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Annals of Hematology

, Volume 97, Issue 6, pp 1061–1069 | Cite as

Variants in FIX propeptide associated with vitamin K antagonist hypersensitivity: functional analysis and additional data confirming the common founder mutations

  • Behnaz Pezeshkpoor
  • Katrin J. Czogalla
  • Michael Caspers
  • Ann-Cristin Berkemeier
  • Kerstin Liphardt
  • Suvoshree Ghosh
  • Marco Kellner
  • Silvia Ulrich
  • Anna Pavlova
  • Johannes Oldenburg
Original Article

Abstract

One of the most common and unwanted side effects during oral anticoagulant therapy (OAT) is bleeding complications. In rare cases, vitamin K antagonist (VKA)-related bleeding events are associated with mutations affecting the F9 propeptide at amino acid position 37 due to a substitution of alanine to either valine or threonine. Based on our actual cohort of 18 patients, we update the knowledge on this rare phenotype and its origin. A founder mutation for both variants was reconfirmed by haplotype analysis of intronic and extragenic short tandem repeat (STR) polymorphisms with a higher prevalence in Switzerland than in other regions of Europe. Screening of healthy individuals for the presence of these F9 gene mutations did not identify any of these variants, thus proving the rare occurrence of this genotype. Furthermore, both variants were expressed in vitro and warfarin dose responses were studied. Our warfarin dose response analysis confirmed higher sensitivity of both variants to warfarin with the effect being more apparent for Ala37Thr. Thus, although F9 propeptide mutation-associated hypersensitivity to VKA is a rare phenomenon, awareness towards this bleeding phenotype is important to identify patients at risk.

Keywords

FIX Propeptide F9 Thr37 F9 Val37 Hypersensitivity to VKA 

Notes

Author contributions

BP, KJC, and JO designed the study. MC, MK, AC, and KL performed the experiments. BP, KJC, MC, MK, SG, KL, AP, and JO analyzed and interpreted the data. SU revised the manuscript and provided the clinical data of the patients. BP, KJC, and MC wrote the manuscript.

Funding information

This work was supported by a grant from the Stiftung Hämotherapie-Forschung to Michael Caspers.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individuals participating in the study.

Supplementary material

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277_2018_3264_MOESM4_ESM.docx (50 kb)
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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Behnaz Pezeshkpoor
    • 1
    • 2
  • Katrin J. Czogalla
    • 1
    • 2
  • Michael Caspers
    • 1
    • 2
  • Ann-Cristin Berkemeier
    • 1
    • 2
  • Kerstin Liphardt
    • 1
    • 2
  • Suvoshree Ghosh
    • 1
    • 2
  • Marco Kellner
    • 3
  • Silvia Ulrich
    • 4
  • Anna Pavlova
    • 1
    • 2
  • Johannes Oldenburg
    • 1
    • 2
  1. 1.Institute of Experimental Haematology and Transfusion MedicineUniversity Clinic BonnBonnGermany
  2. 2.Center for Rare Diseases Bonn (ZSEB)University Clinic BonnBonnGermany
  3. 3.Zahnarztpraxis Dr. KellnerWürzburgGermany
  4. 4.Clinic of PulmonologyUniversity Hospital of ZürichZürichSwitzerland

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