PB1114 - Major bleedings in a patient with warfarin hypersensitivity and factor IX propeptide variant, p.Ala37Thr, treated with a direct oral anti Xa inhibitor.

Tuesday, June 25, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

Antonella Tufano, MD, PhD

ASSISTANT PROFESSOR
DEPARTMENT OF CLINICAL MEDICINE AND SURGERY , FEDERICO II UNIVERSITY OF NAPLES
Naples, Campania, Italy

Co-Author(s)

CF

Carmine Fierarossa

RESIDENT
DEPARTMENT OF CLINICAL MEDICINE AND SURGERY. Federico II University of Naples
Naples, Campania, Italy
FC

Ferdinando Cirillo

biologist
DEPARTMENT OF CLINICAL MEDICINE AND SURGERY. Federico II University of Naples
Naples, Campania, Italy
CM

Ciro Miele

RESIDENT
Federico II University of Naples
Naples, Campania, Italy
FC

Filomena Capasso

biologist
2. UOC Laboratory medicine of hematology and hemostasis; Federico II University Hospital, Naples, Italy
Naples, Campania, Italy
LB

Luigi Bisceglia

PROFESSOR
Division of Medical Genetics IRCCS, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
San Giovanni Rotondo, Puglia, Italy
GV

Gennaro Vecchione

PROFESSOR
Division of Medical Genetics IRCCS, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
San Giovanni Rotondo, Puglia, Italy
IF

Ignazio Frangipane

RESIDENT
DEPARTMENT OF CLINICAL MEDICINE AND SURGERY. Federico II University of Naples
Naples, Campania, Italy
EC

Ernesto Cimino

assistant professor
DEPARTMENT OF CLINICAL MEDICINE AND SURGERY. Federico II University of Naples
Naples, Campania, Italy
MD

Matteo Di Minno

Professor
Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
Naples, Campania, Italy

Background: Bleedings are the most common side effects during treatment with vitamin K antagonists (VKAs). In rare occasions, VKA-related bleeding episodes can be associated with mutations affecting the FIX propeptide, at amino acid position 37 (Ala37Val, Ala37Thr) that modify the affinity of the mutated propeptide to the binding of γ-glutamyl carboxylase, inducing a hypersensitivity to VKA.

Aims: We report a case of a 51-year-old patient who was referred to our outpatient clinic because of severe bleeding complications during warfarin treatment.

Methods: The patient has given informed consent to publish the case report.

Results: A 51-year-old man, with no personal/family history of hemorrhagic diseases, was evaluated for recurrent spontaneous and severe intramuscular and cutaneous bleedings, during warfarin treatment for the presence of a prosthetic mechanical aortic valve. Laboratory evaluation revealed an INR within the therapeutic range (2-3), with a markedly prolonged aPTT ratio (4,2). Laboratory parameters significantly improved when warfarin was switched with low-molecular-weight heparin (LMWH), with INR and aPTT normalization. A markedly reduced level of FIX (1%), was found, contrasting with the normal levels observed after discontinuing warfarin or when administering LMWH. Gene analysis revealed a missense mutation p.Ala37Thr, affecting exon 2 of the F9 gene. The genetic variant involves a guanosine to adenosine transition at nucleotide 6346 (6346G>A), which results in an alanine to threonine aminoacid substitution in the FIX, leading to reduced affinity of the γ-glutamyl carboxylase. As an alternative to VKA, treatment with apixaban 5 mg twice daily and aspirin 100 mg daily was started, with no recurrence of hemorrhage and normalization of INR and aPTT al 1-month follow-up.

Conclusion(s): Although FIX variant p.Ala37Thr-associated VKA hypersensitivity is a rare phenomenon, awareness towards this complication is important to identify patients at risk. The efficacy/safety of direct factor Xa inhibitors in patients with mechanical heart valve and this genetic variant requires future large evidence.