Infection drives excessive platelet inhibition during P2Y12 inhibitor therapy in coronary artery disease

Background P2Y12 inhibitors are a cornerstone of cardiovascular pharmacotherapy. However, bleeding events remain their leading complication and are frequently observed in patients with concomitant infection. We recently demonstrated that infection renders platelets hyporeactive toward agonist activation. We hypothesized that this inflammatory platelet dysfunction amplifies the pharmacodynamic response to P2Y12 inhibitors, resulting in an increased bleeding risk. Purpose We aimed to assess how the potency of P2Y12 inhibitor therapy is altered during infection and sepsis. Methods In this prospective study, we recruited two cohorts comprising (i) a discovery cohort (n=89 patients; n=38 sepsis, n=33 infection without fulfilling the sepsis criteria, n=18 healthy controls) and (ii) a validation cohort (30 patients with coronary artery disease (CAD); n=15 with infection, n=15 without infection). We determined platelet function comprehensively using flow cytometry (PAC-1 binding following ADP stimulation), light transmission aggregometry, a microfluidic system on a collagen/tissue factor–coated surface under high shear (1000 s⁻¹), and the VerifyNow point-of-care device. Results In our discovery cohort, ADP-induced GPIIb/IIIa activation was reduced in infection and blunted in sepsis patients. In healthy controls, cangrelor induced a dose-dependent inhibition with complete suppression of GPIIb/IIIa activation at 1 µM. In contrast, a 100-fold lower concentration (10 nM) fully abolished ADP-induced activation in infection patients. Baseline maximal aggregation upon ADP stimulation was only moderately reduced in infection (57% vs. 67% in controls). However, 10 nM cangrelor reduced aggregation to 22% in infection, whereas aggregation in controls remained largely preserved (51%). Under arterial shear, baseline thrombus formation was comparable (22% vs. 21%), yet 10 nM cangrelor reduced platelet surface coverage to 9% in infection versus 17% in controls, revealing a heightened sensitivity to P2Y12 inhibition under inflammatory conditions. We recruited a validation cohort comprising patients with established CAD receiving clopidogrel for P2Y12 inhibition. Concomitant infection was associated with near-absent ADP-induced activation, markedly reduced aggregation (10% vs. 39%, p<0.0001), and impaired thrombus formation (8% vs. 16%, p<0.0001) (Fig. 1A,B). Strikingly, VerifyNow testing demonstrated a profound shift toward "low platelet reactivity" (LPR) (<94 platelet reactivity units (PRU)) in infection patients compared to non-infection CAD patients (93% vs. 13%), with values clearly falling below the established “optimal platelet reactivity” (OPR) window (95–208 PRU) for clopidogrel therapy (Fig. 1C), reflecting an increased pharmacodynamic response. Conclusion In infection, P2Y12 inhibitor therapy is frequently functionally overdosed. Infection represents a novel and clinically relevant determinant of P2Y12 inhibitor response.