The humoral pathophysiology of immune thrombocytopenia: How close are we to patient-specific disease treatment?

Abstract

Primary immune thrombocytopenia (ITP) is an autoimmune disease in which soluble humoral immune factors, especially anti-platelet autoantibodies, can drive thrombocytopenia by accelerating platelet clearance and impairing platelet production. The classical humoral mechanisms of ITP include autoantibodies triggering macrophage Fc gamma receptor (FcγR)-mediated phagocytosis of platelets in the spleen or liver. Work over several decades has expanded this model beyond FcγRs to include platelet desialylation with hepatic clearance pathways, complement activation with platelet-bound complement fragments, platelet apoptosis signatures, and autoantibody effects on megakaryocytes and thrombopoiesis. Specific autoantibody characteristics such as specificity, subclass, and glycosylation preferentially drive certain mechanisms which shape autoantibody pathogenicity. These mechanisms are not uniform across patients or stable over time, which likely contributes to variable responses to therapy. Here we provide an in-depth review of the evidence supporting key humoral effector pathways in ITP and outline practical opportunities and limitations for pairing therapies to inferred mechanisms. Finally, we identify knowledge gaps, including pathway-relevant biomarkers, prospective studies linking biomarkers to treatment outcomes, and gaps in the development of targeted therapies for pathways such as platelet desialylation.