Background: Elevated platelet surface expression of the chemokine receptors CXCR4 and CXCR7 in coronary artery disease-(CAD) patients influences prognosis following myocardial infarction-(MI). Although CXCR4 supports a pro-thrombotic profile, CXCR7 mediates an anti-thrombotic response following ligation with its physiological ligand.

Aims: To validate the significance of CXCR7-axis in regulating thromboinflammatory response following myocardial infarction and in the context of heparin induced thrombocytopenia-(HIT).

Methods: MI/RI model in mice, HIPA, aggregometry, flowcytometry, ex vivo thrombus formation, lipidomic (UHPLC-ESI-QTOF-MS/MS) analysis, were performed. Sera and corresponding IgG fractions were isolated from patients with clinically and serologically confirmed HIT (4Ts score 6-8, ELISA and HIPA positive) and non-HIT subjects.

Results: CAD patients having platelet CXCR7 surface expression ≥median showed significantly reduced aggregation. Administration of a pharmacological CXCR7 agonist improved functional recovery, regulated platelet activation and thrombotic response 24hrs-post-MI/RI, without affecting bleeding time or coagulation profile. It also reduced HIT⁺ sera/IgG-induced platelet aggregates in HIPA, and thrombus formation ex vivo. CXCR7 agonist checked the formation of platelet-leukocyte aggregates in peripheral circulation post-MI/RI in vivo; similarly, counteracted HIT⁺ sera/IgG induced platelet-neutrophil aggregate formation ex vivo. Release of pro-inflammatory mediators from HIT⁺IgG activated platelets and levels of pro-inflammatory chemokines-cytokines in murine plasma post-MI/RI were reduced in presence of CXCR7 agonist. Mechanistic basis of this anti-thrombotic action revealed that CXCR7 agonist significantly altered the platelet lipidome favouring the generation of several anti-thrombotic lipid mediators including 12-HETrE, which acted through prostacyclin receptor, triggering adenylyl cyclase activity, and elevation of platelet inhibitory cAMP levels. On the contrary, CXCR7 agonist counteracted generation and release of pro-thrombotic lipid mediators (lysophosphatidylinositol, lysophosphatidylcholine, arachidonic acid, thromboxane, 12-HETE) from stimulated platelets, which affected intraplatelet activatory signalling cascade and therefore functional response.

Conclusions: CXCR7 ligation alters the platelet lipidome to regulate thrombotic and thromboinflammatory response, which might be utilized as a potential anti-thrombotic strategy following MI and in HIT without enhancing bleeding risk.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/targeting-the-chemokine-receptor-cxcr7-favours-an-anti-thrombotic-platelet-lipidome-and-regulates-thromboinflammatory-functions/