Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + INTRODUCTION Download Section PDF Listen +++ ++ Venous thromboembolism (deep venous thrombosis and/or pulmonary embolism) is a common disorder, which is estimated to affect 900,000 patients each year in the United States. Pulmonary embolism may cause sudden or abrupt death, underscoring the importance of prevention as the critical strategy for reducing death from pulmonary embolism. Of the estimated 600,000 cases of nonfatal venous thromboembolism in the United States each year, approximately 60 percent present clinically as deep venous thrombosis and 40 percent present as pulmonary embolism. Most clinically important pulmonary emboli arise from proximal deep venous thrombosis (thrombosis involving the popliteal, femoral, or iliac veins). Upper extremity deep venous thrombosis also may lead to clinically important pulmonary embolism. Other less common sources of pulmonary embolism include the deep pelvic veins, renal veins, inferior vena cava, right side of the heart, and axillary veins. Acquired and inherited risk factors for venous thromboembolism have been identified (for inherited thrombophilia see Chap. 89). The risk of thromboembolism increases when more than one predisposing factor is present. + CLINICAL FEATURES Download Section PDF Listen +++ ++ The clinical features of deep venous thrombosis and pulmonary embolism are nonspecific. +++ Venous Thrombosis ++ The clinical features of venous thrombosis include leg pain, tenderness, and asymmetrical swelling, a palpable cord representing a thrombosed vessel, discoloration, venous distention, prominence of the superficial veins, and cyanosis. In exceptional cases, patients may present with phlegmasia cerulea dolens (occlusion of the whole venous circulation, extreme swelling of the leg, and compromised arterial flow). In 50 to 85 percent of patients, the clinical suspicion of deep venous thrombosis is not confirmed by objective testing. Conversely, patients with florid pain and swelling, suggesting extensive deep venous thrombosis, may have negative results by objective testing. Patients with minor symptoms and signs may have extensive deep venous thrombi. Although the clinical diagnosis is nonspecific, prospective studies have established that patients can be categorized as low, moderate, or high probability for deep venous thrombosis using clinical prediction rules that incorporates signs, symptoms, and risk factors. +++ Pulmonary Embolism ++ The clinical features of acute pulmonary embolism include the following symptoms and signs that may overlap: — Transient dyspnea and tachypnea in the absence of other clinical features. — Pleuritic chest pain, cough, hemoptysis, pleural effusion, and pulmonary infiltrates noted on chest radiogram caused by pulmonary infarction or congestive atelectasis (also known as ischemic pneumonitis or incomplete infarction). — Severe dyspnea and tachypnea and right-side heart failure. — Cardiovascular collapse with hypotension, syncope, and coma (usually associated with massive pulmonary embolism). — Several less common and nonspecific clinical presentations, including unexplained tachycardia or arrhythmia, resistant cardiac failure, wheezing, cough, fever, anxiety/apprehension, and confusion. All of these clinical features are nonspecific and can be caused by a variety of cardiorespiratory disorders. Patients can be assigned to categories of pretest probability using implicit clinical judgment, or clinical decision rules. + DIAGNOSIS Download Section PDF Listen +++ ++ Objective diagnostic testing is required to confirm or exclude the presence of venous thromboembolism. An appropriately validated assay for plasma fibrin degradation product D-dimer, if available, provides a simple, rapid, and cost-effective first-line exclusion test in patients with low, unlikely, or intermediate clinical probability. Integrated diagnostic strategies for deep venous thrombosis and pulmonary embolism are presented in Fig. 90–1 and Fig. 90–2, respectively. ++ FIGURE 90–1 Diagnosis of patients with suspected first episode of deep venous thrombosis (DVT). *Negative D-dimer can be used to exclude acute DVT, without the need for further diagnostic testing with compression ultrasonography (CUS), if the patient has low, unlikely, moderate, or intermediate clinical probability. Ultrasonography should be performed in patients with a high clinical probability. A negative D-dimer can also be used with a negative CUS at