Abstract
Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by immune-mediated destruction of platelets and impaired platelet production. Although autoantibodies have historically been central to the understanding of ITP, current evidence demonstrates that its pathogenesis extends well beyond humoral mechanisms to involve complex dysregulation of both innate and adaptive immune responses. Multiple immune pathways—including autoreactive B and T cells, dendritic cell activation, and regulatory T cell deficiency—contribute to disease onset, progression, and chronicity. Moreover, ITP encompasses a broad spectrum of clinical and immunological subtypes, including primary idiopathic forms and secondary ITP associated with autoimmune diseases, infections, and inborn errors of immunity. This review offers a novel perspective on ITP pathogenesis, emphasizing the active immunoregulatory role of platelets as contributors to immune dysregulation. Far from being passive targets, platelets in ITP actively shape immune responses through crosstalk with immune cells, particularly CD4+ T helper (Th) and CD8+ cytotoxic T cells. This interaction, primarily mediated via the P-selectin–PSGL-1 axis, promotes Th1/Th17 polarization, enhances autoantibody production, and accelerates platelet destruction. In parallel, platelet-derived microparticles (PMPs) act as potent immune effectors by delivering pro-inflammatory cytokines and autoantigens that sustain chronic immune activation. Prolonged platelet activation also gives rise to a distinct subpopulation known as “hairy platelets”—exhausted, granule-depleted cells with altered surface phenotypes and sustained pro-inflammatory potential. Although functionally exhausted in terms of coagulation, these platelets retain immunostimulatory capacity through persistent phosphatidylserine exposure and cytokine release. By reframing platelets as active participants in the pathogenesis of ITP, this review proposes that targeting platelet activation, platelet–T cell interactions, and PMP release may represent innovative therapeutic strategies. Such approaches could offer more precise and personalized treatment options, particularly for patients with chronic or refractory disease, by restoring immune balance and improving long-term outcomes.
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•Activated platelets in ITP act as potent pro-inflammatory effectors, amplifying immune dysregulation and driving chronic inflammation.•Procoagulant platelets—functionally “exhausted” and sometimes morphologically “hairy”—are granule-depleted, PS-exposing cells that release microparticles, fueling immune dysfunction and inflammatory cascades.•Platelet–T cell interactions via the P-selectin–PSGL-1 axis activate T helper and cytotoxic T cells, perpetuating autoimmune responses and accelerating platelet destruction.•Platelet-derived microparticles carry pro-inflammatory cytokines and autoantigens, sustaining chronic immune activation and promoting autoreactive immune responses.•Therapeutically targeting platelet activation, platelet–T cell interactions, and platelet microparticle release offers a precise strategy for managing chronic and refractory ITP, with the potential to improve patient outcomes.