosis, or pregnancy) must be excluded.

Complications

Complications of DVT include Pulmonary embolism, varicose veins, and chronic venous insufficiency.

Prevention

Prophylactic measures may diminish the incidence of venous thrombosis in hospitalized patients. Choice of therapy is dependent on stratification of individual patient risk factors.

A. Nonpharmacologic Measures
Venous stasis can be minimized by several simple maneuvers. Elevation of the foot of the bed 15-20 degrees encourages venous outflow. Slight flexion of the knees is desirable. A footboard enables the patient to perform leg exercises (ankle flexion and extension) while in bed. Sitting in a chair for long periods in the early postoperative period should be avoided. Early ambulation is ideal. Graduated compression stockings and sequential compression devices have proven efficacy in reducing risk of calf vein thrombosis and are particularly useful in moderate-risk and high-risk patients in whom anticoagulation is contraindicated. They function by increasing venous flow, decreasing venous stasis, and increasing the release of endothelial fibrinolytic factors and are safe for use on almost all patients. They have not been shown to decrease the incidence of pulmonary emboli.

B. Anticoagulation
Low-dose unfractionated heparin, 5000 units subcutaneously twice daily, and low-molecular-weight heparin (LMWH), eg, with enoxaparin, 30 mg subcutaneously twice daily, have both been shown to reduce significantly the incidence of postoperative Deep venous thrombosis and pulmonary embolus. LMWH appears to be more effective in the orthopedic surgery patient and is associated also with a lower risk of bleeding complications (1-5% with enoxaparin versus 2-12% with unfractionated heparin). Use of heparin products is contraindicated in patients with recent craniotomy, intracranial bleeding, or severe gastrointestinal bleeding. Either medication must be withheld 12 hours prior to placement or removal of an epidural catheter to avoid epidural hematoma. Coagulation studies are unaffected with prophylactic dosing, but the platelet count must be monitored for early detection of heparin-induced thrombocytopenia, which occurs with peak incidence at 5-10 days of treatment. Warfarin is seldom used for perioperative DVT prophylaxis except for orthopedic surgery, but may be indicated for long-term management of minimally ambulatory patients. Lifetime anticoagulation with low-dose warfarin or prophylactic vena caval filter placement is considered in patients with hypercoagulable state or paralysis.

Treatment

The standard treatment of DVT is systemic anticoagulation with heparin (initial bolus 100 units/kg followed by 10 units/kg/h, dosed to a goal partial thromboplastin time of 1.5-2 times normal). This reduces the risk of Pulmonary embolism and decreases the rate of thrombophlebitis recurrence by 80%. Systemic anticoagulation does not directly lyse thrombi but stops propagation and allows natural fibrinolysis to occur.

Warfarin is started after therapeutic heparinization. The two therapies should overlap to diminish the possibility of a hypercoagulable state, which can occur during the first few days of warfarin administration because warfarin also inhibits synthesis of the natural anticoagulant proteins C and S. The recommended treatment for the first episode of uncomplicated DVT is 3-6 months of warfarin to maintain a goal INR of 2.0-3.0. After a second episode, warfarin is continued indefinitely. The risk for recurrent venous thrombosis is increased markedly in the presence of factor V Leiden mutations, homozygous activated protein C resistance, antiphospholipid antibody, and deficiencies of antithrombin III and of protein C or protein S, so lifelong anticoagulation is also recommended for these conditions.

Recently, enoxaparin at therapeutic dosing (1 mg/kg subcutaneously twice daily) has been shown to be equally safe and effective for treatment of DVT. Enoxaparin does not require monitoring of its anticoagulant effect because of its predictable dose-response relationship, so it has been promoted for use in outpatient treatment. Unfractionated heparin inhibits thrombin by complexing thrombin and antithrombin III. The enoxaparin molecule is too small to inhibit thrombin in this manner; its main therapeutic effect comes from inhibition of factor Xa activity, which accounts for its lower risk of bleeding complications and thrombocytopenia. It has also demonstrated less protein C and S inhibition, less complement activation, and a lower risk of osteoporosis.

Current research efforts are directed toward creation of an oral thrombin inhibitor. This is expected to have a more favorable dose-response curve and side effect profile than warfarin.

Many studies have evaluated the efficacy of fibrinolytic agents in the treatment of acute DVT. Although faster clot lysis and increased venous patency are observed with alteplase versus heparin, this has not translated to a decreased incidence of postphlebitis syndrome. Risk of bleeding complications is higher with alteplase and does not appear to be reduced by selective catheterization for local administration. To be effective, it is felt that alteplase should be instituted within 1 week after clot formation, before extensive fibrin cross-linking can occur. One indication for alteplase is acute iliofemoral venous thrombosis complicated by massive extremity edema and cyanosis. In this setting, iliofemoral thrombectomy is unsuccessful in as many as 50% of patients, often because of inability to effectively treat distal thrombosis.
Treatment of isolated calf vein thrombosis is controversial, as it is associated with a low risk of pulmonary emboli. However, if untreated, 25% progress to the proximal deep veins, where the incidence of chronic venous insufficiency is 25% and that of fatal Pulmonary embolism is 10%. Patients with symptomatic calf vein thrombosis should be anticoagulated; asymptomatic patients may be followed expectantly with serial ultrasound examination.
Prognosis
With early and effective treatment, prognosis in most cases is good. Mortality is related to pulmonary embolus, which occurs in 60% of patients with inadequately treated proximal lower extremity thrombosis.

Breddin HK et al: Effects of a low-molecular weight heparin on thrombus regression and recurrent thromboembolism in patients with deep-vein thrombosis. N Engl J Med 2001; 344:626.

Francis CW et al: Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty. A randomized, double-blind trial. Ann Intern Med 2002; 137:648.

Hirsh J et al: Clinical trials that have influenced the treatment of venous thromboembolism: a historical perspective. Ann Intern Med 2001;134:409.

Kearon C et al: Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003;349:631.

Lee AY et al: Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:109.

Wells PS et al: Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003;349:1203.