Aspirin Non-Responders in the Elderly Population with High Vascular Risk

Coordinating Institution: Centre Hospitalier de Luxembourg , CRP Sante
From: 01/12/2004
To: 30/11/2005
Budget: 72,489.00€
Contact(s): Metz René

Summary

Aspirin (ASA) reduces the relative risk of major vascular events and vascular death by ~20% after ischemic stroke and acute coronary syndrome. However, the antiplatelet properties of ASA are not uniform between individuals and recurrent events in some patients may be caused by “ASA resistance” or ASA non-responsiveness. The elderly high vascular risk population has been poorly studied. To measure platelet aggregation we use the PFA-100, a point-of-care platelet aggregometer that functions by aspirating a blood sample through a capillary tube at high shear rate, and through a small slit aperture. The time for a platelet plug to occlude the slit aperture, reported in seconds as closure time, is inversely related to platelet activity.

Rather than measuring platelet aggregation directly, another approach to quantify the activity of aspirin is to measure the levels of the products of COX-1 enzyme action. Reduced levels of these products would be expected as a result of ASA administration. ThromboxaneA2 (TXA2) is unsuitable for measurement since it is a highly unstable compound with a short half-life. TXA2 is rapidly hydrated to form the more stable TXB2 and converted to 11-hydro-TXb2 that can be detected in the urine and serves as an indirect measure of TXA2 activity in vivo.

The availability of these tests allowed us to identify ASA responsiveness in routine clinical practice in the elderly. The following figure shows the good correlation of the PFA-100 and the low TXB2 values. On the x-axis you see the PFA-100 closure times and on the y-axis the urinary concentration of TXB2.

Copidogrel, another antiplatelet agent that, given alone or in addition to aspirin, is effective in reducing the composite end point of death from cardiovascular causes, nonfatal myocardial infarction or stroke in high risk patients. As for ASA, laboratory assays of platelet response to clopidogrel show a wide inter-individual variability with some patients also being classified as “non-responders” or “resistant to clopidogrel”. We studied in patients taking clopidogrel alone or in combination with ASA with the PFA-100, the TXB2 urinary excretion and the VASP analysis. VASP (Vasodilator Stimulated Phosphoprotein) is an intracellular protein which participates in the regulation of the dynamics of the platelet cytoskeleton and activation of GP IIb/IIIa. The phosphorylation/dephosphorylation properties of VASP have been utilised to evaluate the quality of the P2Y12 inhibition by clopidogrel by flow cytometry and appear to be a promising and reliable test of treatment efficacy using clopidogrel.

Figure: The following figure shows the good correlation of the PFA-100 and the low TXB2 values. On the x-axis you see the PFA-100 closure times and on the y-axis the urinary concentration of TXB2.