presentation to exclude acute DVT without the need for a repeat CUS. **CUS is performed with imaging of the common femoral vein in the groin and of the popliteal vein in the popliteal fossa extending distally 10 cm from midpatella. A repeat CUS is required in 5 to 7 days to detect extending calf vein thrombi. In centers with the expertise, a single negative result of full-leg duplex ultrasonography (CUS plus flow evaluation) is sufficient to exclude acute DVT. ‡CUS that indicates noncompressibility of deep vein segments is highly predictive of DVT (>95%) and provides an indication for antithrombotic therapy in most patients. If CUS is positive at a single site isolated in the groin, additional testing with venography, computed tomography, or magnetic resonance imaging should be performed because of the potential for false-positive CUS results from disorders producing vein compression in the groin (e.g., tumor mass). (Source: William Hematology, 8th ed, Chap. 134, Fig. 134–1, p. 2188.) Graphic Jump LocationView Full Size||Download Slide (.ppt) ++ FIGURE 90–2 Integrated strategy for diagnosis of patients with suspected pulmonary embolism (PE) using CT angiography (CTA) as the primary imaging test. *Negative D-dimer alone can be used as an exclusion test with high negative predictive value (>97%) in patients with low or moderate probability by the clinical assessment. Patients with a high clinical probability should undergo imaging with CTA or combined CTA-CT Venography (CTV). **Positive results on CTA or combined CTA-CTV, in patients with a high or moderate probability of pulmonary embolism by the clinical assessment, have positive predictive value of 90 percent or more for venous thromboembolism. Similarly, abnormal results by compression ultrasonography (CUS) of the proximal deep veins of the legs have high positive predictive value for proximal vein thrombosis and provide an indication to give antithrombotic therapy. If the patient has a low probability by the clinical assessment, positive results by CTA or CTA-CTV in the main or lobar pulmonary arteries are still highly predictive (97%) for the presence of pulmonary embolism; further testing is recommended for patients with low clinical probability and positive CTA results only of segmental or subsegmental arteries, and the options include pulmonary arteriography or serial CUS. ‡Negative results by CTA or by combined CTA-CTV have high negative predictive value (96%) in patients with low probability by the clinical assessment. For patients with moderate clinical probability, the negative predictive value for combined CTA-CTV is also high (92%), but slightly lower for CTA alone (89%); in this latter group, and in patients with a high probability by the clinical assessment, serial CUS or pulmonary arteriography are recommended options. Source: William Hematology, 8th ed, Chap. 134, Table 134–2, p. 2190. Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ Venous Thrombosis ++ Enzyme-linked immunosorbent assay (ELISA) and quantitative rapid ELISA for D-dimer have high sensitivity (96%) and negative likelihood ratios of approximately 0.10 for deep venous thrombosis in symptomatic patients. Compression ultrasonography of the proximal veins performed at presentation can safely exclude clinically important deep venous thrombosis in symptomatic patients (with the exception of pelvic thrombosis, which may be missed by ultrasound examination). The positive predictive value of a positive ultrasonographic result isolated to the calf veins may vary among centers based on expertise and thrombosis prevalence. To detect calf vein thrombi that were initially missed but may have progressed to proximal venous thrombosis, ultrasonography is repeated after 5 to 7 days. In centers with the expertise, a single comprehensive evaluation of the proximal and calf veins with duplex (Doppler) ultrasonography is sufficient. Measurement of D-dimer using an appropriate assay method can be combined with ultrasonograph imaging of the leg veins. If the two tests are negative at presentation, repeat ultrasonograph imaging is unnecessary. +++ Pulmonary Embolism ++ If capability for combined computed tomographic angiography (CTA) and computed tomographic venography (CTV) exists, it is the preferred approach for most patients with suspected pulmonary embolism because it provides a definitive basis to give or withhold antithrombotic therapy in more than 90 percent of patients. CTA is not inferior to using ventilation–perfusion