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Chronic Thromboembolic Pulmonary Hypertension

By Peter F. Fedullo, MD

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Objectives

1. Understand the natural history of chronic thromboembolic pulmonary hypertension (CTEPH).

2. Characterize the clinical presentation of CTEPH.

3. Delineate the appropriate diagnostic evaluation for patients with suspected CTEPH.

4. Define the criteria for surgical referral.

5. Identify the common complications following pulmonary thromboendarterectomy.

Key words

chronic thromboembolic pulmonary hypertension; pulmonary embolism; pulmonary hypertension; pulmonary thromboendarterectomy; venous thromboembolism

Abbreviation

CTEPH = chronic thromboembolic pulmonary hypertension

Natural History

Although complete anatomic recovery after acute pulmonary embolism may not occur, the natural history of acute pulmonary embolic disease under most circumstances involves sufficient thromboembolic resolution to restore normal pulmonary hemodynamics, gas exchange, and exercise tolerance. Chronic thromboembolic pulmonary hypertension (CTEPH), which occurs in a minority of patients following acute embolism, represents an alternate natural history. Although exact incidence figures are not available, it is likely, based on the number of embolic survivors and the number of patients referred for thromboendarterectomy, that CTEPH occurs in no more than 0.1 to 0.2% of patients who experience an embolic event.1 Survival without intervention is poor and, as in other forms of pulmonary hypertension, it is proportional to the degree of pulmonary hypertension and right ventricular dysfunction at the time of diagnosis. In one study, the 5-year survival rate was 30% when the mean pulmonary artery pressure was > 40 mm Hg and 10% when it was > 50 mm Hg.2 In another study, a mean pulmonary artery pressure > 30 mmHg appeared to serve as a threshold value portending a poor prognosis.3

Why certain patients experience incomplete thromboembolic embolic resolution has not been established. A defect in fibrinolytic activity has not been identified and the only identifiable thrombophilic tendency in patients referred for pulmonary thromboendarterectomy has been the presence of antiphospholipid antibodies and/or a lupus anticoagulant in approximately 10 to 20% of patients.4,5 In many patients presenting with CTEPH, the initial embolic event may have been subclinical, overlooked, or misdiagnosed. However, even in patients in whom the diagnosis of acute venous thromboembolism is made and appropriate therapy instituted, recent data would suggest that incomplete anatomic and hemodynamic recovery may be more common than previously suspected. In a review of 157 patients with symptomatic, acute pulmonary embolism from the THESEE (Tinzaparine ou Heparine Standard: Evaluations lÕEmbolie Pulmonaire) study, 104 patients (66%) had residual perfusion defects 3 months after the acute event. Of these, 13 patients (8.2%) had residual pulmonary vascular obstruction of ≥ 50% as determined by perfusion scanning.6

Given what appears to be a large number of patients with persistent postembolic pulmonary vascular obstruction, it also remains uncertain why only a relatively small number develop pulmonary hypertension and what factors determine the rate of progression of their disease. Although the overall extent of pulmonary vascular obstruction appears to play a central role, the effects of circulating vasoconstrictors, immune-related events, the development of a hypertensive pulmonary arteriopathy, or an individual genetic predisposition to pulmonary hypertension may contribute to this outcome.

Months to years may pass between the initial thromboembolic event and the onset of clinical decline. Diagnostic oversight following symptom onset, often of a prolonged duration, is also common. As a result, the diagnosis of CTEPH usually is not made until the degree of pulmonary hypertension is advanced, with most patients manifesting a pulmonary vascular resistance of > 600 dyneásácm-5. The pathophysiologic events responsible for progression of the pulmonary hypertension during this time frame remain uncertain. It is possible that in certain patients the hemodynamic and symptomatic decline is related to recurrent embolic events or in situ pulmonary artery thrombosis. However, in the overwhelming majority of patients with sequential perfusion scans available for review, the pulmonary hypertension has progressed in the absence of perfusion scan change, suggesting that the increasing pulmonary vascular resistance is arising from events in the distal pulmonary vascular bed rather than from obstruction of the central arteries. This premise is supported by lung biopsy findings obtained at the time of thromboendarterectomy that demonstrate changes in the microvasculature, similar to those seen in other forms of small-vessel pulmonary hypertension, distal to both obstructed and nonobstructed central arteries.7

Diagnostic delay appears to be related to various causes: the often nonspecific clinical presentation of the disease and, early in its natural history, its subtle physical examination findings; failure by practitioners to consider disorders of the pulmonary vascular bed in patients with unexplained dyspnea; a tendency to discount the possibility of chronic thromboembolic disease in the absence of a documented history of acute thromboembolism; and a lack of awareness of the disease entity by many physicians.

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