The Effects of Cyclosporine and Aspirin on Platelet Function in Normal Dogs

Abstract

BackgroundCyclosporine increases thromboxane synthesis in dogs, potentially increasing the thrombogenic properties of platelets.Hypothesis/ObjectivesOur hypothesis was that the concurrent administration of low‐dose aspirin and cyclosporine would inhibit cyclosporine‐associated thromboxane synthesis without altering the antiplatelet effects of aspirin. The objective was to determine the effects of cyclosporine and aspirin on primary hemostasis.AnimalsSeven healthy dogs.MethodsA randomized, crossover study utilized turbidimetric aggregometry and a platelet function analyzer to evaluate platelet function during the administration of low‐dose aspirin (1 mg/kg PO q24h), high‐dose aspirin (10 mg/kg PO q12h), cyclosporine (10 mg/kg PO q12h), and combined low‐dose aspirin and cyclosporine. The urine 11‐dehydro‐thromboxane‐B2 (11‐dTXB 2)‐to‐creatinine ratio also was determined.ResultsOn days 3 and 7 of administration, there was no difference in the aggregometry amplitude or the platelet function analyzer closure time between the low‐dose aspirin group and the combined low‐dose aspirin and cyclosporine group. On day 7, there was a significant difference in amplitude and closure time between the cyclosporine group and the combined low‐dose aspirin and cyclosporine group. High‐dose aspirin consistently inhibited platelet function. On both days, there was a significant difference in the urinary 11‐dTXB 2‐to‐creatinine ratio between the cyclosporine group and the combined low‐dose aspirin and cyclosporine group. There was no difference in the urinary 11‐dTXB 2‐to‐creatinine ratio among the low‐dose aspirin, high‐dose aspirin, and combined low‐dose aspirin and cyclosporine groups.Conclusions and Clinical ImportanceLow‐dose aspirin inhibits cyclosporine‐induced thromboxane synthesis, and concurrent use of these medications does not alter the antiplatelet effects of aspirin.

Effects of immunosuppressive agents on the hemostatic system in normal dogs

“…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.…”

“…Eight healthy Walker Hound dogs, 4 intact females and 4 neutered males, with a median age of 2 years (range, 1.3–7.3 years) were used in our study. A sample size calculation was performed using data from a previous study that measured urinary 11‐dehydro‐thromboxane B 2 (11‐dTXB 2 ) concentrations in dogs receiving cyclosporine . Based on the differences in means and standard deviations, and using a power of 0.8 and alpha of 0.05, a total of at least 7 dogs per treatment group was determined to be needed to detect a significant difference of 50% among groups.…”

“…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 .…”

Effects of aspirin dose escalation on platelet function and urinary thromboxane and prostacyclin levels in normal dogs

“…Currently used standard low or antiplatelet dosages (0.5–1 mg kg −1 day −1 ) of aspirin, however, do not reliably inhibit platelet function (Dudley et al., ; Haines et al., ; Hoh et al., ). Platelet function in dogs will, in contrast, be consistently inhibited by high dosages of aspirin (Thomason et al., ), suggesting that, if dogs are treated with high enough doses of aspirin, there is an increased likelihood of inhibition of platelet function. Unfortunately, as the aspirin dosage increases, so does the risk of undesirable inhibition of prostacyclin, and of aspirin‐induced side effects.…”