Effects of immunosuppressive agents on the hemostatic system in normal dogs

Abstract

BackgroundIn dogs, the effects of immunosuppressive medications on hemostasis are not well known.Hypothesis/ObjectivesThe objective was to determine the effects of immunosuppressive medications on primary and secondary hemostasis. Our hypothesis was that cyclosporine and prednisone would increase markers of hypercoagulability and thromboxane synthesis, while azathioprine, mycophenolate mofetil, and leflunomide would have minimal effects on hemostasis.AnimalsEight healthy dogs.MethodsA randomized, cross‐over study used aggregometry, the PFA‐100 platelet function analyzer, viscoelastometry, platelet count, and prothrombin and activated partial thromboplastin times to evaluate hemostasis during the administration of prednisone, azathioprine, cyclosporine, mycophenolate mofetil, and leflunomide for 1 week each at standard oral doses. Urine 11‐dehydro‐thromboxane‐B2 (11‐dTXB2) and 6‐keto‐prostaglandin‐F1α (6‐keto‐PGF1α) concentrations, normalized to urine creatinine concentration, were measured.ResultsThe aggregometry amplitude decreased from 51 ± 21 to 27 ± 14 (P = .002) during leflunomide treatment (ADP activation), but there were no differences in amplitude (P = .240) for any medications when platelets were activated with collagen. For all medications, there were no significant differences in viscoelastometry indices (ACT, P = .666; ClotRate, P = .340; and platelet function, P = .411) and platelet count (P = .552). Compared with pretreatment values, urinary 11‐dTXB2‐to‐creatinine ratio increased (P = .001) after drug administration (from 3.7 ± 0.6 to 5.6 ± 1.1). Cyclosporine was associated with an increase (P < .001) in the 6‐keto‐PGF1α‐to‐creatinine ratio (from 10.3 ± 4.6 to 22.1 ± 5.3).Conclusions and Clinical ImportanceMost immunosuppressive drugs do not enhance platelet function or coagulation in healthy dogs, suggesting that these medications might not predispose hypercoagulable dogs to thromboembolism. The results of our study need to be correlated with the clinical outcomes of hypercoagulable dogs.

Effects of Aspirin and Prednisone on Platelet Function and Thromboxane Synthesis in Healthy Dogs

“…As expected, thromboxane concentrations in both the aspirin and prednisone groups were significantly decreased compared to the placebo group. The results of our study contrast with results of a prior study in healthy dogs administered the same prednisone dose and using the same assay to measure 11-dTXB 2 (31). In that study, an 80% increase in thromboxane concentration was noted after administration of the same prednisone dosage for 7 days to healthy dogs, although the increase was not consistent among dogs.…”

“…In previous studies, there have been contrasting results regarding platelet reactivity during the administration of immunosuppressive doses of prednisone. Similar to our study, Thomason et al did not detect a significant difference in platelet function following administration of immunosuppressive doses of prednisone to healthy dogs (31). In contrast, despite using the same agonist to initiate platelet aggregation, Romao et al demonstrated increased platelet aggregation in dogs treated with an immunosuppressive, but not an anti-inflammatory, dose of prednisone (32).…”

The in vitro effect of antirheumatic drugs on platelet function

“…Our finding is congruent with a recent study, which investigated the platelet aggregatory effect of leflunomide in 8 healthy dogs with LTA after 7 days treatment with leflunomide 20 With tocilizumab, the initial screening demonstrated an effect on ADP-, TRAPand collagen-induced platelet aggregation with 96-well LTA, but no effect on flow cytometric platelet aggregation. A previous study demonstrated no effect on TRAPinduced platelet aggregation in spiked samples from five healthy individuals 23 .…”

Effects of clopidogrel and prednisone on platelet function in healthy dogs

“…In contrast, fewer studies have been performed in dogs, with variable results, that have assessed the effects of exogenous glucocorticoids on platelet reactivity. One study did not detect a significant difference in platelet function after administration of prednisone (2 mg/kg PO q24h) to healthy dogs 24 . In contrast, another study identified increased platelet aggregation in dogs treated with prednisone at a dosage of 2 mg/kg PO q12h, but not at a prednisone dosage of 1 mg/kg PO q12h 25 .…”