title: Thrombosis and inflammation as multicellular processes: significance of cell-cell interactions.
abstract: Platelet activation as a result of vascular injury provokes endothelial cells to respond in a manner which limits or reverses the occlusive consequences of platelet accumulation. If the agonistic forces are strong, platelet accumulation is irreversible. In vitro data from our laboratory have repeatedly demonstrated that platelets become unresponsive to all agonists when in proximity to endothelial cells. This unresponsiveness is due to at least three separate endothelial "thromboregulatory" systems: eicosanoids, endothelium-derived relaxing factor (EDRF/NO), and most importantly an endothelial cell ecto-nucleotidase which metabolizes released platelet adenosine diphosphate (ADP) with consequent restoration of platelets to the resting state. This nucleotidase is operative in the complete absence of EDRF/NO and eicosanoids, indicating that the latter two are dispensable thromboregulators. We have solubilized the human endothelial cell ectoADPase, as well as that from placental tissue. Candidate proteins from a purified ADPase fraction are now being studied in further detail. An understanding of the molecular biology of the ADPase gene may lead to development of therapeutic agents such as soluble forms of the enzyme as well as approaches toward up-regulation of ectoADPase activity. This could result in "early thromboregulation", i.e. prevention and/or reversal of platelet accumulation at sites of vascular damage via immediate metabolic removal of the prime platelet agonist-ADP.
authors.affiliation: Departement of Veterans Affairs Medical Center, New York, NY 10021, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Marcus
authors.forename: L B
authors.initials: LB
authors.lastname: Safier
authors.forename: M J
authors.initials: MJ
authors.lastname: Broekman
authors.forename: N
authors.initials: N
authors.lastname: Islam
authors.forename: J H
authors.initials: JH
authors.lastname: Fliessbach
authors.forename: K A
authors.initials: KA
authors.lastname: Hajjar
authors.forename: W E
authors.initials: WE
authors.lastname: Kaminski
authors.forename: E
authors.initials: E
authors.lastname: Jendraschak
authors.forename: R L
authors.initials: RL
authors.lastname: Silverstein
authors.forename: C
authors.initials: C
authors.lastname: von Schacky
mesh_terms: D000244:Adenosine Diphosphate / Q000502:physiology; D001081:Apyrase / Q000502:physiology; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000473:pathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015777:Eicosanoids / Q000502:physiology; D004730:Endothelium, Vascular / Q000293:injuries / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology*; D009569:Nitric Oxide / Q000502:physiology; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology; D013927:Thrombosis / Q000188:drug therapy / Q000473:pathology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D018840:HSP70 Heat-Shock Proteins; D009569:Nitric Oxide; D000244:Adenosine Diphosphate; D001081:Apyrase; D001241:Aspirin