Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy

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 phospholipid scrambling is responsible for the rare Scott syndrome and decreased procoagulant activity. A novel EPHB2 defect in a familial bleeding syndrome demonstrates a role for this tyrosine kinase receptor independent of the classical model of its interaction with ephrins. Such advances highlight 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 essential 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.

Inherited Platelet Disorders: An Updated Overview

“…Nowadays, early, accurate molecular diagnosis of IPD undoubtedly facilitates clinical management, particularly in the serious, potentially fatal types, in which genotype is related to prognosis and severity of hematological and/or extra-hematological disease, such as congenital amegakaryocytic thrombocytopenia (CAMT), familial platelet disorder with predisposition to hematological malignancies (FPD/AML), MYH9-RD, Wiskott-Aldrich syndrome (WAS), Hermansky-Pudlak syndrome (HPS) or Chediak-Higashi Syndrome (CHS) [ 8 , 26 ]. Nevertheless, HTS also has its limitations, such as managing the vast amount of molecular data obtained, which can only be addressed with the help of bioinformatics experts, and the accurate interpretation of the pathogenicity of the candidate variants [ 2 , 146 , 149 ].…”

“…Approximately half of all inherited thrombocytopenias, as well as some inherited platelet function disorders, are syndromes in which the congenital platelet defect is associated with a high probability of clinically relevant alterations in other cell types, organs, or tissues, or with developing neoplastic disease [ 5 , 8 , 26 , 129 ]. In light of their considerable clinical relevance, we will highlight the following:…”

“…Because it is a recessive autosomal disorder, only homozygote subjects exhibit moderate-severe mucocutaneous bleeding starting in childhood, whereas heterozygote individuals tend to be asymptomatic [ 1 , 8 , 163 ]. On the other hand, some ITGA2B and ITGB3 heterozygous variants can cause autosomal dominant inherited thrombocytopenia [ 39 ].…”

“…The two main groups of IPD are: Inherited thrombocytopenias, in which the most conspicuous defect is the low number of circulating normal-sized, large, or small platelets [ 4 , 5 , 6 ] ( Figure 1 , Table 1 ) Inherited platelet function disorders, characterized by dysfunctional, typically hypofunctional, platelets resulting from defects of the membrane receptors, granules, elements involved in signal transduction, or other defects of the biochemical platelet machinery [ 7 , 8 ] ( Figure 1 , Table 2 , Table 3 and Table 4 ) …”

“…Inherited platelet function disorders, characterized by dysfunctional, typically hypofunctional, platelets resulting from defects of the membrane receptors, granules, elements involved in signal transduction, or other defects of the biochemical platelet machinery [ 7 , 8 ] ( Figure 1 , Table 2 , Table 3 and Table 4 )…”