Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia

Abstract

Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current theory suggests that antibody-mediated platelet destruction occurs in the spleen, via macrophages through Fc–FcγR interactions. However, we and others have demonstrated that anti-GPIbα (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcγR pathways. Here, we generate mouse anti-mouse monoclonal antibodies (mAbs) that recognize GPIbα and GPIIbIIIa of different species. Utilizing these unique mAbs and human ITP plasma, we find that anti-GPIbα, but not anti-GPIIbIIIa antibodies, induces Fc-independent platelet activation, sialidase neuraminidase-1 translocation and desialylation. This leads to platelet clearance in the liver via hepatocyte Ashwell–Morell receptors, which is fundamentally different from the classical Fc–FcγR-dependent macrophage phagocytosis. Importantly, sialidase inhibitors ameliorate anti-GPIbα-mediated thrombocytopenia in mice. These findings shed light on Fc-independent cytopenias, designating desialylation as a potential diagnostic biomarker and therapeutic target in the treatment of refractory ITP.

Protein kinase A determines platelet life span and survival by regulating apoptosis

“…However, this suggestion does not exclude the possibility that some pathological stimuli induce platelet apoptosis through other mechanisms. For example, platelet apoptosis induced by antiGPIbα antibodies was observed here and reported previously (42). Apoptotic platelets expose PS and release microparticles that incur a procoagulant profile, leading to generation of thrombin.…”

“…Autoantibody-induced platelet apoptosis results in rapid platelet destruction in ITP patients (4,42). Therefore, incubation of normal platelets with serum from ITP patients that contains autoantibodies induced platelet apoptosis (Figure 8, A and B).…”

Regulating billions of blood platelets: glycans and beyond

“…Recent findings show that certain anti-GPIba antibodies trigger platelet desialylation, a process that deviates platelet clearance from splenic macrophage Fc receptors to the hepatic AMR, showing that FcgR-independent mechanisms of ITP exist. 102,103 The mechanisms of how anti-GPIba-antibody binding leads to desialylation remain to be established. It is likely that platelets secrete active Neu1 and Neu3 upon antibody binding and/or platelet activation.…”

Cholesterol in platelet biogenesis and activation

“…49 Recent studies indicate an additional mechanism regulating platelet production in which aged desialylated platelets bind the hepatic Ashwell-Morell receptor and thereby stimulate hepatocyte TPO production. 57,58 Increased platelet turnover is often associated with increased platelet biogenesis via elevated TPO. The newly generated platelets are larger, more dense, and RNA rich, and these so-called reticulated platelets are generally more active than the more mature platelets.…”