CH 1541/2-1

Regulatory molecular mechanisms governing immunothrombotic adversities in heparin-induced thrombocytopenia: validation of novel therapeutic strategies

01/01/2025 to 31/12/2027

Platelet express the noncanonical G-protein coupled chemokine receptor CXCR7. Recently we have validated the potential of CXCR7 as an anti-thrombotic mediator in arterial thrombosis, and following myocardial infarction through a profound modulation of the platelet lipidome that consequently substantiates platelet inhibitory signalling through the cAMP-PKA pathway. The proposed project, aims to disclose the molecular mediators of thrombo-inflammation in HIT with a particular focus on the therapeutic validation of the CXCR7-cAMP axis. The main research objectives of the proposed project are: I. To investigate the therapeutic potential of targeting CXCR7 in HIT-induced platelet-mediated thrombo-inflammatory functions (in vitro and ex vivo studies) in conjunction with neutrophils II. To explore the molecular mechanisms (through phosphoproteomics, lipidomics evaluation in response to HIT-monoclonal antibody triggered FcγRIIA mediated platelet activation) governing enhanced thrombotic risk in HIT. Translational perspective will focus on delineating the regulatory effect of the CXCR7-cAMP axis (in vitro. ex vivo) to combat thrombotic disposition in HIT patients. III. Preclinical evaluation of the use of pharmacological CXCR7-agonist compared to antiplatelet therapy iloprost as a therapeutic strategy to regulate immunothrombotic complications in HIT (in vivo studies with murine models). IV. To analyse possible changes in CXCR7 expression in HIT patients as a potential novel drug target on platelets and neutrophils (clinical study) and ascertain its anti-thromboinflammatory efficacy in ex vivo studies. If the results of this study show the anticipated outcome, planning for prospective clinical studies to assess the use of CXCR7 agonist as a new treatment of HIT will be initiated. In addition, the expression of CXCR7 will be implemented in the routine diagnostic approach for HIT to supplement other laboratory assays.