Platelet Activation is Increased in Cyclosporin A-Induced Hypertensive Rats

Abstract

One of the most severe side effects of the immunosuppressive agent, cyclosporin A (CsA), is increased risk of thromboembolic complications and drug-related hypertension. Because platelets might be involved in these processes, we tested the possibility of CsA affecting platelet activation, which might contribute to these adverse drug reactions. The experiments were done using Wistar rats, treated or not (control) with CsA (Sandimmun Neoral), 5 and 30 mg/kg/day, for 7 weeks. Systolic, diastolic, and mean blood pressures, intracellular free calcium concentration ([Ca2+]i), platelet serotonin (5-HT) contents, and aggregation were determined, at weeks 0, 2, and 7 of treatment. Inositol phosphates (InsP) production, platelet thromboxane A2 (TXA2) generation, and morphology of platelets, through electron microscopy studies, also were compared. It was demonstrated that blood pressures increased in the CsA-treated groups, when compared with the control group, after 2 and 7 weeks of administration. CsA at both "attack" and "maintenance" doses increased basal, 5-HT, and thrombin-evoked [Ca2+]i after 2 and 7 weeks versus the control group. However, basal and evoked InsP production was stimulated by 5 mg/kg of CsA, but inhibited by 30 mg/kg, when compared with the control. Platelet 5-HT contents decreased significantly after 2 and 7 weeks in the CsA-treated groups, when compared with the control group. Collagen-induced whole blood platelet aggregation increased drastically in the "attack" CsA-treated group, whereas adenosine diphosphate (ADP)-induced platelet aggregation did not reach statistical significance. Finally, in vitro basal, collagen-, and ADP-evoked platelet TXA2 generation increased in both CsA concentrations, versus the control. In conclusion, our study demonstrates that both CsA doses alter platelet calcium homeostasis (even affecting the calcium fluxes differently), 5-HT and TXA2 contents and aggregation, which might contribute to the development and/or maintenance of high blood pressures and increased risk of thromboembolic complications.

Cyclosporin A does not affect platelets in children with idiopathic nephrotic syndrome

“…In our patients, the median pre-dose concentration of CyA was 99 ng/ml. Therefore differences of platelet effects in our study and those of Reis et al [32] and Naik et al [16] could be attributed to differences in the blood concentration of CyA.…”

“…Reis et al [32] showed that collagen-induced platelet aggregation was increased in rats treated with CyA. In contrast, the aggregation induced by ADP was not changed.…”

“…Since the data are conflicting, we postulate that the enalapril therapy (in 5 of 16 CyAtreated patients) had an insignificant influence on the results of our study. Previous studies assessing the influence of CyA on platelet function have produced controversial results [15,16,17,18,19,31,32,33]. To date, the influence of immunosuppressive therapy on platelet function in renal transplant recipients has been most widely studied [15,33].…”

Drug- not carrier-dependent haematological and biochemical changes in a repeated dose study of cyclosporine encapsulated polyester nano- and micro-particles: Size does not matter

“…CsA is known to increase platelet activation/aggregation increasing the risk of thromboembolic complications and hypertension (Reis et al, 2000). Significantly higher platelet counts were observed in Neoral  treated rats but not with nCsA or mCsA at any dose; the mean platelet volume (MPV) remained the same across all CsA treatments.…”

Enhancement by cyclosporine A and tacrolimus of serotonin-induced formation of small platelet aggregation

“…Serotonin is thought to be participating in at least part of this reaction, supporting the results of previous reports in which CsA was assumed to activate serotonin-related platelet activation. 7,9 Although the details of the mechanisms remain to be clarified, Tc as well as CsA may promote thrombotic events in patients treated with BMT.…”