title: A novel mutation in the F5 gene (factor V Amsterdam) associated with bleeding independent of factor V procoagulant function.
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.
authors: Department of Experimental Vascular Medicine, and Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and.
authors: Marisa L R
authors: http://orcid.org/0000-0001-6473-7368
authors: ML
authors: Cunha
authors: Department of Experimental Vascular Medicine, and.
authors: Kamran
authors: K
authors: Bakhtiari
authors: Department of Experimental Vascular Medicine, and.
authors: Jorge
authors: J
authors: Peter
authors: Department of Experimental Vascular Medicine, and.
authors: J Arnoud
authors: JA
authors: Marquart
authors: Department of Experimental Vascular Medicine, and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands.
authors: Joost C M
authors: http://orcid.org/0000-0002-4198-6780
authors: JC
authors: Meijers
authors: Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and.
authors: Saskia
authors: http://orcid.org/0000-0002-1006-6420
authors: S
authors: Middeldorp
mesh_terms: D017398:Alternative Splicing; D025861:Blood Coagulation Disorders, Inherited / Q000097:blood / Q000235:genetics*; D004247:DNA / Q000235:genetics; D059472:Exome; D005165:Factor V / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000097:blood / Q000235:genetics; D008297:Male; D009154:Mutation; D009426:Netherlands; D010375:Pedigree; D010446:Peptide Fragments / Q000097:blood / Q000737:chemistry / Q000235:genetics; D013917:Thrombin / Q000096:biosynthesis
chemical_list: D008074:Lipoproteins; D010446:Peptide Fragments; C035876:factor V clotting antigen; C051928:lipoprotein-associated coagulation inhibitor; D005165:Factor V; D004247:DNA; D013917:Thrombin