Effects of Cyclosporin on the Antiplatelet Effect of Aspirin in Normal Dogs JOURNAL SCAN

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.

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