Lounes K C, Soria C, Mirshahi S S, Desvignes P, Mirshahi M, Bertrand O, Bonnet P, Koopman J, Soria J
Laboratoire Sainte Marie, Laboratoire de Biochimie A, and INSERM E 99-12, Hôtel-Dieu, Paris, France.
Blood. 2000 Nov 15;96(10):3473-9.
Congenital homozygous dysfibrinogenemia was diagnosed in a man with a history of 2 thrombotic strokes before age 30. His hemostatic profile was characterized by a dramatically prolonged plasma thrombin clotting time, and no clotting was observed with reptilase. Complete clotting of the abnormal fibrinogen occurred after a prolonged incubation of plasma with thrombin. The release of fibrinopeptides A and B by thrombin and of fibrinopeptide A by reptilase were both normal. Thrombin-induced fibrin polymerization was impaired, and no polymerization occurred with reptilase. The polymerization defect was characterized by a defective site "a," resulting in an absence of interaction between sites A and a, indicated by the lack of fragment D(1) (or fibrinogen) binding to normal fibrin monomers depleted in fibrinopeptide A only (Des-AA fm). By SDS-PAGE, the defect was detected on the gamma-chain and in its fragment D(1). The molecular defect determined by analysis of genomic DNA showed a single base change (A-->T) in exon VIII of the gamma-chain. The resulting change in the amino acid structure is gamma 330 aspartic acid (GAT) --> valine (GTT). It is concluded that the residue gamma-Asp(330) is essential for the normal functioning of the polymerization site a on the fibrinogen gamma-chain.
一名在30岁前有2次血栓性中风病史的男性被诊断为先天性纯合子异常纤维蛋白原血症。他的止血特征表现为血浆凝血酶凝血时间显著延长，用蛇毒凝血酶检测时未观察到凝血现象。血浆与凝血酶长时间孵育后，异常纤维蛋白原完全凝血。凝血酶释放纤维蛋白肽A和B以及蛇毒凝血酶释放纤维蛋白肽A均正常。凝血酶诱导的纤维蛋白聚合受损，蛇毒凝血酶不能诱导聚合。聚合缺陷的特征是存在缺陷位点“a”，导致位点A和a之间缺乏相互作用，这表现为片段D(1)（或纤维蛋白原）不能与仅缺乏纤维蛋白肽A的正常纤维蛋白单体（Des-AA fm）结合。通过SDS-PAGE分析，在γ链及其片段D(1)上检测到缺陷。通过对基因组DNA的分析确定的分子缺陷显示γ链外显子VIII中有一个单碱基变化（A→T）。氨基酸结构的相应变化是γ330天冬氨酸（GAT）→缬氨酸（GTT）。得出的结论是，γ-Asp(330)残基对于纤维蛋白原γ链上聚合位点a的正常功能至关重要。
