DEFINITION
Pulmonary hypertension and subsequent right-sided heart failure as a result of chronic thromboembolic disease is a relatively uncommon condition, occurring in 1% to 5% of adult patients who survive an acute pulmonary embolic event. The unresolved thromboembolic material undergoes chronic fibrotic changes and causes an obstructive lesion that is unresponsive to any medical therapy. The signs and symptoms are related to those of pulmonary hypertension and the subsequent right-sided heart failure. Once chronic pulmonary hypertension develops, the prognosis is poor, and this prognosis is even worse in patients without an intracardiac shunt. The survival of patients with chronic thromboembolic pulmonary hypertension is inversely related to the magnitude of pulmonary artery systolic pressure and pulmonary vascular resistance. When the mean pulmonary artery pressure in patients with thromboembolic disease exceeds 50 mm Hg, the 5-year mortality rate approaches 90%.
ETIOLOGY
The etiology of chronic thromboembolic pulmonary hypertension is related to the same causative factors as those for deep venous thrombosis and acute pulmonary embolism (PE). One or more elements of Virchow’s triad (venous stasis, hypercoagulable state, and intimal injury) are typically present. Although a good portion of patients have no history of deep venous thrombosis (DVT) or PEs, approximately 20% have an underlying hypercoagulopathy. The thromboembolic material within the pulmonary vascular tree generally resolves in time in the majority of patients suffering from acute PE. However, in a certain group of patients, the embolic material persists and eventually transforms into fibrotic obstruction of the pulmonary vasculature.
Key Facts
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Chronic thromboembolic pulmonary hypertension seems to be an extension of the etiologic factors and natural history of acute PE.
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Benign DVT and venous thromboembolic events (TEs) are the major causes in chronic obstruction of the pulmonary vasculature.
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Hypercoagulable conditions or abnormal fibrinolytic pathways predisposing patients to DVT or venous TE are vague and present in only a subgroup of patients.
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The presence of a lupus anticoagulant or anticardiolipin antibodies can be established in about 10% to 24% of patients with chronic thromboembolic disease.
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Protein C, protein S, and antithrombin III deficiencies appear in less than 5% of the patients.
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Factor V Leiden is present in 4% to 6.5% of the patients with CTEPH.
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In patients who survive an acute PE, approximately 20% to 50% have unresolved thromboembolic material.
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Approximately 4% to 5% of patients with unresolved pulmonary emboli will develop chronic pulmonary hypertension.
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Other causes
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Intravascular devices
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Increasing incidence of placement.
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Indwelling venous catheters.
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Pacemaker leads
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Implantable defibrillator leads
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Ventriculoatrial (VA) shunts in patients with a history of hydrocephalus
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Generally, patients with indwelling catheters and intravascular devices have recurrent small thromboemboli.
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These typically get lodged in the segmental and subsegmental branches of the pulmonary vascular tree, making surgical removal somewhat more challenging.
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Unilateral disease
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In rare patients, the disease is confined to one side only ( Fig. 53-1 ).
Figure 53-1
Specimen removed from a patient with unilateral disease. Note that the disease is more common in women and typically seen in the left lung.
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These seem to be in a different category than the patients with typical CTEPH.
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Typically these patients are women and the disease is confined to the left side only
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There is no history of DVT or PE, nor is there history of hypercoagulopathy
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There seems to be an underlying pulmonary vasculopathy related to the left side with subsequent thrombosis
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In a subgroup of these patients, there will be no reperfusion to the affected lung despite complete endarterectomy
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Secondary thrombosis
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In rare cases, the clot within the pulmonary vasculature is secondary to other underlying conditions such as
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Pulmonary vasculitis
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Sarcoidosis
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Fibrosing mediastinitis
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Tumors
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Rarely, the cause of chronic pulmonary obstruction and pulmonary hypertension is not related to clot and is secondary to a sarcoma ( Fig. 53-2 ).
Figure 53-2
Specimen removed from a patient with advanced pulmonary sarcoma involving both right and left lungs. Note the gelatinous and glistening appearance of the tumor.
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Pulmonary sarcomas are rare, although their exact incidence is unknown.
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Tumors generally arise from the main pulmonary artery at the supravalvular level but may be valvar or at the subvalvular/right ventricular outflow tract level.
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Prognosis is poor; however, long-term survival with aggressive removal of the tumor and reconstruction of the remaining pulmonary arteries, pulmonary valve, and right ventricular outflow tract (if involved) is rarely possible.
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CLINICAL FEATURES
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There are no specific signs or symptoms for chronic thromboembolic pulmonary hypertension.
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Symptoms
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The most common symptom associated with CTEPH, as with all other causes of pulmonary hypertension and right-sided heart failure, is exertional dyspnea.
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Dyspnea is out of proportion to any abnormalities found on clinical examination.
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As with complaints of easy fatigability, dyspnea that initially occurs only with exertion is often attributed to anxiety or being out of shape.
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Syncope or presyncope (light-headedness during exertion) is another common symptom of pulmonary hypertension. Generally, it occurs in patients with more advanced disease and higher pulmonary arterial pressures.
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Nonspecific chest pains or tightness occur in approximately 50% of patients with more severe pulmonary hypertension.
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Hemoptysis can occur in all forms of pulmonary hypertension and probably results from abnormally dilated vessels that are distended by increased intravascular pressures.
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Peripheral edema, early satiety, and epigastric or right upper quadrant fullness or discomfort develop as the right heart failure progresses.
