Faculty Opinions recommendation of Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia.
This study provides important new insights into the mechanisms of platelet clearance in immune thrombocytopenia (ITP). During the course of ITP, platelets are targeted by autoimmune antibodies – most of them directed against αIIbβ3 (GPIIbIIIa) and/or the GPIb complex – and cleared from the circulation. This destruction of platelets has been generally considered to occur in the spleen, via binding of the Fc portion of the immunoglobulin to FcγR on tissue macrophages of the reticuloendothelial system. However, because previous studies in humans and mice have pointed towards a distinct, Fc-independent mechanism of platelet clearance that is utilized by anti-GPIbα, but not anti-GPIIbIIIa antibodies, the molecular basis remained elusive. In this study, the authors generated new mouse anti-mouse antibodies (mAbs) to show that anti-GPIbα, but not anti-GPIIbIIIa antibodies, induces Fc-independent platelet activation and removal of the sialic acid caps of carbohydrate chains, referred to as desialylation. This was demonstrated for human and mouse platelets, using in vitro as well as in vivo experiments. Desialylation subsequently resulted in platelet clearance in the liver via the Ashwell-Morell receptor. Inhibiting desialylation with sialidase inhibitors increased platelet lifespan and ameliorated anti-GPIbα-mediated thrombocytopenia in mice. Of note, anti-GPIbα antibodies also induced platelet depletion via an Fc-dependent mechanism and potentially other mechanisms. Hence, it remains to be established to which extent desialylation is responsible for platelet depletion in ITP patients with anti-GPIbα antibodies and whether sialidase inhibition is a suitable approach to increase their platelet counts. Initial clinical observations in ITP patients treated with the neuraminidase inhibitor oseltamivir appear promising. The results from this paper are highly convincing and concisely presented. This study serves as a starting point for a new area of ITP research that may ultimately result in the development of novel therapeutical approaches for patients refractory to current treatments. Since anti-GPIbα antibodies are the gold standard for platelet depletion in experimental mouse studies, basic research will also benefit from a better understanding of the underlying mechanisms.