Variants in FIX propeptide associated with vitamin K antagonist hypersensitivity: functional analysis and additional data confirming the common founder mutations
- 1 Downloads
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.
KeywordsFIX Propeptide F9 Thr37 F9 Val37 Hypersensitivity to VKA
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.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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 was obtained from all individuals participating in the study.
- 1.Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D’Angelo A, Pengo V, Erba N, Moia M, Ciavarella N, Devoto G, Berrettini M, Musolesi S (1996) Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy Lancet 348(9025):423–428PubMedGoogle Scholar
- 9.Harbrecht U, Oldenburg J, Klein P, Weber D, Rockstroh J, Hanfland P (1998) Increased sensitivity of factor IX to phenprocoumon as a cause of bleeding in a patient with antiphospholipid antibody associated thrombosis. J Intern Med 243(1):73–77. https://doi.org/10.1046/j.1365-2796.1998.00252.x CrossRefPubMedGoogle Scholar
- 10.Oldenburg J, Kriz K, Wuillemin WA, Maly FE, von Felten A, Siegemund A, Keeling DM, Baker P, Chu K, Konkle BA, Lammle B, Albert T (2001) 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). Thromb Haemost 85(3):454–457PubMedGoogle Scholar
- 11.Ulrich S, Brand B, Speich R, Oldenburg J, Asmis L (2008) Congenital hypersensitivity to vitamin K antagonists due to FIX propeptide mutation at locus -10: a (not so) rare cause of bleeding under oral anticoagulant therapy in Switzerland. Swiss Med Wkly 138(7–8):100–107. 2008/07/smw-12022Google Scholar
- 14.Oldenburg J, Quenzel EM, Harbrecht U, Fregin A, Kress W, Muller CR, Hertfelder HJ, Schwaab R, Brackmann HH, Hanfland P (1997) Missense mutations at ALA-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy. Br J Haematol 98(1):240–244. https://doi.org/10.1046/j.1365-2141.1997.2213036.x CrossRefPubMedGoogle Scholar
- 16.Goodeve AC, Reitsma PH, McVey JH Nomenclature of genetic variants in hemostasis. J Thromb Haemost 9(4):852–855Google Scholar
- 17.Fregin A, Czogalla KJ, Gansler J, Rost S, Taverna M, Watzka M, Bevans CG, Muller CR, Oldenburg J (2013) A new cell culture-based assay quantifies vitamin K 2,3-epoxide reductase complex subunit 1 function and reveals warfarin resistance phenotypes not shown by the dithiothreitol-driven VKOR assay. J Thromb Haemost 11(5):872–880. https://doi.org/10.1111/jth.12185 CrossRefPubMedGoogle Scholar
- 19.Winship PR, Nichols CE, Chuansumrit A, Peake IR (1993) An MseI RFLP in the 5′ flanking region of the factor IX gene: its use for haemophilia B carrier detection in Caucasian and Thai populations. Br J Haematol 84(1):101–105. https://doi.org/10.1111/j.1365-2141.1993.tb03031.x CrossRefPubMedGoogle Scholar
- 30.Kumar S, Haigh JR, Tate G, Boothby M, Joanes DN, Davies JA, Roberts BE, Feely MP (1990) Effect of warfarin on plasma concentrations of vitamin K dependent coagulation factors in patients with stable control and monitored compliance. Br J Haematol 74(1):82–85. https://doi.org/10.1111/j.1365-2141.1990.tb02542.x CrossRefPubMedGoogle Scholar
- 33.van der Heijden JF, Rekke B, Hutten BA, van der Meer FJ, Remkes MG, Vermeulen M, Buller HR, Reitsma PH (2004) Non-fatal major bleeding during treatment with vitamin K antagonists: influence of soluble thrombomodulin and mutations in the propeptide of coagulation factor IX. J Thromb Haemost 2(7):1104–1109. https://doi.org/10.1111/j.1538-7836.2004.00768.x CrossRefPubMedGoogle Scholar