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Essentials of Diagnosis
Surgery (especially orthopedic), immobility, and malignancy are common risk factors.
Typical complaints include acute limb pain and swelling for deep venous thrombosis; pleuritic chest pain and shortness of breath for pulmonary embolism.
Physical findings are nonspecific and often absent.
Confirmation with diagnostic imaging is required.
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General Principles in Older Adults
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Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third leading cause of cardiovascular death in the United States. More than 400,000 deaths annually are attributed to VTE. VTE risk increases with age. VTE risk for patients older than age 70 years is approximately 1% per year. Table 32–4 lists the inherited and acquired risk factors for VTE. Despite a known association between VTE and inherited thrombophilias, testing for these disorders is rarely indicated in geriatric patients. Patients with idiopathic VTE, without an identifiable etiology, should undergo age- and gender-appropriate cancer screening. Following a complete history, physical examination, and basic laboratory testing, additional testing using CT scans, bronchoscopy, bone marrow evaluation, and other evaluations are used to investigate underlying abnormalities.
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The signs and symptoms of VTE are nonspecific. Therefore, a clinical diagnosis is not acceptable. Patients may present with nonspecific constitutional, limb or cardiopulmonary complaints. High clinical suspicion and imaging is required to exclude VTE.
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Up to 50% of DVTs are asymptomatic. Clinical symptoms include limb pain, swelling, erythema, and increased warmth. Superficial thrombophlebitis may present with localized erythema and tenderness associated with a palpable superficial venous cord. The Homan sign—pain on squeezing the calf or with passive dorsiflexion of the foot—is commonly referred to and noted on examination. However, it lacks sensitivity or specificity for diagnosing DVT and is unreliable for clinical diagnosis.
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The symptoms of PE are equally nonspecific. Patients may present with tachycardia and tachypnea without associated complaints. When present, chest pain may be pleuritic in nature. Dyspnea, cough, near syncope, and palpitations are common. Hemoptysis is uncommon and usually associated with pulmonary infarction. Syncope is a common admitting complaint and PE is frequently overlooked in the differential diagnosis, leading to delays in diagnosis and management.
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No laboratory test is specific to diagnosis VTE. In the appropriate clinical setting, a negative D-dimer may be used to exclude VTE from the differential diagnosis. D-dimer is frequently positive following surgery, trauma, hospitalization, pregnancy, and in older adults. Therefore, it is best utilized in the outpatient ambulatory setting in patients at low-risk for VTE. A positive D-dimer is not helpful.
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VTE patients should have CBC, CMP, and urinalysis performed to identify underlying disorders associated with VTE. Abnormalities on the initial laboratory testing should be used to direct additional testing or imaging that may be warranted. Antiphospholipid antibody testing may be helpful in the geriatric population. Testing for lupus anticoagulant and anticardiolipin antibodies may influence the duration of therapy and the choice of anticoagulation. Testing for other thrombophilias is less likely to be helpful. Protein C, protein S and antithrombin deficiency testing are virtually never warranted in older adults.
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Patients with acute PE should have biomarker assessment, including troponin and BNP (B-type natriuretic peptide) or NT-proBNP (N-terminal pro brain natriuretic peptide), to look for evidence of myocardial injury. Both troponin and BNP, when normal, have a high negative predictive value for in-hospital and 30 days postdischarge mortality. When the biomarkers are normal they may be used to risk stratify patients for accelerated hospital discharge.
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Venography is rarely required, but remains the gold standard for diagnosing DVT. Duplex ultrasound has become the test of choice to diagnose or exclude DVT. It is widely available, noninvasive, and well tolerated. Duplex ultrasound relies on the inability to completely compress the lumen of the vein using externally applied pressure. Intraluminal echogenicity is less specific for DVT. Secondary changes in the venous waveforms are also evaluated. Normal waveforms are phasic with respiration and augment with calf compression. The failure to augment or loss of phasicity, monophasic waveforms, may indicate proximal obstruction. Only venous segments that are adequately visualized can be assessed for DVT. This is a limitation that is frequently misunderstood. If a venous segment is not fully evaluated, DVT cannot be excluded. The sensitivity and specificity of duplex ultrasound for DVT diagnosis are approximately 98%. If there is negative testing but high clinical suspicion, especially for iliac, inferior vena cava (IVC), or calf vein DVT, repeat duplex imaging in 5–7 days is likely warranted.
