A novel mutation in the F5 gene (factor V Amsterdam) associated with bleeding independent of factor V procoagulant function

Marisa L. R. Cunha, Kamran Bakhtiari, Jorge Peter, J. Arnoud Marquart, Joost C. M. Meijers, Saskia Middeldorp

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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
Original languageEnglish
Pages (from-to)1822-1825
JournalBlood
Volume125
Issue number11
DOIs
Publication statusPublished - 2015

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