lung scanning for excluding the diagnosis of pulmonary embolism when either test is used together with venous ultrasonography of the legs. Single-detector spiral CT is highly sensitive for large emboli (segmental or larger arteries) but is much less sensitive for emboli in subsegmental pulmonary arteries. Multidetector row CT, together with the use of contrast enhancement, has further improved the utility of CT for the diagnosis of pulmonary embolism, also in subsegmental pulmonary arteries. Contrast-enhanced CTA has the advantage of providing clear results (positive or negative), good characterization of nonvascular structures for alternate or associated diagnoses, and the ability to simultaneously evaluate the deep venous system of the legs (computed tomographic venography [CTV]). Ventilation-perfusion lung scanning is another imaging option for the diagnosis of pulmonary embolism. A normal perfusion lung scan excludes the diagnosis of clinically important pulmonary embolism. A high-probability lung scan result (i.e., large perfusion defects with ventilation mismatch) has a positive predictive value for pulmonary embolism of 85 percent and provides a diagnostic endpoint to give antithrombotic treatment in most patients. The major limitation of lung scanning is that the results are inconclusive in most patients, even when considered together with the pretest clinical probability. The nondiagnostic lung scan patterns are found in approximately 70 percent of patients with suspected pulmonary embolism. MRI appears to be highly sensitive for pulmonary embolism and is a promising diagnostic approach. However, clinically important interobserver variation exists in the sensitivity for pulmonary embolism, ranging from 70 to 100 percent. Pulmonary angiography using selective catheterization of the pulmonary arteries is a relatively safe technique for patients who do not have pulmonary hypertension or cardiac failure. If the expertise is available, pulmonary angiography should be used when other approaches are inconclusive and when definitive knowledge about the presence or absence of pulmonary embolism is required. Objective testing for nonsymptomatic deep venous thrombosis is useful in patients with suspected pulmonary embolism, particularly those with nondiagnostic lung scan results or inconclusive CT results. Detection of proximal venous thrombosis by objective testing provides an indication for anticoagulant treatment, regardless of the presence or absence of pulmonary embolism, and prevents the need for further testing. + LONG-TERM SEQUELAE OF VENOUS THROMBOEMBOLISM Download Section PDF Listen +++ ++ The postthrombotic syndrome is a frequent complication of deep venous thrombosis. Symptoms of the postthrombotic syndrome are pain, heaviness, swelling, cramps, and itching or tingling of the affected leg. Ulceration may occur. Symptoms usually are aggravated by standing or walking and improve with rest and elevation of the leg. Application of a properly fitted graded compression stocking, as soon after diagnosis as the patient's symptoms will allow and continued for at least 2 years, is effective in reducing the incidence of postthrombotic symptoms, including moderate-to-severe symptoms. Chronic thromboembolic pulmonary hypertension is a serious complication of pulmonary embolism and may occur in 1 to 3 percent of patients. Chronic thromboembolic pulmonary hypertension may be suspected if clinical signs and symptoms of pulmonary embolism persist over months despite adequate treatment and can be confirmed by echocardiography and ventilation-perfusion lung scanning. + TREATMENT Download Section PDF Listen +++ ++ The objectives of treatment in patients with established venous thromboembolism are to: — Prevent death from pulmonary embolism. — Prevent morbidity from recurrent venous thrombosis or pulmonary embolism. — Prevent or minimize the postthrombotic syndrome. Antithrombotic treatment is highly effective for venous thromboembolism. The principles of antithrombotic treatment are outlined in Chap. 88. Treatment is initiated with unfractionated or low molecular weight (LMW) heparin or a heparin derivative for 5 to 10 days (see Table 90–1). Long-term antithrombotic treatment is currently achieved by administration of vitamin K antagonists (e.g., warfarin). New oral anticoagulant agents are currently being evaluated. The appropriate duration of oral anticoagulant treatment for venous thromboembolism is at least 3 months in patients