Novel mechanisms linking platelet activation to antiphospholipid syndrome

Curr Opin Immunol. 2026 May 29;101:102791. doi: 10.1016/j.coi.2026.102791. Online ahead of print.

ABSTRACT

Antiphospholipid syndrome (APS) is a thromboinflammatory disorder in which antiphospholipid antibodies (aPL), particularly anti-β2GPI, initiate a complex, graded platelet activation that integrates immune signaling with coagulation. Clinical and multiparametric flow-cytometric evidence demonstrates a sustained prothrombotic platelet endotype characterized by enrichment of tissue factor-positive (TF^pos)-platelets, an increase in the number of TF^pos-platelet-leukocyte heteroaggregates, and in the expression of classical adhesion markers (P selectin, activated αIIbβ3) despite anticoagulation. These abnormalities correlate with high-risk aPL profiles and likely contribute to residual thrombotic risk not captured by conventional coagulation biomarkers. Pathogenic anti-β2GPI – especially Domain 1 specific-IgG – induce a selective, early procoagulant TF^pos-phenotype in the absence of full adhesive activation. This phenotype reflects peripheral ApoER2-dependent signaling rather than bone marrow-driven megakaryocyte programming. Inflammatory mediators, notably IL6, act as indispensable amplifiers, converting the TF-only phenotype into a broader thromboinflammatory program involving P-selectin expression, integrin activation, phosphatidylserine exposure, and formation of multicellular immunothrombotic units. Omics-based profiling corroborates a chronically primed platelet state with dysregulated inhibitory checkpoints (CD73-adenosine-cAMP axis), enhanced ADP/P2Y₁₂ signaling, and membrane remodeling conducive to procoagulant differentiation. TF^pos-platelets emerge as a mechanistically grounded biomarker candidate of thrombotic propensity and a potential therapeutic target. Ex vivo data show distinct pharmacological sensitivity since aspirin and P2Y₁₂ inhibition attenuate both adhesive and TF-dependent procoagulant programs, whereas hydroxychloroquine selectively modulates classical activation markers but not platelet-associated TF. These observations delineate separable adhesive vs. procoagulant platelet modules and support a precision medicine framework in which quantification and targeted suppression of TF^pos-platelets may attenuate the basal prothrombotic milieu and mitigate APS-related thrombotic risk.

PMID:42214306 | DOI:10.1016/j.coi.2026.102791