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Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension

Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension
Literature review current through: Jan 2024.
This topic last updated: Sep 29, 2023.

INTRODUCTION — Chronic thromboembolic pulmonary hypertension (CTEPH) is a condition where pulmonary hypertension (PH) occurs due to pulmonary artery obstruction from unresolved thromboembolic disease [1,2]. CTEPH is a late complication of acute pulmonary embolus and is classified as group 4 PH (ie, PH due to pulmonary artery obstruction) (table 1 and table 2). The identification of CTEPH as a cause of PH is important since it has a different therapeutic strategy compared with other classes of PH.

The incidence, pathogenesis, clinical features, and diagnosis of CTEPH are reviewed here. Treatment of CTEPH is discussed separately. (See "Chronic thromboembolic pulmonary hypertension: Initial management and evaluation for pulmonary artery thromboendarterectomy" and "Chronic thromboembolic pulmonary hypertension: Pulmonary thromboendarterectomy" and "Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy".)

The approach outlined in this topic is, for the most part, consistent with guidelines set out by several international societies [3-5].

EPIDEMIOLOGY — The true incidence of CTEPH is unknown but estimated to be between 1 and 5 percent among survivors of acute pulmonary embolus (PE) [6-12].

One retrospective series reported that among 899 patients with PE, approximately 1 percent developed CTEPH [13].

In contrast, three prospective series reported that between 2.8 and 4.8 percent of patients developed CTEPH in a two-year period following the diagnosis of PE [7,8,12].

Another review of 16 studies suggested a prevalence of 0.5 percent in the general population and 3 percent in survivors of PE [10].

In patients with acute PE, the development of CTEPH is rare after two years [10].

PATHOGENESIS — It is thought that CTEPH may represent the final manifestation of unresolved pulmonary embolus (PE). However, it is unknown why some patients with acute PE develop CTEPH and others do not [14]. The most popular theory is that CTEPH may be due to an underlying hypercoagulable state, but several alternative theories exist.

Hypercoagulable state — Several studies suggest that an underlying hypercoagulable state may be responsible for CTEPH in some patients. Observational studies have found elevated levels of factor VIII (defined as >230 IU/dL) in patients with CTEPH compared with healthy controls (41 versus 5 percent) [15,16]. In addition, antiphospholipid antibodies, have been identified in 10 to 20 percent of patients with CTEPH [12,15,17,18]. However, not all hypercoagulable abnormalities have been associated with CTEPH [19]. For example, activated protein C resistance or abnormal fibrinolytic activity have not been consistently identified in patients with CTEPH and less than 1 percent of patients with CTEPH have deficiencies of antithrombin, protein C, or protein S [18]. Similarly, another study reported no difference in factor V Leiden (FVL) or Prothrombin G20210A (PT) variants in patients with CTEPH compared with patients who had PE but did not develop CTEPH [20].

Alternative hypotheses — Alternative hypotheses also exist.

One hypothesis postulates that patients who develop CTEPH represent those few patients with PE whose endogenous fibrinolytic mechanisms are overcome by the age, extent, or location of the obstructing embolus.

Another hypothesis proposes that patients with CTEPH have fibrin variants that are resistant to plasmin-mediated lysis [21].

Although the majority of experts now agree that there is compelling evidence to support a thromboembolic basis for the disease, a final hypothesis suggests that pulmonary arteriopathy or in situ thrombosis may underlie certain cases [22]. This is based upon the recognition that a substantial number of patients with CTEPH do not have a prior documented history of venous thromboembolism, that animal models of CTEPH are difficult to produce by repeatedly embolizing thrombotic material, and that most hypercoagulable states do not appear to confer risk for CTEPH.

RISK FACTORS — Although several risk factors for CTEPH have been cited in patients with acute pulmonary embolus, none are consistent or strong enough to advocate routine surveillance for CTEPH, following an acute thromboembolic episode [9,11,23-26]. While the threshold should be low to suspect CTEPH following acute pulmonary embolism (PE), we suggest that patients with PE who report new or persistent dyspnea or exercise intolerance after three months of anticoagulant treatment be followed clinically with targeted diagnostic tests for the development of either chronic thromboembolic disease (CTED) or CTEPH. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Monitoring and follow-up'.)

