Nonsteroidal anti-inflammatory drugs have been widely used to provide short- and long-term analgesia and anti-inflammatory benefits to human and veterinary patients. By inhibiting the key enzyme, COX, in the arachidonic acid pathway, NSAIDs induce both analgesic and toxic effects.1,2 At least 2 isoenzymes of COX (COX-1 and COX-2) have been identified in humans and other animals.1,3 Cyclooxygenase-1 is considered a constitutive form of the COX enzyme; it is found in basal conditions in many cells and is responsible for such functions as gastric cytoprotection, regulation of renal blood flow, and regulation of platelet activity.4 In contrast, COX-2 is considered an inducible form of the COX enzyme; it is found in extremely low amounts in physiologically normal tissues but is rapidly induced in inflammatory conditions.1,2
Toxic effects of NSAIDs are thought to result mainly from inhibition of COX-1.3 As such, COX-2–selective NSAIDs have been developed in an attempt to minimize the adverse effects associated with the COX-1 inhibition of traditional NSAIDs.3,5,6 Clinical trials7–11 in dogs have identified several NSAIDs that are COX-2–selective inhibitors, including carprofen, deracoxib, firocoxib, and meloxicam. Although these NSAIDs are selective for inhibition of COX-2, most have varying degrees of inhibitory activity against COX-1.
An increased incidence of myocardial infarction and other adverse cardiovascular events has been associated with the use of COX-2–selective NSAIDs in humans.12,13 To our knowledge, no such reports have been made for veterinary species. The increased incidence of adverse cardiovascular events associated with COX-2 inhibitors in humans may be attributed to the induction of an imbalance in 2 systemic prostaglandins, TXA2 and PGI2.14 Thromboxane A2 is a product of COX-1 in platelets and induces vascular constriction and platelet aggregation in the circulation, whereas PGI2, a COX product of endothelial cells, inhibits platelet aggregation and induces vasodilation.15,16 Cyclooxygenase-2 inhibitors may lead to decreased concentrations of PGI2, which would leave the actions of TXA2 unopposed and potentially contribute to a prothrombotic environment in the circulation.14,17
Aspirin (formerly known as acetylsalicylic acid) is a COX-1 inhibitor and is generally considered to have antithrombotic effects as a result of irreversible acetylation of COX-1 in platelets, which prevents TXA2 production and induces antithrombotic effects for the lifespan of the platelets.18 Studies18–20 have revealed platelet inhibition induced by aspirin administered at antithrombotic (0.5 mg/kg, PO, q 12 h) and anti-inflammatory (≤ 10 mg/kg, PO, q 12 to 24 h) dosages.
Because COX-2–selective inhibitors are expected to spare production of COX-1 in platelets, they are thought to have little effect on platelet function. However, despite the increasing use of COX-2–selective inhibitors in veterinary medicine, there is limited information available regarding the effects of these NSAIDs on hemostasis in dogs.
Studies on platelet function after administration of COX-2 inhibitors have provided variable results. Platelet inhibition has resulted from administration of carprofen or meloxicam in some studies19,21,22 but not in others.19,23–27 A study19 of dogs with osteoarthritis revealed an increase in coagulation measured by use of thromboelastography (which was suggestive of hypercoagulability) after treatment with the COX-2–selective inhibitor deracoxib for 14 days. In that study,19 NSAID treatment did not result in an altered ratio of 6-keto PGF1α to TXB2 concentrations.
Controlled, blinded, randomized trials conducted to examine the effects of commonly used NSAIDs administered at therapeutic dosages on hemostasis in healthy dogs are lacking. The study reported here was conducted to examine the effects of 4 commonly used NSAIDs (aspirin, carprofen, deracoxib, and meloxicam) on platelet function and plasma 6-keto PGF1α and TXB2 concentrations in healthy dogs.
Activated partial thromboplastin time
1-stage prothrombin time
PFA-100, Dade-Behring, Mississauga, ON, Canada.
Equine muscle adenosine 5'-diphosphate, Sigma-Aldrich Co, St Louis, Mo.
Synthetic PAF-16, EMD Biosciences, San Diego, Calif.
Acetylsalicylic acid, Pharmascience Inc, Montreal, QC, Canada.
Rimadyl, Pfizer Animal Health Canada, Kirkland, QC, Canada.
Deramaxx, Novartis Animal Health Canada Inc, Mississauga, ON, Canada.
Metacam, Boehringer Ingelheim Canada Ltd, Burlington, ON, Canada.
Adiva 120, Bayer Inc, Toronto, ON, Canada.
Amelung KC 4 delta analyzer, Trinity Biotech, Ireland.
Research pipette, Eppendorf, Mississauga, ON, Canada.
Chrono-log 440VS, Chrono-log Corp, Haverton, Pa.
Thromboxane B2 EIA kit, Cayman Chemical Co, Ann Arbor, Mich.
6-keto-PGF1α EIA kit, Cayman Chemical Co, Ann Arbor, Mich.
SpectraMax miniplate reader, Biotek Instruments, Winooski, Vt.
SAS, version 9.1.3, SAS Institute Inc, Cary, NC.
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