An atypical IgM class platelet cold agglutinin induces GPVI-dependent aggregation of human platelets

Isabel M. Sánchez Guiu; Irene Martínez-Martinez; Constantino Martínez; José Navarro-Fernandez; Faustino Garcia-Candel; Francisca Ferrer-Marín; Vicente Vicente; Steve P. Watson; Robert K. Andrews; Elizabeth E. Gardiner; María L. Lozano; José Rivera

doi:10.1160/TH14-11-0945

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2015; 114(02): 313-324
DOI: 10.1160/TH14-11-0945

Cellular Haemostasis and Platelets

Schattauer GmbH

An atypical IgM class platelet cold agglutinin induces GPVI-dependent aggregation of human platelets

Isabel M. Sánchez Guiu

¹Centro Regional de Hemodonación, Hospital Universitario Morales Meseguer, Universidad de Murcia, IMIB-Arrixaca, Spain

,

Irene Martínez-Martinez

¹Centro Regional de Hemodonación, Hospital Universitario Morales Meseguer, Universidad de Murcia, IMIB-Arrixaca, Spain

,

Constantino Martínez

¹Centro Regional de Hemodonación, Hospital Universitario Morales Meseguer, Universidad de Murcia, IMIB-Arrixaca, Spain

,

José Navarro-Fernandez

¹Centro Regional de Hemodonación, Hospital Universitario Morales Meseguer, Universidad de Murcia, IMIB-Arrixaca, Spain

,

Faustino Garcia-Candel

²Servicio de Hematología, Hospital Universitario Virgen de la Arrixaca, Spain

,

Francisca Ferrer-Marín

¹Centro Regional de Hemodonación, Hospital Universitario Morales Meseguer, Universidad de Murcia, IMIB-Arrixaca, Spain

,

Vicente Vicente

¹Centro Regional de Hemodonación, Hospital Universitario Morales Meseguer, Universidad de Murcia, IMIB-Arrixaca, Spain

,

Steve P. Watson

³Birmingham Platelet Group, College of Medical and Dental Sciences, University of Birmingham, UK

,

Robert K. Andrews

⁴Australian Centre for Blood Diseases, Monash University Melbourne, Melbourne, Victoria, Australia

,

Elizabeth E. Gardiner

⁴Australian Centre for Blood Diseases, Monash University Melbourne, Melbourne, Victoria, Australia

,

María L. Lozano

¹Centro Regional de Hemodonación, Hospital Universitario Morales Meseguer, Universidad de Murcia, IMIB-Arrixaca, Spain

,

José Rivera

¹Centro Regional de Hemodonación, Hospital Universitario Morales Meseguer, Universidad de Murcia, IMIB-Arrixaca, Spain

› Institutsangaben

Abstract

Summary

Platelet cold agglutinins (PCA) cause pseudothrombocytopenia, spurious thrombocytopenia due to ex vivo platelet clumping, complicating clinical diagnosis, but mechanisms and consequences of PCA are not well defined. Here, we characterised an atypical immunoglobulin (Ig)M PCA in a 37-year-old woman with lifelong bleeding and chronic moderate thrombocytopenia, that induces activation and aggregation of autologous or allogeneic platelets via interaction with platelet glycoprotein (GP)VI. Patient temperature-dependent pseudothrombocytopenia was EDTA-independent, but was prevented by integrin αIIbβ3 blockade. Unstimulated patient platelets revealed elevated levels of bound IgM, increased expression of activation markers (P-selectin and CD63), low GPVI levels and abnormally high thromboxane (TX)A₂ production. Patient serum induced temperature- and αIIbβ3-dependent decrease of platelet count in allogeneic donorcitrated platelet-rich plasma (PRP), but not in PRP from Glanzmann’s thrombasthenia or afibrinogenaemia patients. In allogeneic platelets, patient plasma induced shape change, P-selectin and CD63 expression, ¹⁴C-serotonin release, and TXA₂ production. Activation was not inhibited by aspirin, cangrelor or blocking anti-Fc receptor (FcγRIIA) antibody, but was abrogated by inhibitors of Src and Syk, and by a soluble GPVI-Fc fusion protein. GPVI-deficient platelets were not activated by patient plasma. These data provide the first evidence for an IgM PCA causing platelet activation/aggregation via GPVI. The PCA activity persisted over a five-year follow-up period, supporting a causative role in patient chronic thrombocytopenia and bleeding.

Keywords

Cold agglutinin - human platelet antigens - platelet activation - platelet glycoprotein VI - thrombocytopenia - plasma and platelet lipid composition

Volltext

Referenzen

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