While an algorithm (that used electrocardiography and brain natriuretic peptide without echocardiography) has been used to exclude CTEPH in symptomatic patients following acute PE, it needs validation and may not exclude other conditions such as chronic thromboembolic disease or exercise-related PH, which may benefit from therapy [27].

General — Several small observational studies have described possible predictors for the development of CTEPH following acute PE. One study suggested that in patients with acute PE, right ventricular (RV) dysfunction might be an independent predictor for the development of CTEPH [9]; however, another study reported an expected rate of CTEPH (3 percent) in this population despite thrombolysis [11]. Other cited risk factors include unprovoked PE, a diagnostic delay of the acute event (eg, two weeks), large thrombi, recurrent embolic events, thrombophilic disorders (eg, antiphospholipid antibody syndrome), ventriculo-atrial shunts, chronic intravenous lines or pacemakers, history of cancer, inflammatory bowel disorders, splenectomy, chronic osteomyelitis, female sex advanced age, non-O blood groups, persistent vascular obstruction, and comorbidities at the time of VTE diagnosis [9,12,23-25,28,29].

Chronic thromboembolic disease (CTED) — A population of patients has been identified with post-embolic exercise intolerance and evidence of chronic thromboembolic disease in the absence of resting PH [30-32]. This condition has variably been referred to as "chronic thromboembolic disease (CTED)" or "post-PE syndrome" and appears to affect a substantially larger number of patients than those who develop CTEPH [31]. While there is no agreed upon definition, CTED is characterized by evidence of chronic thromboembolic disease with a mean pulmonary artery pressure (mPAP) <20 mmHg.

Symptoms vary. Exercise intolerance can occur and may be due to increased dead space ventilation related to pulmonary vascular obstruction and/or RV dysfunction and limitation of maximal cardiac output with exercise.

Diagnosis usually requires hemodynamic measurement. We typically have a lower threshold to evaluate patients with CTED for CTEPH with right heart catheterization, even in the absence of echocardiographic evidence of PH. Whether CTED can be distinguished from CTEPH by CT is unclear [33].

The optimal approach to management of patients with CTED remains uncertain. In a series of 1019 patients undergoing pulmonary endarterectomy, 42 patients met the hemodynamic criteria for CTED (ie, mPAP <20 mmHg). Among those with CTED, patients who had evidence of CTED on computed tomographic (CT) pulmonary angiography (CTPA) underwent endarterectomy [32]; there were no deaths and all patients reported a significant improvement in symptoms and functional status.

The natural history of CTED is poorly understood. In one study of 113 patients with CTED (mPAP <24 mmHg), no hemodynamic deterioration occurred at one year, although eight patients had undergone pulmonary endarterectomy [34]. Among 63 patients who were followed up at three years, none experienced hemodynamic deterioration, but none experienced significant improvement in symptoms. Mortality was 8 percent over 37 months with over three-quarters of patients dying from cancer.

CLINICAL FEATURES

Features of pulmonary hypertension — Patients with CTEPH usually present with the features of PH, typically complaining of progressive dyspnea and exercise intolerance [3,35]. Occasionally, a patient with a delayed presentation will present with the symptoms and signs of right ventricular dysfunction, such as peripheral edema, exertional chest pain, syncope, or near-syncope. The symptoms and signs of PH are provided separately. (See "Approach to the patient with dyspnea" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)

Features specific to thromboembolism — Specific to CTEPH, many patients provide a distant history of acute pulmonary embolus (PE) or a history consistent with an acute venous thromboembolic (VTE) event (eg, pleuritic chest pain, lower extremity discomfort, or a prolonged atypical pneumonia) months to years prior to the onset of the dyspnea [36]. However, a documented history of VTE may be absent in up to 38 percent of patients [36]. The absence of a diagnosis of VTE is not surprising since it is frequently overlooked in the population at large [37]. Thus, the clinician should elicit subtle findings in the history, such as a hospitalization or surgical procedure following which the patient experienced persistent exertional dyspnea or exercise intolerance.

