JOURNAL SCAN
Effects of Cyclosporin on the Antiplatelet Effect of Aspirin in Normal Dogs
Thomason J , Archer , T et al 2016 . The Effects of Cyclosporin and Aspirin on Platelet Function in Normal Dogs . Journal of Veterinary Internal Medicine Vol 30 ( 6 ): 1022 -1030 Summarised by : Dr Liesel van der Merwe , BVsc MMedVet ( Med ) Small Animals
Why they did it : Mortality rates for IMHA are high and thromboembolic disease , especially pulmonary thromboembolism , is the most common cause of death . Dogs with IMHA are hypercoagulable and hyperactive platelets are one of the causes . Activated platelets release vasoactive molecules : serotonin and thromboxane A2 which contribute to a hypercoagulable state
Treatment of IMHA in dogs consists of immunosuppressive medications , drugs which inhibit haemostasis and supportive care . Glucocorticoids are the cornerstone of therapy but cyclosporine ( Cxs ) has become popular because of its perceived safety and minimal adverse effects . In humans , CxS increases platelet synthesis of thromboxane A2 . Thromboxane A2 triggers vasoconstriction , causes platelet activation and enhances platelet aggregation all of which increase blood stasis and promote coagulation . This side-effect is similar in dogs on immunosuppressive doses of CxS , thus therapy used in IMHA may enhance coagulopathy in these already at risk patients .
Drugs which inhibit haemostasis are routinely used prophylactically in dogs with IMHA , with low dose ( LD ) aspirin the most practical and affordable option . Use of LD aspirin has been shown to increase survival in dogs with IMHA . Aspirin is a COX- which irreversible inhibits platelet function by blocking thromboxane A2 production amongst other prostaglandins . Anti-inflammatory doses of aspirin ( 10mg / kg po bid ) reliably inhibits platelet function but can cause other complications such as acute renal failure and gastrointestinal complications - lower , less reliable , doses are typically recommended for anti-platelet effect : 0.5 – 1mg / kg oid . Aspirin has been shown to decrease the urinary thromboxane : creatinine ratio . It is currently unknown if CxS counteracts the effects of the aspirin therapy .
How they did it Seven healthy dogs underwent a 4-way randomised cross-over study . The dogs were given either LD aspirin at 1mg / kg po oid , high dose ( HD ) aspirin at 9.9mg / kg bid po , Cyclosporine at 9.9mg / kg po bid or combined LD aspirin / CxS therapy at the abovementioned . All drugs were administered per os for 7 days followed by a 14 day wash-out period .
Samples were collected for platelet function testing and urinary thromboxane analysis on day 0 ( baseline prior to administration ), and again on D3 and D7 . Samples were collected at estimated CxS peak levels determined previously to be 2 hours post oral administration . Samples for platelet analysis were collected in sodium-citrate . Platelet function analysis was assessed by two methods :
• Turbidometric platelet aggregometry using collagen as an agonist and testing the platelet rich plasma ( PRP ) harvested from the sample . A dog was considered an “ aspirin responder ” if there was a > 25 % decrease in the percentage aggregation , as measured with amplitude , compared to D0 .
• Platelet function analyser ( PFA-100 ): assesses platelet function under high shear forces . The instrument cutoff is > 300sec and a dog was considered an aspirin responder if the " closure time " was > 300sec
Urine ( 2-5ml ) was collected using US-guided cystocentesis . Urinary 11-dehydro-thromboxane was measured using a standard kit validated in dogs . The urinary 11-dTXB2 : creatinine ratio was calculated .
What they found : Based on turbidometric aggregometry 43 % of patients treated with LD aspirin were considered responsive after 3D and 71 % at 7D . Aspirin resistance does occur in human and animals medicine and there are no pre-treatment tests to predict .
The LD / HD and LD / CxS groups all showed a decrease from D0 to D7 : from 48.3 % to 10.3 % in the LD group , 53.3 % to 1.5 % in the HD group and from 51.8 % to 3 % in the LD / CxS group . The CxS group remained unchanged at 63.5 % to 56 %. There was a significant ( p < 0.0001 ) decrease in amplitude in the HD aspirin group on D3 compared to the other groups . On D7 there was a significant difference between the LD and HD aspirin group ( p = 0.012 ), and between the HD aspirin group and CxS group ( P < 0.0001 ). There was also a significant difference between the LD aspirin + CxS combined group and the CxS group ( p < 0.0001 ) but no significant difference with the LD aspirin group .
With THE PFA analysis the LD / HD and LD / CxS groups all showed increases in times from D ) to D7 : the LD group from 112 sec to 243.5 sec , HD group from 110 sec to 300 sec , and LD / CxS group from 103 sec to 266 sec . The CxS group remained unchanged at 130.5 sec to 126.5 sec .
In the TPA and turbidometric assays the HD aspirin provided a more reliable antiplatelet effect but the side effects of the higher doses can be a problem
With the urine thromboxane : creatinine ratio the aspirin groups ( HD and LD ) remained essentially unchanged and the CxS group increased as anticipated . The combination group showed an initial increase in urinary thromboxane loss but this decreased by D7 . There was a significant difference between the LD aspirin + CxS group and the CXs group on D3 ( p = 0.268 ) and D7 ( p < 0.0001 ). On both days there was no difference among the groups with aspirin
Take home message : The addition / use of cyclosporine with the LD aspirin did not counteract the anti-platelet effects of the aspirin . A dose somewhere in-between the LD and HD aspirin may be more reliable and still not give major side effects . vet360
Issue 06 | DECEMBER 2016 | 34