TISSUE FACTOR IS ASSOCIATED WITH THE NONBACTERIAL THROMBOTIC ENDOCARDITIS INDUCED BY A HYPOBARIC HYPOXIC ENVIRONMENT IN RATS

High-altitude hypoxia causes a hypercoagulable state. In our previous study on the blood coagulation system in rats, nonbacterial thrombotic endocarditis (NBTE) developed after 4-12 weeks' exposure to the equiv alent of 5500 m in altitude. We hypothesized that TF (tissue factor)-p roducing cells in the cardiac valves might be induced by the hypobaric hypoxic environment (HHE) and then trigger NBTE, A total of 170 male Wistar rats were housed in a chamber at the equivalent of 5500 m altit ude for 1-12 weeks. We measured TF activity in the plasma and studied morphological changes in Introduction the mitral valves using immunohi stochemical and immunoelectrical methods for TF protein and in situ hy bridization for TF mRNA. After 4 weeks or more of exposure to HHE, 28 of the 56 surviving rats had developed NBTE. After 4-8 weeks' exposure to HHE, the plasma TF activity level was significantly higher than in control rats. There was a significant correlation between plasma TF a ctivity and the incidence of NBTE. After 1 weeks' exposure to HHE, imm unoreactivity for TF protein was detected in foamy macrophages and str omal cells in the cardiac valves. In rats with NBTE, TF protein was pr esent in foamy macrophages and spindle stromal cells and focally prese nt in the extracellular matrix. TF mRNA was detected in some foamy mac rophages within the thrombus, TF protein was localized to the rough en doplasmic reticulum and plasma membrane of many macrophages, some fibr oblasts, and a few endocardial cells. TF is associated with the pathog enesis of the NBTE induced by exposure to HHE. The accumulation of TF- producing macrophages during exposure to HHE may be responsible for in itiating thrombus formation.