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Computed tomography venography (CTV) and magnetic resonance venography (MRV) may be used for diagnosis especially when imaging the IVC and pelvic veins. CTV can easily be added to CT PE imaging. This does not require additional contrast but the radiation exposure is significant. MRV does not use radiation and does not always require contrast. It may be helpful in evaluating patients with acute and chronic DVT. However, imaging may not be readily available and claustrophobia may limit some patient’s ability to perform testing. CTV and MRV may be used as an alternative to venography to confirm the diagnosis of DVT when duplex imaging is nondiagnostic.
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Up to 50% of patients with DVT may have clinically asymptomatic PE. Clinical suspicion for PE should prompt appropriate testing. Chest x-ray may be normal and is frequently nonspecific. When abnormal, findings of volume loss, atelectasis, effusions, or infiltrates predominate. Classically described Westermark sign (focal oligemia), Hampton hump (wedge-shaped pleural based density), and pulmonary artery enlargement are uncommon. Electrocardiogram findings are also frequently nonspecific. The most common finding is sinus tachycardia. The classically described S1Q3T3 changes may be seen with large PE and right ventricular strain.
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Computed tomography pulmonary angiogram (CTPA) is the most widely available and commonly used test for diagnosing PE. It is readily available and well tolerated. PE is diagnosed as an intraluminal filling defect within the pulmonary arteries. With advanced technology, scanners can complete imaging to the level of the subsegmental pulmonary arteries in a single breathhold. It requires contrast and may be limited in patients with renal insufficiency. Timing of the contrast bolus is essential, and in some patients may limit the sensitivity and specificity of the examination, especially for more peripheral emboli. CTPA can also be used to evaluate for radiographic signs of right heart strain associated with large PE. A right ventricle to left ventricle ratio >0.9 measured on a 4-chamber view is consistent with right-heart strain.
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Ventilation-perfusion (V/Q) lung scanning is still used to diagnose of acute PE. However, in many centers availability is limited. The testing should be performed in the setting of a normal chest x-ray and when there is high clinical pretest probability for PE. Nondiagnostic intermediate or indeterminant scans are common. Only scans that are read as normal or near normal or high probability are helpful to exclude or diagnose PE.
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Pulmonary angiography remains the gold standard for diagnosing PE, although it has been essentially replaced by CTPA imaging. The contrast and radiation exposure are similar and CTPA is less invasive. If CTPA imaging is nondiagnostic and there is a need to diagnose or exclude PE then angiography is the test of choice. Despite widely held beliefs that angiography is too invasive to use regularly, complications related to angiography are infrequent.
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Echocardiography is not a diagnostic test for PE although echocardiographic information may be helpful to risk-stratify patients for thrombolytic therapy or for accelerated hospital discharge. Echocardiography is used to evaluate right-heart dysfunction. Right-heart strain portends a worse in-hospital outcome compared to patients without evidence for right ventricle volume overload. Findings on echocardiogram include right ventricle dilation, septal flattening or deviation toward the left ventricle, tricuspid regurgitation, and elevated right ventricle systolic pressure.
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Differential Diagnosis
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Unilateral leg pain, erythema and swelling are common symptoms. Within the differential diagnosis one must consider superficial thrombophlebitis, popliteal cyst with or without rupture, traumatic injury such as a sprain or ruptured calf muscle, cellulitis, and acute inflammation associated with chronic venous insufficiency (CVI). In patients with a low pretest clinical probability, a negative D-dimer excludes DVT and eliminates the need for additional testing.
