Characterisation of patients with Glanzmann thrombasthenia and identification of 17 novel mutations

Kirstin Sandrock-Lang; Johannes Oldenburg; Verena Wiegering; Susan Halimeh; Sentot Santoso; Karin Kurnik; Lars Fischer; Dimitrios A. Tsakiris; Michael Sigl-Kraetzig; Brigitte Brand; Martina Bührlen; Katharina Kraetzer; Niklas Deeg; Martin Hund; Eileen Busse; Anja Kahle; Barbara Zieger

doi:10.1160/TH14-05-0479

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 113(04): 782-791
DOI: 10.1160/TH14-05-0479

Coagulation and Fibrinolysis

Schattauer GmbH

Characterisation of patients with Glanzmann thrombasthenia and identification of 17 novel mutations

Kirstin Sandrock-Lang

¹Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany

,

Johannes Oldenburg

²Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany

,

Verena Wiegering

³Department of Pediatric Hematology, Oncology and Neurooncology, University Children’s Hospital Würzburg, Germany

,

Susan Halimeh

⁴Coagulation Centre Rhine Ruhr, Duisburg, Germany

,

Sentot Santoso

⁵Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University of Giessen, Germany

,

Karin Kurnik

⁶Dr. von Hauner’s Children’s Hospital, Paediatric Haemophilia Centre, Munich, Germany

,

Lars Fischer

⁷Division of Pediatric Oncology, University Hospital of Leipzig, Leipzig, Germany

,

Dimitrios A. Tsakiris

⁸Department of Haematology, University Hospital Basel, Basel, Switzerland

,

Michael Sigl-Kraetzig

⁹Practice for pediatrics with haemophilia treatment center, Blaubeuren and IPFW Blaubeuren – München, Munich, Germany

,

Brigitte Brand

¹⁰Division of Hematology, University Hospital, Zurich, Switzerland

,

Martina Bührlen

¹¹Center for Thrombosis and Hemostasis, Professor-Hess-Kinderklinik, Klinikum Bremen-Mitte, Bremen, Germany

,

Katharina Kraetzer

¹Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany

,

Niklas Deeg

¹Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany

,

Martin Hund

¹Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany

,

Eileen Busse

¹Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany

,

Anja Kahle

¹Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany

,

Barbara Zieger

¹Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany

› Author Affiliations

Abstract

Summary

Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder characterised by quantitative and/or qualitative defects of the platelet glycoprotein (GP) IIb/IIIa complex, also called integrin αIIbβ3. αIIbβ3 is well known as a platelet fibrinogen receptor and mediates platelet aggregation, firm adhesion, and spreading. This study describes the molecular genetic analyses of 19 patients with GT who were diagnosed on the basis of clinical parameters and platelet analyses. The patients’ bleeding signs include epistaxis, mucocutaneous bleeding, haematomas, petechiae, gastrointestinal bleeding, and menorrhagia. Homozygous or compound heterozygous mutations in ITGA2B or ITGB3 were identified as causing GT by sequencing of genomic DNA. All exons including exon/intron boundaries of both genes were analysed. In a patient with an intronic mutation, splicing of mRNA was analysed using reverse transcriptase (RT)-PCR of platelet-derived RNA. In short, 16 of 19 patients revealed 27 different mutations (ITGA2B: n=17, ITGB3: n=10). Seventeen of these mutations have not been published to date. Mutations in ITGA2B or ITGB3 were identified as causing GT in 16 patients. We detected a total of 27 mutations in ITGA2B and ITGB3 including 17 novel missense, nonsense, frameshift and splice site mutations. In addition, three patients revealed no molecular genetic anomalies in ITGA2B or ITGB3 that could explain the suspected diagnosis of GT. We assume that these patients may harbour defects in a regulatory element affecting the transcription of these genes, or other proteins may exist that are important for activating the αIIbβ3 complex that may be affected.

Keywords

Glanzmann thrombasthenia - platelet function defect - glycoprotein αIIbβ3

Full Text

References

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