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.
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Authors | Marisa L R Cunha, Kamran Bakhtiari, Jorge Peter, J Arnoud Marquart, Joost C M Meijers, Saskia Middeldorp |
Journal | Blood
(Blood)
Vol. 125
Issue 11
Pg. 1822-5
(Mar 12 2015)
ISSN: 1528-0020 [Electronic] United States |
PMID | 25634741
(Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2015 by The American Society of Hematology. |
Chemical References |
- Lipoproteins
- Peptide Fragments
- factor V clotting antigen
- lipoprotein-associated coagulation inhibitor
- Factor V
- DNA
- Thrombin
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Topics |
- Alternative Splicing
- Blood Coagulation Disorders, Inherited
(blood, genetics)
- DNA
(genetics)
- Exome
- Factor V
(chemistry, genetics, metabolism)
- Female
- Humans
- Lipoproteins
(blood, genetics)
- Male
- Mutation
- Netherlands
- Pedigree
- Peptide Fragments
(blood, chemistry, genetics)
- Thrombin
(biosynthesis)
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