Characterization of an Anti-Factor VIII Inhibitor Related To P.Arg2178Cys Mutation in A Patient with Mild Haemophilia A

Special Article: Hemophilia

J Blood Disord 2023; 10(3): 1080.

Characterization of an Anti-Factor VIII Inhibitor Related To P.Arg2178Cys Mutation in A Patient with Mild Haemophilia A

Chamouni P¹; Souissi M¹; Fretigny M²; Billoir P³; Le Cam Duchez V¹; Barbay V¹

1Hemophilia Care Center, Rouen University Hospital, F 76000 Rouen, France

2Laboratory of Genetic and Molecular Biology, Hospices Civils de Lyon, France

3Vascular Hemostasis Unit, Normandie Univ, UNIROUEN, INSERM U1096, Rouen University Hospital, F 76000 Rouen, France

*Corresponding author: Pierre Chamouni Service d’Hématologie Biologique, Centre Hospitalier Universitaire Charles Nicolle, 1 rue de Germont, 76031 Rouen, France Tel: +33 02 32 88 02 49; Fax: + 33 02 32 88 04 19 Email: pierre.chamouni@chu-rouen.fr

Received: October 12, 2023 Accepted: October 20, 2023 Published: October 27, 2023

Abstract

In patients with inherited mild haemophilia treated with clotting factor concentrates, the risk of inhibitor development is lower than in severe haemophilia. We report the observation of a 38-year-old man, with mild haemophilia A, previously treated for mucosal bleeding, who presented no major immunization risk factors except an exon 23 missense mutation p.Arg2178Cys in the F8 gene in the C1 domain. He developed an inhibitor against Octocog alfa. The implication of the mutation in this particular immunization process is well known. Characterization of this inhibitor has been extended as a type I inhibitor with classical epitope mapping and solely directed against exogenous factor VIII. Due to the occurrence of an anamnestic response associated with a high titre inhibitor, we had recourse to Eptacog alfa during a critical bleeding situation.

Keywords: Mild haemophilia A; Factor VIII concentrate (Octocog alfa); Inhibitor; Epitope mapping; F8 gene mutation

Essentials

Unexpected anti-factor VIII inhibitor in a patient with mild haemophilia A.

Inhibitor (initially and after anamnestic response) directed only against exogenous factor VIII.

Specificity of the inhibitor against domains A1, A2 and C1.

Genetic abnormality: exon 23 missense mutation p.Arg2178Cys of the C1 domain.

Case report

A 38-year-old white European man, with mild haemophilia A (FVIII at 0.11 IU/dL), carrying the exon 23 missense mutation p.Arg2178Cys in the F8 gene (legacy numbering: Arg2159Cys or R2159C) in the C1 domain, was followed in our centre. An intravenous desmopressin therapeutic test performed at 18 years showed a satisfactory response (FVIII: 0.19 IU/dL at T0H, 0.70 IU/dL at T1H, 0.43 IU/dL at T4H). His vWF levels and platelet functions were normal. His blood type was A.

At the age of 30 years, a kite surfing accident occurred resulting in a subcutaneous haematoma extending over the entire right lower limb, associated with a first left metacarpal hand fracture, for which he underwent surgical repair under Octocog alfa (Advate®) prophylaxis. This represented our patient’s first contact with a FVIII concentrate (5 Exposure Days (EDs)). One month later, he required prophylactic Octocog alfa administration (3 EDs) for the removal of the osteosynthesis material.

At the age of 35 years, he had a nosebleed unresponsive to desmopressin and antifibrinolytic agent at recommended therapeutic dose, requiring nasal packing under Octocog alfa prophylaxis (2 EDs). At the age of 36 years, he underwent the avulsion of three impacted wisdom teeth, under Octocog alfa prophylaxis (2 EDs) and antifibrinolytic agent. Eight days later, he was administered the same treatment, for bleeding due to an open pressure sore.

At the age of 38 years, he had three nosebleeds over a 3-week period, unresponsive to desmopressin and antifibrinolytic agent, requiring Octocog alfa (ADVATE®) injections with a satisfactory response.

Before the last Octocog alfa treatment, biological monitoring showed an Activated Partial Prothrombin Time (APTT) of 1.44, fibrinogen at 3.25g/l. Later, and for the first time a low titre positive FVIII inhibitor at 0.94 BU/ml was detected using the Nijmegen-Bethesda assay, with concomitant FVIII at 0.28 IU/dL few hours after desmopressine nasal administration (Table 1). A week after the last Octocog alfa injection, the inhibitor increased to 5 BU/ml. Within the next days, recombinant activated factor VII concentrate (Eptacog alfa Novoseven®) was administered for a complementary bilateral nasal cauterization procedure.

Citation: Chamouni P; Souissi M; Fretigny M; Billoir P; Le Cam Duchez V; Barbay V. Characterization of an Anti-Factor VIII Inhibitor Related To P.Arg2178Cys Mutation in A Patient with Mild Haemophilia A. J Blood Disord 2023; 10(3): 1080.