Advances in understanding the pathogenesis of hereditary macrothrombocytopenia

Janine Collins, William J Astle, Karyn Megy, Andrew D Mumford, Dragana Vuckovic

Research output: Contribution to journalReview article (Academic Journal)peer-review

1 Citation (Scopus)

Abstract

Low platelet count, or thrombocytopenia, is a common haematological abnormality, with a wide differential diagnosis, which may represent a clinically significant underlying pathology. Macrothrombocytopenia, the presence of large platelets in combination with thrombocytopenia, can be acquired or hereditary and indicative of a complex disorder. In this review, we discuss the interpretation of platelet count and volume measured by automated haematology analysers and highlight some important technical considerations relevant to the analysis of blood samples with macrothrombocytopenia. We review how large cohorts, such as the UK Biobank and INTERVAL studies, have enabled an accurate description of the distribution and co-variation of platelet parameters in adult populations. We discuss how genome-wide association studies have identified hundreds of genetic associations with platelet count and mean platelet volume, which in aggregate can explain large fractions of phenotypic variance, consistent with a complex genetic architecture and polygenic inheritance. Finally, we describe the large genetic diagnostic and discovery programmes, which, simultaneously to genome-wide association studies, have expanded the repertoire of genes and variants associated with extreme platelet phenotypes. These have advanced our understanding of the pathogenesis of hereditary macrothrombocytopenia and support a future clinical diagnostic strategy that utilises genotype alongside clinical and laboratory phenotype data.

Original languageEnglish
Pages (from-to)25-45
Number of pages21
JournalBritish Journal of Haematology
Volume195
Issue number1
Early online date30 Mar 2021
DOIs
Publication statusPublished - Oct 2021

Bibliographical note

Funding Information:
JC is supported by an MRC Clinical Research Training Fellowship (MR/P02002X/1). AM is supported by the Bristol National Institute for Health Research (NIHR) Biomedical Research Centre. The authors would like to thank Dr Kate Downes for her specialist input on the ThromboGenomics platform, Dr Barbara De la Salle for providing data on the haematology analysers registered with UK NEQAS, Professor Kathleen Freson for her expertise in hereditary platelet disorders, and Professor Willem H Ouwehand for his critical review of the manuscript. We thank the NIHR BioResource and its volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health Research Cambridge Biomedical Research Centre and NHS Blood and Transplant. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. We thank all contributors to the INTERVAL study, with full recognition of this work in the included references. This review used the UK Biobank Resource under Application Number 13745.

Funding Information:
JC is supported by an MRC Clinical Research Training Fellowship (MR/P02002X/1). AM is supported by the Bristol National Institute for Health Research (NIHR) Biomedical Research Centre. The authors would like to thank Dr Kate Downes for her specialist input on the ThromboGenomics platform, Dr Barbara De la Salle for providing data on the haematology analysers registered with UK NEQAS, Professor Kathleen Freson for her expertise in hereditary platelet disorders, and Professor Willem H Ouwehand for his critical review of the manuscript. We thank the NIHR BioResource and its volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health Research Cambridge Biomedical Research Centre and NHS Blood and Transplant. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. We thank all contributors to the INTERVAL study, with full recognition of this work in the included references. This review used the UK Biobank Resource under Application Number 13745.

Publisher Copyright:
© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Fingerprint

Dive into the research topics of 'Advances in understanding the pathogenesis of hereditary macrothrombocytopenia'. Together they form a unique fingerprint.

Cite this