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Some patients with chronic pulmonary thromboembolic disease present after a small acute pulmonary embolus that may produce acute symptoms of right heart failure.
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Signs and physical examination
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The physical signs of pulmonary hypertension are the same regardless of the underlying pathophysiology.
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Initially, the jugular venous pulse is characterized by a large A-wave. As the right side of the heart fails, the V-wave becomes predominant as tricuspid regurgitation progresses.
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The right ventricle is usually palpable near the lower left sternal border.
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Pulmonary valve closure may be audible in the left second intercostal space.
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Occasional patients with advanced disease are hypoxic and slightly cyanotic. Clubbing is an uncommon finding.
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The second heart sound is often narrowly split and varies normally with respiration; P2 is accentuated. A sharp systolic ejection click may be heard over the pulmonary artery.
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As the right side of the heart fails, a right atrial gallop usually is present, and tricuspid insufficiency develops.
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Because of the large pressure gradient across the tricuspid valve in pulmonary hypertension, the murmur is high pitched and may not exhibit respiratory variation. These findings are quite different from those usually observed in tricuspid valvular disease.
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A murmur of pulmonic regurgitation may also be detected.
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A specific auscultatory finding to CTEPH is a loud flow murmur heard over the back. This is thought to be related to flow through large bronchial collaterals or flow through stenosed pulmonary vessels.
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DIAGNOSIS
To ensure the diagnosis in patients with right-sided heart failure as a result of chronic pulmonary thromboembolism, a standardized evaluation is recommended for all patients who present with unexplained pulmonary hypertension. This workup includes a variety of imaging studies, as well as right-heart catheterization.
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Electrocardiogram
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The electrocardiogram demonstrates findings of right ventricular hypertrophy.
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Right axis deviation
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Dominant R-wave in V1
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Pulmonary function tests
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Pulmonary function tests are necessary to exclude obstructive or restrictive intrinsic pulmonary parenchymal disease as the cause for the hypertension.
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Echocardiogram
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Perhaps the most useful screening test is a two-dimensional surface echocardiography with Doppler imaging.
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The standard echo helps to define the presence and severity of right-sided heart failure, tricuspid regurgitation, and severity of pulmonary hypertension.
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In addition, it is also helpful to rule out certain other causes, such as Eisenmenger’s syndrome.
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Demonstrates right-sided chamber enlargement and right ventricular hypertrophy.
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The main pulmonary artery is usually enlarged.
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The intraventricular septum may appear flattened and often exhibits paradoxical motion, with encroachment of the right ventricular septum into the left ventricle in systole.
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Varying degrees of tricuspid regurgitation are usually present.
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Continuous wave Doppler scanning of the tricuspid regurgitation jet is helpful in the estimation of the pulmonary artery systolic pressure.
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Because exercise characteristically increases the pulmonary hypertension, echocardiography with exercise should always be applied whenever the disease is suspected but when the resting echocardiogram demonstrates only subtle abnormalities.
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Radiologic studies:
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Plain chest radiograph
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May be normal even in patients with severe pulmonary hypertension.
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May show either apparent vessel cutoffs of the lobar or segmental pulmonary arteries or regions of oligemia, suggesting vascular occlusion.
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Central pulmonary arteries are generally enlarged, and the right ventricle may also be enlarged without any enlargement of the left atrium or ventricle.
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Ventilation/perfusion scan
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The ventilation/perfusion lung scan is the fundamental test for establishing the diagnosis of unresolved pulmonary thromboembolism.
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An entirely normal lung scan excludes the diagnosis of both acute or chronic, unresolved thromboembolism.
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The usual lung scan pattern in most patients with primary pulmonary hypertension either is relatively normal or shows a diffuse nonuniform perfusion.
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When subsegmental or larger perfusion defects are noted on the scan, even when matched with ventilatory defects, pulmonary angiography is appropriate to confirm or rule out thromboembolic disease.
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Computed tomography (CT) scan
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In recent years higher resolution helical CT scans of the chest have been used more frequently in diagnosis of pulmonary thromboembolic disease.
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The presence of large clots in lobar or segmental vessels generally confirms the diagnosis ( Fig. 53-3 ).
Figure 53-3
Computed tomography scan of a patient with significant proximal pulmonary thromboembolic disease. Please note the arrows indicating presence of clot in pulmonary arteries bilaterally.
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Evidence of organized thrombus lining the pulmonary vessels in an eccentric fashion
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Enlargement of the right ventricle and the central arteries
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Variation in size of segmental arteries
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Parenchymal changes characteristic of pulmonary infarction.
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CT scans can be helpful in differentiating thromboembolic disease from other causes such as mediastinal fibrosis, lymph nodes, or tumors.
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Pulmonary angiogram
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Still the gold standard for diagnosis of CTEPH, although more and more centers are relying on the diagnostic power and the noninvasive nature of high-resolution CT scans and magnetic resonance imaging (MRI) scans.
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Combined with right-sided heart catheterization, this method allows measurements of hemodynamic numbers and calculation of pulmonary vascular resistance.
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Organized thromboembolic lesions do not have the appearance of the intravascular filling defects seen with acute pulmonary emboli.
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Experience is essential for the proper interpretation of pulmonary angiograms in patients with unresolved, chronic embolic disease.
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Organized thrombi appear as unusual filling defects, webs, or bands, or completely thrombosed vessels that may resemble congenital absence of the vessel ( Fig. 53-4 ).
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