In vitro and ex vivo studies of the effects of immunosuppressive agents on human platelets

This work investigates the effects of immunosuppressants on platelet activity in renal allograft recipients and end-stage renal failure patients.;Methods: Blood from patients with end-stage renal failure (n=21) was incubated with physiological doses of cyclosporine, tacrolimus, and rapamycin. Non-stimulated and stimulated platelets were analysed for P-selectin expression and fibrinogen binding as measures of platelet activity.;Ex vivo platelet activity was assessed in transplant recipients taking rapamycin, cyclosporine, tacrolimus, or azathioprine (n=18 for each).;Results: 1. Platelet-bound fibrinogen was increased by incubation with cyclosporine, tacrolimus, and rapamycin. This effect was exaggerated in stimulated platelets; 2. Cyclosporine, tacrolimus, and rapamycin increased P-selectin expression in resting platelets. Positive dose effects were exhibited by the calcineurin inhibitors. Decreased P-selectin expression was observed with calcineurin inhibitor and rapamycin exposure in stimulated patients; 3. Resting and stimulated platelets from patients taking cyclosporine, tacrolimus and rapamycin bound less fibrinogen and expressed less P-selectin than controls; 4. Platelets exposed to rapamycin in vitro exhibited clumping. This was not seen ex vivo and platelet activation was lower in patients taking rapamycin compared to controls; 5. Larger spleen size was observed with rapamycin, cyclosporine, and tacrolimus use compared to the azathioprine group. All three drugs were associated and increased platelet size.;Conclusions: This study demonstrates that these immunosuppressants stimulate human platelets in vitro. This may occur through increased P-selectin expression and fibrinogen binding. It also suggests these agents disrupt platelet function in vivo, although the nature of this interaction is less clear. Altered platelet morphology and increased spleen size with rapamycin use may be implicated in rapamycin-induced thrombocytopenia. These results support a role for platelets in renal transplantation and identify several avenues for further study, particularly concerning the role of anti-platelet therapy in the transplant population.