Change of Serum Biomarkers to Post-Thrombolytic Symptomatic Intracranial Hemorrhage in Stroke

Abstract

Background: Symptomatic intracranial hemorrhage (sICH) is a terrible complication after intravenous alteplase in stroke, and numerous biomarkers have been investigated. However, the change of biomarkers to sICH has not been well determined.

Aim: To investigate the association between the change of biomarkers and sICH.

Methods: This is a prospective cohort study, and patients with sICH within 24 h after thrombolysis were enrolled, while patients without sICH were matched by propensity score matching with a ratio of 1:1. The blood samples were collected before and 24 h after intravenous thrombolysis (IVT), and preset 49 serum biomarkers were measured by microarray analysis. Protein function enrichment analyses were performed to detect the association between the change of biomarkers and sICH.

Results: Of consecutive 358 patients, 7 patients with sICH in 24 h were assigned to the sICH group, while 7 matched patients without any ICH were assigned to the non-sICH group. A total of 9 biomarkers were found to significantly change before vs. after thrombolysis between groups, including increased biomarkers, such as brain-derived neurotrophic factor, C-C motif chemokine ligand (CCL)-24, interleukin (IL)-6, IL-10, IL-18, and vascular endothelial growth factor, and decreased biomarkers, such as CCL-11, intercellular adhesion molecule-1, and IL-7.

Conclusions: This is the first study to identify changes in serum biomarkers in patients with sICH after IVT, and found that 6 neuroinflammatory and 3 neuroprotective biomarkers may be associated with brain injury following post-thrombolytic sICH.

Clinical trial registration: https://www.clinicaltrials.gov, identifier: NCT02854592.

Keywords: alteplase; biomarkers; intravenous thrombolysis; microarray analysis; symptomatic intracranial hemorrhage.

Figure 1

Flow diagram. sICH, symptomatic intracranial hemorrhage.

Figure 2

Results of detected biomarkers in the microarray analysis. (A) The scatter plot for detected biomarkers; the X-axis represents the average of serum levels in the sICH group, while the Y-axis represents the average of serum levels in the non-sICH group; compared with the non-sICH group, the blue point represents biomarkers with decrease in the sICH group, while the red point represents biomarkers with increase. sICH, symptomatic intracranial hemorrhage. (B) The volcano plot for detected biomarkers; the X-axis represents the average of change in serum levels between two groups while the Y-axis represents the –log10 p; the cyan point represents the biomarkers with a significant difference, while the red point represents the biomarkers without significant difference. sICH, symptomatic intracranial hemorrhage. (C) The column plot for identified biomarkers; the X-axis represents the identified biomarkers, while the Y-axis represents the average of serum levels in two groups; the deep color represents the sICH group, while the light color represents the non-sICH group. (D) The heatmap for identified biomarkers; the red color represents biomarkers with an increase, while the blue color represents the biomarkers with decrease; the darker the color, the more significant the difference of biomarkers. BDNF, brain-derived neurotrophic factor; CCL-11, C-C motif chemokine ligand (CCL)-11; CCL-24, C-C motif chemokine ligand (CCL)-24; ICAM-1, intercellular adhesion molecule-1; IL-10, interleukin-10; IL-18, interleukin-18; IL-6, interleukin-6; IL-7, interleukin-7; VEGF, vascular endothelial growth factor; and sICH, symptomatic intracranial hemorrhage.

Figure 3

Protein function analysis of identified biomarkers. (A) Top 20 significantly enriched biological processes of identified biomarkers; the X-axis represents the enrichment, while the Y-axis represents the biological process. (B) The molecular function enriched by identified biomarkers; the X-axis represents the enrichment, while the Y-axis represents the molecular function. (C) The cellular component enriched by identified biomarkers; the X-axis represents the enrichment, while the Y-axis represents the cellular component. (D) The pathway enriched by identified biomarkers; the X-axis represents the enrichment, while the Y-axis represents the pathway. The deeper the color, the larger the value of p; the larger the circle, the bigger the counts.

Figure 4

Protein–protein interaction network of identified biomarkers. BDNF, brain-derived neurotrophic factor; CCL-11, C-C motif chemokine ligand (CCL)-11; CCL-24, C-C motif chemokine ligand (CCL)-24; ICAM-1, intercellular adhesion molecule-1; IL-10, interleukin-10; IL-18, interleukin-18; IL-6, interleukin-6; IL-7, interleukin-7; and VEGF, vascular endothelial growth factor.