title: Increased expression of procoagulant activity on the surface of human platelets exposed to heavy-metal compounds.
abstract: One of the essential roles for platelets in haemostasis is in the potentiation of blood clotting due to the contribution of anionic phospholipid from the surface of the cells, as an essential cofactor to the proteolytic reactions of coagulation (platelet procoagulant activity). Only a limited number of agonists are known to initiate platelet procoagulant activity. In this study the rate of thrombin formation on the platelet surface was observed to increase in a dose-dependent manner upon treatment of washed platelets with heavy-metal compounds. Unlike the immediate increase observed upon treatment of platelets with calcium ionophore, A23187, the change due to these agents was progressive, approaching a maximum after 10 min. The maximum-fold acceleration of the rate of thrombin formation compared with control platelets was calculated for HgCl2 (56-fold), AgNO3 (42-fold) phenylmercuriacetate (24-fold) and thimerosal (14-fold), compared with 70-fold observed for calcium ionophore. The increase in procoagulant activity due to HgCl2 coincided with a large increase in intracellular calcium and phosphorylation of 22 and 45 kDa proteins. It is considered that the mechanism responsible for the increase in procoagulant activity is exposure of anionic phospholipids. This was detected by a 2-fold increase in the binding of 125I-annexin V upon addition of HgCl2, compared with resting platelets (3-fold on treatment of platelets with calcium ionophore). In contrast to the generation of activity by A23187 and other known agonists of this reaction, heavy-metal compounds appeared to cause little or no release of microparticles from the platelet surface. Since HgCl2 did not cause aggregation of platelets or significant release of serotinin, these findings may give further support to the need for exposure and ligation of glycoprotein IIb:IIIa for vesiculization to occur. Treatment of platelets with heavy metals may constitute a new approach to investigating the early changes in the cell membrane which lead to increased expression of anionic phospholipid.
authors.affiliation: Thrombosis Research Institute, London, U.K.
authors.forename: C A
authors.initials: CA
authors.lastname: Goodwin
authors.forename: C P
authors.initials: CP
authors.lastname: Wheeler-Jones
authors.forename: S
authors.initials: S
authors.lastname: Namiranian
authors.forename: S
authors.initials: S
authors.lastname: Bokkala
authors.forename: V V
authors.initials: VV
authors.lastname: Kakkar
authors.forename: K S
authors.initials: KS
authors.lastname: Authi
authors.forename: M F
authors.initials: MF
authors.lastname: Scully
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D001777:Blood Coagulation; D001792:Blood Platelets / Q000201:enzymology*; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000648:ultrastructure; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008628:Mercury / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D010974:Platelet Aggregation; D011516:Prothrombin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
chemical_list: D017304:Annexin A5; D010750:Phosphoproteins; D012701:Serotonin; D011516:Prothrombin; D008628:Mercury; D002118:Calcium