with a first episode of proximal venous thrombosis or pulmonary embolism secondary to a transient or reversible risk factor. Patients with a first episode of idiopathic (unprovoked) venous thromboembolism should be treated for at least 6 months. The decision on the duration of antithrombotic treatment should be individualized, taking into consideration the estimated risk of recurrent venous thromboembolism, risk of bleeding, and patient compliance and preference. Patients with a first episode of venous thrombosis and a single thrombophilic risk factor (e.g., factor V Leiden) do not need prolonged antithrombotic treatment. Prolonged or even indefinite therapy is recommended for patients with recurrent thrombosis and/or persistent strong risk factors (e.g., active cancer or antiphospholipid antibodies) in whom risk factors for bleeding are absent and in whom good anticoagulant control can be achieved. If indefinite anticoagulant treatment is given, the risk-to-benefit ratio of continuing such treatment should be reassessed at periodic intervals. Long-term treatment with subcutaneous LMW heparin for 3 to 6 months is at least as effective as, and in cancer patients is more effective than, oral vitamin K antagonists. However, the repeated subcutaneous injections are not always well tolerated by patients. Insertion of an inferior vena cava filter is indicated for patients with acute venous thromboembolism and an absolute contraindication to anticoagulant therapy. In patients with a temporary absolute contraindication to anticoagulant treatment (i.e., intercurrent bleeding or the need to undergo an invasive procedure), a retrievable inferior vena cava filter is preferable. The use of a permanent vena cava filter results in an increased incidence of recurrent deep venous thrombosis 1 to 2 years after insertion (increase in cumulative incidence at 2 years increases from 12% to 21%). If a permanent filter is placed, long-term anticoagulant treatment should be given as soon as safely possible to prevent morbidity from recurrent deep venous thrombosis. ++Table Graphic Jump LocationTABLE 90–1REGIMENS OF LOW-MOLECULAR-WEIGHT HEPARIN AND FONDAPARINUX FOR TREATMENT OF VENOUS THROMBOEMBOLISMView Table||Download (.pdf) TABLE 90–1 REGIMENS OF LOW-MOLECULAR-WEIGHT HEPARIN AND FONDAPARINUX FOR TREATMENT OF VENOUS THROMBOEMBOLISM Drug# Regimen Enoxaparin 1.0 mg/kg BID* Dalteparin 200 IU/kg once daily† Tinzaparin 175 IU/kg once daily‡ Nadroparin 5700 IU BID for 50–70 kg§ Reviparin 4200 IU BID for 46–60 kg¶ Fondaparinux 7.5 mg once daily for 50–100 kg** *A once-daily regimen of 1.5 mg/kg can be used but probably is less effective in patients with cancer.†After 1 month, can be followed by 150 IU/kg once daily as an alternative to an oral vitamin K antagonist for long-term treatment.‡This regimen can also be used for long-term treatment as an alternative to an oral vitamin K antagonist.§3800 IU BID if patient weighs <50 kg or 7600 IU BID if patient weighs >70 kg.¶3500 IU BID if patient weighs 35–45 kg or 6300 IU BID if patient weighs >60 kg.**5 mg once daily if patient weighs <50 kg or 10 mg once daily if patient weighs >100 kg.#Drug brand names: dalteparin, Fragmin; enoxaparin, Lovenox; fondaparinux, Arixtra; tinzaparin, Innohep; nadroparin, Fraxiparine.Source: William Hematology, 8th ed, Chap. 134, Table 134-2, p. 2192 +++ Venous Thromboembolism in Pregnancy ++ Adjusted-dose subcutaneous heparin is an appropriate long-term anticoagulant regimen for pregnant patients with venous thromboembolism (see also Chap. 88). LMW heparin does not cross the placenta, and initial experience suggests these agents are safe for treatment of venous thromboembolism in pregnant patients. With regard to safety advantages, LMW heparin causes less thrombocytopenia and potentially less osteoporosis than unfractionated heparin. An additional advantage is that LMW heparin is effective when given once daily, whereas unfractionated heparin requires twice-daily injection. Therapeutic LMW heparin in pregnancy should be monitored regularly with measurement of plasma anti-factor Xa activity. After delivery antithrombotic treatment may be switched to vitamin K antagonists. Breastfeeding while using vitamin K antagonists is possible, provided that the baby receives the usual vitamin K administration that is common in breastfed infants. ++ For more detailed discussion, see Gary E. Raskob, Russel D. Hull, Graham F. Pineo: Venous Thrombosis. Chap. 134, p. 2185 in Williams Hematology, 8th ed.