Studies on pathophysiology of surgical thromboembolic diseases with special reference to impaired regulation of blood coagulation.

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during the two-year term of this research project, We studied the mechanisms of blood coagulation and its regulation involved in the pathogenesis of surgical thromboembolic diseases. We analyzed 5 families with an antithrombin III (AT III) deficiency, 1 with a molecular abnormality of AT III, 3 with a protein C (PC) deficiency, 1 with an abnormal PC and 14 with a congenital dysfibrinogenemia. The molecular abnormality of AT III was found to have a conformation and antigenic determinants distinctly different from those of normal molecules although its molecular weight was identical with normal one. This structural perturbation apparently brought about defective neutralization of activated coagulation factors including thrombin, and impaired binding to heparin and vascular endothelial cell surfaces. This abnormal molexules thus fails to regulate thrombus formation. As to an abnormal PC designated as PC-Tochigi found in an 18-year-old thrombophilic female, we identified an Arg to Trp subs … More titution at position 12 of the heavy chain by gene analysis. Since this position is involved in the cleavage site by a physiological activator, thrombin, the abnormal PC could not be converted to an enzyme to exert regulation of thrombus formation. This abnormal molecule is, to our best knowledge, the first abnormal molecule of PC heretofore reported and elucidated at the molecular level in relation to defective functions. Since the incidences for thromboembolic diseases including deep vein thrombosis and pulmonary embolism are significantly higher in these patients, systemic surveys for these hereditary abnormalities of regulatory proteins of blood coagulation seem to be urgent. Concerning abnormal fibrinogens, we could pinpoint amino acid substitutions in all the 14 families, i.e., 4 cases of <gamma>Arg 275 to Cys, 2 each of A <alpha> Arg 16 to his and <gamma> Arg 275 to His, and 1 each of A <alpha> Pro 18 to Leu, <gamma>Asn 308 to Lys, <gamma>Met 310 to Thr and <gamma>Asp 330 to Tyr. Dysfunctional fibrinogens may not necessarily be related to thromboembolic or bleeding tendencies clinically, but informations obtained on these abnormal molecules were certainly of great help to better understand the mechanisms of thrombus formation at the molecular as well as clinical levels. Monoclonal antibodies against various plasma and endothelial cell-derived proteins were prepared and characterized. Many of them have been utilized for the analyses of hereditary abnormalities as well as acquired diseases related to thromboembolism and their usefulness was verified and reported as listed in the attached biblioqraphy. Less