Qualitative disorders of platelets and megakaryocytes

Summary.  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 α IIb β 3 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 α , 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 α ‐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 , TP α ) 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.