SwitzerlandTo cite this article: Fontana P, Nolli S, Reber G, de Moerloose P. Biological effects of aspirin and clopidogrel in a randomized cross-over study in 96 healthy volunteers. J Thromb Haemost 2006; 4: 813-9.Summary. Background: Some data suggest that biological ÔresistanceÕ to aspirin or clopidogrel may influence clinical outcome. Objective: The aim of this study was to evaluate the relationship between aspirin and clopidogrel responsiveness in healthy subjects. Methods: Ninety-six healthy subjects were randomly assigned to receive a 1-week course of aspirin 100 mg day )1 followed by a 1-week course of clopidogrel (300 mg on day 1, then 75 mg day), or the reverse sequence, separated by a 2-week wash-out period. The drug effects were assessed by means of serum TxB 2 assay, platelet aggregation tests, and the PFA-100 Ò and Ultegra RPFA-Verify Now Ò methods. Results: Only one subject had true aspirin resistance, defined as a serum TxB 2 level > 80 pg lL )1 at the end of aspirin administration and confirmed by platelet incubation with aspirin. PFA-100 Ò values were normal in 29% of the subjects after aspirin intake, despite a drastic reduction in TxB 2 production; these subjects were considered to have aspirin pseudo-resistance. Clopidogrel responsiveness was not related to aspirin pseudo-resistance. Selected polymorphisms of platelet receptor genes were not associated with either aspirin or clopidogrel responsiveness. Conclusions: In healthy subjects, true aspirin resistance is rare and aspirin pseudo-resistance is not related to clopidogrel responsiveness.

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Background— Formation of platelet plug initiates hemostasis after vascular injury and triggers thrombosis in ischemic disease. However, the mechanisms leading to the formation of a stable thrombus are poorly understood. Connexins comprise a family of proteins that form gap junctions enabling intercellular coordination of tissue activity, a process termed gap junctional intercellular communication . Methods and Results— In the present study, we show that megakaryocytes and platelets express connexin 37 (Cx37). Deletion of the Cx37 gene in mice shortens bleeding time and increases thrombus propensity. Aggregation is increased in murine Cx37 −/− platelets or in murine Cx37 +/+ and human platelets treated with gap junction blockers. Intracellular microinjection of neurobiotin, a Cx37-permeant tracer, revealed gap junctional intercellular communication in platelet aggregates, which was impaired in Cx37 −/− platelets and in human platelets exposed to gap junction blockers. Finally, healthy subjects homozygous for Cx37–1019C, a prognostic marker for atherosclerosis, display increased platelet responses compared with subjects carrying the Cx37–1019T allele. Expression of these polymorphic channels in communication-deficient cells revealed a decreased permeability of Cx37–1019C channels for neurobiotin. Conclusions— We propose that the establishment of gap junctional communication between Cx37-expressing platelets provides a mechanism to limit thrombus propensity. To our knowledge, these data provide the first evidence incriminating gap junctions in the pathogenesis of thrombosis.