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ABSTRACT

  • Human platelets participate in a number of adhesive events that are crucial for repair of the vasculature. Although lacking in protein synthetic capability, platelets come equipped with a variety of membrane receptors and intracellular organelles that make them highly efficient “adhesion machines” for mediating the primary hemostatic process. Adhesion itself is an activating event, and it results in the transmission of signals to the cell interior by virtue of cell-surface receptors that form cytoplasmic connections with intracellular kinases, G proteins, and cytoskeletal components. Platelet activation, in turn, elicits the secretion of several types of intracellular granules, the contents of which serve to embellish further the formation of the platelet plug by providing additional adhesive ligands that can add to the local concentration of intercellular glue molecules.

  • The αIIbβ3 integrin receptor (also called glycoprotein [GP] IIb-IIIa) is the most abundant receptor on the platelet surface, representing nearly 15 percent of total surface protein. Glanzmann thrombasthenia is a rare, inherited, autosomal recessive bleeding disorder, the hallmark of which is the failure of platelets to bind fibrinogen and aggregate following stimulation by physiological agonists such as ADP, thrombin, epinephrine, or collagen. Underlying this disorder are abnormalities of either the αIIb or β3 gene. Glanzmann thrombasthenia is characterized by significant mucocutaneous bleeding beginning at an early age. Nearly 200 individuals with Glanzmann thrombasthenia have been described in the literature and 75 molecular defects have been identified in 61 kindreds. The molecular abnormalities have ranged from major deletions and inversions easily detectable by Southern blot analysis to single point mutations identified only by nucleotide sequence analysis of the genome or platelet mRNA-derived PCR products.

  • The GPIb complex is crucial for initial attachment and proper adhesion to the extracellular matrix of a damaged vessel. Bernard-Soulier syndrome represents the second most recognized inherited platelet disorder, and is characterized by a prolonged bleeding time, giant platelets, normal platelet aggregation with ADP, collagen, and epinephrine, but absent platelet agglutination in the presence of ristocetin. The Bernard-Soulier syndrome is an autosomal recessive disorder in which most patients have a decrease to absence of all four members of the GPIb complex, each encoded by a separate gene: GPIbα, GPIbβ, GPIX, and GPV. These genes have been cloned and characterized, and a growing number of patients have had the responsible defect defined on a molecular level. Defects in the GPIb complex are also responsible for another bleeding disorder—platelet-type (or pseudo-) von Willebrand disease—in which the platelet receptor exhibits increased affinity for von Willebrand factor (VWF).

  • In addition to amino acid changes that disrupt function and result in bleeding diatheses, several platelet membrane glycoproteins have naturally occurring allelic forms within the human gene pool. Two clinically recognized immunologic syndromes are attributable to “platelet-specific” polymorphisms. Neonatal alloimmune thrombocytopenia is characterized by neonatal thrombocytopenia due to passively transmitted maternal antibodies directed against a platelet antigen inherited from the father and lacking on maternal platelets. Posttransfusion purpura is quite rare, and is characterized by acute, usually severe, thrombocytopenia ...

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