Hemostatic activation and outcome after recombinant tissue plasminogen activator therapy for acute ischemic stroke

BACKGROUND AND PURPOSE - Early thrombolytic therapy with intravenous recombinant tissue plasminogen activator (rtPA) improves clinical outcome in acute ischemic stroke (AIS), but impaired endogenous fibrinolysis, thrombin generation, and vascular injury may hamper the efficacy of thrombolysis. We investigated in an exploratory, post hoc analysis the relationship between hemostatic markers and clinical outcomes among patients included in the National Institute of Neurological Disorders and Stroke (NINDS) rtPA Stroke Study. METHODS - Tissue plasminogen activator (tPA) antigen, thrombin-antithrombin complex (TAT), soluble thrombomodulin, and fibrinogen levels were measured in patients with AIS included in the NINDS rtPA Stroke Study from plasma samples collected at baseline, at 2 hours after treatment, and after 24 hours. RESULTS - TAT and tPA antigen levels peaked at 2 hours selectively in the rtPA treatment group, whereas fibrinogen levels dropped at 2 hours and remained low after 24 hours (P<0.0001 for interaction effects between time and treatment). At 24 hours, higher levels of tPA antigen were associated with a lower chance of favorable outcome (odds ratio [OR]=0.34; 95% CI, 0.14 to 0.82) selectively in the rtPA group, and higher levels of TAT (OR=1.72; 95% CI, 1.26 to 2.34) in the entire cohort and of thrombomodulin selectively in the rtPA group (OR=4.45; 95% CI, 1.26 to 15.67) were associated with higher 3-month mortality. CONCLUSIONS - Hemostatic activation after AIS appears to be independently associated with clinical outcome in patients treated with rtPA. However, because we have tested for multiple associations, some may have been identified by chance alone and require further confirmatory studies. On the basis of this exploratory analysis, there is a rationale to investigate the safety and efficacy of protocols in which rtPA is complemented by agents that are antithrombotic and enhance fibrinolysis.