Regulatory potential of antibody-mediated procoagulant platelets in immunothrombosis: Focus on Fc-gamma-RIIA signaling

• Applicant: Dr. Jan Zlamal
• Subject Area: Clinical Immunology and Allergology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572840153

Heparin-induced thrombocytopenia type II (HIT) is a potentially life-threatening adverse event characterized by a drop in platelet count and high risk of thrombosis following the administration of the widely used anticoagulant heparin. Platelets (PLTs), small anucleated cells derived from megakaryocytes, were early assumed for being important contributors in the complex prothrombotic pathophysiology of HIT. It has been proposed that cross-linking of innate immune platelet Fc-gamma-RIIA by anti-platelet factor 4 (PF4)/heparin HIT immunoglobulin G (IgG) immune complexes leads to increased platelet clearance as well as platelet activation which is assumed to account for the prothrombotic milieu in HIT. However, detailed knowledge regarding the relevance of PLTs in the complex prothrombotic pathophysiology of HIT is missing. This is of high clinical relevance, given that conventional platelet inhibitors (e.g. aspirin) are ineffective and alternative non-heparin anticoagulants often fail to prevent HIT-mediated thrombosis or are associated with bleeding complications. A better understanding of prothrombotic PLT-mediated effector mechanisms that are not targeted by conventional antithrombotics could help to further prevent thromboembolic events in HIT patients. In my previous work, I identified a potential pathophysiological role of different antibody-induced Fc-gamma-RIIA-mediated platelet subpopulations in HIT. HIT antibody-induced procoagulant PLTs, characterized by an increased expression of the platelet surface activation marker CD62p (P-selectin) and, most importantly, elevated externalization of the negatively charged membrane phospholipid phosphatidylserine (PS), were observed to be important mediators of increased thrombin and immunothrombosis ex vivo. While these findings suggest an essential role of procoagulant PLTs in the prothrombotic condition in HIT, direct clinical translation remains limited as data from in vivo studies are lacking. In the proposed project, I aim to dissect the pathophysiological relevance of antibody-induced procoagulant PLT PS as key driver of prothrombotic coagulopahty in vivo. Using cutting edge intravital imaging platforms and a novel humanized mouse model, I aim to identify how HIT antibody-induced procoagulant PLT PS contributes to immunothrombosis in vivo. Findings from these studies will contribute to the current understanding of antibody-mediated immunothrombosis and may decipher novel pathomechanisms, innovative treatment targets and novel diagnostic markers that will help to prevent onset of thromboembolic complications in patients with HIT or other anti-PF4-related prothrombotic diseases.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Wolfgang Bergmeier