Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of γ Ala327Thr:: formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism
Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of γ Ala327Thr:: formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism
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DOI：
10.1182/blood-2003-07-2569
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发表时间：
2004-04-15
期刊：
影响因子：
20.3
通讯作者：
Sakata, Y
中科院分区：
文献类型：
--
作者：
Hamano, A;Mimuro, J;Sakata, Y
在一名43岁的男性复发性血栓栓塞中发现了嗜血栓性纤维蛋白原异常东京V。基于对患者纤维蛋白原基因、异常纤维蛋白原肽的氨基酸序列和去糖基化实验的分析，显示纤维蛋白原Tokyo V具有γ Ala 327 Thr的氨基酸取代和γ Asn 325处可能的额外糖基化，因为该突变赋予了Winked糖基化共有序列Asn-X-Thr。该突变导致功能受损和低纤维蛋白原血症（纤维蛋白原减少）。来源于患者纤维蛋白原的纤维蛋白单体的聚合严重受损，在钙的存在下进行部分校正，导致非常低的凝血酶原时间。此外，在因子XIII和钙的存在下，凝血酶处理后形成大量可溶性交联纤维蛋白。然而，东京V衍生的纤维蛋白是抵抗组织纤溶酶原激活剂（tPA）催化的纤溶酶消化降解。Tokyo V纤维蛋白的结构出现严重扰动，因为在缠结的纤维蛋白网络内部存在大孔，并且纤维末端在边界处。总之，这些数据表明，东京V纤维蛋白凝块是脆弱的，因此，纤维蛋白溶解抗性的不溶性纤维蛋白和可溶性纤维蛋白聚合物可能会释放到循环中，部分原因是患者的复发性栓塞发作。(C)2004年，美国血液学会。
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 gamma Ala327Thr and possibly extra glycosylation at gamma Asn325 because the mutation confers the Winked 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. (C) 2004 by The American Society of Hematology.