Platelets-neutrophils aggregation: platelet heterogeneity as a promising resource of new targets for therapeutic intervention

• Applicant: Irina Patalakh, Ph.D.
• Subject Area: Cell Biology ; Biochemistry ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537809747

Thromboinflammation is a pathological condition in which inflammation and thrombosis influence one another, triggering abnormal pro-coagulant and pro-inflammatory events. This crosstalk can manifest itself in the formation of platelet-leukocyte aggregates which can act as mobile platforms for thrombi generation obstructing blood flow in the microvasculature, leading to tissue damage and escalation of inflammation. In particular, neutrophil functions have been shown to be significantly impacted by the interaction with platelets, resulting in the increased release of chemokines and ROS following integrin-mediated outside-in signaling. Likewise, neutrophils rapidly accumulate at sites of local inflammation inducing and amplifying platelet activation. This uncontrolled amplification of clotting/inflammation irreversibly shifts the hemostatic balance, contributing to the development of coagulopathy, thrombocytopenia, systemic inflammation or multiple organ failure. This study aims to characterize the platelet-leukocyte aggregates in order to identify potential targets for future therapeutic treatments. A particular focus lies on the identification of proteins involved in platelet and neutrophil heterotypic aggregation induced by the neutrophil agonist granulocyte colony stimulating factor (G-CSF) and the platelet agonist thrombin. In addition, this study will elucidate the ability of activated protein C (APC) and protease-activated receptor (PAR-1) to modulate the homoand heterotypic aggregation of neutrophils and platelets. All studies in this project are planned to be performed ex vivo, using fresh blood from healthy blood donors and healthy stem cell apheresis donors after obtaining their informed consent. Flow cytometry and confocal microscopy will be employed to detect homo- and heterotypic aggregates after staining with appropriate fluorescent markers, as well as impedance aggregation to test the functional activity of platelets in whole blood. The results will help to assess the prospects for using platelet-neutrophil aggregates as a potential therapeutic target in the treatment and prevention of thrombotic complications. It may also be possible to discover the regulatory mechanisms responsible for the interaction of neutrophils with aggregating and pro-coagulant platelets, which will narrow down the search for inhibitors that can block platelet-neutrophil aggregation.

• DFG Programme: WBP Position