Recent advances in inherited platelet disorders

Abstract

Purpose of review The increasing use of high throughput sequencing and genomic analysis has facilitated the discovery of new causes of inherited platelet disorders. Studies of these disorders and their respective mouse models have been central to understanding their biology, and also in revealing new aspects of platelet function and production. This review covers recent contributions to the identification of genes, proteins and variants associated with inherited platelet defects, and highlights how these studies have provided insights into platelet development and function. Recent findings Novel genes recently implicated in human platelet dysfunction include the galactose metabolism enzyme UDP-galactose-4-epimerase in macrothrombocytopenia, and erythropoietin-producing hepatoma-amplified sequence receptor transmembrane tyrosine kinase EPHB2 in a severe bleeding disorder with deficiencies in platelet agonist response and granule secretion. Recent studies of disease-associated variants established or clarified roles in platelet function and/or production for the membrane receptor G6b-B, the FYN-binding protein FYB1/ADAP, the RAS guanyl-releasing protein RASGRP2/CalDAG-GEFI and the receptor-like protein tyrosine phosphatase PTPRJ/CD148. Studies of genes associated with platelet disorders advanced understanding of the cellular roles of neurobeachin-like 2, as well as several genes influenced by the transcription regulator RUNT-related transcription factor 1 (RUNX1), including NOTCH4. Summary The molecular bases of many hereditary platelet disorders have been elucidated by the application of recent advances in cell imaging and manipulation, genomics and protein function analysis. These techniques have also aided the detection of new disorders, and enabled studies of disease-associated genes and variants to enhance understanding of platelet development and function.

Role of Thrombopoietin Receptor Agonists in Inherited Thrombocytopenia

“…There are other ITs such as Wiskott–Aldrich syndrome (WAS) where the decreased PC results from both an ineffective platelet production from premature proplatelet formation, and from increased platelet clearance. There are other mechanisms such as apoptosis (CYCS-RT), deficient glycosylation (GNE-RD and GALE-RD), mutations affecting ion gradient (STIM1-RD), increased tyrosine phosphorylation (SRC-RD), RNA degradation (SLFN14-RT) or poorly developed demarcation membrane system in Mks (sitosterolemia) [ 4 , 5 , 11 , 14 , 15 , 16 ]. The knowledge of these mechanisms could be the basis for the management of these complex disorders.…”

“…The technique is now widely available in research and clinical practice and has been established as the gold standard for identifying the molecular pathology underlying monogenic diseases [ 2 ]. These techniques have allowed the identification of up to 40 genes as being causative of ITs [ 2 , 4 ], but despite the recent molecular progress in the diagnosis, in nearly 50% of patients with IT the genetic basis of these conditions remains unknown [ 5 ]. Less progress has been made in the therapeutic management of patients, which is based mainly on the transfusion of platelet concentrates [ 6 ].…”

“…The introduction of thrombopoietin (TPO) receptor agonists (RA) in the last ten years for different disorders, not only for immune thrombocytopenia (ITP), aplastic anemia (AA), but also for thrombocytopenia after hematopoietic stem cell transplantation (HSCT), open a new therapeutic possibility in ITs [ 7 , 8 , 9 , 10 ]. In this review we do not intend to update the advances in the molecular knowledge of ITs, which have been approached recently [ 4 , 5 , 11 ] but to raise the possibility of using this new class of agents, according to current evidence. We conducted a literature review of the MEDLINE, PubMed, and Cochrane databases using the subject headings ‘Inherited thrombocytopenia’, and the keywords ‘thrombocytopenia’, ‘thrombopoietin receptor agonists’, ‘thrombopoietin mimetics’, ‘romiplostim’, and ‘eltrombopag’ up to 12 February 2021.…”

Clinical management, ethics and informed consent related to multi‐gene panel‐based high throughput sequencing testing for platelet disorders: Communication from the SSC of the ISTH

“…IPD are extremely heterogeneous, with more than 60 genes now known to be associated with these disorders 1 . These genes can be classified according to their predicted role in platelet formation and function 2,3 (Table S1). IPD typically result in mild to severe bleeding symptoms, spontaneous or related to hemostatic challenges including trauma, surgery, pregnancy, and delivery.…”

Severe Bleeding Diathesis in Siblings with Platelet Dysfunction due to a Novel Nonsense RASGRP2 Mutation

“…1 Among them are dysfunctions in platelet activation pathways caused by RASGRP2 mutations encoding the RasGRP2 protein, also known as calcium-and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI). 1,2 RasGRP2 is a guanine exchange factor (GEF) that facilitates substrate dissociation in guanosine triphosphatases (GTPases), termed Ras. These GTPases are important regulators in cell signaling.…”