Low α2-Plasmin Inhibitor Antigen Levels on Admission Are Associated With More Severe Stroke and Unfavorable Outcomes in Acute Ischemic Stroke Patients Treated With Intravenous Thrombolysis

Abstract

BackgroundIntravenous administration of recombinant tissue plasminogen activator (rt-PA) fails to succeed in a subset of acute ischemic stroke (AIS) patients, while in approximately 6–8% of cases intracerebral hemorrhage (ICH) occurs as side effect.ObjectiveHere, we aimed to investigate α2-plasmin inhibitor (α2-PI) levels during thrombolysis and to find out whether they predict therapy outcomes in AIS patients.Patients/MethodsIn this prospective, observational study, blood samples of 421 AIS patients, all undergoing i.v. thrombolysis by rt-PA within 4.5 h of their symptom onset, were taken before and 24 h after thrombolysis. In a subset of patients (n = 131), blood was also obtained immediately post-lysis. α2-PI activity and antigen levels were measured by chromogenic assay and an in-house ELISA detecting all forms of α2-PI. α2-PI Arg6Trp polymorphism was identified in all patients. Stroke severity was determined by NIHSS on admission and day 7. Therapy-associated ICH was classified according to ECASSII. Long-term outcomes were defined at 3 months post-event by the modified Rankin Scale (mRS).ResultsMedian α2-PI activity and antigen levels showed a significant drop immediately post-lysis and increased to subnormal levels at 24 h post-event. Admission α2-PI levels showed a significant negative stepwise association with stroke severity. Patients with favorable long-term outcomes (mRS 0–1) had significantly higher admission α2-PI antigen levels (median:61.6 [IQR:55.9–70.5] mg/L) as compared to patients with poor outcomes (mRS 2–5: median:59.7 [IQR:54.5–69.1] and mRS 6: median:56.0 [IQR:48.5–61.0] mg/L, p < 0.001). In a Kaplan–Meier survival analysis, patients with an α2-PI antigen in the highest quartile on admission showed significantly better long-term survival as compared to those with α2-PI antigen in the lowest quartile (HR: 4.54; 95%CI:1.92–10.8, p < 0.001); however, in a multivariate analysis, a low admission α2-PI antigen did not prove to be an independent risk factor of poor long-term outcomes. In patients with therapy-related ICH (n = 34), admission α2-PI antigen levels were significantly, but only marginally, lower as compared to those without hemorrhage.ConclusionsLow α2-PI antigen levels on admission were associated with more severe strokes and poor long-term outcomes in this cohort. Our results suggest that in case of more severe strokes, α2-PI may be involved in the limited efficacy of rt-PA thrombolysis.