Essentials of Diagnosis
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Clinicians should be aware of individual risk factors for development of pulmonary embolism. General Considerations
Venous thromboembolism (VTE), a common medical problem, is the third most common vascular disease and carries a high morbidity and mortality. It is characterized by intravenous thrombus formation either as a deep venous thrombosis (DVT) in leg veins or as a pulmonary embolism (PE), a thrombus migrating to the lung circulation from proximal leg veins or the pelvis. Risk of venous thromboembolism rises with increasing age, up from 1:10,000 in childhood to 1:100 in the elderly. It is estimated that DVT occurs in 1 of 1000 adults and PE in 10–25% of these patients. Both conditions are difficult to diagnose due to their nonspecific symptoms and signs. As a result, many cases are recognized only postmortem or after a thrombus has migrated to the lung circulation. Therefore, it is extremely important to identify patients at risk to facilitate prompt diagnosis and management (Table 19–1). An algorithm can be instrumental in doing this. Because the thrombi originate in the legs, PE is potentially avoidable if preventive therapy, such as anticoagulation or compression stockings, is used in high-risk situations. |
Differential Diagnosis
Treatment
PE and DVT comprise a systemic disease with similar therapeutic strategies. Treatment options are growing due to new pharmaceutical developments and are outlined below. Unfractionated Heparin Heparin is considered by most to be first line therapy in confirmed PE, and low-molecular-weight heparin is currently first line therapy for DVT. Heparin acts by enhancing the effect of antithrombin III, which results in inactivation of thrombin (factor IIa), factor Xa, factor V, and factor VIII. Heparin is effective in reducing mortality among patients with PE. Initial dosing is best achieved via a weight-based nomogram using an initial bolus of 80 U/kg followed by a continuous infusion of 18 U/kg/h and monitored by following the activated partial thromboplastin time (PTT). Several retrospective and randomized trials have concluded that the risk of recurrent venous thromboembolism is reduced if the PTT is maintained at levels between 1.5 and 2.3 times normal. However, circulating factors such as heparin-binding proteins can decrease the effect of heparin. Therefore, some advocate monitoring of plasma heparin levels (goal of 0.2-0.4 IU/mL) in the treatment of acute thrombosis. It is important to avoid underanticoagulation as inadequate heparinization in the first 24 h heightens the risk of recurrent PE. The minimum duration of heparin administration in the setting of acute thrombosis appears to be 5 days. Oral warfarin should be started in this time window. Heparin may be discontinued 24–48 h after an international normalized ratio (INR) of >2.0 is reached on the PT test used to monitor warfarin effect. There is a 1% incidence of heparin-induced thrombocytopenia (HIT) with heparin use, which can lead to paradoxical arterial or venous thrombus formation (heparin-induced thrombocytopenia and thrombosis, HITT). In this setting in the presence of heparin, platelet factor 4/heparin complexes induce platelet aggregation. Reduction in platelet count is seen in the first 5–7 days of therapy and is unusual beyond 2 weeks. Because of this, the American College of Chest Physicians (ACCP) guidelines recommend checking a platelet count between Days 3 and 5 of therapy. Should the platelet count drop below 100,000/ Low-Molecular Weight Heparin Therapy for venous thromboembolic disease has recently expanded to include low-molecular-weight heparins (LMWH). Several options are available (Table 19–3). These molecules have a mean molecular weight of 4000–5000 Da, compared to unfractionated heparin, with a higher mean molecular weight of 15,000 Da. Advantages of LMWH are a subcutaneous route of administration, lack of need for laboratory monitoring or dose adjustment, and reduction in length of required hospitalization. Several randomized controlled trials have successfully compared the efficacy of LMWH to unfractionated heparin in the setting of acute thrombosis and concluded that LMWH appears to be at least as effective as unfractionated heparin in DVT and stable pulmonary embolism. However, ACCP guidelines have suggested these minimal requirements for use of LMWH, particularly in the outpatient setting: DVT or PE without evidence of hemodynamic instability, hypoxemia, absence of severe renal insufficiency, appropriate support for