ACKR3/CXCR7 Regulates Nonenzymatic and Enzymatic Lipid Oxidation in Heparin Induced Thrombocytopenia

Introduction Anti-thrombotic mediator ACKR3/CXCR7 alters the platelet lipidome by limiting generation of prothrombotic lipids, while favouring antiplatelet lipids that trigger the platelet inhibitory signalling cascade through IP receptor AC-cAMP-PKA pathway. Current investigation explores the impact of CXCR7 in regulating enzymatic and nonenzymatic lipid oxidation in Heparin Induced Thrombocytopenia (HIT) and compares its effects with iloprost. Method Lipidomics analysis by UHPLC-QTOF-MS/MS and micro-UHPLC-ESI-QTrap-MS/MS; platelet CXCR7 surface expression, intraplatelet oxLDL (anti-oxLDL) generation and lipid peroxidation (C11-BODIPY 581/591 ), mitochondrial superoxide (MitoSOXred) generation and procoagulant transformation (Annexin-V, CD62P) by flow cytometry, phosphorylation of SykTyr 525/526 , SykTyr 323 by immunoblot analysis. Results Surface expression of CXCR7 on platelets was substantially enhanced by HIT-IgG. Targeting CXCR7 with a pharmacological agonist significantly countered HIT-IgG induced procoagulant transformation of platelets assessed by externalization of thrombogenic phospholipid phosphatidylserine and CD62P surface expression, like iloprost. HIT-IgG induced intraplatelet ROS generation, which was downregulated by CXCR7-agonist, and iloprost. HIT-IgG caused intraplatelet lipid oxidation by both enzymatic (COX-1, 12-LOX) and ROS driven non-enzymatic means. HIT-IgG triggered nonenzymatic intraplatelet oxLDL formation and lipid peroxidation was substantially reduced by CXCR7 agonist, like iloprost. Moreover, CXCR7-agonist significantly decreased HIT-IgG induced generation of thrombo-inflammatory oxylipins by enzymatic means through platelet COX-1 (TxA 2 ), 12-LOX (12-HETE). Similar effects were observed in a whole blood system whereby HIT-IgG increased generation of leukocyte specific 5-LOX (5-HETE), 15-LOX (15-HETE) produced oxylipins, that were downregulated by CXCR7-agonist. Most importantly, presence of CXCR7-agonist intercepted transcellular lipid metabolism between platelet and leukocytes. Reduced generation of 5,12-diHETE, 12,20-diHETE, 13-HODE, 9-HODE was observed. Like platelet 12-LOX, Syk is a major effector kinase downstream of FcγRIIA- induced platelet activatory signalling cascade, and therefore considered as a potential therapeutic target in immunothrombotic complications. Pretreatment of platelets with CXCR7-agonist regulated Syk Tyr525/526 , Syk Tyr323 phosphorylation induced by HIT-IgG and collagen related peptide downstream of FcγRIIA engagement. Conclusion Considering the regulatory impact of CXCR7-agonist on intraplatelet lipid oxidation, platelet 12-LOX and Syk activities, therapeutic targeting of CXCR7 may modulate immunothrombotic complications arising from FcγRIIA induced platelet activation in HIT. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany