Multirefractory primary immune thrombocytopenia; targeting the decreased sialic acid content

Abstract

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.

Keywords:

• Anti-GPIbα
• multirefractory ITP
• oseltamivir
• platelet activation
• sialic acid

Author contributions

MLL and NR were the principal investigators. NR, JC, MLL, MEMB, and AM carried out platelet studies. NR, MEMC, RMC, FV, NG, EG, RB, IF, MEMB, TGL, JRGP, VV and MLL evaluated the patients´clinical background, therapies and responses to treatments. NR, JC, MEMB, VV, MLL interpreted the biological and clinical results. NR and MLL wrote the manuscript. All authors critically reviewed and approved the paper.

Acknowledgements

The authors would like to thank the patients and their physicians: Rosa Ferrer (Hospital De Dénia, Spain), Ignacio Sánchez-Serrano (Hospital Comarcal del Noroeste, Caravaca de la Cruz, Murcia, Spain), Nuria Bermejo (Hospital San Pedro de Alcántara, Cáceres, Spain), Ana María Rodriguez-Huerta (Hospital General Universitario Gregorio Marañón, Madrid, Spain), Elena Sebastián (Hospital Infantil Universitario Niño Jesús, Madrid, Spain), Jose María-Bastida (Hospital Universitario Salamanca, Spain), Esther Chica (Hospital Universitario de Getafe, Madrid, Spain), Jose María Guinea de Castro (Hospital Universitario de Alava, Spain), Carmen María Fernández (Hospital de la Vega Baja, Orihuela, Spain), Jorge Monserrat-Coll (Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain), Reyes Jiménez-Barcenas (Hospital Universitario Virgen del Rocío, Sevilla, Spain), María Del Carmen De Cos Höhr (Hospital Universitario Puerta del Mar, Cádiz, Spain), Antonio Cerveró (Hospital General Universitario de Valencia, Spain).

Declaration of interest

The authors declare no competing financial interests. This study was supported by CIBERER CB15/00055, Fundación Séneca (19873/GERM/15) and by research grants from ISCIII & FEDER (PI17/01311).

Supplementary material

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Additional information

Funding

This work was supported by the Fundación Séneca [19873/GERM/15]; Instituto de Salud Carlos III [CB15/00055, PI17/01311].