Translational immunothrombosis in autoimmune Heparin-Induced thrombocytopenia: targeting the FcγRIIa–Syk–BTK and complement pathways

Autoimmune heparin-induced thrombocytopenia (aHIT) represents a severe variant of immune-mediated thrombocytopenias (IMTs) in which anti-platelet factor 4 (PF4) antibodies activate platelets independently of heparin, leading to both thrombosis and thrombocytopenia. Despite its clinical significance, aHIT remains poorly understood and lacks evidence-based immunomodulatory treatments. This narrative translational review integrates mechanistic and therapeutic insights from immune thrombocytopenia (ITP) and antiphospholipid syndrome (APS) to identify shared pathogenic pathways relevant to aHIT. Literature from 2015 to 2025 was analyzed across PubMed, Scopus, Web of Science, and ClinicalTrials.gov, focusing on FcγRIIa-Syk-BTK signaling and complement activation as central drivers of platelet activation and clearance. Preclinical and clinical data indicate that targeting these axes with Syk inhibitors (fostamatinib), BTK inhibitors (rilzabrutinib, zanubrutinib), and complement inhibitors (sutimlimab) can restore platelet counts and mitigate immune-driven thrombosis. These findings underscore the therapeutic potential of pathway-specific interventions in aHIT, highlighting the need for biomarker-guided, translational trials to validate their efficacy and safety. Bridging mechanistic evidence from ITP and APS provides a framework for precision immunotherapy in autoimmune HIT.