Early detection of inhibitory proteins in hemophilia patients

Hemophilia A is a rare congenital bleeding disorder caused by a deficiency in one of the coagulation proteins, specifically factor VIII. Because hemophilia A is caused by an X-linked genetic variant, this condition is predominantly present in men. It is one of the most common coagulation factor deficiencies, affecting approximately 2200 males in the Dutch population. Patients with hemophilia A receive treatment with factor VIII concentrates to prevent spontaneous bleeding and manage acute bleeding episodes. However, a significant concern in this treatment is the development of factor VIII neutralizing proteins, known as inhibitors, which render therapy ineffective and increase the risk of bleeding, ultimately leading to decreased survival.

The presence of an inhibitor can be confirmed with the Nijmegen Bethesda Assay (NBA), an internationally standardized test. However, the cutoff level of this assay is not sensitive enough to detect inhibitors in the early phase. Consequently, when factor VIII treatment is administered to a patient with a very low-titer inhibitor, the inhibitor may be boosted, resulting in bleeding complications and a high rate of mortality. Therefore, a more sensitive assay is needed to detect these very low-titer inhibitors. The availability of a more sensitive assay may provide the opportunity to adjust a patient’s treatment plan early, enabling a switch to other hemostatic products instead of factor VIII concentrates to prevent these complications.

Our research group, from the Department of Hematology, in collaboration with the Laboratory of Hematology, has developed a novel assay capable of detecting these very low-titer inhibitors. The paper entitled “The Nijmegen ultra-sensitive Bethesda Assay detects very low-titer factor VIII inhibitors in patients with congenital and acquired hemophilia A” (Thrombosis Research, October 2023), written by Lars Valke and Marieke Verhagen, describes the assay’s methods, as well as its analytical and clinical validation. The next step is to prospectively implement this assay in young hemophilia patients to correlate the results of this novel inhibitor assay with the clinical bleeding phenotype in relation to treatment with factor VIII concentrates.

Read the study here

The Nijmegen ultra-sensitive Bethesda Assay detects very low-titer factor VIII inhibitors in patients with congenital and acquired hemophilia A - ScienceDirect. Valke, L., et al., The Nijmegen ultra-sensitive Bethesda Assay detects very low-titer factor VIII inhibitors in patients with congenital and acquired hemophilia A. Thromb Res, 2023. 231: p. 112-120.

Photo, from left to right:

Dominique Maas, Daniëlle Meijer, Lars Valke, Sterre Willems, Saskia Schols, Marieke Verhagen, and Waander van Heerde.