Platelet aggregometry testing during aspirin or clopidogrel treatment and measurement of clopidogrel metabolite concentrations in dogs with protein‐losing nephropathy

Abstract

Background Dogs with protein‐losing nephropathy (PLN) are treated with antiplatelet drugs for thromboprophylaxis but no standardized method exists to measure drug response. It is also unknown if clopidogrel metabolite concentrations [CM] differ between healthy and PLN dogs. Objectives Assess response to aspirin or clopidogrel in PLN dogs using platelet aggregometry (PA) and compare [CM] between healthy and PLN dogs. Animals Six healthy and 14 PLN dogs. Methods Platelet aggregometry using adenosine diphosphate (ADP), arachidonic acid (AA), and saline was performed in healthy dogs at baseline and 1‐week postclopidogrel administration to identify responders or nonresponders. A decrease of ≥60% for ADP or ≥30% for AA at 1 or 3 hours postpill was used to define a responder. At 1 and 3 hours postclopidogrel, [CM] and PA were measured in healthy and PLN dogs. Platelet aggregometry was performed in PLN dogs at baseline, 1, 6, and 12 weeks after clopidogrel or aspirin administration. Results In PLN dogs receiving clopidogrel, PA differed from baseline at all time points for ADP but not for AA at any time point. Most dogs responded at 1 or both time points except for 1 dog that showed no response. For PLN dogs receiving aspirin, no differences from baseline were observed at any time point for either ADP or AA. No differences in [CM] were found at either time point between healthy and PLN dogs. Conclusions and Clinical Importance Platelet aggregometry may represent an objective method to evaluate response to clopidogrel or aspirin treatment and PLN dogs appear to metabolize clopidogrel similarly to healthy dogs.

Evaluation of thrombin generation in dogs administered clopidogrel

“…The prevalence of clopidogrel resistance in dogs is not established. In one study, most dogs with protein losing nephropathy had laboratory evidence of platelet inhibition in the face of clopidogrel administration, but one dog failed to respond in the expected way ( 26 ). Veterinary practitioners might encounter situations when monitoring the platelet inhibitory of clopidogrel in an individual dog would be desirable.…”

“…Recently, genetic polymorphisms in cats have been identified that contribute to individual variation to clopidogrel (25). Individual variation to clopidogrel dosing was also noted in some dogs with protein losing nephropathy (26). It therefore might be prudent to undertake therapeutic monitoring in some patients, to prevent overdosing and adverse bleeding events, as well as underdosing and failure to achieve an antithrombotic effect (27).…”

Whole blood platelet impedance aggregometry with the ROTEM platelet device: comparison of 2 anticoagulants and storage times for the establishment of canine reference intervals

“…AUC decreased significantly in dogs treated with clopidogrel and tested in a Multiplate analyzer using ADP as agonist, and therefore, distinguishing impaired from normal platelet function is still possible. 43,47 Poor correlation of methods of platelet function testing in dogs was identified comparing thromboelastographic platelet mapping to whole blood platelet aggregometry with the Multiplate analyzer and platelet function analysis using citrated whole blood. It is suggested that population-based RIs are unsuitable for most platelet function tests, and that subject-based RIs are preferable because biological variation in platelet aggregation should be considered.…”

Drug-Dosing Adjustment in Dogs and Cats with Chronic Kidney Disease

“…Dose adjustments seem to not be required in humans with CKD [87,88]; however, the marked variability in pharmacokinetics of clopidogrel justifies its cautious use in patients with advanced CKD [80,88,89]; a lower antiplatelet effect has been observed in CKD patients [90]. Drug metabolism may not be altered in dogs with PLN and early CKD [91].…”

“…Hence, a lower antiplatelet effect of clopidogrel was observed in CKD patients [90] and has been associated with an increased risk of death, death from bleeding, and hospitalization for bleeding in patients with ESKD [88]; as a result, the summary of product characteristics of clopidogrel recommends caution when using clopidogrel in the CKD population [80]. Clinical studies on clopidogrel in dogs and cats with CKD are lacking; according to a recent study, no differences in clopidogrel metabolite concentrations were found between healthy dogs and those with PLN and early CKD stages, suggesting that the drug's metabolism is not altered in these patients [91]. Nevertheless, caution should be adopted when administering clopidogrel in dogs and cats with advanced CKD.…”