Thrombin Generation Capacity is Associated With Worse Outcome in r-tPA Treated Patients With Stroke

Recombinant tissue plasminogen activator (r-tPA) remains the cornerstone of reperfusion therapy in patients with stroke. However, response to r-tPA is highly variable and not fully explained by clinical factors with many patients not achieving a good outcome despite thrombolysis treatment. In 78 patients with acute ischemic stroke treated with r-tPA, thrombin generation capacity was measured in plasma. Functional outcome was assessed at 90 days using the modified Rankin Scale (mRS). In addition, inflammatory markers were analyzed to identify factors associated with increased thrombin generation in this patient population. Thrombin generation capacity was significantly greater in patients with worse 90-day mRS (mRS > 2) compared to those with good 90-day mRS (mRS ≤ 2; 254 nM vs. 210 nM; p = 0.0007). This association remained significant after adjustment for admission NIHSS, age, sex, stroke etiology, and atrial fibrillation (OR: 1.68, 95% CI: 1.10-2.58; p = 0.017). In vitro, increased thrombin was associated with denser fibrin clot structure and prolonged clot lysis time in response to tPA. In patients, peak thrombin levels correlated positively with inflammatory and coagulation markers, including interleukin (IL)-6 (r = 0.421, p = 0.009), IL-8 (r = 0.382, p = 0.018), and fibrinogen (r = 0.415, p = 0.02), and inversely with α2-macroglobulin (α2M; r=-0.327, p = 0.048). Elevated thrombin generation is associated with worse outcomes in patients with acute ischemic stroke treated with r-tPA. This procoagulant state may promote formation of denser, thrombolysis-resistant thrombi and help explain interindividual variability in outcome following treatment. Thrombin generation capacity may serve as a useful biomarker to improve risk stratification and predict variability in thrombolytic response.