Effects of Ultra-Low-Dose Aspirin in Thrombosis and Haemorrhage.

BACKGROUND: Aspirin is the oldest and possibly the most widely used pharmacologically active substance still used in allopathic medicine. Its effect on fever and inflammation has paved the way to its anti-thrombotic effect. Dilutions of aspirin have been tested for many years in the University of Bordeaux, in humans as well as in animal models. METHODS: This article is a review of the totality of articles published by the Laboratory of Hematology of the Faculty of Pharmacy of the University of Bordeaux, reporting different doses and dilutions of aspirin, different kinds of inhibitors, transgenic mice and animal models of disease such as portal hypertension and cirrhosis. RESULTS: Homeopathic dilutions of aspirin, notably 15 cH, have shown a pro-thrombotic effect in humans and in in-vivo animal studies. Longitudinal studies in rats have also shown an initial anti-thrombotic effect followed by a pro-thrombotic effect of aspirin several days after a single high-dose administration. This pro-thrombotic effect seems to act by inhibiting the cyclooxygenase (COX)-2 pathway in studies performed with COX selective inhibitors and in knock-out mice without COX-1 or COX-2. This effect may explain the thrombo-embolic complications described after aspirin withdrawal for the purposes of surgery or after non-compliance with anti-platelet therapy, and it may be beneficial in normalising primary haemostasis and decreasing haemorrhage in animal models of portal hypertension and cirrhosis. CONCLUSIONS: Aspirin 15 cH acts through the inhibition of the COX-2 pathway producing a clear pro-thrombotic effect. Further studies should clarify if the pro-thrombotic effect of aspirin withdrawal and the effect of aspirin 15 cH are related, as secondary effects of the same drug. Clarifying this last outcome may be of great significance to public health.

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension.

AIM: To study the mechanism involved in the potentially beneficial effect of ultra low dose aspirin (ULDA) in prehepatic portal hypertension, rats were pretreated with selective COX 1 or 2 inhibitors (SC-560 or NS-398 respectively), and subsequently injected with ULDA or placebo. METHODS: Portal hypertension was induced by portal vein ligation. Platelet activity was investigated with an in-vivo model of laser induced thrombus production in mesenteric circulation and induced hemorrhagic time (IHT). Platelet aggregation induced by ADP and dosing of prostanoid products 6-keto-PGF1alpha, TXB2, PGE2 and LTB4 were also performed. RESULTS: The portal hypertensive group receiving a placebo showed a decreased in vivo platelet activity with prolonged IHT, an effect that was normalized by ULDA. SC-560 induced a mild antithrombotic effect in the normal rats, and an unmodified effect of ULDA. NS-398 had a mild prothrombotic action in portal hypertensive rats, similar to ULDA, but inhibited a further effect when ULDA was added. An increased 6-keto-PGF1alpha was observed in portal hypertensive group that was normalised after ULDA administration. TXA2 level after ULDA, remained unchanged. CONCLUSION: These results suggest that the effect of ULDA on platelet activity in portal hypertensive rats, could act through a COX 2 pathway more than the COX 1, predominant for aspirin at higher doses.

Modifications produced by indomethacin and L-NAME in the effect of ultralow-dose aspirin on platelet activity in portal hypertension.

In our previous study, we demonstrated the effect of ultralow-dose aspirin (ULDA) on platelet activity and bleeding in rats with portal hypertension (PHT) produced by portal vein ligation (PVL). This paper reports modifications in this effect caused by blocking NO production by nitro arginine methyl ester (NAME) and cyclooxygenase (COX) activity with indomethacin. PVL rats and sham-operated controls were treated with placebo, indomethacin or NAME and 30 min thereafter with placebo or ULDA treatment. Platelet activity was studied by a model of in vivo laser-induced thrombus production in the mesenteric circulation, induced hemorrhage time (IHT) and platelet aggregation ex vivo induced by adenosine diphosphate in an aggregometer. The PVL group receiving placebo showed a decreased platelet activity with prolonged IHT, an effect that was reversed by ULDA. Indomethacin induced a decreased platelet activity in the control rats and a prolonged IHT. In PHT with ULDA, in vivo platelet activity was enhanced but the normalization of IHT observed in rats without indomethacin was blunted. The addition of NAME normalized the diminished in vivo platelet aggregation and increased the IHT observed in PVL animals. These changes decreased the effect of ULDA in both sham-operated and PVL animals. The effect of indomethacin was more clearly modified by ULDA than the effect of NAME, thus suggesting that modifications in the COX pathway might alter the effect of ULDA. The simultaneous administration of indomethacin and ULDA could inhibit its beneficial effect on bleeding in rats with PHT.

Platelet aggregation in portal hypertension and its modification by ultra-low doses of aspirin.

Aspirin (ASA) is widely accepted as antithrombotic drug, but several reports point out that its use in ultra-low doses (ULD) has prothrombotic properties. In this study, we evaluate the effect of portal hypertension in rats on platelet aggregation in an in vivo arterial thrombosis model induced by a laser beam. Portal hypertension was produced by calibrated stenosis of the portal vein. ASA in ULD was injected to both control and portal hypertensive groups. Platelet aggregation induced by ADP, prothrombin time, activated partial thromboplastin time, fibrinogen and induced hemorrhagic time test were also performed. Portal hypertensive rats showed a diminished number of emboli and duration of embolization in the laser procedure and an increase in induced hemorrhagic time. These changes were reverted by one injection of ASA at ULD. This observation could be of importance for primary prevention or the treatment of recurrence in upper digestive tract hemorrhage in portal hypertensive patients.