Abstract
The antithrombotic action of aspirin (acetylsalicylic acid) is due to inhibition of
platelet function by acetylation of the platelet cyclooxygenase (COX) at the functionally
important amino acid serine529. This prevents the access of the substrate (arachidonic acid) to the catalytic site
of the enzyme at tyrosine385 and results in an irreversible inhibition of platelet-dependent thromboxane formation.
Aspirin is an approximately 150- to 200-fold more potent inhibitor of the (constitutive)
isoform of the platelet enzyme (COX-1) than the (inducible) isoform (COX-2) which
is expressed by cytokines, inflammatory stimuli, and some growth factors. This explains
the different dosage requirements of aspirin as an antithrombotic (COX-1) and an anti-inflammatory
drug (COX-2), respectively.
Aspirin is the “gold standard” antiplatelet agent for prevention of arterial thromboses.
The optimum dose of aspirin as an antithrombotic drug can differ in different organ
circulations. While 100 mg/day is sufficient for prevention of thrombus formation
in the coronary circulation, higher doses may be required for the prevention of vascular
events in the cerebral and peripheral circulation. However, any effective antiplatelet
dose of aspirin is associated with an increased risk of bleeding. Therefore, the individual
benefit/risk ratio determines the administration of the compound.
There are no known prostaglandin-independent mechanisms for the antithrombotic action
of aspirin in clinical use. Thus, platelet activation caused by other factors remains
unchanged and might result in a resistance against inhibition of platelet function
by aspirin. This involves platelet activation by shear stress and ADP. Additionally,
there is no “sparing” of endothelial prostacyclin synthesis in clinical conditions
of atherosclerotic endothelial injury. In this case, inhibition of COX-1 by aspirin
will also reduce the amount of precursors for vascular prostacyclin synthesis, provided,
for example, from adhering platelets.
Keywords:
Aspirin resistance - atherosclerosis - cyclooxygenase isoforms - platelets - thromboxane
A2
