Box 34.1 MAJOR RISK FACTORS FOR VENOUS THROMBOEMBOLISM

    VTE is an important women’s health concern. Pregnancy is a well-recognized risk factor for VTE. In addition, oral contraceptive pills, especially those containing third-generation progestins, and estrogen plus progestin hormone replacement therapy have been associated with an elevated risk of VTE.

    Recently recognized is the pivotal role that inflammation plays in promotion of VTE. Infection, blood transfusion, and other inflammatory states activate platelets which release procoagulant microparticles.

THROMBOPHILIA AND HYPERCOAGULABLE ASSESSMENT

A history of VTE at a young age, multiple family members with VTE, idiopathic or recurrent VTE, or recurrent spontaneous abortions should raise suspicion for thrombophilia. Laboratory evaluation for hypercoagulable states should focus on major thrombophilias such as factor V Leiden mutation resulting in activated protein C resistance, prothrombin gene mutation 20210, anticardiolipin antibodies, and lupus anticoagulant. Deficiencies of antithrombin III, protein C, and protein S are less common, and testing for these disorders may be inaccurate in the setting of anticoagulation.

PATHOPHYSIOLOGY OF DEEP VEIN THROMBOSIS

DVT most often results from a combination of pathophysiological states of stasis, hypercoagulability, and endothelial injury. Although the deep veins of the lower extremity are the most common location for DVT, thrombosis may also form in the veins of the upper extremity and pelvis. Damage from DVT may lead to dysfunction of the valves of the deep venous system and, ultimately, the postthrombotic syndrome. Chronic lower extremity edema and calf discomfort characterize the postthrombotic syndrome and are associated with reduction in quality of life and impaired functional status. Postthrombotic syndrome is also associated with an increased risk of recurrent VTE.

PATHOPHYSIOLOGY OF PULMONARY EMBOLISM

Most pulmonary emboli originate from thrombus in the deep pelvic or lower extremity veins. Thrombi embolize through the inferior vena cava and right heart and eventually lodge in the pulmonary arteries, where they cause hemodynamic and gas exchange abnormalities.

    The size of the embolus, the patient’s underlying cardiopulmonary reserve, and the extent of compensatory neurohumoral adaptations determine the hemodynamic impact of acute PE. Direct physical obstruction of the pulmonary arterial tree, hypoxemia, and release of potent pulmonary arterial vasoconstrictors as a result of PE cause an acute increase in pulmonary vascular resistance and RV afterload. Sudden RV pressure overload may lead to RV dilatation and hypokinesis, tricuspid regurgitation, and ultimately, acute RV failure. PE patients with acute RV failure may rapidly decompensate and manifest systemic arterial hypotension, cardiogenic shock, and cardiac arrest. In the setting of pericardial constraint, acute RV dilatation and an elevation in diastolic pressure result in flattening of the interventricular septum with deviation toward the left ventricle (LV) in diastole and impairment of LV filling. In addition, pressure overload may increase RV wall stress and result in ischemia or infarction by increasing myocardial oxygen demand while simultaneously limiting supply (Figure 34.1).

    Acute PE results in gas exchange abnormalities by a combination of ventilation-perfusion mismatch, increases in total dead space, and right-to-left shunt. Arterial hypoxemia and an increased alveolar-arterial gradient are the most commonly observed abnormalities of gas exchange.

    Up to 4% of patients who survive acute PE may develop disabling chronic thromboembolic pulmonary hypertension.

Diagnosis

DEEP VEIN THROMBOSIS

Clinical Findings

Patients with lower extremity DVT will often note a cramping or pulling sensation of the calf that may be exacerbated by ambulation. Physical findings of warmth, edema, tenderness, a palpable cord, or prominent venous collaterals may be present. Importantly, some patients may not demonstrate any abnormalities on physical examination.

Laboratory Evaluation

A nonspecific marker of endogenous fibrinolysis, D-dimer, is increased in VTE as well as in many other systemic illnesses. D-dimer levels will be elevated due to other conditions such as acute myocardial infarction, pneumonia, cancer, the postoperative state, and second or third trimester pregnancy. However, D-dimer testing may produce false negative results in the setting of a small thrombus burden such as isolated calf DVT.

Imaging

Duplex venous ultrasonography is the initial imaging test of choice in the evaluation of suspected lower and upper extremity DVT (Figure 34.2). Noncompressibility of a vein is diagnostic of DVT. Alternative imaging modalities for assessment of patients with suspected DVT, including computed tomography (CT), magnetic resonance (MR), and contrast venography, may be warranted when ultrasonography is inadequate, such as when acute-on-chronic thrombosis is suspected. In addition, anatomical limitations may hinder ultrasonographic evaluation of the pelvic veins and upper extremity veins proximal to the clavicle.

