Endothelial Health and Immune Complexes in Acquired Hemophilia A

• Applicant: Olga Oleshko, Ph.D.
• Subject Area: Hematology, Oncology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567894753

Acquired hemophilia A (AHA) and congenital hemophilia A (CHA) are both bleeding disorders caused by a lack of factor VIII (FVIII) activity. However, they differ significantly in how bleeding presents: while patients with CHA often suffer from joint bleeds, this is rarely seen in AHA, where patients experience massive subcutaneous hematomas and muscle hemorrhages. The reason for this striking difference remains unknown. Interestingly, the antibodies (inhibitors) that neutralize FVIII in AHA and CHA with inhibitors (CHAWI) are very similar in structure and behavior. This has led us to shift focus from the antibodies themselves to the role of FVIII in the body. In AHA, FVIII is still present but bound by antibodies, forming so-called FVIII-containing immune complexes (FVIII-IC). In contrast, FVIII is entirely absent in CHAWI unless infused. We hypothesize that these FVIII-IC may interact with the endothelium and contribute to the unique bleeding pattern seen in AHA. Therefore, this project aims to investigate how FVIII-IC interact with endothelial cells and how this interaction might contribute to bleeding in AHA. We will explore this question in three work packages: WP1: Study how FVIII-IC bind to and affect endothelial cells under static (non-flow) conditions. WP2: Examine how these interactions change under flow conditions that mimic blood circulation. WP3: Use an ex vivo model of primary hemostasis to explore how FVIII-IC and patient-derived antibodies affect endothelial function and interactions with platelets. Through this work, we hope to uncover a new layer of complexity in the bleeding disorder AHA. Rather than being caused solely by a lack of clotting activity, bleeding in AHA may also involve direct effects on the blood vessels themselves. Understanding this could open the door to new therapeutic strategies that protect vascular health alongside traditional treatments aimed at restoring coagulation.

• DFG Programme: Research Grants