Procoagulant platelets in antiphospholipid syndrome

Background Antiphospholipid syndrome (APS) is an autoimmune disease characterized by persistent risk for thrombosis despite therapeutic anticoagulation. Reliable biomarkers that enable stratification of thrombotic risk in APS patients are lacking. Hence, a better understanding of the mechanisms of coagulopathy in APS is urgently needed. Procoagulant platelets (PCPs) are reported to promote atypical arterial as well as venous thrombosis. Methods We investigated the prevalence and the clinical relevance of antibody-mediated PCPs in a cross-sectional, bicentric cohort of patients with APS. The contribution of PCPs to APS antibody-mediated thrombosis was analyzed by flow cytometry and a microfluidic thrombosis model, and in a novel humanized mouse model. Results Antibody-induced PCP formation was observed in 38 of 82 APS patients (46%). The ability of APS sera to induce PCPs was asociated with lower platelet counts (p value 0.02) and recurrent thrombotic events (p value 0.03). Mechanistic studies identifed platelet Fc-gamma-RIIA/spleen tyrosine kinase (SYK) signaling pathway as a potential molecular target to prevent multicellular APS-mediated immunothrombosis. Additionally, high-dose intravenous immunoglobulin (IVIG) inhibited procoagulant platelet formation, neutrophil extracellular trap release and immunothrombosis in vitro as well as in vivo. Conclusion PCPs may be a potential biomarker for recurrent thrombosis and serve as a therapeutic target to reduce thrombotic risk in APS. Our data propose SYK inhibition as well as high-dose IVIG as adjunctive strategies in selected high-risk APS patients.