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


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.

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

Author information




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.

Corresponding author

Correspondence to Johannes Oldenburg.

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The authors declare that they have no conflict of interest.

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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.

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

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Pezeshkpoor, B., Czogalla, K.J., Caspers, M. et al. Variants in FIX propeptide associated with vitamin K antagonist hypersensitivity: functional analysis and additional data confirming the common founder mutations. Ann Hematol 97, 1061–1069 (2018).

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  • FIX
  • Propeptide
  • F9 Thr37
  • F9 Val37
  • Hypersensitivity to VKA