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The signs and symptoms associated with PE are also nonspecific. Other cardiopulmonary, vascular and inflammatory etiologies must be excluded. Included in the differential diagnosis are myocardial injury, pericarditis, congestive heart failure, pneumonia, pleuritis, pneumothorax, aortic dissection, and musculoskeletal sprain, strain, or contusion.
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The risk of postthrombotic syndrome (PTS) after DVT is significant. Many patients develop symptoms within 2 years following the initial event. Extensive DVT and recurrent events increase PTS risk. The use of compression stockings for 2 years following DVT may decrease this risk by up to 50%. A minority of patients (<5%) will develop chronic thromboembolic disease (CTED) after PE. There are no clinical factors, biomarkers, or other strategies to determine which patients are at risk. Patients presenting with progressive dyspnea or right-heart dysfunction following PE should be evaluated for CTED.
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General Considerations
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Anticoagulation is the mainstay of treatment for VTE. Appropriate therapy should be started when the diagnosis of VTE is considered. In patients at low risk for complications from anticoagulation, data collection and diagnostic testing should not delay the initiation of anticoagulation. Intravenous unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux are appropriate initial therapies for VTE.
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Patients with DVT without signs or symptoms of PE can frequently be treated either solely or at least partially as an outpatient. Arranging home therapy, self-injection teaching and patient education required staff time and dedication but many patients are able to successfully perform the necessary tasks. Clinically stable patients with PE can frequently be assessed using echocardiography and biomarkers such as troponin and BNP. When normal, patients can be treated either inpatient or using an accelerated discharge plan. Close clinical follow up after discharge should be arranged for all VTE patients.
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Patients with a contraindication to anticoagulation should be managed by IVC filter insertion. However, appropriate anticoagulation should be initiated once the anticoagulation risk has resolved.
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UFH should be administered using weight-based bolus and infusion dosing. The activated partial thromboplastin time (aPTT) or anti-Xa assay should be titrated to keep the patient within the appropriate therapeutic range. It is important to recognize that the aPTT therapeutic range is institution specific and awareness of local protocols is necessary. In patients in whom thrombolysis may be considered, UFH is the drug of choice because of its short half-life and the ability to easily monitor therapy.
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LMWHs provide the opportunity for once- or twice-daily dosing. Ease of administration also facilitates accelerated discharge or home therapy for appropriate patients. The available LMWHs are all renally excreted. Dose adjustment or avoidance is required with creatinine clearance <30 mL/min. Monitoring with LMWH specific anti-Xa assay may be prudent in patients with borderline renal function, with low body mass, or the morbidly obese. The assay must be drawn 4 hours after the dose. A target LMWH anti-Xa between 0.6 and 1.0 is appropriate for q 12 hour dosing, whereas a target of 1.0–2.0 is appropriate for daily dosing regimens. Patients who develop VTE in the setting of an underlying malignancy are best managed with LMWH monotherapy for the initial 3–6 months of treatment. Patients can then be reassessed for continuing LMWH or switching to warfarin therapy for the duration of their treatment.
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Fondaparinux is a pentasaccharide molecule approved for treating both DVT and PE, when therapy is initiated in the hospital. Dosing is weight based. Patients who weigh <50 kg should receive 5 mg daily; who weigh 50–100 kg should be dosed at 7.5 mg daily; and who weigh >100 kg should receive 10 mg daily. Monitoring is not used. Fondaparinux is renally excreted. It should be used cautiously with renal insufficiency and is not appropriate with a creatinine clearance <30 mL/min. The half-life is approximately 17 hours. The drug should be avoided when there is a need for intervention or a high risk of bleeding. There is no antidote to reverse the effects of fondaparinux.
