Use of Oral Anti-Xa Inhibitor in Prosthetic Mechanical Aortic Valve with Warfarin Hypersensitivity Due to the FIX p.(Ala37Thr) Propeptide Variant: Case Report and Literature Review

Abstract

Bleeding is the most common side effect during treatment with vitamin K antagonists (VKAs). Sometimes, VKA use causes bleeding episodes due to rare variants in the factor IX (FIX) propeptide that modify the affinity of FIX propeptide to the binding of γ-glutamyl carboxylase. We report on a 51-year-old patient who presented with recurrent spontaneous and severe intramuscular and cutaneous bleedings during VKA (warfarin) treatment for the presence of a prosthetic mechanical aortic valve. Laboratory evaluation revealed INR within the therapeutic range with markedly prolonged aPTT and a large reduction of FIX levels. Laboratory parameters significantly improved when warfarin was switched with low-molecular-weight heparin. Next-generation sequencing analysis revealed the variant p.(Ala37Thr) in the F9 gene, which has been previously associated with VKA sensitivity. As an alternative to warfarin, apixaban 5 mg twice daily and aspirin 100 mg daily were started, with no thrombosis or recurrence of hemorrhage and normalization of INR, aPTT, and FIX levels, at 12-month follow-up. We also performed a literature search across PubMed and Scopus, until January 2025. The analysis evidenced five case reports and two case series. The mechanisms of this rare VKA hypersensitivity have also been reviewed. In conclusion, while VKA hypersensitivity is a rare phenomenon, awareness of this complication and the current accessibility to molecular testing make it important to identify patients at risk. The efficacy/safety of direct thrombin or factor Xa inhibitors in patients with a mechanical heart valve and VKA hypersensitivity due to the F9 p.(Ala37Thr) variant deserves more attention and further investigation.

Keywords

vitamin K antagonist hypersensitivity - variant p.(Ala37Thr)in the F9 gene - DOAC

Publikationsverlauf

Eingereicht: 24. Dezember 2024

Angenommen: 26. Februar 2025

Accepted Manuscript online:
27. Februar 2025

Artikel online veröffentlicht:
25. März 2025

• References

• 1 Stanley TB, Humphries J, High KA, Stafford DW. Amino acids responsible for reduced affinities of vitamin K-dependent propeptides for the carboxylase. Biochemistry 1999; 38 (47) 15681-15687
• 2 Moyer TP, O'Kane DJ, Baudhuin LM. et al. Warfarin sensitivity genotyping: a review of the literature and summary of patient experience. Mayo Clin Proc 2009; 84 (12) 1079-1094
• 3 Shikata E, Ieiri I, Ishiguro S. et al. Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and gamma-glutamyl carboxylase) gene variants with warfarin sensitivity. Blood 2004; 103 (07) 2630-2635
• 4 Flockhart DA, O'Kane D, Williams MS. et al; ACMG Working Group on Pharmacogenetic Testing of CYP2C9, VKORC1 Alleles for Warfarin Use. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet Med 2008; 10 (02) 139-150
• 5 Lyon E, McMillin G, Melis R. Pharmacogenetic testing for warfarin sensitivity. Clin Lab Med 2008; 28 (04) 525-537
• 6 Sekhri A, Lisinschi A, Furqan M. et al. The conundrum of “warfarin hypersensitivity”: prolonged partial thromboplastin time from factor IX propeptide mutation. Am J Ther 2016; 23 (03) e911-e915
• 7 Tamura A, Wada H, Ikejiri M, Miyata T, Habe K, Tomimoto H. Major bleeding in a patient with warfarin-hypersensitive and factor IX propeptide variant, p.Ala37Thr, who was treated with a direct oral anti-Xa inhibitor. Ann Hematol 2019; 98 (01) 209-210
• 8 Ryu R, Tran R. DOACs in mechanical and bioprosthetic heart valves: a narrative review of emerging data and future directions. Clin Appl Thromb Hemost 2022;28:10760296221103578
• 9 Hao Z, Jin DY, Stafford DW, Tie JK. Vitamin K-dependent carboxylation of coagulation factors: insights from a cell-based functional study. Haematologica 2020; 105 (08) 2164-2173
• 10 Chu K, Wu SM, Stanley T, Stafford DW, High KA. A mutation in the propeptide of factor IX leads to warfarin sensitivity by a novel mechanism. J Clin Invest 1996; 98 (07) 1619-1625
• 11 Price PA, Fraser JD, Metz-Virca G. Molecular cloning of matrix Gla protein: implications for substrate recognition by the vitamin K-dependent gamma-carboxylase. Proc Natl Acad Sci U S A 1987; 84 (23) 8335-8339
• 12 Foster DC, Rudinski MS, Schach BG. et al. Propeptide of human protein C is necessary for gamma-carboxylation. Biochemistry 1987; 26 (22) 7003-7011
• 13 Oldenburg J, Quenzel EM, Harbrecht U. et al. 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 1997; 98 (01) 240-244
• 14 Pezeshkpoor B, Czogalla KJ, 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 2018; 97 (06) 1061-1069
• 15 Ulrich S, Brand B, Speich R, Oldenburg J, Asmis L. 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 2008; 138 (7-8): 100-107
• 16 Oldenburg J, Kriz K, Wuillemin WA. et al; Study Group on Hereditary Warfarin Sensitivity. 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 2001; 85 (03) 454-457
• 17 Odnoczko E, Falkowska J, Baran B, Buczma A, Stefanska-Windyga E, Windyga J. Severe bleeding due to hypersensitivity to vitamin K antagonist caused by the c.109G>A (p.Ala37Thr) mutation in the F9 gene in a patient with mechanical heart valve prosthesis. Thromb Res 2019; 174: 59-61
• 18 Bejjani A, Khairani CD, Assi A. et al. When direct oral anticoagulants should not be standard treatment: JACC state-of-the-art review. J Am Coll Cardiol 2024; 83 (03) 444-465
• 19 Eikelboom JW, Connolly SJ, Brueckmann M. et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013; 369 (13) 1206-1214
• 20 Jawitz OK, Wang TY, Lopes RD. et al. Rationale and design of PROACT Xa: a randomized, multicenter, open-label, clinical trial to evaluate the efficacy and safety of apixaban versus warfarin in patients with a mechanical on-X aortic heart valve. Am Heart J 2020; 227: 91-99
• 21 Wang TY, Svensson LG, Wen J. et al. Apixaban or warfarin in patients with an on-X mechanical aortic valve. NEJM Evid 2023; 2 (07) a2300067
• 22 Otto CM, Nishimura RA, Bonow RO. et al; Writing Committee Members. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. J Am Coll Cardiol 2021; 77 (04) 450-500
• 23 Van Gelder IC, Rienstra M, Bunting KV. et al; ESC Scientific Document Group. 2024 ESC guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2024; 45 (36) 3314-3414
• 24 Olie RH, Winckers K, Rocca B, Ten Cate H. Oral anticoagulants beyond warfarin. Annu Rev Pharmacol Toxicol 2024; 64: 551-575
• 25 Johansson I, Benz AP, Kovalova T. et al. Outcomes of patients with a mechanical heart valve and poor anticoagulation control on warfarin. Thromb Haemost 2024; 124 (07) 613-624
• 26 Kristensen SR. Warfarin treatment of a patient with coagulation factor IX propeptide mutation causing warfarin hypersensitivity. Blood 2002; 100 (07) 2676-2677
• 27 Baker P, Clarke K, Giangrande P, Keeling D. Ala-10 mutations in the factor IX propeptide and haemorrhage in a patient treated with warfarin. Br J Haematol 2000; 108 (03) 663