Marchi Rita, Carvajal Zoila, Meyer Michael, Soria Jeannette, Ruiz-Saez Arlette, Arocha-Piñango Carmen Luisa, Weisel John W
Centro de Medicina Experimental, Instituto Venezolano de Investigaciones Científicas, Laboratorio de Hemostasia IVIC, Apartado 21827, Caracas, República Bolivariana de Venezuela.
Thromb Res. 2006;118(5):637-50. doi: 10.1016/j.thromres.2005.10.016. Epub 2006 Jan 9.
Fibrinogen Guarenas is a dysfibrinogenemia with a nonsense mutation at G4731T that causes an Aalpha-chain truncation at Ser 466. This abnormal fibrinogen is associated with a bleeding diathesis, severe in the proposita and mild in one brother, even though the fibrinogen levels in plasma are normal. All other family members are asymptomatic. Fibrinogens from the proposita and one family member, the mother of the proposita, both heterozygous for the mutation, were studied. Turbidity curves of fibrin polymerization showed that the lateral association of protofibrils was impaired and the maximum rate of polymerization was slightly diminished. The binding of albumin to fibrinogen was increased compared to control due to the presence of a free sulfhydryl group because of the missing disulphide bridge between Aalpha-Cys 442-472 in the mutated molecules. The abnormal fibrinogen formed much less alpha-polymer, and gamma-dimer formation was delayed compared to the control. Plasminogen activation by t-PA in the presence of fibrin was decreased. When Guarenas clots were perfused with fibrinolytic enzymes, clot degradation was retarded. Clot structure studied by confocal 3D microscopy showed that the fibrin network was dense, made up of thin and highly branched fibers, which accounted for the decreased flow rates by buffer permeation and increased rigidity of the fibrin clots, measured using a torsion pendulum. It seems that the increased clot rigidity, decreased porosity, hypofibrinolysis and t-PA induced fibrinolysis, by itself are not necessarily associated with thrombotic disorders in dysfibrinogenemia.
瓜雷纳斯纤维蛋白原是一种异常纤维蛋白原血症，在G4731T处存在无义突变，导致αA链在Ser 466处截断。这种异常纤维蛋白原与出血素质有关，先证者病情严重，其一个兄弟病情较轻，尽管血浆中的纤维蛋白原水平正常。所有其他家庭成员均无症状。对先证者和一名家庭成员（先证者的母亲，均为该突变的杂合子）的纤维蛋白原进行了研究。纤维蛋白聚合的浊度曲线表明，原纤维的横向缔合受损，聚合的最大速率略有降低。由于突变分子中Aα-Cys 442-472之间缺少二硫键，存在游离巯基，与对照相比，白蛋白与纤维蛋白原的结合增加。与对照相比，异常纤维蛋白原形成的α聚合物少得多，γ二聚体的形成延迟。在纤维蛋白存在的情况下，t-PA对纤溶酶原的激活作用降低。用纤维蛋白溶解酶灌注瓜雷纳斯凝块时，凝块降解受到阻碍。通过共聚焦3D显微镜研究凝块结构表明，纤维蛋白网络致密，由细且高度分支的纤维组成，这解释了缓冲液渗透导致的流速降低以及使用扭摆测量的纤维蛋白凝块硬度增加。似乎凝块硬度增加、孔隙率降低、纤维蛋白溶解不足以及t-PA诱导的纤维蛋白溶解本身不一定与异常纤维蛋白原血症中的血栓形成疾病相关。
