Effects of Immunosuppressive Drugs on Platelet Aggregation and Soluble P-Selectin Levels in Renal Transplant Patients

Abstract

Background/aim. Post-transplant cardiovascular events are associated with increased morbidity and mortality after renal transplantation. Though renal transplantation eliminates cardiovascular disease risk factors by restoring renal function, it introduces new cardiovascular risks derived partly from immunosuppressive medications. In this study, to assess the effects of various immunosuppressive drugs on platelet function of renal transplant patients, we measured soluble P selectin levels (sP-selectin) and performed platelet aggregation studies in patients who have undergone renal transplantation. Methods. sP-selectin levels and platelet aggregation induced by 5 μM adenosine diphosphate (ADP), 5 μM epinephrine, 1.25 mg/mL ristocetin, and 2 μg/mL collagen were studied by whole blood platelet lumiaggregometer in 40 renal transplant patients. Patients in group 1 (n = 24) were treated with cyclosporine/mycophenolate mofetil/ methylprednisolone, and group 2 (n = 16) were treated with tacrolimus/mycophenolate mofetil/methylprednisolone. Effects were compared with those in control groups of hypertensive subjects and healthy subjects. Results. Platelet aggregation values induced by ADP, epinephrine, ristocetin, and collagen were lower in cyclosporine-treated patients than tacrolimus-treated patients, hypertensive subjects, and healthy subjects, though the difference was not statistically significant (p > 0.05). sP-selectin levels were appreciably higher in cyclosporine-treated patients, and statistically significant differences were observed compared with those of tacrolimus-treated patients (p < 0.05), hypertensive subjects (p < 0.01), and healthy subjects (p < 0.05). Conclusion. We conclude that cyclosporine-treated renal transplant patients show enhanced platelet activation in which anti-platelet therapy should be considered, in addition to management of other conventional cardiovascular risk factors, to decrease the cardiovascular morbidity and mortality in this high risk population.

Effects of immunosuppressive agents on the hemostatic system in normal dogs

“…Because both azathioprine and mycophenolate mofetil have similar mechanisms of action, it was expected that these medications would have similar results. The results of our study are similar to previous studies performed in humans that did not identify a significant change in measures of hemostasis during treatment with azathioprine or mycophenolate mofetil …”

The Effects of Cyclosporine on Platelet Function and Cyclooxygenase Expression in Normal Dogs

“…This is due partly to the perception that cyclosporine has a more favorable adverse effect profile when compared with other immunosuppressive agents . Recent studies in humans, however, have shown that cyclosporine can alter the platelet plasma membrane, increase the thrombogenic properties of platelets, and accelerate thrombin generation . Approximately 50% of dogs with IMHA have been shown to be in a hypercoagulable state, predisposing these patients to complications such as pulmonary thromboembolism (PTE) .…”

“…The exact mechanisms of PTE are not completely understood, but it is hypothesized that predisposing prothrombotic conditions involves both blood platelets and the clotting system . Results of several studies in humans have suggested that cyclosporine may enhance platelet reactivity, a finding that necessitates a better understanding of how canine platelets interact with this medication, and if drug administration is a potential risk factor for PTE. A recent pilot study performed in our laboratory using a small number of dogs found increased platelet P‐selectin expression (an adhesion protein with procoagulant and proinflammatory properties) after administration of cyclosporine .…”

Immunophilins and Thrombotic Disorders

“…2). It has been shown that soluble Pselectin, responsible of platelet adhesion, is enhanced in patients treated with CsA, compared to FK506 and control platelets [111]. Surface expression of P-selectin is enhanced in resting platelets of renal transplanted patients, and it was further enhanced after stimulation with thrombin in patients treated with CsA and FK506 [109].…”

“…The role of immunophilins and cyclophilins in platelet activity and aggregation still remains controversial, with studies reporting thrombocytopenia [99][100][101][102][103][104][105][106], platelet hyperactivity [108][109][110] or platelet activity inhibition [111][112] in patients. This controversy might be attributed to the number of intracellular pathways altered by these inhibitors (See Fig.…”