A unique physical finding in some patients with CTEPH is the presence of flow murmurs over the lung fields. These subtle bruits appear to originate from turbulent flow through partially obstructed or recanalized pulmonary arteries and are present in approximately 30 percent of patients with CTEPH [38]. They are high pitched and blowing in quality, heard most commonly over the posterior lung fields rather than the precordium, accentuated during inspiration, and frequently heard only during periods of breath-holding. They have not been described in patients with other types of PH.

Chest radiographic imaging — Specific to CTEPH, pulmonary embolic disease may cause areas of hypoperfusion and/or hyperperfusion, as well as evidence of old unilateral or bilateral pleural disease [35,39]. However, in many cases, the chest radiograph may be normal or simply have the nonspecific findings of PH (image 1). Chest radiographic features of PH are provided separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Imaging'.)

DIAGNOSTIC EVALUATION — The diagnosis of CTEPH is typically delayed due to the nonspecific clinical presentation of PH and low rate of CTEPH as a complication of venous thromboembolism (VTE) [3,23,40]. All patients with suspected PH benefit from referral to a specialized PH center.

Once CTEPH is suspected, we suggest a stepwise approach to diagnosis that also concurrently includes determination of surgical eligibility, in the event that a diagnosis of CTEPH is actually confirmed (algorithm 1). This approach involves ventilation/perfusion (V/Q) scanning, CT pulmonary angiography (CTPA) if indicated, right heart catheterization (RHC), and contrast pulmonary angiography.

The diagnosis is dependent upon imaging that uses contrast-enhancement, (eg, CTPA and contrast-enhanced pulmonary angiography) to identify chronic thromboembolism in the proximal or distal vasculature. Thus, when CTEPH is suspected in those with contrast allergies or renal insufficiency, every effort should be made to ensure that patients undergo optimal testing with provisions for an adverse effect of contrast. (See 'Patients with contrast allergy or renal insufficiency' below.)

Suspecting CTEPH during evaluation of pulmonary hypertension — Testing for PH typically includes echocardiography, pulmonary function testing, V/Q lung scanning, CT of the chest, and RHC, the latter of which is typically the final step in confirming PH. CTEPH may be suspected during this work-up (eg, segmental mismatched defects on V/Q scanning, obstructing thrombus on chest CT, documented history of VTE, or bruits in the lung fields). Alternatively CTEPH may be suspected during a formal evaluation for the etiology after the diagnosis of PH is made on RHC so that PH can be classified appropriately (table 1). (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)

The suspicion for CTEPH should also be high among patients with dyspnea and/or exercise intolerance or patients with PH and the following:

A history of a VTE

Symptoms consistent with prior VTE (see "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism" and "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity")

Risk factors for VTE (see "Overview of the causes of venous thrombosis")

Risk factors for CTEPH following VTE (see 'Risk factors' above)

If CTEPH is suspected before RHC is performed and evidence of thromboembolic disease is suggested by V/Q scanning or confirmed by CTPA, we advocate referral to a specialized CTEPH center where RHC, pulmonary angiography, and simultaneous assessment for surgery can be more readily performed. (See 'Ventilation perfusion lung scanning' below and 'Computed pulmonary arteriography' below and 'Digital subtraction pulmonary angiography' below and "Chronic thromboembolic pulmonary hypertension: Initial management and evaluation for pulmonary artery thromboendarterectomy", section on 'Evaluation for pulmonary thromboendarterectomy'.)

In certain patients, RHC at rest may demonstrate only a modest degree of PH. In this situation, we sometimes repeat the measurements after a short period of exercise (preferably formal exercise testing). Exercise-related increases in cardiac output may be accompanied by a disproportionate elevation of the pulmonary artery pressure due to the loss of the normal compensatory mechanisms of pulmonary artery distension and recruitment [41]. This hemodynamic information provides objective evidence to explain an individual's symptoms and may reflect an early but clinically relevant stage in the development of CTEPH.

Ventilation perfusion lung scanning — In patients presenting with newly diagnosed PH or patients with suspected CTEPH, we suggest a V/Q lung scanning as the initial imaging procedure of choice.

Evidence of chronic thromboembolic disease is seen on V/Q scan as at least one (usually several) segmental or larger mismatched V/Q defects (image 2). A normal V/Q scan accurately excludes chronic thromboembolic disease with a sensitivity of 96 to 97 percent and a specificity of 90 to 95 percent [42].

