Pathologic Lesions of Chronic Thromboembolic Pulmonary Hypertension
Acute venous thromboembolism resolves in most cases. However, an estimated 0.5%-3.8% of pulmonary embolism (PE) survivors develop chronic thromboembolic pulmonary hypertension (CTEPH) resulting from mechanical obstruction of the pulmonary arteries [1-3]. Most patients with CTEPH have experienced a PE in their lifetime; however, up to 25% of patients have never reported a thrombotic event . Patients may present with exertional dyspnea, fatigue, palpitations, lightheadedness or syncope. CTEPH is diagnosed by precapillary pulmonary hypertension (mean pulmonary arterial pressure > 25 mm Hg and pulmonary arterial wedge pressure ≤ 15 mm Hg) on right heart catheterization and abnormal ventilation perfusion scintigraphy (VQ scan) including at least one mismatched perfusion defect with confirmatory imaging by either computed tomography (CT) angiography or pulmonary angiography .
CTEPH is primarily caused by the transformation of incomplete resolution of thrombi into fibrotic organized fibrotic scar tissue. Residues of organized thromboembolic material can be found in large pulmonary arteries, frequently called "webs," can adhere to the arterial wall, and are composed of collagen, fibroblasts and inflammatory cells . Neovascularization then follows, presumably as the effect of clot organization. Inflammatory markers, such as IL-8, VEGF and basic fibroblastic growth factor, stimulate angiogenesis and facilitate thrombus resolution .
Pathologic examination of lung biopsy, or an autopsy of patients with CTEPH, disclose the full range of pulmonary hypertensive lesions in the small pulmonary arteries . Muscle hypertrophy of the arteries and arterioles and medial thickness is the most common finding, but eccentric intimal fibrosis, concentric laminar intimal fibroelastosis and internal fibromuscular proliferation is also seen. Organized thrombi is present in small pulmonary arteries. Plexiform lesions, the typical histological hallmark of idiopathic pulmonary arterial hypertension (IPAH), is described by one group , but not seen by another group . These histopathologic findings are very similar to those seen in patients with IPAH, making it challenging to pathologically discriminate between the two groups of patients.
Impaired fibrinolysis and altered fibrinogen structure and function may also be implicated in the failure of thrombus resolution . Inherited thrombophilia and anti-phospholipid antibodies have been found in 17% and 10% of CTEPH patients, respectively . However, the frequency of protein S or C deficiency, factor V Leiden mutation and the prothrombin 2021G mutation have not consistently been found to be more common in CTEPH than in the general population .
Pulmonary hypertension develops once a threshold level of pulmonary vascular obstruction is reached, and right ventricular changes are seen when over half of the effective pulmonary vascular bed is affected . Interestingly, studies have demonstrated a poor correlation between the degree of vascular occlusion by thrombi and the severity of hemodynamic compromise, which suggest additional processes contributing to the development of CTEPH .
Despite the advances in the last years, we still don't fully understand the cause of thrombus non-resolution, which for most is considered the initial trigger for CTEPH pathogenesis. It is not known whether the development of CTEPH is related to the extent and location of the thrombi, or due to a genetic predisposition or if the use of thrombolysis reduces its incidence. Further research in these complex areas will advance the early diagnosis and expand treatment options of patients with CTEPH. ■
Disclosure Statement: Dr. Rivera-Lebron receives consulting fees from Gilead and serves as site PI for a clinical trial from Actelion. Dr. Risbano has received consulting fees from Gilead and Actelion and serves as the site PI for clinical trials from Actelion and United Therapeutics; he is the recipient of a grant from Gilead for an investigator sponsored research project.
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