outpatient administration and surveillance, and low bleeding risk. Alternate Anticoagulant Drugs For acute anticoagulation, there are new anticoagulant options under development including a pentasaccharide Fondaparinux that is a Factor x inhibitor with even smaller molecular size than LMWH, and possibly less toxicity. The direct thrombin inhibitors lepirudin, hirudin, and argatroban are currently available for use in HIT or HITT when heparin is contraindicated. There is also clinical experience with dextran and danaparoid for those patients who cannot use heparin or LMWH. Therapy with danaparoid is monitored by an antifactor xa assay. Warfarin Sodium (Coumadin) Coumadin is the common coumarin derivative used in the United States. Coumarins function by inhibiting several vitamin K-dependent proteins including factors II, VII, IX, and X and two anticoagulant factors: protein C and S. Overlap therapy with heparin in the setting of acute VTE is needed to avoid a paradoxical procoagulant effect in early warfarin therapy. Coumadin must be administered for several days in order to reach therapeutic levels. Therapy is monitored by checking the INR, which represents a standardization of the prothrombin time. Effective therapy for VTE is usually achieved with an INR of 2.0–3.0. Warfarin is potentially teratogenic and should not be used during pregnancy. Thrombolytic Therapy Although first used 30 years ago, thrombolytic therapy including streptokinase, urokinase, and tissue plasminogen activator followed by heparin therapy remains a limited part of treatment for PE (Table 19–4). This is due to the marginal improvement over heparin or LMWH alone, and the risk of intracerebral bleeding. Use in PE has been limited to the hemodynamically unstable patient. Recently, a trial of treatment of the hemodynamically stable patient with acute right heart failure demonstrated by echocardiogram has suggested that the bleeding risk can be lowered by changing the dose and duration of the thrombolytic agent. The role of thrombolytic treatment in improving outcome in PE still, however, remains controversial. Vena Caval Filters In clinical practice, vena caval interruption is accomplished by surgery or a placement of a filter. The purpose is to prevent embolization of venous thromboses to the lung when the risk of anticoagulation is high, such as for a person with a recent gastrointestinal bleed, or when anticoagulation in therapeutic doses has failed to prevent a pulmonary embolism. The data on use of vena caval filters are mixed. A randomized controlled trial in Europe compared filter use to no filter in 400 patients with DVT. Although acute risk of PE was lower for those receiving a filter (1.1% vs. 4.8%), outcomes at 2 years demonstrated a 1.87-fold increase in risk of recurrent DVT for persons with the filter. There was no difference in 2-year mortality between groups. Thus the frequent use of filters should probably be minimized, especially as sole treatment for pulmonary embolism. ACCP guidelines recommend the placement of filters in cases of acute thrombus when anticoagulation is contraindicated and cases in which there is recurrent thrombus despite adequate anticoagulation. Direct Vascular Infusion of Thrombolytic Agents/Embolectomy Data on the use of both direct thrombolytic infusion into the pulmonary circulation and embolectomy are limited. However, for patients with pulmonary embolism and hemodynamic instability who fail to respond to thrombolysis or have contraindications these options may be considered. |
L or by 50%, heparin should be discontinued and alternative therapy chosen. Diagnostic tests for heparin-induced antibodies are notoriously inaccurate and include a high rate of false negative results. Thus, clinical suspicion should drive cessation of heparin even when the assay is nondiagnostic. Other heparin-associated complications include bleeding and osteoporosis. Contraindications to anticoagulation include recent major bleeding including cerebral hemorrhage or gastrointestinal bleed. Heparin induces osteopenia, which poses problems for the postmenopausal or pregnant patient. Duration of Therapy
Other Considerations
