The natural history of acute and chronic thromboembolic disease: the search for the missing link.

In the USA, and worldwide, acute venous thromboembolism remains a major cause of morbidity and mortality. It is estimated that 600,000 episodes of acute pulmonary embolism occur each year in the USA that result in 50,000±100,000 deaths [1]. Despite the magnitude of the disease and extensive investigative efforts into its pathogenesis, diagnosis and therapy over the last four decades (1960±2000), the late natural history of those who survive an embolic event has not been well characterized. Data based predominately on clinical follow-up suggest that thromboembolic resolution with restoration of normal gas exchange and exercise tolerance occur in the overwhelming majority of patients who experience an acute embolic event [2]. Characterization of the anatomic and haemodynamic outcomes following acute thromboembolism, however, has been far less comprehensive [3]. Serial angiographic studies have been limited to a relatively small number of patients. Even in these, however, only partial resolution is apparent in many patients as long as 21 days after the acute event [4, 5]. When serial perfusion scans have been performed, ~15% to 25% of patients show only partial resolution as defined by persistent abnormal perfusion patterns on lung scans performed several months after the primary embolic event [6, 7]. These figures may misrepresent the degree of thromboembolic resolution since perfusion scanning in chronic thromboembolic disease may understate the actual extent of angiographic obstruction [8]. The frequency with which evidence of prior pulmonary embolism can be found on careful dissection of the pulmonary arteries suggests that asymptomatic events may occur commonly and that complete thromboembolic resolution following an acute embolic event may represent the exception rather than the rule. Haemodynamic follow-up data following acute thromboembolism have been equally sparse. Early resolution of pulmonary vascular obstruction occurs by two mechanisms: mechanical changes in thrombus location and endogenous thrombolysis. Following these early events, organization and recanalization further alleviate the degree of pulmonary vascular obstruction [1]. As noted previously, most sequential data regarding resolution in humans are based on perfusion scans, not angiographic or haemodynamic data. Although reperfusion can occur with restoration of as little as 20% of the normal luminal diameter, these areas may continue to serve as high resistance areas that contribute to elevations of pulmonary artery pressure. Significant organized residuals, and therefore abnormal pulmonary haemodynamics at rest or with exercise, may persist in patients whose scans return to normal. That this may be the case is suggested by the experience with pulmonary angioscopy at University of California, San Diego (UCSD) Medical Center (CA, USA). Evidence of web formation, recanalization and luminal narrowing can be encountered in areas of vascular distribution associated with normal angiographic and perfusion scan findings. How often such residuals persist and how often mild degree of postembolic, subclinical pulmonary hypertension occurs is not known. Recent information, however, has shed some light on the question. In a recent study, 1year echocardiographic follow-up and 5-year clinical follow-up of 78 patients hospitalized with acute pulmonary embolism were reported [9]. An early dynamic phase followed by a protracted stable phase of pulmonary artery pressure decline after an acute thromboembolic event was identified. The time to achieve the stable phase was 38 days and was independent of whether the therapeutic intervention was thrombolytic therapy or heparin. In patients with a pulmonary artery systolic pressure >50 mmHg at the time of diagnosis of the acute episode, the risk for persistent pulmonary hypertension increased three-fold; four patients (5.1%) developed chronic pulmonary hypertension and three subsequently underwent successful pulmonary thromboendarterectomy. In contrast to acute venous thromboembolic disease, in which the early natural history has been well defined, the early haemodynamic progression of chronic thromboembolic pulmonary hypertension (CTEPH) remains uncertain [10]. The symptomatic history has been well described [11]. Following a documented venous thromboembolic event, symptomatic recovery occurs although often not to a level equivalent to that prior to the acute event. In patients without a documented acute thromboembolic event, many can provide a history consistent with that diagnosis. They may describe an episode of pleurisy, lower extremity muscle strain, or prolonged, atypical pneumonia. Or, they may describe a hospitalization or surgical procedure from which they never fully recovered. That an episode of venous thromboembolism is not diagnosed, or is misdiagnosed, is not surprising given recent data that confirm the often subtle clinical presentation of a venous thromboembolic event and the frequency with which misdiagnosis occurs [12, 13]. Following a period of clinical University of California, San Diego (UCSD), USCD Medical Center, Pulmonary and Critical Care Division, San Diego, CA, USA.