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

Abstract

Background: Cyclosporine has been shown to alter platelet plasma membranes and have a hypercoagulable effect in humans, leading to thromboembolic complications.Hypothesis/Objectives: Our hypothesis was that by modulating platelet reactivity, cyclosporine increases the risk of thromboembolic complications. The objective was to determine the effects of cyclosporine on primary hemostasis in normal dogs.Animals: Eight healthy, intact female dogs. Methods: A repeated-measures design utilized flow cytometry to evaluate platelet expression of platelet reactivity markers (P-selectin and phosphatidylserine) and COX-1 and COX-2 during the administration of 2 cyclosporine dosages (19 mg/kg q12h [immunosuppressive dosage] and 5 mg/kg q24h [atopy dosage]). Urine 11-dehydro-thromboxane-B 2 (11-dTXB 2 ) concentration was normalized to urine creatinine concentration, and platelet function was analyzed by PFA-100.Results: After a week of the immunosuppressive dosage, all platelet reactivity markers showed a significant decrease in mean fluorescent intensity (MFI). After the atopy dosage, only P-selectin and COX-2 MFI demonstrated a change from baseline, decreasing by 29% (P = .013) and 31% (P = .003), respectively. Urinary 11-dTXB 2 -to-creatinine ratio significantly increased at all time points during the immunosuppressive dosage, but no significant change occurred during administration of the atopy dosage. PFA-100 closure times using collagen/ADP cartridges increased by 62% (P = .008) with the immunosuppressive dosage and decreased by 45% with the atopy dosage (P = .035). No significant changes in closure times occurred with collagen/epinephrine cartridges.Conclusions and Clinical Importance: Our study suggests that, similar to what is observed in humans, cyclosporine alters the platelet plasma membrane and increases thromboxane production in dogs, especially at immunosuppressive dosages.

Effects of immunosuppressive agents on the hemostatic system in normal dogs

“…In our study, similar to previous studies, the administration of cyclosporine to healthy dogs was not associated with a change in measures of platelet function such as aggregometry or PFA‐100 analysis, or measures of secondary hemostasis such as PT, PTT, and viscoelastometry. These results suggest that any increase in thromboxane was either insufficient to alter platelet function, or that the concurrent increase in prostacyclin synthesis negated any platelet activating tendencies of cyclosporine.…”

“…In dogs with IMHA, cyclosporine is widely used as an adjunctive treatment to corticosteroids . As has been reported in humans, cyclosporine, especially at the time of peak blood drug concentrations, will increase synthesis of thromboxane in dogs in a dose‐dependent manner . Our study demonstrated there was a significant increase in thromboxane synthesis after drug administration.…”

“…All drugs were administered for 7 days, followed by a recovery period of at least 21 days between dosing. In previous cyclosporine studies, changes in thromboxane production were seen within one week of commencing the drug, and had returned to pretreatment values within 2 weeks of discontinuing the medications . After the recovery period, the dogs switched groups, and the study was continued until all dogs had received all medications.…”

“…Cyclosporine has become a popular drug for the treatment of IMHA in dogs . In dogs, as in humans, administration of cyclosporine is associated with a significant increase in thromboxane A 2 synthesis, especially at the time of peak blood drug concentrations in dogs receiving immunosuppressive dosages of cyclosporine . Thromboxane A 2 , which is primarily produced by activated platelets, triggers vasoconstriction, and enhances platelet activation and aggregation, which decreases blood flow, promotes coagulation, and could predispose patients to excessive thrombus formation .…”

ACVIM consensus statement on the treatment of immune‐mediated hemolytic anemia in dogs

“…Ketoconazole has been used to decrease PO cyclosporine dosages in dogs by as much as 75%, although individual responses vary . Experimentally, PO cyclosporine increases some markers of platelet activation in normal dogs, which may be a concern in dogs with IMHA, in which hypercoagulability and thromboembolism may be major contributors to patient mortality . However, the clinical relevance of this phenomenon remains unclear.…”