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Ferrata Storti Foundation
Haematologica 2020 Volume 105(8):2004-2019
Inherited thrombocytopenias: history, advances and perspectives
Alan T. Nurden and Paquita Nurden
Institut Hospitalo-Universitaire LIRYC, Pessac, France
ABSTRACT
Over the last 100 years the role of platelets in hemostatic events and their production by megakaryocytes have gradually been defined. Progressively, thrombocytopenia was recognized as a cause of bleeding, first through an acquired immune disorder; then, since 1948, when Bernard-Soulier syndrome was first described, inherited thrombo- cytopenia became a fascinating example of Mendelian disease. The platelet count is often severely decreased and platelet size variable; asso- ciated platelet function defects frequently aggravate bleeding. Macrothrombocytopenia with variable proportions of enlarged platelets is common. The number of circulating platelets will depend on platelet production, consumption and lifespan. The bulk of macrothrombocy- topenias arise from defects in megakaryopoiesis with causal variants in transcription factor genes giving rise to altered stem cell differentiation and changes in early megakaryocyte development and maturation. Genes encoding surface receptors, cytoskeletal and signaling proteins also fea- ture prominently and Sanger sequencing associated with careful pheno- typing has allowed their early classification. It quickly became apparent that many inherited thrombocytopenias are syndromic while others are linked to an increased risk of hematologic malignancies. In the last decade, the application of next-generation sequencing, including whole exome sequencing, and the use of gene platforms for rapid testing have greatly accelerated the discovery of causal genes and extended the list of variants in more common disorders. Genes linked to an increased platelet turnover and apoptosis have also been identified. The current challenges are now to use next-generation sequencing in first-step screening and to define bleeding risk and treatment better.
History
In the late 19th 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 pro- duced 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 sec- ondary 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 re-named the Bernard-Soulier syndrome (BSS).4 Strikingly, many platelets were enlarged and some were giant. A key to the molec- ular defect was the platelet deficit of sialic acid, a negatively charged monosaccha- ride terminating many of the oligosaccharides of platelet glycoproteins (GP) and
Correspondence:
ALAN NURDEN
nurdenat@gmail.com
Received: April 23, 2020. Accepted: May 8, 2020. Pre-published: June 11, 2020.
doi:10.3324/haematol.2019.233197
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/8/2004
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