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When Platelets Go Bad: “Bloody” Powerful Tools to Figure Out the Cause

December 6, 2020

Dr. Psaila presents her talk “Single Cell Approaches
to Elucidate Novel and Aberrant Pathways
in Megakaryocytes.”

Recent years have seen tremendous advances in the understanding of megakaryocyte development (megakaryopoiesis) and the role of platelets in disease. Platelets, anucleate fragments of megakaroycytes, have long-established roles that they play in thrombosis and hemostasis. The Scientific Program session “Molecular Basis of Platelet/Megakaryocyte Dysfunction: Novel Approaches” (live Q&A Sunday, December 6, at 2:00 p.m. Pacific time) chaired by Dr. Angara Koneti Rao focuses on three state-of-the-art approaches used to study the basic biology of megakaryocytes and platelets and to obtain new insights into their dysregulation in disease processes.

The first speaker, Dr. Bethan Psaila, discusses the application of single-cell multi-omic approaches to studying normal and aberrant pathways of megakaryocyte differentiation. “Multi-omics” is an approach in which the data sets from multiple “’omes,” such as the genome, proteome, transcriptome, epigenome, metabolome, and others are obtained and analyzed. These offer substantial capabilities in the study of complex biological systems and cells. Dr. Psaila addresses changes in megakaryopoiesis during development, specifically focusing on the mechanisms of myelofibrosis related to megakaryocyte-biased hematopoiesis. The session covers cutting-edge techniques including single-cell approaches to identify specific megakaryocyte subpopulations that have distinct signatures, metabolic and inflammatory, as well as recent research and novel approaches to targeting malignant megakaryocytes.

Induced pluripotential stem cells (iPSCs) are cells that have been reprogrammed back into an embryonic-like pluripotent state that enables the development of an unlimited source of any type of human cell. The second speaker, Dr. Mortimer Poncz, addresses the role that iPSCs have played in highlighting mechanisms of disease in inherited platelet/megakaryocyte disorders. The talk discusses Runt-related transcription fact 1 (RUNX1), a transcription factor central to hematopoiesis that is implicated in a clinical disorder termed “familial platelet disorder associated with myeloid malignancy” (FPDMM). FPDMM is known to be associated with quantitative and qualitative platelet defects and an increased risk of myeloid leukemia. Remarkably, studies of iPSCs derived from patients with FPDMM recapitulate the defect in megakaryopoiesis and have led to new insights into the pathogenesis of this disorder. The speaker details the mechanism underlying megakaryocyte deficiency and activation of proinflammatory pathways during megakaryocyte development. In keeping with the highly translational nature of this work, the talk describes development of potential therapeutics that work by preventing the defect seen in FPDMM iPSC cells. As a clinician with translational research interests, I am extremely excited to hear this bedside-to-bench-to-bedside story!

The third speaker in this session, Dr. Kathleen Freson, details the value of next-generation sequencing (NGS) in providing new insights into platelet and megakaryocyte biology. NGS refers to the massively parallel sequencing technology that has revolutionized genetic testing. Dr. Freson discusses the power of NGS in the context of platelets and megakaryocytes by addressing the observation that NGS-based multigene panel tests comprising all platelet disorder genes known today, can diagnose a significant subset of patients with platelet function and formation disorders. The session also explores the implications of performing such testing: Many disease-related genes are still unknown, and testing may unearth totally unexpected genes that may be implicated in novel platelet disorders. The speaker addresses the ensuing challenges in being able to provide biochemical and clinical correlations of novel findings using disease models, platelet transcriptomics, and functional assays, which will be critical to proving causality and understanding the role of the identified genes in platelet and megakaryocyte biology. Overall, this is an exciting session with a description of a technological tour de force for understanding the biology of platelets and megakaryocytes in the context of dysregulation and disease.

Attendees with clinical and translational interests in platelets may also enjoy the Education Program session “Platelet Transfusions for Hematology/Oncology Patients: Taking a More Granular Look” (live Q&A Sunday, December 6, at 9:30 a.m. Pacific time), which looks at key issues in the use of platelet transfusion therapy to prevent and treat bleeding in patients with hematology-oncology disorders. The session includes a discussion of prophylactic platelet transfusions, platelet transfusion refractoriness, and platelet ABO/Rh matching in this context. Additionally, the Education Program session “Chronic Transfusion Support: Challenging Cases” (live Q&A Monday, December 7, at 11:30 a.m. Pacific time) will also be relevant to attendees with platelet-focused interests. This session will review protocols to optimize transfusion therapy in patients with chronic transfusion needs, including for platelets.

Dr. Padmanabhan indicated no relevant conflicts of interest.

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