Association of Thrombin Generation With Leukocyte Inflammatory Profile in Patients With Acute Ischemic Stroke

Background and Objectives Thrombosis is central to the pathogenesis of acute ischemic stroke, with higher thrombin generation being associated with increased stroke risk. The immune system may contribute to thrombin generation in stroke and thus may offer novel strategies for stroke prevention. This study addresses the research question regarding the relationship of thrombin generation to leukocyte gene expression in patients with acute ischemic stroke. Methods We isolated RNA from whole blood and examined the relationship to thrombin generation capacity in patients with acute ischemic stroke. Due to its effects on thrombin generation, patients on anticoagulants were excluded from the study. The relationship of gene expression with peak thrombin was evaluated by analysis of covariance across peak thrombin quartiles adjusted for sex and age. Results In 97 patients with acute ischemic stroke, peak thrombin was variable, ranging from 252.0 to 752.4 nM. Increased peak thrombin was associated with differences in thromboinflammatory leukocyte gene expression, including a decrease in ADAM metallopeptidase with thrombospondin type 1 motif 13 and an increase in nuclear factor κB (NF-κB)–activating protein, protein disulfide isomerase family A member 5, and tissue factor pathway inhibitor 2. Pathways associated with peak thrombin included interleukin 6 signaling, thrombin signaling, and NF-κB signaling. A linear discriminant analysis model summarizing the immune activation associated with peak thrombin in a first cohort of stroke could distinguish patients with low peak thrombin from high peak thrombin in a second cohort of 112 patients with acute ischemic stroke. Discussion The identified genes and pathways support a role of the immune system contributing to thrombus formation in patients with stroke. These may have relevance to antithrombotic strategies for stroke prevention. ADAMTS13 = : ADAM metallopeptidase with thrombospondin type 1 motif 13; FVIIa= : coagulation factor VIIa; FX= : coagulation factor X; IL= : interleukin; LDA= : linear discriminant analysis; NF-κB= : nuclear factor κB; NKAP = : NF-κB–activating protein; PDI= : protein disulfide isomerase; PDIA5 = : protein disulfide isomerase family A member 5; TFPI2 = : tissue factor pathway inhibitor 2