PULMONARY EMBOLISM

Clinical Findings

Dyspnea is the most frequently reported symptom in patients with acute PE. Whereas pleuritic pain, cough, or hemoptysis may indicate a smaller peripherally located PE, severe dyspnea, cyanosis, or syncope suggest massive PE. Tachypnea is the most common physical finding. Patients without underlying cardiopulmonary disease may appear anxious but well compensated despite anatomically large PE. Systemic arterial hypotension, cardiogenic shock, or cardiac arrest suggests massive PE. Patients with submassive PE have preserved systolic blood pressure but may exhibit signs of RV failure, including tachycardia, jugular venous distension, tricuspid regurgitation, or an accentuated sound of pulmonic closure.

Clinical Decision Rule

Simplified clinical decision rules assist clinicians in synthesizing important elements of the history and physical examination into an overall assessment of likelihood of PE. In the Christopher study, the diagnosis of PE was excluded or established in three straightforward steps: (1) a dichotomized clinical decision rule (categorizing patients as high or nonhigh clinical probability for PE), (2) D-dimer testing, and (3) chest CT. Study investigators used a generally accepted clinical decision rule known as the “Wells criteria,” which assigns 3 points for symptoms and signs of DVT, 3 points for an alternative diagnosis less likely than PE, 1.5 points for heart rate >100 beats per minute, 1.5 points for recent surgery or immobilization, 1.5 points for previous VTE, 1 point for hemoptysis, and 1 point for malignancy undergoing therapy or palliation within 6 months of presentation (table 34.1). Patients are categorized as “PE unlikely” for scores ≤4 and “PE likely” for scores >4. Patients who were classified as “PE unlikely” underwent D-dimer testing and were referred to chest CT only if the result was positive, whereas patients in the “PE likely” category proceeded directly to chest CT. PE was excluded in patients categorized as “PE unlikely” with negative D-dimer results and in patients with negative chest CT scans. This simplified clinical algorithm permitted a management decision in 98% of patients and was associated with a low risk of VTE.

Laboratory Evaluation

D-dimer, as measured by enzyme-linked immunosorbent assay (ELISA), is particularly helpful in the evaluation of patients with suspected PE, especially in the emergency setting. Because of its high negative predictive value, D-dimer can be used to exclude PE in outpatients with low clinical decision rule scores without the need for further costly testing. Inpatients should proceed directly to imaging as the initial test for PE, because most will already have an increased D-dimer due to comorbid illness.

Electrocardiogram

The electrocardiogram (EKG) may detect RV strain while also suggesting alternative diagnoses such as myocardial infarction. Signs of RV strain due to PE include incomplete or complete right bundle branch block, T wave inversions across the anterior precordium, as well as an S wave in lead I and a Q wave and T wave inversion in lead III (S1Q3T3). Some patients may demonstrate signs of increased adrenergic tone with resting sinus tachycardia, but others may not demonstrate any electrocardiographic abnormalities.

Imaging

The chest x-ray (CXR) constitutes an important part of the evaluation of patients with suspected PE because it may suggest alternative diagnoses such as pneumonia. A normal or near-normal CXR in a patient with dyspnea or hypoxemia suggests PE. However, the majority of patients with PE will have some radiographic abnormality such as cardiomegaly or pleural effusion.

    Contrast-enhanced chest CT has emerged as the dominant diagnostic imaging modality for the evaluation of suspected acute PE (Figure 34.3). The improved resolution of multidetector CT scanners has markedly reduced the frequency of nondiagnostic studies. In the Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) trial, chest CT was found to be accurate for the exclusion of the vast majority of patients suspected of PE. Consider performing further diagnostic testing if clinical suspicion and chest CT results are discordant. In general, CT venography as a routine “add-on” to chest CT is not recommended unless patients are at high risk of DVT due to active cancer or prior VTE.

    Alternative imaging modalities utilized in the evaluation of patients with suspected PE include ventilation-perfusion lung scanning, MR angiography, and invasive contrast pulmonary angiography. Ventilation-perfusion lung scanning is most often used for patients with severe renal impairment, anaphylaxis to intravenous iodinated contrast, or pregnancy. Although it avoids the risks of iodinated contrast and ionizing radiation, MR angiography is not as sensitive as chest CT for detection of PE and has demonstrated more promise for the imaging of DVT. Invasive diagnostic pulmonary angiography is reserved for the rare circumstance when other noninvasive imaging studies are inconclusive and a high clinical suspicion for PE persists.

    Transthoracic echocardiography is insensitive for the diagnosis of PE, even though it plays a critical role in the risk stratification of patients with proven acute PE. Transthoracic echocardiography is superb for the detection of RV dysfunction due to RV pressure overload in the setting of acute PE. RV dilatation and hypokinesis, paradoxical interventricular septal motion toward the LV, tricuspid regurgitation, and pulmonary hypertension are characteristic echocardiographic findings.

An Integrated Approach to Diagnosis

Both the Christopher study and PIOPED II highlight the importance of a diagnostic algorithm that integrates an assessment of clinical probability with laboratory testing and imaging with chest CT (Figure 34.4). The use of an integrated algorithm permits management decisions to be made in the majority of patients with suspected PE and is associated with a low risk of VTE.

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