V/Q scanning is useful for differentiating proximal large vessel, obstructive types of PH (ie, group 4 PH such as CTEPH or pulmonary artery sarcoma) from distal small vessel types, such as group 1 pulmonary arterial hypertension (PAH) who usually have normal scan findings or a mottled perfusion scan characterized by subsegmental defects.

However, in patients with CTEPH, V/Q lung scanning has some limitations:

V/Q scanning may understate the extent of central pulmonary vascular obstruction [43]. Channels through central obstructing lesions or partial flow around them (a result of complex patterns of recanalization and organization that follow an embolic event) allow the radioisotopic agent to reach the periphery of the lung. These areas may appear normal or as hypoperfused gray zones, depending upon the distribution of flow.

V/Q scanning is sensitive but not specific. Any disease process that obstructs pulmonary vascular flow without a corresponding obstruction of ventilation may result in mismatched defects. Other pulmonary hypertensive disorders other than CTEPH that can also be associated with segmental or large perfusion defects on V/Q lung scanning include pulmonary artery sarcoma, pulmonary veno-occlusive disease, fibrosing mediastinitis, large vessel pulmonary vasculitis, and extrinsic pulmonary vascular compression (arterial or venous) (table 2). (See 'Differential diagnosis' below.)

Consequently, most patients with CTEPH also require CTPA as a complementary study to V/Q scanning. Although some data suggest that CTPA may be noninferior to V/Q lung scanning as the initial test of choice for CTEPH [44,45], other data suggest that radiologists frequently miss CTEPH findings, leading to a falsely low sensitivity for CTPA [46], unless it is read by a radiologist with expertise in CTEPH [45]. Even when interpreted properly, a negative CT scan cannot exclude the possibility of CTEPH, and for this reason, V/Q scanning remains the preferred initial imaging test for evaluating patients with CTEPH [3].

Computed pulmonary arteriography — For patients whose V/Q lung scanning suggests CTEPH, we perform a CTPA. The main purpose of CTPA is the exclusion of select possibilities in the differential diagnosis (eg, pulmonary artery tumors, pulmonary artery stenosis, fibrosing mediastinitis). In addition, CTPA may confirm the presence of thromboembolic disease and help define the surgical accessibility of the obstructing thrombotic lesions. [47]. (See "Mediastinal granuloma and fibrosing mediastinitis", section on 'Fibrosing mediastinitis'.)

Specific findings of CTEPH on CTPA include organized thromboembolic material lining the arterial wall resulting in an eccentric filling defect or apparent wall thickening, abrupt vessel narrowing often with post-stenotic dilation, linear or band like filling defect, or a completely obstructed vessel (image 3) [48]. Multiplanar reformations that provide views of the arteries along their long axis are helpful in the detection of flattened peripheral organized thrombi, arterial stenosis and obstructions that might be missed on the cross-sectional images. Enlarged bronchial arteries are present in the majority of patients in response to the chronic pulmonary arterial obstruction. Common but nonspecific parenchymal abnormalities include mosaic attenuation and peripheral wedge-shaped or irregular linear opacities due to scarring from previous pulmonary infarcts. Mosaic attenuation in CTEPH is characterized by regions of decreased attenuation and vascularity and adjacent areas of increased attenuation and vascularity. General CT findings of PH may also be seen. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Imaging'.)

Limitations of chest CTPA include the following:

CTPA is less sensitive than V/Q scan or pulmonary angiography. Thus, a negative CT scan does not exclude the possibility of CTEPH [3].

CTPA is particularly poor in detecting chronic thromboemboli at the segmental level, a level currently accessible to surgical intervention [49].

CTPA is limited in its ability to differentiate an acute intraluminal thrombus from a well-endothelialized chronic thrombus.

CTPA sensitivity is dependent upon expert interpretation [45].