Prophylaxis Clearly, prevention of thrombus is preferred to treatment, as the sequelae of PE include pulmonary hypertension, hypoxemia, and death. Identification of high-risk conditions or diseases should be pursued whenever possible. Causal factors for VTE can be determined for a majority of cases. The ACCP guidelines note conditions of high risk and make recommendations for prevention in surgical settings such as general surgery, hip and knee surgery, hip fracture, and neurosurgery. Medical conditions are less well studied but myocardial infarction, congestive heart failure, stroke, malignancy, pregnancy and the postpartum period, and intensive care unit illness also pose high risk. Oral contraceptive pills and hormone replacement therapy confer a mild increase in risk, which may be higher in those with underlying genetic risk factors. Risk of thrombosis also increases with age, obesity, and prolonged travel. Absolute criteria for preventive therapy for situations other than surgery are not straightforward. Prevention includes heparin, 5000 U subcutaneously twice a day, LMWH, and compressive pneumatic stockings. A combination of the anticoagulant with compression stockings may be better than one or the other alone in certain high-risk situations. Recommendations for surgical prophylaxis are outlined by the ACCP consensus conference on antithrombotic therapy as summarized in Table 19–5. Hypercoagulable/Genetic Risk Factor Assessment The growing knowledge of genetic risk factors for VTE has captured the imagination but outstrips knowledge of clinical application. Many identified risk factors involve the activated protein C endogenous anticoagulant system, including the factor V Leiden (FVL) mutation where FVL fails to bind to the activated protein C complex and switch off thrombosis. Genetic polymorphisms such as FVL lead to underactivity of this endogenous anticoagulant system, as do high levels of factor VIII and low levels of protein C or protein S. Other well-characterized procoagulant conditions associated with higher risk of venous thromboembolism include the antithrombin (AT) deficiency, formerly called AT III. High levels of homocysteine and the prothrombin 20210 G-A point mutation are moderate risk factors. Abnormalities of the fibrinolytic system that are not yet fully characterized likely enhance risk as well. These include high levels of or mutations in fibrinogen and the plasminogen activator inhibitor, PAI-1. Although there is much interest in the inherited genetic polymorphisms, acquired conditions often pose a hypercoagulable risk. The lupus anticoagulant, measured as an elevated anticardiolipin antibody, is a common example. There is growing recognition that hypercoagulability risks may be acquired rather than only inherited. Acquired inflammatory conditions, including malignancy, infection, and collagen vascular disease, may induce a hypercoagulable state and thrombus formation. Combinations of genetic and acquired risk may result in a synergistic increase in thrombosis risk. In addition to heightened risk from a genetic plus an acquired risk factor, two or more genetic risk factors also appear to act synergistically to increase risk of VTE. A genetic panel of tests is frequently ordered at the time of clinical diagnosis of PE. Assessment for a hypercoagulable state should be considered in persons younger than age 45 with thrombosis, for those with a positive family history, and/or in the setting of recurrent VTE. For genetic testing, the timing of sample accrual is not important, however, factor levels, antithrombin, and protein S and protein C activity are affected by disease and use of anticoagulant drugs. Patients may be inappropriately labeled protein C deficient, for example, if samples are taken during presentation with an acute clot. Optimal timing of samples is at least 3 weeks after stopping all anticoagulant medications. Although debatable, a standard hypercoagulable work-up should start with prothrombin time (PT), activated partial thromboplastin time (PTT), and anticardiolipin antibody (aCL) or lupus anticoagulant, using the latter to assess for antiphospholipid syndrome, which is relatively common in adults with unexplained thrombosis. For persons younger than age 45, with multiple recurrent thromboses or thrombosis in the absence of clinical risk factors, where there is a higher likelihood of inherited risk, a genetic work-up may be slightly more extensive and include antithrombin, protein C, protein S, and factor V Leiden. Good outcome data are, however, lacking for this recommendation. Suspected Pulmonary Embolism in Pregnancy In the evaluation of suspected pulmonary embolism, ventilation–perfusion scanning appears to be a safe diagnostic study and may be used in conjunction with lower extremity ultrasound in the setting of a nondiagnostic scan. Regarding therapy for acute venous thromboembolism, unfractionated heparin or LMWH should be utilized as warfarin clearly has teratogenic effects. |
Prognosis
