Inherited thrombocytopenias: history, advances and perspectives

Abstract

In the late 19 th century improvements to the light microscope led to anucleate platelets being visualized in great numbers in human blood. Early pioneers in the field of platelet research included the Canadian William Osler, a Paris hematologist, George Hayem, who performed the first accurate platelet count, and the Italian Giulio Bizzozero. 1 In 1906, James Homer Wright confirmed that platelets were produced by bone marrow megakaryocytes. 2 When, in 1951, Harrington et al. 3 observed purpura in a child of a mother with immune thrombocytopenic purpura, a maternal factor was said to be destroying the platelets. Anti-platelet antibodies were identified as the cause and platelet transfusions, immunosuppressive therapy and splenectomy became standard treatments. Acquired thrombocytopenia, often with defective platelet function, has many causes. For example, it may be an immune response linked to blood transfusions and drugs, a direct consequence of viral or bacterial infections, be the result of other hematologic disorders or be secondary to many major illnesses. However, some thrombocytopenias are inherited and Professors Jean Bernard and Jean-Pierre Soulier in Paris were pioneers in this domain, describing in 1948 what they called in French "dystrophie thrombocytaire hémorragipare congénitale", later renamed the Bernard-Soulier syndrome (BSS). 4 Strikingly, many platelets were enlarged and some were giant. A key to the molecular defect was the platelet deficit of sialic acid, a negatively charged monosaccharide terminating many of the oligosaccharides of platelet glycoproteins (GP) and

Regulation of Platelet Production and Life Span: Role of Bcl-xL and Potential Implications for Human Platelet Diseases

“…Thrombocytopenias related to a defect in platelet production are frequently observed in inherited thrombocytopenia [ 70 ]. These latter are due to various defects: (i) nearly absence of MKs in the rare cases of MPL or TPO mutations; (ii) defects in MK differentiation due to mutations in transcription factors (FLI1, RUNX1, GATA1, ETV6, IKZF5); and (iii) defects in proplatelet formation due to mutations in genes coding for proteins involved in the cytoskeleton such as GPIB, Filamin A, MYH9, Actinin B, and DIAPH1.…”

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

“…[1][2][3][4][5][6][7][8][9][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.…”

“…3,4,94 When no genetic diagnosis has been achieved with standard approaches, gene analysis should be expanded to evaluate complex copy number variations, deep variants in non-coding regions and secondary defects involving the action of microRNA or retrotransposons, as we have detailed elsewhere. 11 Currently the diagnosis of IPD is based largely on the concept of a monogenic heritable platelet disease, but a proportion of these diseases may be di-or polygenic in origin. Families with unexplained heritability may have unrecognized variants or other changes in regulatory regions in combinations that only advanced technologies may help to resolve.…”

“… 12 Rare gain-of-function monoallelic variants in cytoplasmic and membrane proximal domains promote spontaneous conformational changes that result in macrothrombocytopenia, as detailed in our companion paper. 11 Significantly, recent data obtained by next-generation sequencing have begun to reveal combinations of variants in different genes that modify the GT phenotype. 22 …”

“…This can be secondary to mutations of genes for membrane receptors: P2RY12 , GP6 , TBXA2R , EPHB2 , G6b-B ; or genetic defects often accompanied by thrombocytopenia ( Online Supplementary Table S1) . 11 Applying next-generation sequencing procedures targeting 329 preselected genes, Leo et al analyzed 18 patients including six with secretion defects, highlighting 49 genes not previously known to be causal of IPD. 77 Gorski et al performed a similar study using whole exome sequencing of 14 patients with bleeding caused by primary platelet secretion defects.…”