Department of Experimental Vascular Medicine, and Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and.
Department of Experimental Vascular Medicine, and.
Blood. 2015 Mar 12;125(11):1822-5. doi: 10.1182/blood-2014-08-592733. Epub 2015 Jan 29.
We investigated a small Dutch family with a bleeding diathesis, prolonged prothrombin, and activated partial thromboplastin times, in whom no classifying diagnosis was made. The 2 affected relatives had severely decreased in vitro thrombin generation, and levels of tissue factor pathway inhibitor (TFPI) were strongly increased. To identify the genetic cause of the bleeding diathesis, we performed whole exome sequencing analysis of all living relatives. We found a novel gain-of-function mutation in the F5 gene (c.C2588G), which leads to an aberrant splicing of F5 and ultimately to a short factor V protein (missing 623 amino acids from the B domain), which we called factor V Amsterdam. Factor V Amsterdam binds to TFPI, prolonging its half-life and concentration. This is the second report of an association between a shorter form of factor V and increased TFPI levels, resulting in severely reduced thrombin generation and a bleeding tendency.
我们研究了一个有出血倾向、凝血酶原时间和活化部分凝血活酶时间延长的荷兰小家族，该家族未做出明确诊断。2 名受影响的亲属体外凝血酶生成严重减少，组织因子途径抑制剂 (TFPI) 水平显著升高。为了确定出血倾向的遗传原因，我们对所有在世的亲属进行了全外显子组测序分析。我们在 F5 基因中发现了一个新的功能获得性突变 (c.C2588G)，导致 F5 异常剪接，最终导致因子 V 蛋白变短（从 B 结构域缺失 623 个氨基酸），我们称之为因子 V 阿姆斯特丹。因子 V 阿姆斯特丹与 TFPI 结合，延长其半衰期和浓度。这是第二个报道短型因子 V 与 TFPI 水平升高相关的病例，导致严重的凝血酶生成减少和出血倾向。
