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[Section Outline]

Definition and Natural History !!navigator!!

Venous thromboembolism (VTE) includes both deep-vein thrombosis (DVT) and pulmonary embolism (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. 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, pacemakers, and internal cardiac defibrillators have increased the occurrence of upper extremity DVT. In the absence of PE, the major complication of DVT is postthrombotic syndrome, which causes chronic leg swelling and discomfort due to damage to the venous valves of the affected leg. In its most severe form, postthrombotic 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. Medical conditions that increase the risk of VTE include cancer and antiphospholipid antibody syndrome. A variety of other risk factors have been identified, including immobilization during prolonged travel, obesity, smoking, surgery, trauma, pregnancy, estrogen-containing contraceptives, postmenopausal hormone replacement, and inflammatory diseases (e.g., inflammatory bowel disease, psoriasis).

Massive PE, with thrombosis affecting at least half of the pulmonary vasculature, often includes dyspnea, syncope, hypotension, and cyanosis. Submassive PE includes RV dysfunction in the setting of normal systemic arterial pressure. Low-risk PE, which includes normal RV function and systemic arterial pressure, has an excellent prognosis.

Clinical Evaluation !!navigator!!

History !!navigator!!

DVTs often present with progressive lower calf discomfort. For PE, unexplained dyspnea is the most common presenting symptom. Chest pain, cough, or hemoptysis can indicate pulmonary infarction with pleural irritation. A substantial fraction of pts hospitalized for syncope have PE.

Physical Examination !!navigator!!

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 !!navigator!!

Normal D-dimer level 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 acid-binding protein, and brain natriuretic peptide levels can be seen in PE. The electrocardiogram can show an S1Q3T3 sign in PE, but that finding is not frequently observed.

Imaging Studies !!navigator!!

Venous ultrasonography can detect DVT by demonstrating loss of normal venous compressibility. For pts with nondiagnostic venous ultrasound studies, CT or MRI can be used to assess for DVT. Many 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 can identify 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 !!navigator!!

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 Fig. 135-1. Imaging Tests Useful to Diagnose DVT and PE. 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

Deep-Vein Thrombosis and Pulmonary Embolism

ANTICOAGULATION

Although anticoagulants do not dissolve existing clots in DVT or PE directly, they limit further thrombus formation and allow fibrinolysis to occur. Three general approaches can be used for anticoagulation in DVT and PE: (1) Parenteral therapy with unfractionated heparin (UFH), low molecular weight heparin (LMWH), or fondaparinux with overlapping transition to warfarin; (2) parenteral therapy switching after 5 days to an oral anticoagulant such as dabigatran or edoxaban; or (3) oral anticoagulation monotherapy with rivaroxaban or apixaban (both are anti-Xa agents) with a 3-week or 1-week loading dose, respectively, followed by a maintenance dose without parenteral anticoagulation.

The classical treatment approach of UFH with a target activated partial thromboplastin time (aPTT) of 60-80 s is being utilized less frequently. With that approach, UFH is typically administered with a bolus of 80 U/kg followed by a continuous infusion of approximately 18 U/kg per hour. 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 LMWHs such as enoxaparin and dalteparin. Laboratory monitoring is not required, but doses are adjusted for renal impairment or obesity. Fondaparinux, a synthetic parenteral alternative to UFH, does not require laboratory monitoring but does require dose adjustment for body weight and renal insufficiency. Fondaparinux does not cause heparin-induced thrombocytopenia; alternatives for heparin-induced thrombocytopenia pts include direct thrombin inhibitors (e.g., argatroban or bivalirudin).

After initiating treatment with a parenteral agent, warfarin has traditionally been used for long-term oral anticoagulation. Warfarin can be initiated soon after a parenteral agent is given; however, at least 5 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 due to effects of genetics, diet, and other drugs; dosing often begins at 5 mg/d, with adjustment based on the INR. Warfarin should be avoided in pregnant pts.

Rivaroxaban and apixaban, direct factor Xa inhibitors, are approved as monotherapy for acute and extended treatment of DVT and PE, without a parenteral “bridging” anticoagulant. Dabigatran, a direct thrombin inhibitor, and edoxaban, a factor Xa inhibitor, are approved for treatment of VTE after an initial 5-day course of parenteral anticoagulation. Novel oral anticoagulants, including rivaroxaban, apixaban, and dabigatran, have the advantages of fixed dose regimens, rapid onset of effective anticoagulation, no laboratory monitoring, and fewer drug and dietary interactions.

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. There is no specific reversal agent for bleeding caused by fondaparinux or factor Xa inhibitors. However, the dabigatran antibody, idarucizumab, is a rapidly acting antidote for dabigatran. Severe bleeding while anticoagulated with warfarin can be treated with prothrombin complex concentrate; milder hemorrhage or markedly elevated INR values can be treated with vitamin K.

For DVT isolated to an upper extremity or calf that has been provoked by surgery, trauma, estrogen, or an indwelling central venous catheter or pacemaker, 3 months of anticoagulation is typically prescribed. For an initial episode of provoked or unprovoked proximal leg DVT or PE, the recurrence rate is high after cessation of anticoagulation. For pts with cancer and VTE, LMWH is typically used as monotherapy without warfarin and continued indefinitely unless the pt is rendered cancer-free. American College of Chest Physicians guidelines recommend considering anticoagulation for an indefinite duration with a target INR between 2 and 3 for pts with idiopathic VTE and a low bleeding risk. An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 1.5 and 2. Another approach for pts at lower risk of recurrence, especially if there is an important reason to avoid long-term anticoagulation, is to consider low-dose aspirin after completing the initial period of standard 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 (Fig. 135-2. Acute Management of Pulmonary Thromboembolism). 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 massive PE, although the risk of hemorrhage is significant. Low-dose, ultrasound-facilitated, catheter-directed thrombolysis (potentially combined with mechanical clot removal techniques) can be used for pts with submassive or massive PE or with extensive femoral, iliofemoral, or upper extremity DVT. Surgical embolectomy also can be considered for massive PE.

If PE pts develop chronic thromboembolic pulmonary hypertension, surgical intervention (pulmonary thromboendarterectomy) can be performed.

To reduce pt discomfort, below-knee graduated compression stockings can be used after a DVT.

Prevention of DVT and PE in hospitalized pts is often performed with low-dose UFH or LMWH. Betrixaban, a direct factor Xa inhibitor, is approved for VTE prophylaxis in acutely ill medical pts during hospitalization and continuing for a total duration of 5-6 weeks.

Outline ⬆

Section 9. Pulmonology