Digital subtraction pulmonary angiography — For patients in whom V/Q scanning and CTPA are suggestive of CTEPH, we suggest digital subtraction pulmonary angiography (DSPA), which is considered the gold standard in confirming the diagnosis and determining surgical eligibility. Biplanar pulmonary angiography (ie, anterior and lateral imaging), which is standard in most CTEPH centers, improves visualization of the lobar and segmental branches of the pulmonary artery, thereby enhancing interpretation (image 4). In specialized centers, RHC is often performed in conjunction with DSPA. Although RHC is often performed at local or PH centers prior to referral, DSPA should be performed in a specialized CTEPH center and as such requires referral. Expertise in the performance and interpretation of RHC in combination with DSPA is present in CTEPH centers as is the availability of surgical or catheterization teams capable of performing either a thromboendarterectomy procedure or balloon pulmonary angioplasty. (See "Chronic thromboembolic pulmonary hypertension: Initial management and evaluation for pulmonary artery thromboendarterectomy", section on 'Evaluation for pulmonary thromboendarterectomy'.)

Five angiographic patterns are associated with the presence of CTEPH due to organized thromboembolic material (image 5). One or more of these findings may be seen:

Pouch defects

Pulmonary artery webs or bands (thin, ribbon-like, fibrotic structures traversing the artery)

Intimal irregularities

Abrupt narrowing of the major pulmonary arteries

Obstruction of lobar or segmental vessels at their origin, with complete absence of blood flow to the pulmonary segments that are normally perfused by those vessels

The safety of performing pulmonary angiography in patients with PH is a common concern. Many clinicians believe that the vasodilation induced by the contrast agent might induce hypotension. However, this does not appear to be a legitimate concern. This was addressed in a study that measured pulmonary and systemic hemodynamics during pulmonary angiography [50]. Multiple bolus injections of nonionic contrast media did not cause any major adverse hemodynamic effects, even in the presence of severe PH. All of the patients received supplemental oxygen.

Other imaging — Other imaging modalities, including magnetic resonance pulmonary angiography (MRPA), dual-energy CT, and cone-beam CT, have also shown promise for detailing the pulmonary vasculature [51-53]. None, however, are being routinely used for the diagnosis or preoperative evaluation of CTEPH. However, they may be useful when standard testing such as DSPA is limited. For example, MRPA is sometimes used to support a diagnosis when pulmonary angiography is contraindicated in patients with severe right ventricular failure and shock or when V/Q scan or CTPA cannot be performed or are indeterminate. (See 'Profound right ventricular failure' below.)

Special populations

Patients with contrast allergy or renal insufficiency — In patients with suspected CTEPH who have a known contrast allergy or renal insufficiency, we make every attempt to perform contrast-enhanced studies. The rationale for this approach is predicated on the importance of defining the degree of hemodynamic impairment and the location and extent of the thromboembolic obstruction prior to thromboendarterectomy. (See "Patient evaluation prior to oral or iodinated intravenous contrast for computed tomography" and "Prevention of contrast-associated acute kidney injury related to angiography".)

Profound right ventricular failure — In patients who have profound right ventricular failure with shock, the risk of DSPA may be prohibitive. In such cases, the diagnosis of CTEPH and evaluation for thromboendarterectomy can be undertaken based on the results of less invasive imaging studies such as CTPA and MRPA. (See 'Other imaging' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of CTEPH involves that of the symptoms of PH, the causes of PH, and conditions associated with obstruction of the pulmonary artery.

Symptoms of PH – The differential diagnosis of the symptoms of PH is wide and usually distinguished by the extensive testing performed during the evaluation of PH itself. These data are discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial differential diagnosis'.)

Etiologies of PH – When the initial diagnostic evaluation indicates that the likely cause of the dyspnea and exercise intolerance is PH, the various types of PH become the alternative possible diagnoses (table 1), the details of which are discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)

Obstruction of the pulmonary artery – Conditions that can cause obstruction of pulmonary artery (PA) flow and some of which mimic CTEPH radiographically are included on the table (table 2). These conditions are rare and include malignant and nonmalignant pulmonary artery tumors [54,55], arteritis (in the absence of connective tissue disease; eg, Takayasu’s arteritis [56]), congenital pulmonary artery stenosis [57], fibrosing mediastinitis (see "Mediastinal granuloma and fibrosing mediastinitis", section on 'Clinical presentation'), and parasitic disease, such as hydatidosis (echinococcus) [58].

