title: Adhesive interactions of platelets and their blockade.
abstract: Formation of thrombi, which constitute the main mechanism of occlusive cardiovascular diseases, is mediated by blood platelets and fibrinogen. At least three stimulatory pathways can activate platelets, yet only one is sensitive to inhibition by aspirin (cyclooxygenase). Aspirin-insensitive pathways, mediated by protein kinase C and myosin light-chain kinase, lead to a change of platelet shape, with an attendant striking increase in their surface (pseudopods) followed by exposure of receptors for fibrinogen and vWf on GPIIb-IIIa. Another receptor for vWf (GPIb), independent of known pathways of platelet activation, seems to function primarily in vessels with a high shear rate. The multistep processes of platelet activation can be circumvented by the blockade of platelet receptors for adhesive molecules, present in subendothelium and in plasma. However, platelet receptors exposed on GPIIb-IIIa share common structural features with the endothelial receptor for vitronectin. Blockade of platelet GPIIb-IIIa with synthetic peptides containing the RGD sequence, or with certain monoclonal antibodies, may inadvertently cause detachment, or prevent attachment, of endothelial cells in a zone of vascular injury. The peptide analogs of human fibrinogen gamma chain sequence 400-411 possess high selectivity for platelet GPIIb-IIIa because they do not cause detachment of endothelial cells. Thus, endothelial regrowth in the zone of vascular injury following thrombolysis and/or angioplasty will go unperturbed. The significance of adhesive proteins interacting with their receptors transcends the issue of the fundamental mechanism of platelet aggregation of platelet thrombus formation. A molecular model of the adhesive interaction between fibrinogen domains and GPIIb-IIIa will probably be the most amenable to construction. Once such a model is established and its allosteric regulation is unraveled, its utility for further development of improved antiplatelet receptor blockers as antithrombotic drugs, that are both selective and potent will become a reality.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2363.
authors.forename: J
authors.initials: J
authors.lastname: Hawiger
mesh_terms: D000595:Amino Acid Sequence; D001792:Blood Platelets / Q000502:physiology*; D002318:Cardiovascular Diseases / Q000503:physiopathology; D005340:Fibrinogen / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D010973:Platelet Adhesiveness; D010980:Platelet Membrane Glycoproteins / Q000502:physiology*; D013927:Thrombosis / Q000503:physiopathology
chemical_list: D010980:Platelet Membrane Glycoproteins; D005340:Fibrinogen