Aspirin in the 21st century
Understanding the intricacies of platelet activation and inhibition
Prof Carlo Patrono – Catholic University School of Medicine, Rome, Italy
Could you tell us about some of your research into platelet activation and inhibition?
The most recent one and the one I will be discussing at this meeting has to do with platelet activation in diabetes mellitus. We have done studies demonstrating enhanced platelet activation in both type 1 and type 2 diabetes mellitus and have characterised some of the mechanisms responsible for this platelet activation. More recently we have been interested in aspirin pharmacodynamics in people with diabetes and found that in a substantial fraction of the type 2 diabetic population like the elderly, non-insulin dependent diabetics there is an alteration in the way in which aspirin affects platelet COX-1, its primary anti-platelet target, meaning that there is a diminished duration of the anti-platelet effect during the 24 hour dosing interval of aspirin which is typically administered once daily because of the reversible nature of its mechanism of action. In this fraction of the type 2 diabetic population we see substantial recovery of platelet COX-1 activity, particularly between 12-24 hours after dosing. We think that this may be due in part to altered bone marrow megakaryocyte production of the cyclooxygenase enzymes affecting the rate of turnover of COX-1 in circulating platelets and in part may be due to obesity which is often associated with type 2 diabetes which impacts on the pharmacokinetics of low dose aspirin, reducing its systemic bioavailability and therefore its capacity to acetylate the COX enzyme in the platelet precursors in the bone marrow.
What are the clinical implications of that part of your research?
The clinical implication is the possibility of tailoring or personalising anti-platelet therapy in people with type 2 diabetes but also in other clinical conditions that we have investigated like essential thrombocythemia personalising therapy, meaning that you can administer aspirin twice daily rather than once daily to overcome this time dependent recovery of platelet COX-1 activity.
Can you tell us about your work in malignant neoplasms?
Yes, that’s the disease I was talking about earlier, essential thrombocythemia which is one of these myeloproliferative neoplasms characterised by abnormal platelet production. In these kinds of patients we found that this phenomenon is very evident in virtually all patients with essential thrombocythemia. There is this time dependent recovery of platelet COX-1 activity during the 24 hour dosing interval of aspirin administration. In fact, a personalised approach such as giving aspirin twice daily is already being recommended in some guidelines, haematology guidelines, for the management of essential thrombocythemia.
What research have you been doing in colorectal cancer?
We like to think, and in fact I’ve put this forward, this hypothesis, some ten years ago, that platelets may be involved both in the early phase of colorectal carcinogenesis and also in the spreading of metastasis. Therefore I propose that, at least in part, the anti-cancer effect of aspirin may be related to inhibition of platelet activation. This hypothesis is consistent with the lack, an apparent lack, of dose dependence of the anti-cancer effect of aspirin which you see exactly at the same low dose regimens given once daily that are being used for cardiovascular prevention. So our hypothesis is that there might be a common mechanism of disease related to participation of platelets in both coronary atherothrombosis and colorectal cancer which might explain a similar impact of low dose aspirin on the two processes.
What about using antiplatelet agents other than aspirin?
Nobody has yet looked as to whether other antiplatelet agents share this anti-cancer effect that has been demonstrated with aspirin but it’s certainly an interesting potential development of the field.
