Supervisors info:
Αργυρή Γιαλεράκη, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Μαριάννα Πολίτου, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Κωνσταντίνος Κωνσταντόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Summary:
Platelets (PLT) are the key molecules mediating haemostasis via adhesion, activation and clot formation at the site of injury. PLT are the smallest cells of the blood, have no nucleus but multiple organelles in their cytoplasm, two of which are specific to these cells: δ-granules and α-granules. The contents of these granules are secreted during the activation of platelets, leading to their aggregation. The PLT are produced by megakaryocytes (MKs), their giant bone marrow precursors, through a complex and highly regulated process. Before platelets can be released into the blood stream, the megakaryocytes undergo several cycles of endomitosis to become polylobulated with a high DNA content and accumulate massive amounts of proteins and membranes. The mature megakaryocytes, through a well driven cytoskeletal process, extend cytoplasmic protrusions, termed proplatelets, into the bone marrow sinusoids to release platelets. The process of megakaryopoiesis involves more than 75 genes, coding for transcription and translation factors, cytoskeletal proteins, granule biogenesis, membrane receptors and signaling proteins, which regulate megakaryocyte differentiation and platelet formation and release. Variants in any of these genes may cause a PLT disorder. Inherited platelet disorders (IPDs) are a heterogeneous group of rare diseases (of autosomal dominant, recessive or X-linked inheritance) characterized by either a qualitative or quantitative platelet defect, but not infrequently, IPDs combine thrombocytopenia and impaired platelet function. IPD patients present with a widely-variable bleeding diathesis, including mucous membrane bleedings such as epistaxis and gingival bleeding, but they may also present with serious life threatening bleedings following surgery or trauma. Many congenital PLT disorders are associated with other clinical syndromic manifestations. The estimated prevalence of IDPs is 1:10,000 to 1:1,000,00 births, although this figure is probably underestimated because they are often misdiagnosed as immune thrombocytopenia (ITP). A recent study showed that 0.329% of subjects in the general population have a clinically meaningful loss-of-function variant in a platelet-associated gene. Because of the rarity of these disorders, databases and modern genomics techniques such as WES and NGS, have become vital to IPDs research and elucidation. The current review describes IPDs, illustrates their clinical phenotype and molecular basis, and classifies them according to defects: A. of transcriptional and translational factors related to megakaryopoiesis and PLT production (14), B. of platelet surface receptors (6), C. of cytoskeletal and structural proteins (15), D. of biosynthesis, transport and secretion of α- and δ-granules (9), E. in apoptosis (7), F. in signaling pathways (13).
Keywords:
Platelets, Megakaryocytes, Inherited platelet disorders, Platelet function disorders
