Reversible or irreversible, that is the question? The impact of reversibility of P2Y12 receptor inhibition on a thrombus formation.

Kjersti Tunströmer et al. nicely demonstrated in a recent original investigation published in the Platelets journal that despite the wide use of antiplatelet drugs in patients with coronary artery disease (CAD), we still know little about their effect on blocking the P2Y12 receptor on thrombus formation and therefore possibly the quality of treatment. Recently, tailored treatment in some clinical scenarios and selected populations is expected to become a key issue in up-to-date optimal pharmacotherapy. It is especially important for a clinician to understand the basic difference between the mechanisms of action of thienopyridines (ticlopidine, clopidogrel and prasugrel) which are irreversibly inhibiting the P2Y12 receptor, and therefore due to the dosing regimen, in the interval between drug administration create a “mosaic” of platelet population comprising with low P2Y12- and high P2Y12+ ADP reactivity. On the other hand, ticagrelor, which represents the cyclopentyltriazolopyrimidine group, is an already active drug and is proposed to produce a rapid, substantial, and consistent antiplatelet effect, but also favorable safety profile (1). In order to have an understanding of the appropriate clinical utility of the drugs being evaluated, it is valid to compare those two types of antiplatelet treatment.

This study adds an important part to the current discussion on the important differences between reversible and irreversible P2Y12 inhibitors, even at the level of the European Society of Cardiology (ESC) guidelines and the recent favorable results of the prasugrel trial in patients with acute coronary syndrome from 2023 (2). Based on these guidelines, ESC recommends using potent P2Y12 receptor inhibitors in STEMI patients before PCI, and this treatment regimen should be followed in majority of patients for 12 months. However, in the ISAR-REACT 5 trial, ticagrelor-based strategies with deferred loading doses were inferior to prasugrel-based strategies with routine pre-treatment in patients with NSTE -ACS (3). These two potent P2Y12 inhibitors were then the subject of intense discussions regarding their mechanism of action and possible clinical implications.
The authors of the commented research paper nicely highlighted some new features of both drugs, but most importantly the implications for hemostatic function, and therefore the timing of inhibition for each drug. In order to prevent excessive bleeding, platelet aggregates are the primary components of the hemostatic plug. As a result, it is possible that ticagrelor's immediate inhibitory effect on thrombus formation may have contributed to the increased bleeding complications associated with its use in large clinical trials. The authors have shown no significant difference in the sizes and platelet counts of thrombi formed from a 100% P2Y12+ platelet population when compared to a chimeric platelet population (90% vs 10% P2Y12-), explaining why the differences in antithrombotic efficacy between irreversible and reversible inhibitors are smaller than expected. Importantly, the authors found the negative association between the percentage of P2Y12- inhibited platelets and the total number of new platelets that were recruited to thrombi. This trend that was observed stronger during later time points of their experiments, and that was likely caused by accelerated “thrombus cooling,” caused by decreased paracrine signaling, in the P2Y12 mosaic thrombus platelet population, and therefore rapidly diminished GP IIb/IIIa activation in platelets located at the thrombus surface.

The above detailed mechanisms of action described by the authors of this original article on two of the most important antiplatelet drugs used in the treatment of patients with acute coronary syndromes are well aligned with the discussion of possible similarities and differences that might be related to clinical sequelae observed in large outcome clinical trials. It is however interesting, and still open to debate whether the mechanisms of thrombus formation, demonstrated in the commented article, would be significantly different if the blood samples were collected from patients naive to any antiplatelet drugs, but with cardiovascular risk factors (such as type 2 diabetes) and an acute myocardial infarction, where platelet turnover rates are much higher.