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Blood, 15 April 2004, Vol. 103, No. 8, pp. 3045-3050.
Prepublished online as a Blood First Edition Paper on January 8, 2004; DOI 10.1182/blood-2003-07-2569.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of  Ala327Thr: formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism
Akiei Hamano,
Jun Mimuro,
Motonori Aoshima,
Takeyoshi Itoh,
Noboru Kitamura,
Susumu Nishinarita,
Katsuhiro Takano,
Akira Ishiwata,
Yuji Kashiwakura,
Kazuki Niwa,
Tomoko Ono,
Seiji Madoiwa,
Teruko Sugo,
Michio Matsuda, and
Yoichi Sakata
From the Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical School, Tochigi-ken, Japan; the Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan; and the Department of Internal Medicine, Akiru General Municipal Hospital, Tokyo, Japan.
Thrombophilic dysfibrinogen Tokyo V was identified in a 43-year-old man with recurrent thromboembolism. Based on analyses of the patient fibrinogen genes, the amino acid sequence of the aberrant fibrinogen peptide, and deglycosylation experiments, fibrinogen Tokyo V was shown to have an amino acid substitution of  Ala327Thr and possibly extra glycosylation at Asn325 because the mutation confers the N-linked glycosylation consensus sequence Asn-X-Thr. The mutation resulted in impaired function and hypofibrinogenemia (hypodysfibrinogen). Polymerization of fibrin monomers derived from patient fibrinogen was severely impaired with a partial correction in the presence of calcium, resulting in very low clottability. Additionally, a large amount of soluble cross-linked fibrin was formed upon thrombin treatment in the presence of factor XIII and calcium. However, Tokyo V–derived fibrin was resistant to degradation by tissue plasminogen activator (tPA)–catalyzed plasmin digestion. The structure of Tokyo V fibrin appeared severely perturbed, since there are large pores inside the tangled fibrin networks and fiber ends at the boundaries. Taken together, these data suggest that Tokyo V fibrin clots are fragile, so that fibrinolysis-resistant insoluble fibrin and soluble fibrin polymers may be released to the circulation, partly accounting for the recurrent embolic episodes in the patient. (Blood. 2004;103:3045-3050)
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