Impairments of the Protein C System and Fibrinolysis in Infection-Associated Stroke

Abstract

Background and Purpose Infection/inflammation appears to be an important predisposing risk factor for brain infarction, but little is known regarding underlying molecular mechanisms. We examined the hypothesis that patients with brain infarction preceded by infection/inflammation within 1 week could be identified by a distinctive procoagulant laboratory profile characterized by abnormalities in the protein C system and endogenous fibrinolysis. Methods We performed a case-control study examining the relationship between preceding systemic infectious/inflammatory syndromes and selected immunohematologic variables in 36 patients with acute brain infarction and 81 control subjects (community control subjects [n=47] and hospitalized nonstroke neurological patient controls [n=34]). Results The stroke group had a lower mean level of the circulating antithrombotic enzyme activated protein C (APC) (4.33±0.34% [log-transformed percentage of control value, mean±SD]) than community control subjects (4.51±0.27%, P <.02) or hospitalized neurological patient controls (4.57±0.31%, P <.005). The lowest circulating APC levels were found in the stroke group with antecedent infection/inflammation within 1 week preceding index brain infarction (4.23±0.4%, n=12). Within the stroke group, circulating APC levels were inversely related to IgG isotype anticardiolipin antibody titers ( r =−.55, P <.001). Only the stroke group with infection/inflammation within 1 week had elevated plasma C4b binding protein compared with control subjects (141±61% versus 112±44%, P <.05). Stroke patients with antecedent infection/inflammation had a distinctively lower ratio of active tissue plasminogen activator to plasminogen activator inhibitor (0.11±0.04, n=9) than other stroke patients (0.19±0.06, n=9, P <.01) and control subjects (0.22±0.16, n=17, P <.02). Conclusions Impairments in the protein C pathway and endogenous fibrinolysis may contribute to the increased risk for brain infarction after recent (≤1 week) infection/inflammation. A decrease in the circulating anticoagulant APC may be related to elevated antiphospholipid antibody titers.