Platelet Aggregation and Exposure of Fibrinogen Receptors by Prostaglandin Endoperoxide Analogues

Abstract

Two stable analogues of prostaglandin endoperoxides—9.11-azo-prostanoid III (9-11-azo PGH2) and 9,11-methanoepoxy PGH2 (U46619 compound)—caused aggregation of washed human platelets and release of α-granule contents. Platelet aggregation induced by these compounds was potentiated by the addition of purified human fibrinogen in a dose-dependent manner. Incubation of prostaglandin endoperoxide analogues with washed platelets in a nonstirred system exposed fibrinogen receptors. Enzymes that remove adenosine diphosphate (ADP) [apyrase and creatine phosphate in the presence of creatine Phosphokinase (CP/CPK)], adenosine triphosphate (ATP), a competitive antagonist of ADP, and 5' parafluorosulfonylbenzoyl adenosine (FSBA), an affinity label for ADP binding sites, all blocked platelet aggregation and binding of 125I-fibrinogen to platelets stimulated by prostaglandin endoperoxide analogues. In contrast, these compounds did not prevent platelet shape change induced by prostaglandin endoperoxide analogues. Apyrase, CP/CPK. ATP, and FSBA reversed platelet aggregation stimulated by ADP or prostaglandin endoperoxide analogues. Carbocyclic thromboxane-A2 (CTA2), a stable analogue of thromboxane-A2, blocked shape change and platelet aggregation and caused disaggregation of platelets stimulated by prostaglandin endoperoxide analogues. However, CTA2 did not inhibit ADP-induced platelet shape change and aggregation, and it did not disaggregate platelets that were previously aggregated by ADP. The mechanism of platelet aggregation induced by analogues of prostaglandin endoperoxides appears to involve (A) initial release of ADP and fibrinogen, (B) ADP-induced exposure of platelet membrane fibrinogen receptors, and (C) fibrinogen binding to the exposed receptors resulting in platelet aggregation. The occupation of prostaglandin endoperoxide receptors is required during all stages of this process.