Genetic Predisposition to Bleeding during Oral Anticoagulant Therapy: Evidence for Common Founder Mutations (FIXVal-10 and FIXThr-10) and an Independent CpG Hotspot Mutation (FIXThr-10)

J. Oldenburg; K. Kriz; W. A. Wuillemin; F. E. Maly; A. von Felten; A. Siegemund; D. M. Keeling; P. Baker; K. Chu; B. A. Konkle; B. Lämmle; T. Albert; the Study Group on Hereditary Warfarin Sensitivity

doi:10.1055/s-0037-1615604

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2001; 85(03): 454-457
DOI: 10.1055/s-0037-1615604

Review Article

Schattauer GmbH

Genetic Predisposition to Bleeding during Oral Anticoagulant Therapy: Evidence for Common Founder Mutations (FIXVal-10 and FIXThr-10) and an Independent CpG Hotspot Mutation (FIXThr-10)

Authors

J. Oldenburg

¹Institute of Experimental Haematology and Transfusion Medicine, University of Bonn, Bonn, Germany

²Institute of Human Genetics, University of Würzburg, Biozentrum, Würzburg, Germany
K. Kriz

³Inselspital/University Hospital, Central Haematology Laboratory, Bern, Switzerland
W. A. Wuillemin

³Inselspital/University Hospital, Central Haematology Laboratory, Bern, Switzerland
F. E. Maly

⁴Institute of Clinical Chemistry, University Hospital Zürich, Zürich, Switzerland
A. von Felten

⁵Thrombosis and Haemostasis Laboratory, Zürich, Switzerland
A. Siegemund

⁶Department of Internal Medicine, University of Leipzig, Leipzig, Germany
D. M. Keeling

⁷Department of Haematology, The John Radcliffe Hospital, Oxford, United Kingdom
P. Baker

⁷Department of Haematology, The John Radcliffe Hospital, Oxford, United Kingdom
K. Chu

⁸Division of Hematology, 310A Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
B. A. Konkle

⁹Division of Hematology, University of Pennsylvania School of Medicine, PMC, MAB 103, Philadelphia, PA, USA
B. Lämmle

³Inselspital/University Hospital, Central Haematology Laboratory, Bern, Switzerland
T. Albert

²Institute of Human Genetics, University of Würzburg, Biozentrum, Würzburg, Germany

the Study Group on Hereditary Warfarin Sensitivity

Abstract

Summary

The recent discovery of five patients with coumarin sensitive FIX-variants due to a missense mutation in the FIX propeptide, either Ala-10Val or Ala-10Thr, has highlighted a novel type of genetic predisposition to bleeding during oral anticoagulant therapy (OAT). In the present study, we report six additional patients with such FIX variants. Haplotype analysis of FIX polymorphisms revealed a founder effect in the five German and Swiss patients with the Val-10 variant. Also, four Thr-10 variants detected in Germany, Switzerland and Great Britain derived from a common founder. Two Thr-10 variants from USA showed an independent de novo origin at a CpG dinucleotide that in general represents a mutation hotspot. These findings implicate the existence of additional subjects with corresponding variants in the populations of various countries. Even though the rare occurrence of these variants does not justify a general aPTT screening during OAT, it is recommended to monitor each bleeding event during OAT in males in order to exclude a genetic predisposition to bleeding by means of the following testing strategy: a) aPTT-testing in each bleeding complication of male patients during OAT, b) if aPTT is disproportionately prolonged, determination of FIX:C, and c) if FIX:C is disproportionately decreased as compared to FII:C, FVII:C and FX:C, sequencing of exon 2 of the FIX gene. This strategy will provide a cost-effective and safe procedure to identify patients that carry the FIX variants. Moreover, such a strategy accumulates data about the prevalence of these FIX mutations in a given population.

Keywords

Factor IX gene - warfarin sensitivity - oral anticoagulation - founder effect

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Referenzen

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