Qualitative disorders of platelets and megakaryocytes.
Qualitative disorders of platelet function and production form a large group of rare diseases which cover a multitude of genetic defects that by and large have as a common symptom, excessive mucocutaneous bleeding. Glanzmann thrombasthenia, is enabling us to learn much about the pathophysiology of integrins and of how alphaIIb beta3 functions. Bernard-Soulier syndrome, an example of macrothrombocytopenia, combines the production of large platelets with a deficit or non-functioning of the major adhesion receptor of platelets, the GPIb-IX-V complex. Amino acid substitutions in GPIb alpha, may lead to up-regulation and spontaneous binding of von Willebrand factor as in Platelet-type von Willebrand disease. In disorders with defects in the MYH9 gene, macrothrombocytopenias are linked to modifications in kidney, eye or ear, whereas other inherited thrombocytopenias variously link a low platelet count with a propensity to leukemia, skeletal defects, learning impairment, and abnormal red cells. Defects of secretion from platelets include an abnormal alpha-granule formation as in the gray platelet syndrome (with marrow myelofibrosis), and of organelle biogenesis in the Hermansky-Pudlak and Chediak-Higashi syndromes where platelet dense body defects are linked to abnormalities of other lysosomal-like organelles including melanosomes. Finally, defects involving surface receptors (P2Y(12), TPalpha) for activating stimuli, of proteins essential for signaling pathways (including Wiskott-Aldrich syndrome), and of platelet-derived procoagulant activity (Scott syndrome) show how studies on platelet disorders are helping unravel the pathways of primary hemostasis.
Nurden
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Institut Fédératif de Recherche N 4, CHU Bordeaux, Pessac, France. alan.nurden@cnrshl.u-bordeaux2.fr
D001606:Bernard-Soulier Syndrome / Q000097:blood; D001791:Blood Platelet Disorders / Q000097:blood* / Q000175:diagnosis*; D001792:Blood Platelets / Q000378:metabolism; D003029:Coagulants; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D010974:Platelet Aggregation; D011485:Protein Binding; D015398:Signal Transduction; D013915:Thrombasthenia / Q000097:blood; D013921:Thrombocytopenia / Q000097:blood; D015854:Up-Regulation; D014841:von Willebrand Factor / Q000378:metabolism
D003029:Coagulants; D016023:Integrins; D014841:von Willebrand Factor