In vitro correction of the abnormal multimeric structure of von Willebrand factor in type IIa von Willebrand's disease.
In vitro correction of the abnormal multimeric structure of von Willebrand factor in type IIa von Willebrand's disease.
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IIa 型冯维勒布兰德病中冯维勒布兰德因子异常多聚体结构的体外校正。
DOI：
10.1073/pnas.82.17.5968
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发表时间：
1985
影响因子：
11.1
通讯作者：
M. Rick
中科院分区：
文献类型：
--
作者：
Harvey R. Gralnick;S. Williams;L. McKeown;Pascal MAISONNEUVEt;Christine JENNEAUt;Yvette SULTANt;M. Rick
IIa型血管性血友病（vWd）的特征是血浆和血小板血管性血友病因子（vWf）的最大多聚体缺失和中等大小多聚体减少，以及这些患者的富血小板血浆对利托那的反应减弱。最近证实的其他异常包括存在异常的vWf三联体结构。我们研究了三名患有这种形式vWd的患者的血浆和血小板，发现他们的血浆和血小板都表现出先前描述的异常。由于这些患者vWf的多聚体结构的异质性，我们考虑了合成后事件可能修饰了vWf的可能性。当在5 mM EDTA或5 mM EDTA/亮抑酶肽/N-乙基马来酰亚胺中采集血液时，血浆和血小板vWf的异常多聚体结构部分正常化，因为中间和最大vWf多聚体增加，异常多聚体结构不再明显，并且最快迁移条带（仅在IIa型vWd血浆和血小板中观察到的异常）消失。负责这种降解的酶活性可被归类为钙依赖性蛋白酶。对正常受试者和这些患者的血小板裂解物孵育的正常放射性标记vWf的研究显示，通过正常vWf的降解评估，患者的血小板不含增加量的钙依赖性蛋白酶活性。这些数据表明，患者与IIa型vWd合成异常vWf蛋白，这是在体外蛋白水解降解和蛋白水解降解，可以发挥重要作用，通过修改血浆和血小板vWf多聚体结构的表型表达的vWd。
Type IIa von Willebrand's disease (vWd) has been characterized by the absence of the largest and a reduction in the intermediate-sized multimers of the plasma and platelet von Willebrand factor (vWf) and by the diminished response of the platelet-rich plasma of these patients to ristocetin. Other recently demonstrated abnormalities include the presence of an abnormal triplet structure of vWf. We have studied the plasma and platelets from three patients with this form of vWd and have found that both their plasma and platelets manifest the previously described abnormalities. Because of the heterogeneity of the multimeric structure of the vWf in these patients, we considered the possibility that postsynthetic events may have modified the vWf. When blood was collected in 5 mM EDTA or 5 mM EDTA/leupeptin/N-ethylmaleimide, the abnormal multimeric structure of the plasma and platelet vWf was partially normalized in that the intermediate and the largest vWf multimers were increased, the abnormal multimer structure was no longer as apparent, and the fastest migrating band (an abnormality seen only in the type IIa vWd plasma and platelets) disappeared. The enzymatic activity responsible for this degradation can be classified as a calcium-dependent protease. Studies of normal radiolabeled vWf incubated with platelet lysates from normal subjects and these patients revealed that the patients' platelets did not contain increased amounts of calcium-dependent protease activity as assessed by degradation of normal vWf. These data suggest that patients with type IIa vWd synthesize an abnormal vWf protein that is susceptible to in vitro proteolytic degradation and that proteolytic degradation can play a significant role in the phenotypic expression of vWd by modifying the plasma and platelet vWf multimeric structure.