Platelet Activation Mechanisms and Consequences of Immune Thrombocytopenia

Abstract

Autoimmune disorders are often associated with low platelet count or thrombocytopenia. In immune-induced thrombocytopenia (IIT), a common mechanism is increased platelet activity, which can have an increased risk of thrombosis. In addition, or alternatively, auto-antibodies suppress platelet formation or augment platelet clearance. Effects of the auto-antibodies are linked to the unique structural and functional characteristics of platelets. Conversely, prior platelet activation may contribute to the innate and adaptive immune responses. Extensive interplay between platelets, coagulation and complement activation processes may aggravate the pathology. Here, we present an overview of the reported molecular causes and consequences of IIT in the most common forms of autoimmune disorders. These include idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), drug-induced thrombocytopenia (DITP), heparin-induced thrombocytopenia (HIT), COVID-19 vaccine-induced thrombosis with thrombocytopenia (VITT), thrombotic thrombocytopenia purpura (TTP), and hemolysis, the elevated liver enzymes and low platelet (HELLP) syndrome. We focus on the platelet receptors that bind auto-antibodies, the immune complexes, damage-associated molecular patterns (DAMPs) and complement factors. In addition, we review how circulating platelets serve as a reservoir of immunomodulatory molecules. By this update on the molecular mechanisms and the roles of platelets in the pathogenesis of autoimmune diseases, we highlight platelet-based pathways that can predispose for thrombocytopenia and are linked thrombotic or bleeding events.

Keywords: auto-antibodies; autoimmune disorders; immune thrombocytopenia; platelet; thrombosis.

Figure 1

Overview of mechanisms leading to platelet activation in types of IIT. a| Frequently in ITP, IgG auto-antibodies bind to GPIbα or αIIbβ3 on the platelet membrane. Incidentally multivalent auto-antibodies induce platelet activation via FcγRIIA receptors. The glycoprotein CD40L (CD154) on activated platelets can interact with B cell CD40, inducing B cell proliferation. b| In SLE, immune complex (IC) and DAMPs (e.g., HMGB1 or S100A8/9) activate platelets through binding to surface receptors such as FcγRIIA and Toll-like receptors (TLRs). The IC may also activate the complement system leading to deposition of complement fragments (C1q, C4d) on the platelet surface, which potentiates their activation. c| Anti-cardiolipin, anti-β₂-GPI and anti-prothrombin antibodies can induce platelet activation in APS patients. d| In TTP or HELLP, ultra-large VWF multimers provoke the agglutination of platelets via GPIbα. e| In HIT or VITT, antibodies to PF4/heparin complexes bind and activate platelets via FcγRIIA receptors. For further explanations, see text. Created with Biorender.com.

Figure 2

Mechanisms leading to low platelet count or thrombocytopenia in IIT. a| Auto-antibodies target platelets for destruction by macrophages in the spleen or liver through Fcγ receptor signaling via spleen tyrosine kinase (Syk). b| Platelets decorated with auto-antibodies can also be destroyed via other mechanisms, such as complement activation or desialylation. c| Auto-antibodies binding to megakaryocytes can lead to an impaired platelet production. d| Cytotoxic T cells can directly destroy or inhibit platelets and megakaryocytes. e| Binding of ultra-large VWF multimers to platelets induces microthrombus formation in the absence of functional ADAMTS13 (either inhibited by auto-antibodies or not expressed due to a congenital defect). f| Chemotherapeutic antiproliferative drugs can suppress megakaryocyte development and platelet production. Created with Biorender.com.

Figure 3

FcγRIIA-induced platelet activation and signaling pathways. IgG antibodies or larger immune complexes can activate platelets by dimerization or clustering of FcγRIIA receptors. The tyrosine-based activation motif (ITAM) is then phosphorylated by Src-family kinases (SFK), recruiting and phosphorylating the tyrosine kinase Syk, which in turn activates phosphoinositide 3-kinase (PI3K). The production of phosphatidylinositol-3,4,5-trisphosphate (PIP₃) recruits Bruton’s tyrosine kinase (BTK) and phospholipase Cγ (PLCγ), which leads to activation of downstream responses via IP₃ production and protein kinase C (PKC). The extent of platelet activation is likely dependent on the type of IgG antibodies and immune complexes. Created with BioRender.com.