EACPT Lifetime Award winner Professor Carlo Patrono discussing platelets,
cardiovascular risk and cancer with EACPT Secretary Professor Donald Singer
at 11th EACPT Congress in Geneva 31st August, 2013.
Listen to podcast discussion
DS
I am in Geneva at the 11th EACPT Congress with Professor Carlo Patrono, who
has just received the EACPT Lifetime Achievement Award from our organisation’s cofounder Folke Sjöqvist. Would you start by explaining how you became interested in the
platelet area.
CP Yes, I became interested in platelets in the early 70s because of my interest in
prostaglandins at the time and fundamental discoveries being made by John Vane and
Bengt Samuelsson, particularly the discovery by Bengt Samuelsson of thromboxane A2
as a major arachidonic acid metabolite in platelets.
I was already interested in the pharmacology of platelet inhibition and when thromboxane
was discovered I soon developed a radioimmunoassay for measuring thromboxane B2.
By the late 70s we had developed a simple whole blood method that would allow us to
measure the most sensitive and specific signal of aspirin pharmacodynamics: that is the
production of thromboxane by circulating platelets, a method that could be applied either
to in vitro studies by adding drugs to the whole blood sample or ex vivo studies which led
us to the next step of studying the clinical pharmacology of platelet thromboxane
inhibition.
DS We now know that this is a key way in which aspirin is operating and it is now
recognised clinically around the world that using low dose aspirin is very important in
terms of reducing and preventing risk of cardiovascular disease. How did you become
interested in this concept of using aspirin in this way.
CP Up until the late 70s, the only way that platelet function could be studied, was by
the method described by Gustav Born a well known British Pharmacologist, the son of
Max Born, the Nobel Prize Laureate in Physics.
Not surprisingly Gustav, who used to find in his house people like Albert Einstein and
perhaps as a consequence of his childhood training, devised a very elegant method,
measuring light transmission through a platelet suspension to detect changes in platelet
aggregation as a consequence of adding agonists to this platelet suspension and drugs.
The problem with this technique is that it lacks sensitivity and specificity, because light
transmission would be the end-product of the suspension becoming clearer as a
consequence of the platelet aggregating and going to the bottom of the cuvette. So it
doesn’t tell you specifically which mediators, which receptors, are involved in this signal
that you measure. Using our approach, that is the measurement of thromboxane
production by platelets in whole blood, we were able to measure a signal which is 100%
aspirin sensitive, and highly specific.
This led us to study the clinical pharmacology of platelet inhibition and we found that you
only needed very low doses of aspirin in order to fully inhibit platelet thromboxane
production, particularly by exploiting the cumulative nature of platelet COX-1 inactivation
by repeated daily doses of aspirin because of the irreversible nature of this acetylation
process, which forms the basis of aspirin mechanism of action.
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By the early 80s using this technique we described full inhibition of platelet thromboxane
production by doses as low as 30 mg once daily. This stimulated other people to do
similar studies and this eventually stimulated cardiologists and neurologists around the
world to test the clinical efficacy and safety of these low doses of aspirin.
DS And of course it is really important practically because there is always a risk benefit
with medicines and trying to avoid the unwanted bleeding complications. There are
many other options now available to interfere with platelet function. What do you see the
future of these agents in terms of giving added value for reducing risk of serious
complications in our patients.
CP Well I think we have made substantial progress through the development of new
anti-platelet agents as well as the oral anti-coagulant agents. We are still dealing with
the problem that there is a residual rate of major vascular events that occur after a
clinical diagnosis of an acute coronary syndrome.
This apparently cannot be further reduced by optimal combination anti platelet therapy:
not even with the addition of new oral anti coagulants. So probably one way forward is to
further investigate the mechanisms responsible for this residual risk of atherothrombotic
events.
There are also further developments related to my interest in aspirin, which is the recent
discovery by a group in Oxford led by Peter Rothwell that within the cardiovascular trials
of aspirin, either primary or secondary prevention, there was clear evidence of protection
against various forms of cancer, in particular colorectal cancer.
We are currently intrigued by the possibility that these chemo-preventative effect of
aspirin may be somehow related to its anti platelet properties. Platelet activation at sites
of intestinal mucosal injury may trigger the release of various signals of both lipid and
protein nature that in turn can induce COX-2 in adjacent epithelial and stromal cells of
the intestinal mucosa.
We know from a very large body of evidence that COX- 2 induction and activity plays a
pivotal role in colorectal carcinogenesis. This might explain why you apparently can get
the same protective effects either acting upstream with low doses of aspirin inhibiting
platelet activation or downstream by inhibiting COX-2 activity with COX-2 inhibitors.
Testing the hypothesis that platelets have something to do with early intestinal
carcinogenesis, is currently attracting a lot of my interest and time.
DS That illustrates the importance of keeping a very open mind about off-targets or
new targets for molecules and pathways across different therapeutic areas.
CP Absolutely. We as clinical pharmacologists are in a privileged position. If we
develop an interest for a lateral view outside of our main field of interest like looking at
oncology and not just cardiovascular diseases, I think this can be a source of very
interesting discoveries.
DS
Carlo Patrono, thank you very much indeed.
CP
Thank-you.
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