Summary. Background: Circulating microparticles of various cell types are present in healthy individuals and, in varying numbers and antigenic composition, in various disease states. To what extent these microparticles contribute to coagulation in vivo is unknown. Objectives: To examine the in vivo thrombogenicity of human microparticles. Methods: Microparticles were isolated from pericardial blood of cardiac surgery patients and venous blood of healthy individuals. Their numbers, cellular source, and tissue factor (TF) exposure were determined using¯ow cytometry. Their in vitro procoagulant properties were studied in a ®brin generation test, and their in vivo thrombogenicity in a rat model. Results: The total number of microparticles did not differ between pericardial samples and samples from healthy individuals (P 0.786). In both groups, microparticles from platelets, erythrocytes, and granulocytes exposed TF. Microparticle-exposed TF antigen levels were higher in pericardial compared with healthy individual samples (P 0.036). Pericardial microparticles were strongly procoagulant in vitro and highly thrombogenic in a venous stasis thrombosis model in rats, whereas microparticles from healthy individuals were not [thrombus weights 24.8 (12.2±41.3) mg vs. 0 (0±24.3) mg median and range; P < 0.001]. Preincubation of pericardial microparticles with an inhibitory antibody against human TF abolished their thrombogenicity [0 (0±4.4) mg; P < 0.01], while a control antibody had no effect [19.6 (12.6±53.7) mg; P > 0.05]. The thrombogenicity of the microparticles correlated strongly with their TF exposure (r 0.9524, P 0.001). Conclusions: Human cell-derived microparticles promote thrombus formation in vivo in a TF-dependent manner. They might be the direct cause of an increased thromboembolic tendency in various patient groups.

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GPR147 and its endogenous ligands, RFRPs, are emerging as important actors in hypothalamic-pituitary axis control. The role of this system would be to inhibit gonadotrophin secretion. However, data on the subject are contradictory. The discovery of RF9 (adamantanecarbonyl-RF-2-NH(2)), a GPR147 antagonist, prompted us to use this new tool to further investigate this system in the ewe. Accordingly, we tested the effect of i.c.v. administration of RF9 on gonadotrophin secretion in the ewe during anoestrous and the breeding season. Intracerebroventricular injections of RF9 (from 50-450 nmol) caused a clear elevation in peripheral blood plasma luteinising hormone (LH) concentrations. The effect of RF9 on LH was more pronounced during the anoestrous season. Furthermore, peripheral administration of RF9 as a bolus (2.1, 6.2 and 12.4 μmol per ewe) or as a constant i.v. infusion (2.1, 6.2, 12.4 and 18.6 μmol/h per ewe) to anoestrous acyclic ewes induced a sustained increase in LH plasma concentrations. A pharmacokinetic study showed that RF9 (12.4 μmol bolus i.v.) has an effective half life of 5.5 h in the plasma. Conversely, RF9 is not detectable in the cerebrospinal fluid, suggesting that it does not cross the blood-brain barrier. The increase in LH plasma concentrations induced by RF9 was blocked by previous administration of 1.3 μmol per ewe of gondotrophin-releasing hormone (GnRH) antagonist Teverelix. This suggests that GnRH is involved in the stimulatory effect of RF9 on gonadotrophin secretion. Finally, no variation in LH plasma concentrations could be detected in ovariectomised ewes injected either i.c.v. or i.v. with RFRP3 (VPNLPQRF-NH(2)). The lack of effect of RFRP3 in our experimental setting suggests that the mechanisms involved in RF9 action are probably more complex than previously assumed. Our results indicate that delivery of RF9 in the ewe greatly increases gondadotrophin secretion in both the oestrus and anoestrus season, suggesting a potential new way of controlling reproduction in mammals.

Heparin coating of metallic coronary stents decreases their thrombogenicity but does not improve late vessel patency and neointimal hyperplasia at follow-up in a porcine coronary model.