STUDIES ON THE PATHOPHYSIOLOGY OF THROMBOEMBOLIC DISEASES WITH SPECIAL REFERENCE TO THE UNDERLYING IMPAIRED BLOOD COAGULATION AND ITS REGULATION

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1. Studies on the hereditary dysfibrinogens associated with thrombosis and/or bleeding In fibrinogen (Fbg) Osaka VI, a hereditary dysfibrinogen derived from a 36-year-old woman with a history of severe bleeding on two childbirths, we have identified an exchange of T to A in the stop codon (TAG) of the fibrinogen Bβ-chain gene leading to formation of a codon for Lys (AAG). Thus, 12 amino acid residues are translated to elongate the aberrant Bβ-chain and indeed, this extension has been confirmed by sequence analysis. There is a Cys residue next to the new carboxyl-terminus, which forms a disulfide bridge with its counterpart in another dysfibrinogen molecule. Thus, two types of end-linked Fbg-dimers exist in the patient's Fbg, i.e., a bilayer dimer end-linked at both ends and a longitudinally aligned dimer end-linked at either one of the two carboxyl-terminal ends. These dimers had been predicted by SDS-PAGE run under non-reducing conditions, where two molecular species, i.e., a normal s … More ized and a double-sized Fbg species had been visualized.By transmission electron microscopy, the fibrin fibers appear extremely thin but the fibrin networks are highly branched and compact as compared with those of normal fibrin clots. We thus hypothesized that the abnormal branching may occur at the points in the double-stranded fibrin proitofibrils, where the abnormal dimeric molecules are incorporated. Furthermore, the Osaka VI fibrin clots are mechanically readily compressible leading to form very fragile fibrin clots. These fibrin clots may fail to exert their hemostatic function and thereby lead to easy bleeding (Blood 96(12) : 3779-3785, 2000). These findings seem to be comparable to those of Fbg Marburg associated with thrombosis besides bleeding after surgery. Namely, this dysfibringen also forms fine fibrin fibers and compact fibrin networks, but the fibrin fibers are highly resistant against plasmin, accounting for thromboembolic complications (Blood 91(9) : 3282-3288, 1999).We have also studied the role of oligosacharides linked to Asn residue due to formation of a new glycosylation sequence of Asn-X-Thr/Ser in Fbgs Asahi and Lima (Ann NY Acad Sci, in press). Matsuda, the chief researcher, had chances to review these data at several international congresses and symposia (see the attached publication list).2. Other studies1) We have produced a monoclonal antibody, IF-123, that specifically recognizes elastase-digests of human fibrinogen/fibrin, and its epitope determination and clinical application have been successfully attempted (Blood 96(5) : 1721-1728, 2000).2) A novel strategy for the tumor angiogenesis-targeted gene therapy has been established by generation of angiostatin from endogenous plasminogen by protease gene transsfer in mice (Cancer Gene Therapy 7(5) : 589-596, 2000). Less