Protein C activity may reflect endogenous anticoagulant balance and is associated with stroke severity and functional...

Aging is associated with a shift toward a prothrombotic state, partly driven by alterations in endogenous anticoagulant pathways. Protein C is a key component of this pathway, but the clinical relevance of variation in protein C activity for ischemic stroke has not been fully established. We investigated whether variation in protein C activity is associated with stroke phenotypes, stroke severity, and functional outcomes in acute ischemic stroke (AIS).

We analyzed a prospective registry of patients with AIS admitted between 2016 and 2021. Protein C activity measured at admission was categorized into quartiles. Associations with stroke phenotypes, moderate-to-severe stroke (NIHSS ≥5), and poor 3-month functional outcomes (mRS ≥ 3) were evaluated using multivariable logistic regression. Additional analyses assessed the role of atrial fibrillation (AF) and potential effect modification by age.

Lower protein C activity was associated with a higher prevalence of AF and cardioembolic stroke. The proportion of moderate-to-severe stroke decreased across increasing quartiles of protein C activity (p for trend <0.001). Poor functional outcome also differed across protein C activity quartiles (p < 0.001). In multivariable analyses, higher protein C activity was independently associated with lower odds of moderate-to-severe stroke (OR 0.63 per 1-SD increase) and poor functional outcome (OR 0.71). The association between protein C activity and cardioembolic stroke was markedly attenuated and no longer statistically significant after adjustment for AF. No significant interaction between age and protein C activity was observed for moderate-to-severe stroke.

Protein C activity was consistently associated with stroke severity and may reflect endogenous anticoagulant balance. An association with functional outcome was also observed, although this finding was less consistent across sensitivity analyses. These findings suggest that variation in protein C activity across its observed distribution may provide information that is not fully reflected by conventional laboratory reference categories.