Factor VIII Inhibitors in Mild and Moderate-severity Haemophilia A

Abstract

SummaryTwenty six patients with mild or moderate haemophilia A and inhibitors are described. The inhibitor was detected at a median age of 33 years, after a median of 5.5 bleeding episodes. This usually following intensive replacement therapy. The median presenting inhibitor titre was antihuman 11.6 BU/ml, antiporcine 1.45 BU/ml. Plasma basal factor VIII level declined from a median of 0.08 IU/ml to 0.01 IU/ml following the inhibitor development. This caused spontaneous bleeding in 22 and a bleeding pattern similar to acquired haemophilia in 17. Bleeding was often severe and caused two deaths.The inhibitor disappeared spontaneously, or following immune tolerance induction, in 16 cases after a median of 9 months (range 0.5-46), with a return to the original baseline VIIIC level and bleeding pattern accompanied inhibitor loss. The inhibitor persisted in the remainder of the cases over a median period of 99 months (range 17-433 months) of follow-up. Inhibitors are an uncommon complication of mild haemophilia which frequently persist and may be associated with severe, life-threatening, haemorrhage.Forty-one percent of treated haemophilic family members had a history of factor VIII inhibitors, suggesting a familial predisposition to develop inhibitors in these kindreds. Sixteen patients from 11 families were genotyped. Seven different missense mutations affecting the light chain were detected and two in the A2 domain. Five patients from three families had a mutation causing a substitution of Trp2229 by Cys in the C2 domain which appears to predispose to inhibitor formation since 7 of the 18 affected individuals have a history of inhibitor development.

Prevalence and Incidence of Non-neutralizing Antibodies in Congenital Hemophilia A— A Systematic Review and Meta-Analysis

“…Many questions remain regarding the epitope specificity, FVIII binding affinity and clinical significance of NNAs. Previous studies in patients with hemophilia as well as healthy subjects have found NNAs mostly directed against epitopes on A1, A3, and B domains of the FVIII molecule (11,64,65). Furthermore, Lebreton et al demonstrated a clear immune-dominance of the complete heavy chain (A1, A2, and B-domains) in the epitope profile of NNAs, independent of hemophilia severity (15).…”

Challenges in the Diagnosis and Management of Non-Severe Hemophilia

“…The importance of accurate examinations performed in an expert hemostasis laboratory, including vWF multimers exploration and chromogenic assays for the situation of therapy with EHL or non-factor treatments, is largely accepted [ 34 , 35 , 36 , 37 ]. Chromogenic assays, besides other advantages (lack of influence of lupus anticoagulant and of different clotting specific reagents), are useful for avoiding the important discrepancies between one-stage and chromogenic methods results that can lead to misdiagnosis of hemophilia phenotype.…”

Factor VIII inhibitors in haemophiliacs: a single‐centre experience over 34 years, 1964–97

“…There is a great difference in reported incidence rates of inhibitors in patients with haemophilia. UK Haemophilia Centre Directors statistics from the pre‐HIV era showed that 6% of haemophilia A patients of all severities registered in the U.K. between 1969 and 1980 developed inhibitors (Biggs, 1977; Rizza & Spooner, 1983) and the latest report revealed 57 new factor VIII inhibitors for the years 1990–97 in 5100 haemophilia A patients of all severity registered in the U.K (Hay et al , 1998). Thus most haemophilia centres in the U.K. have only very small numbers of inhibitor patients.…”