Abstract Number: PB0330
Meeting: ISTH 2020 Congress
Background: Some patients with mild/moderate hemophilia A (MHA) develop anti-FVIII inhibitors in spite of the presence innate self FVIII. When inhibitor is developed in MHA, bleeding phenotype becomes severe and hemostatic treatment would be challenging. Genotypic risk of inhibitor development is revealed by INSIGHT study about MHA with inhibitor (MHA-inh), inhibitory mechanism on developed inhibitor was not fully understood, however.
Aims: To clarify the inhibitory mechanism on inhibitor developed in MHA.
Methods: We assessed hemostatic and immunologic properties of inhibitors in 10 MHA-inh. Peak inhibitor titers were 1.0-1,656 BU/mL. In all of them, inhibitor was developed following infusion of large amount of FVIII concentrates for hemostatic treatment or peri-operative management, and severe bleeding occurred after inhibitor development.
Results: Inhibitors of 8 out of 10 patients (A group) inhibited both of FVIII from concentrates (non-self FVIII) and mutated self FVIII which existed in patient’s plasma prior to inhibitor development or which was expressed by BHK cells. However, inhibitors of other 2 patients (B group) inhibited non-self FVIII only. Inhibitors of A group were type 1 antibodies and those of B group were type 2 antibodies. Inhibitors of A group inhibited interaction between FVIII and phospholipids (PL), and this mechanism seemed to cause the inhibition of FVIII activity. By contrast, inhibitors of B group didn’t inhibit FVIII-PL interaction and one of them inhibited to FVIII cleavage by thrombin and FXa. Most mutations on F8 gene of the A group were identical or close site to reported in INSIGHT study, whilst those of B group weren’t reported in that study (P1809L, E272K). In all cases, IgG subtypes of inhibitors were observed in IgG1 and/or IgG4 and inhibitor epitopes didn’t show any tendency.
Conclusions: Inhibitors developed in MHA-inh had same immune-reactivity depending on types of antibody, and all of type 1 inhibitors showed PL-dependent inhibitory mechanism.
To cite this abstract in AMA style:Furukawa S, Nogami K, Shima M. Difference Molecular Profiles of Type 1 and 2 Inhibitor Developed in Mild/Moderate Hemophilia A [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/difference-molecular-profiles-of-type-1-and-2-inhibitor-developed-in-mild-moderate-hemophilia-a/. Accessed January 28, 2022.
« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/difference-molecular-profiles-of-type-1-and-2-inhibitor-developed-in-mild-moderate-hemophilia-a/