Clinical use of cyclosporin A (CsA) has been associated with platelet hypersensitivity and an increased incidence of thrombotic and vasoactive events. The purpose of this study was (1) to confirm that CsA enhances platelet sensitivity to the soluble agonists, adenosine diphosphate (ADP) and epinephrine (EPI), and (2) to determine if this enhancement is mediated by alteration in the availability of platelet surface fibrinogen receptors, a final mediator of platelet activation. Mean log dose of ADP required to achieve complete second-wave platelet aggregation in vitro decreased from 1.90 to 1.49 microM (n = 19, paired t test, P less than 0.05) and 2.86 to 2.11 microM (n = 16, P less than 0.05) following a 15-min and 3-hr incubation in the absence (saline) and presence of CsA (1000 ng/ml), respectively. At the threshold dose of ADP, concurrent thromboxane B2 levels at 15 min were 245 +/- 44 ng/ml (n = 12, saline) and 265 +/- 54 ng/ml (n = 9, CsA; P greater than 0.05). At 3 hr respective levels were 333 +/- 57 and 442 +/- 81 ng/ml (P greater than 0.05). Similar results were obtained with EPI. The number of fibrinogen binding sites in response to 50 microM ADP was determined in washed platelets in the absence and presence of CsA by radioligand binding. In 6 of 7 volunteers, CsA increased fibrinogen receptors from 26,635 +/- 4841 to 35,925 +/- 7290 sites/platelet (means +/- SEM; P less than 0.05). No change in receptor affinity was noted. In conclusion, cyclosporine does augment platelet reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)