Mechanisms underlying failure to resolve thrombi in chronic thromboembolic pulmonary hypertension

Research project P 13834 Mechanisms of disease in CTEPH Irene LANG 11.10.1999 Abnormal thrombus formation and dissolution are associated with several cardiovascular disorders including atherosclerosis and both thromboembolic and hemorrhagic conditions. Research by the applicant and her collaborators over the past three years has resulted in the cloning of several known and unknown genes that were found to be differentially expressed in pulmonary artery wall and thrombotic pulmonary arterial occlusions of patients with chronic thromboembolic pulmonary hypertension. Most strikingly, several genes were identified that are involved in tissue lipid metabolism, e.g., apolipoprotein E receptor 2 (apoER2), lipoprotein lipase (LPL), the LDL receptor glycosylation protein LDL-C and a novel lipoprotein receptor molecule lacking a transmembrane domain. The current proposal is directed at a) searching for infectious agents that potentially induce LPL and subsequently, abnormal organizing growth in these vascular occlusions, at b) defining altered lipid metabolism in chronic pulmonary thromboemboli and chronic deep venous thrombi. A number of clinical observations (12-16) lend strong support to the hypothesis of an infectious origin of nonresolving pulmonary thromboemboli.

CTEPH is the result of single or recurrent pulmonary thromboemboli arising from sites of venous thrombosis. The natural history of pulmonary thromboemboli is to undergo total resolution, or resolution leaving minimal residua, with restoration of normal pulmonary hemodynamics. For reasons still unclear, thromboemboli in CTEPH patients fail to resolve and form endothelialized obstructions of the pulmonary vascular bed including the major branches. After an initial thromboembolic event that may be or may not be symptomatic the patients experience months to years of a `honeymoon period` without any clinical symptoms. Gradually, however, dyspnea on exertion develops. Clinical deterioration parallels the loss of right ventricular functional capacity. Venous thromboembolism can be documented in only 61% of patients, and evidence for recurrence is present in approximately 34%. Still, a large group of patients lack signs of past DVT at the time of diagnosis. Over the past four years efforts of our group have been concentrated on the identification of a plasma marker for chronic thromboembolic pulmonary hypertension. Such a protein would help in the diagnosis of this difficult disease. We investigated 111 consecutive patients diagnosed with CTEPH between April 1994 and December 2001 at the University of Vienna General Hospital, Austria, Department of Cardiology, a referral center for patients with pulmonary hypertension. Plasma FVIII and VWF antigen (VWF:Ag) levels were compared with values obtained from sex and age-matched healthy blood donors (n=82). The data show that FVIII>230IU/dl was more prevalent in CTEPH patients than in PAH patients and controls (p<0.0001). Because elevated FVIII does not confer a definitive pathologic solution of CTEPH, we have pursued another study over the past year directed at the identification of medical conditions conferring an increased risk of CTEPH. We have conducted a prospective case-control-study in 109 consecutive CTEPH patients and 187 consecutive individuals after a pulmonary thromboembolic event and discontinuation of oral anticoagulants who did not develop CTEPH during an observation period of 8434 months. In a multivariate analysis splenectomy, VA shunt and chronic inflammation remained independent risk factors for CTEPH in an unpublished study of 111 patients, with splenectomy increasing the likelihood of CTEPH 22-fold (p<0.0001), VA shunt 40-fold (p=0.0002), and chronic inflammation 17-fold (p<0.0001). In summary, these two studies have led to a new view of thrombosis. Thrombosis is no longer considered a plasmatic event that is limited in a timely fashion, but results from an imbalance of plasmatic factors and an abnormal proliferative response of cells of the vascular wall.