Inhibitors to Factor VIII in a Family with Mild Hemophilia: Molecular Characterization and Response to Factor VIII and Desmopressin

Abstract

SummaryInhibitor development in patients with mild hemophilia is a rare event. We report the occurrence of a persistent, high-responding inhibitor in two affected members of a mild hemophilia A family and discuss the therapeutic approaches employed in these patients in terms of their efficacy and effect on antibody titer. Desmopressin was an effective option for bleeding management, because endogenous factor VIII released by DDAVP was less immunogenic than exogenous factor VIII replacement, which invariably triggered anamnestic responses. Genetic analysis performed to investigate whether or not a peculiar molecular lesion accounted for this particular phenotype identified a G-A transversion at nucleotide 6507 in exon 23. This missense mutation has been already described in mild hemophilia A, but not in patients with inhibitors.

Successful treatment of high titer inhibitors in mild hemophilia A with avoidance of factor VIII and immunosuppressive therapy

“…APCCsÕ are clinically effective for the treatment of acute bleeds in hemophilia with HTI; however they are difficult to monitor, unpredictable and associated with a thrombogenic risk [15,20]. rFVIIa (with and without episodic desmopressin) was successful in controlling bleeding in 5 patients (4 with HTI) with MHA [6,9,10,34] previously reported, and was successful in case 1 presented here. rFVIIa also caries the risk of thrombosis.…”

“…Of the 45 MHA patients with inhibitors described in the literature [1,3À10, 25À30,34À35], 17 had inhibitors which persisted despite treatment. Of these 17 patients, only 6 were treated exclusively with bypassing agents and/or episodic desmopressin with a full avoidance of FVIII [1,3,6,9,10,34]. Perhaps in cases where the inhibitor does not spontaneously abate, avoiding FVIIIC with the help of desmopressin and/or bypassing agents would be of benefit.…”

“…It is, of course, important to treat mild hemophiliacs with desmopressin whenever possible to prevent the occurrence of FVIIIC inhibitors. In MHA with inhibitors, desmopressin has been successful in the treatment of episodic minor bleeds and for minor surgical procedures without anamnesis [1,3,6,7,10,11]. In a patient with MHA and HTI, Thompson et al reported using alternating doses of intranasal desmopressin with FVIII (15 U/kg alternating every other day), following immune tolerance induction.…”

“…Inhibitors in MHA arise later in life, often following intensive FVIII replacement for surgery or trauma and are accompanied by a fall in the basal level of FVIII coagulant activity (FVIIIC). Bleeding frequently is unrecognized leading to a delay in diagnosis and appropriate management resulting in considerable morbidity.The management of inhibitors in MHA patients remains controversial and has included replacement therapy with human, porcine and rFVIII, immune tolerance induction [1,3], IST [4,5,34], and bypassing therapy with APCC [6À8,35], rFVIIa [6,9,10,34] and episodic desmopressin [1,3,6,7,10,11]. Immune tolerance induction, routinely attempted in SHA with HTI, is expensive, and may be ineffective in MHA patients with inhibitors.…”

“…The management of inhibitors in MHA patients remains controversial and has included replacement therapy with human, porcine and rFVIII, immune tolerance induction [1,3], IST [4,5,34], and bypassing therapy with APCC [6À8, 35], rFVIIa [6,9,10,34] and episodic desmopressin [1,3,6,7,10,11]. Immune tolerance induction, routinely attempted in SHA with HTI, is expensive, and may be ineffective in MHA patients with inhibitors.…”