Multirefractory primary immune thrombocytopenia; targeting the decreased sialic acid content

Patients with multirefractory immune thrombocytopenia (ITP) have limited treatment options. Recent data suggest that specific anti-platelet antibodies may cause destruction of platelets by favoring platelet loss of sialic acid. In this multicenter study 35 patients with ITP, including 16 with multirefractory disease, were analyzed for antiplatelet-antibodies, thrombopoietin (TPO) levels, and platelet desialylation. In selected cases, responses to a novel treatment strategy using oseltamivir were tested. We found that antibodies against GPIbα were overrepresented in multirefractory patients compared to responders (n = 19). In contrast to conventional ITP patients, multirefractory patients exhibited a significant increased platelet activation state (granule secretion) and desialylation (RCA-1 binding) (p < 0.05), and a trend toward higher plasma TPO concentrations. The decreased sialic acid content seemed to be restricted to platelet glycoproteins, since other plasma proteins were not hypoglycosylated. A total of 10 patients with multirefractory ITP having remarkable loss of platelet terminal sialic acids were given oseltamivir phosphate. When the antiviral drug was combined with TPO receptor agonists (TPO-RAs) or with immunosuppressant drugs, platelet responses were observed in 66.7% of patients. All responding patients presented with antibodies reactive only against GPIbα. These findings suggest that desialylation may play a key pathogenic role in some multirefractory ITP patients, and provide diagnostic tools for the identification of such patients. Furthermore, we show that sialidase inhibitor treatment in combination with therapies that help to increase platelet production can induce sustained platelet responses in some patients with anti-GPIbα -mediated thrombocytopenia that have failed previous therapies.