The platelet Fc receptor, FcγRIIa

Abstract

Human platelets express FcγRIIa, the low-affinity receptor for the constant fragment (Fc) of immunoglobulin (Ig) G that is also found on neutrophils, monocytes, and macrophages. Engagement of this receptor on platelets by immune complexes triggers intracellular signaling events that lead to platelet activation and aggregation. Importantly these events occur in vivo, particularly in response to pathological immune complexes, and engagement of this receptor on platelets has been causally linked to disease pathology. In this review, we will highlight some of the key features of this receptor in the context of the platelet surface, and examine the functions of platelet FcγRIIa in normal hemostasis and in response to injury and infection. This review will also highlight pathological consequences of engagement of this receptor in platelet-based autoimmune disorders. Finally, we present some new data investigating whether levels of the extracellular ligand-binding region of platelet glycoprotein VI which is rapidly shed upon engagement of platelet FcγRIIa by autoantibodies, can report on the presence of pathological anti-heparin/platelet factor 4 immune complexes and thus identify patients with pathological autoantibodies who are at the greatest risk of developing life-threatening thrombosis in the setting of heparin-induced thrombocytopenia.

Platelets kill bacteria by bridging innate and adaptive immunity via platelet factor 4 and FcγRIIA

“…We recapitulated the key findings of these experiments with micropatterns of living bacteria and co‐cultivation of platelets with these bacteria in the presence of PF4 and anti‐PF4/P antibodies. This not only confirms that platelets strongly interact with immune complexes , but is also indicative that the platelet FcγRIIA may mediate directed movement of platelets. It has been well established that the platelet FcγRIIA is dynamically linked to the integrin αIIbβ3 on the platelet membrane.…”

Dimeric FcγR ectodomains detect pathogenic anti‐platelet factor 4–heparin antibodies in heparin‐induced thromobocytopenia

“…In HIT, pathogenic PF4–heparin IgG complexes engage and aggregate FcγRIIa on platelets , and possibly other FcγRs on monocytes . The size and stoichiometry of IgG ICs are major determinants of both the avidity of interaction with the low‐affinity FcγRs and the capacity of anti‐PF4–heparin antibodies to activate cells.…”

“…The pathogenic ICs bind to FcγRIIa, which is the only FcγR on platelets, triggering their activation and aggregation, leading to thrombosis. Binding to FcγRIIa on monocytes also causes both prothrombotic production of thrombin and tissue factor and the clearance of platelets and thrombocytopenia . Many patients treated with heparin develop antibodies against PF4–heparin, but the presence of antibody–PF4–heparin complexes does not necessarily result in clinical manifestations of thrombosis/thrombocytopenia.…”

Proteolytic processing of platelet receptors

“…In HIT, autoantibodies that recognise platelet factor-4 in combination with heparin, form immune complexes which also engage FcγRIIa. 123 FcγRIIa is a second ITAM-containing signalling receptor, and this binding can trigger significant platelet activation and platelet clearance 124 as well as activation of GPVI shedding pathways. 125…”