In general, chest CT and/or CT pulmonary angiography are capable of detecting these alternative diagnoses. For example, pulmonary artery stenosis appears on imaging as a focal area of narrowing, whereas chronic thromboembolic material appears as a web or a band which is a thin, ribbon-like fibrotic structure that traverses the artery. Identifying the causes of pulmonary artery obstruction (eg, sarcoma, fibrosing mediastinitis, vasculitis, or stenosis) is important since some are amenable to debulking or dilation while others may be fatal. Obstruction from pulmonary arteritis may also be distinguished by appropriate serology.

DIAGNOSIS

Diagnostic criteria — The diagnosis of CTEPH requires that both of the following criteria be met (algorithm 1):

The presence of PH – PH must be present, defined on right heart catheterization (RHC) as a mean pulmonary artery pressure (mPAP) >20 mmHg at rest and the pulmonary vascular resistance is ≥2 Wood units (>160 dynes per second per cm-5) in the absence of an elevated pulmonary capillary wedge pressure (PCWP; ie, PCWP is ≤15 mmHg) [3,59]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Diagnosis'.)

The presence of thromboembolic occlusion of the proximal or distal pulmonary vasculature – Thromboembolic occlusion of the proximal and/or distal pulmonary vasculature must exist and be the presumed cause of the PH (ie, all other causes of PH and pulmonary artery obstruction are excluded). (See 'Ventilation perfusion lung scanning' above and 'Computed pulmonary arteriography' above and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)

After a diagnosis of CTEPH is made some experts perform antiphospholipid antibody testing, which can inform treatment decisions.

Clinical diagnosis before referral to CTEPH center — Since the evaluation is best done in a center with expertise in CTEPH, most clinicians make a provisional clinical diagnosis of CTEPH in patients with PH on echocardiography or right heart catheterization (RHC) who have evidence suggestive of chronic thromboembolic disease on ventilation perfusion (V/Q) lung scan, CT pulmonary angiography, and/or magnetic resonance pulmonary angiography (MRPA). In such cases, the patient is referred to a CTEPH center, where extensive evaluation that includes digital subtraction pulmonary angiography can be readily performed. At such centers, expertise in the performance and interpretation of the studies is present as is the availability of surgical and catheterization teams capable of performing either a thromboendarterectomy procedure or balloon pulmonary angioplasty. (See "Chronic thromboembolic pulmonary hypertension: Pulmonary thromboendarterectomy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Pulmonary hypertension (The Basics)")

SUMMARY AND RECOMMENDATIONS

Pulmonary hypertension (PH) due to chronic thromboembolic disease (CTEPH) is classified as group 4 PH (ie, PH due to pulmonary artery obstruction) (table 1 and table 2). (See 'Introduction' above.)

CTEPH is a late complication of acute pulmonary embolus (PE). The incidence is estimated to be between 1 and 5 percent among survivors of acute PE. The pathogenesis of CTEPH is unknown but may relate to an unidentified hypercoagulable state. (See 'Epidemiology' above and 'Pathogenesis' above.)

In patients with PE, we suggest clinical surveillance with history and examination and targeted diagnostic tests only in patients who report new or persistent dyspnea or exercise intolerance after three months of anticoagulant treatment. Although several risk factors for CTEPH have been cited in patients with acute PE, none are consistent or strong enough to advocate routine surveillance for CTEPH, following an acute thromboembolic episode. (See 'Risk factors' above.)

Patients with CTEPH usually present with the symptoms and signs of PH and typically complain of progressive dyspnea and exercise intolerance. Many patients provide a history of documented venous thromboembolism (VTE) or a history consistent with VTE (eg, pleuritic chest pain, lower extremity discomfort, or a prolonged atypical pneumonia) months to years prior to the onset of symptoms. However, documentation of acute VTE may be absent in almost 40 percent. Specific to CTEPH, flow murmurs may be heard over the lung fields. Areas of hypoperfusion, hyperperfusion, and pleural abnormalities may be seen on chest radiography. (See 'Clinical features' above and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)

Diagnostic evaluation:

Testing for PH of unclear etiology typically includes echocardiography, pulmonary function testing, ventilation/perfusion (V/Q) lung scanning, CT of the chest, and right heart catheterization (RHC). CTEPH may be suspected during this work-up (eg, segmental mismatched defects on V/Q scanning, obstructing thrombus on chest CT, documented history of VTE, or bruits in the lung fields). Alternatively CTEPH may be suspected during a formal evaluation for the etiology after the diagnosis of PH is made on RHC so that PH can be classified appropriately (table 1). (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and 'Diagnostic evaluation' above.)