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Warfarin remains the long-term drug of choice for most patients. In general, the first dose of warfarin may be started on the day of admission. Warfarin, a vitamin K antagonist, interrupts the terminal carboxylation of vitamin K-dependent proteins. Therefore a minimum 4–5 day overlap between the parenteral drug and warfarin is required to ensure the premade vitamin K-dependent proteins have been adequately depleted. For most patients, the target international normalized ratio (INR) is 2.5, with an acceptable range being between 2 and 3. After the minimum 4–5-day overlap, the INR should be >2 on 2 consecutive days before stopping the parenteral drug and maintaining warfarin therapy.
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An oral direct thrombin inhibitor, dabigatran, and oral anti-Xa agents, rivaroxaban and apixaban, have been studied in VTE, but are not yet approved. Potential advantages of these agents are the once- or twice-daily oral administration. These drugs do not require monitoring. The major disadvantage with these agents is a lack of an antidote for easy reversal.
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Patients with extensive DVT or massive PE who are unstable at the time of admission should be assessed for thrombolysis. The use of pharmacomechanical thrombolysis (PMT) or catheter-directed thrombolysis (CDT) are not confined to patients with phlegmasia cerulean dolens or venous gangrene. Patients with extensive DVT may benefit from PMT to help clear the thrombus in an effort to preserve valve function, improve mobility, and decrease symptoms associated with the acute DVT. PMT is not appropriate for all patients with DVT but especially with iliofemoral DVT consideration for PMT should be entertained.
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Patients with massive unstable PE should also be considered for thrombolysis; either systemic infusion or catheter based therapies. Patients with submassive PE with significant cardiopulmonary dysfunction may be appropriate for thrombolytic therapy but the bleeding risks may outweigh the benefits in these patients. The risk for major bleeding in thrombolysis is approximately 15%. The risk for intracranial bleeding is often cited as 1% to 2%. Bleeding risk is increased in patients older than age 70 years. Recent surgery or trauma, gastrointestinal bleeding, uncontrolled hypertension, and recent stroke are contraindications to thrombolysis.
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IVC filter insertion is appropriate in patients with a contraindication to anticoagulation or in whom anticoagulation is complicated by bleeding or thrombosis despite adequate therapeutic anticoagulation. Many IVC filters deployed today are used for relative indications, including underlying cardiopulmonary disease, significant PE, free floating DVT visualized on duplex ultrasound, and patients at high risk for noncompliance with anticoagulation. It is important to realize that IVC filters help manage patients with DVT and prevent massive PE. However, IVC filters do not treat DVT and anticoagulation is required to stop propagation of the DVT, prevent recurrent DVT as well as prevent embolism. Once the absolute or relative risk for anticoagulation has resolved appropriate anticoagulation should be initiated. Patients with an optionally retrievable IVC filter should be assessed for filter retrieval prior to stopping anticoagulation. There is sufficient data to suggest that retained filters may contribute to subsequent DVT. Once they are no longer required, they should be removed if possible.
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Additional Considerations
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Bed rest is frequently advised in DVT or PE; this is actually detrimental to recovery. Studies demonstrate that ambulation is not associated with increased risk for PE but does improve venous patency. Clinically stable patients should be encouraged to ambulate while hospitalized and return to normal activities after discharge.
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Compression is recommended for patients with DVT. The risk of PTS approaches 70% following DVT. Ideally, patients should be prescribed knee-high stocking with a minimum of 20–30 mm Hg compression before discharge. For patients undergoing PMT or with extensive DVT and more severe symptoms, 30–40 mm Hg compression is recommended.
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The optimal duration of therapy for VTE is unknown. Decisions regard continuing or discontinuing anticoagulation should take into account the underlying etiology of the VTE, patient comorbidities, patient preference for anticoagulation, and the estimated risk for recurrence. In general, a situational event following surgery, hospitalization, or other limited risk factors should be treated a minimum of 3 months and until the attributable risk factor is no longer present. Patients with idiopathic VTE require a minimum of 6–12 months of initial anticoagulation. Patients with recurrent VTE, underlying high-risk thrombophilias, or cancer likely require indefinite therapy. However, to determine the optimal duration of therapy, the benefits of anticoagulation need to be weighed against the risk.
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