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Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy
Ferrata Storti Foundation
Haematologica 2021 Volume 106(2):337-350
Paquita Nurden,1 Simon Stritt,2 Remi Favier3 and Alan T. Nurden1
1Institut Hospitalo-Universitaire LIRYC, Pessac, France; 2Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden and 3French National Reference Center for Inherited Platelet Disorders, Armand Trousseau Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
ABSTRACT
Inherited platelet disorders resulting from platelet function defects and a normal platelet count cause a moderate or severe bleeding diathesis. Since the description of Glanzmann thrombasthenia resulting from defects of ITGA2B and ITGB3, new inherited platelet disorders have been discovered, facilitated by the use of high throughput sequencing and genomic analyses. Defects of RASGRP2 and FERMT3 responsible for severe bleeding syndromes and integrin activation have illustrated the critical role of signaling molecules. Important are mutations of P2RY12 encoding the major ADP receptor causal for an inherited platelet disorder with inheritance characteristics that depend on the variant identified. Interestingly, variants of GP6 encoding the major subunit of the collagen receptor GPVI/FcRγ associate only with mild bleeding. The numbers of genes involved in dense granule defects including Hermansky-Pudlak and Chediak Higashi syndromes continue to progress and are updated. The ANO6 gene encoding a Ca2+-activated ion channel required for phospho- lipid scrambling is responsible for the rare Scott syndrome and decreased procoagulant activity. A novel EPHB2 defect in a familial bleeding syn- drome demonstrates a role for this tyrosine kinase receptor independent of the classical model of its interaction with ephrins. Such advances high- light the large diversity of variants affecting platelet function but not their production, despite the difficulties in establishing a clear phenotype when few families are affected. They have provided insights into essen- tial pathways of platelet function and have been at the origin of new and improved therapies for ischemic disease. Nevertheless, many patients remain without a diagnosis and requiring new strategies that are now discussed.
Introduction
In this review we compare clinical, biological and genetic characteristics of inher- ited platelet disorders (IPD) with abnormal platelet function but a normal platelet count (listed in Table 1) and highlight anti-ischemic drugs developed based on the discoveries made regarding these disorders.1-10 A low platelet count does not exclude altered platelet function but we refrain from repeating details for disorders such as Bernard-Soulier and gray platelet syndromes included in our companion paper in this journal and summarized in Online Supplementary Table S1.11 After briefly detailing therapy, we discuss the current lessons and perspectives for clinical practice and highlight how it is important for clinicians to constitute a pivot between genetic platforms and basic research.
Glanzmann thrombasthenia
With a worldwide distribution, Glanzmann thrombasthenia (GT) is the most common platelet function disorder.12 Most importantly, studies on it led to the characterization of the αIIbβ3 integrin mediator of platelet aggregation (Figure 1);
Correspondence:
PAQUITA NURDEN
paquita.nurden@gmail.com
Received: June 13, 2020. Accepted: August 12, 2020. Pre-published: November 5, 2020.
https://doi.org/10.3324/haematol.2020.248153
©2021 Ferrata Storti Foundation
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