Once PH is confirmed, the diagnostic evaluation is focused on the demonstration of chronic thromboembolic material in the pulmonary arteries (algorithm 1):

Ventilation-perfusion (V/Q) lung scanning – For patients in whom CTEPH is suspected, we suggest V/Q lung scanning. A normal V/Q scan accurately excludes chronic thromboembolic disease. Patients with CTEPH generally have at least one (usually several) segmental or larger mismatched ventilation-perfusion defects (image 2). However, V/Q lung scanning often understates the extent of central pulmonary vascular obstruction. In addition, V/Q scanning is not specific since segmental or larger perfusion defects can be seen in pulmonary hypertensive disorders other than CTEPH (eg, pulmonary artery sarcoma, pulmonary veno-occlusive disease, fibrosing mediastinitis, large vessel pulmonary vasculitides, and extrinsic pulmonary arterial or venous compression) (table 2). (See 'Ventilation perfusion lung scanning' above.)

CT pulmonary angiography (CTPA) – For patients whose V/Q lung scanning supports CTEPH, we suggest CTPA. CTPA may confirm the presence of chronic thromboembolic disease and is useful in ruling out select possibilities in the differential diagnosis (eg, pulmonary artery tumors, pulmonary artery stenosis, fibrosing mediastinitis). Findings supportive of CTEPH on CTPA include thromboembolic material adherent to the pulmonary arterial wall, disparity in segmental vessel size, bronchial artery collateral flow, parenchymal abnormalities consistent with prior infarcts, and mosaic attenuation of the pulmonary parenchyma (image 3). However, CTPA is limited in the detection of chronic thromboemboli at the segmental level and in the differentiation of acute intraluminal thrombus from a well-endothelialized chronic thrombus. (See 'Computed pulmonary arteriography' above.)

Digital subtraction pulmonary angiography (DSPA) – For patients with suspected CTEPH and evidence of chronic thromboembolic disease on V/Q scan and CTPA, we suggest digital subtraction pulmonary angiography (DSPA), which is the gold standard in confirming the diagnosis and determining surgical eligibility. Findings include one or more of the following: pouch defects, pulmonary artery webs or bands, intimal irregularities, abrupt narrowing of the major pulmonary arteries, and obstruction of lobar or segmental vessels at their origin (image 5 and image 4). Pulmonary angiography is preferably performed in a specialized CTEPH center since it is also necessary to define the surgical accessibility of the obstructing thrombotic lesions. (See 'Digital subtraction pulmonary angiography' above.)

Other imaging – Magnetic resonance pulmonary angiography (MRPA) is not routinely used as a diagnostic tool for CTEPH unless V/Q scan, CTPA, or DSPA cannot be performed or are indeterminate. (See 'Other imaging' above.)

In patients with suspected CTEPH, the differential diagnosis includes that associated with the symptoms of PH as well the differential associated with the etiologies of PH (table 1) and of pulmonary artery obstruction (table 2). Most of these can be distinguished from each other using the investigations performed during the evaluation of PH and the evaluation of CTEPH. (See 'Differential diagnosis' above and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial differential diagnosis' and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)

Diagnosis:

The diagnosis of CTEPH requires that both of the following criteria be confirmed (see 'Diagnosis' above):

PH, defined on RHC as a mean pulmonary artery pressure >20 mmHg at rest and the pulmonary vascular resistance is ≥2 Wood units (>160 dynes per second per cm-5) in the absence of an elevated pulmonary capillary wedge pressure (ie, PCWP is 15 mmHg). (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Diagnosis'.)

Thromboembolic occlusion of the proximal and/or distal pulmonary vasculature must exist and be the presumed cause of the PH (ie, all other causes of PH and pulmonary artery obstruction are reasonably excluded).

Patients can be referred for surgical evaluation without a RHC diagnosis of PH, based upon echocardiographic findings suggestive of PH in conjunction with V/Q scanning, CTPA, or MRPA findings supportive of thromboembolic disease. (See 'Clinical diagnosis before referral to CTEPH center' above.)

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