Central Immunology Laboratory, Semmelweis University, Budapest, Hungary.
J Thromb Haemost. 2010 Jun;8(6):1273-80. doi: 10.1111/j.1538-7836.2010.03753.x. Epub 2010 Jan 17.
von Willebrand disease (VWD) Vicenza is characterized by low plasma von Willebrand factor (VWF) levels, the presence of ultra-large (UL) VWF multimers and less prominent satellite bands on multimer gels, and the heterozygous amino acid substitution R1205H in the VWF gene. The pathogenesis of VWD Vicenza has been elusive. Accelerated clearance is implicated as a cause of low VWF level.
We addressed the question, whether the presence of ultra-large multimers is a cause, or a result of accelerated VWF clearance, or whether it is an unrelated phenomenon.
PATIENTS/METHODS: We studied the detailed phenotype of three Hungarian patients with VWD Vicenza, expressed the mutant VWF-R1205H in 293T cells and developed a mathematical model to simulate VWF synthesis and catabolism.
We found that the half-life of VWF after DDAVP was approximately one-tenth of that after the administration of Haemate P, a source of exogenous wild-type (WT) VWF (0.81 + or - 0.2 vs. 7.25 + or - 2.38 h). An analysis of recombinant mutant VWF-R1205H showed that the biosynthesis and multimer structure of WT and mutant VWF were indistinguishable. A mathematical model of the complex interplay of VWF synthesis, clearance and cleavage showed that decreasing VWF half-life to one-tenth of normal reproduced all features of VWD Vicenza including low VWF level, ultra-large multimers and a decrease of satellite band intensity.
We conclude that accelerated clearance alone may explain all features of VWD Vicenza.
血管性血友病（VWD）Vicenza 的特点是血浆血管性血友病因子（VWF）水平降低，存在超大（UL）VWF 多聚体，多聚体凝胶上卫星带不明显，VWF 基因存在杂合氨基酸取代 R1205H。VWD Vicenza 的发病机制一直难以捉摸。加速清除被认为是 VWF 水平降低的原因。
我们探讨了超大多聚体的存在是加速 VWF 清除的原因、结果还是无关现象。
患者/方法：我们研究了三名匈牙利 VWD Vicenza 患者的详细表型，在 293T 细胞中表达突变型 VWF-R1205H，并开发了一个数学模型来模拟 VWF 的合成和代谢。
我们发现 DDAVP 后 VWF 的半衰期大约是 Haemate P（外源性野生型（WT）VWF 的来源）后半衰期的十分之一（0.81 +或-0.2 与 7.25 +或-2.38 h）。对重组突变型 VWF-R1205H 的分析表明，WT 和突变型 VWF 的生物合成和多聚体结构无法区分。VWF 合成、清除和裂解复杂相互作用的数学模型表明，将 VWF 半衰期降低至正常的十分之一可重现 VWD Vicenza 的所有特征，包括 VWF 水平降低、超大多聚体和卫星带强度降低。
我们得出结论，仅加速清除就可以解释 VWD Vicenza 的所有特征。
