Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by isolated thrombocytopenia. While traditionally explained by antibody-mediated platelet destruction, recent studies reveal a broader syndrome of immune dysregulation involving both platelet destruction and impaired thrombopoiesis.

The best-established mechanism involves autoantibodies, primarily IgG1 and IgG3, against platelet glycoproteins GPIIb/IIIa and GPIb/IX. Antibody-coated platelets are phagocytosed by macrophages via Fcγ receptors in the spleen and liver. Anti-GPIb antibodies cause platelet desialylation and clearance by the hepatic Ashwell–Morell receptor. Autoantibodies also trigger complement activation, enhancing destruction through C3b deposition.

Beyond humoral immunity, T-cell dysregulation is central. Th1 polarization, characterized by elevated IFN-γ, TNF-α, and IL-2, stimulates macrophage activation and autoreactive B-cell differentiation. In contrast, Th2 cytokines (IL-4, IL-10) are reduced, impairing tolerance. Increased Th17 cells and IL-17 further amplify inflammation and suppress regulatory T-cell (Treg) activity. Indeed, CD4⁺CD25⁺FoxP3⁺ Tregs are both reduced in number and function, with diminished production of IL-10 and TGF-β. This promotes unchecked autoreactive B- and T-cell activity. CD8⁺ cytotoxic T cells have emerged as key players. These cells directly induce apoptosis of platelets and bone marrow megakaryocytes through perforin–granzyme and Fas/FasL pathways, representing antibody-independent platelet destruction. Their expansion is particularly evident in refractory or chronic ITP.

B-cell activation is driven by cytokines from Th1 and follicular helper T cells. The B-cell survival factors BAFF (B-cell activating factor) and APRIL (A proliferation-inducing ligand) are elevated in ITP, allowing autoreactive B cells and long-lived plasma cells to persist. This explains resistance to rituximab, which depletes CD20⁺ B cells but spares plasma cells. The BAFF/APRIL axis is therefore a promising therapeutic target.

In addition to peripheral destruction, impaired thrombopoiesis is critical. Autoantibodies against GPIIb/IIIa and GPIb/IX disrupt megakaryocyte maturation and proplatelet formation. CD8⁺ T cells induce megakaryocyte apoptosis, further reducing platelet production. Bone marrow stromal dysfunction, including reduced secretion of TGF-β, SCF, and CXCL12, exacerbates these defects. A hallmark of ITP is the paradoxically low thrombopoietin (TPO) level despite severe thrombocytopenia. Since TPO synthesis is regulated by megakaryocyte mass rather than platelet count, reduced megakaryocyte numbers and dysfunction result in insufficient TPO and inadequate platelet production.

The cytokine milieu in ITP reflects a proinflammatory imbalance. Increased IFN-γ, TNF-α, and IL-17 reinforce autoimmunity, while decreased IL-10 reflects Treg dysfunction. These changes disrupt tolerance and promote disease chronicity.

In conclusion, ITP is not merely an antibody-driven disorder but a complex immune dysregulation syndrome. Both humoral and cellular mechanisms contribute to platelet destruction, while megakaryocyte impairment and insufficient TPO hinder platelet production. Elevated BAFF/APRIL, Th1/Th17 polarization, Treg deficiency, and cytotoxic T-cell activity represent crucial pathogenic pathways. Advances in molecular biology are redefining ITP pathogenesis and identifying novel therapeutic targets that extend beyond conventional immunosuppression.