Abstract
Background: Although lower hemoglobin levels associate with worse intracerebral hemorrhage (ICH) outcomes, causal drivers for this relationship remain unclear. We investigated the hypothesis that lower hemoglobin relates to increased hematoma expansion risk and poor outcomes using human observational data and assessed causal relationships using a translational murine model of anemia and ICH. Methods: A multicenter, prospective observational cohort study of 2997 patients with ICH enrolled between 2010 and 2016 was assessed. Patients with baseline hemoglobin measurements and serial computed tomography neuroimaging were included for analyses. Patients with systemic evidence of coagulopathy were excluded. Separate regression models assessed relationships of baseline hemoglobin with hematoma expansion (≥33% and/or ≥6 mL growth) and poor long-term neurological outcomes (modified Rankin Scale score of 4-6) after adjusting for relevant covariates. Using a murine collagenase ICH model with serial neuroimaging in anemic versus nonanemic C57/BL6 mice, intergroup differences in ICH lesion volume, lesion volume changes, and early mortality were assessed. Results: Among 1190 ICH patients analyzed, the mean age was 61 years old, and 62% of the cohort were males. Lower baseline hemoglobin levels are associated with increased odds of hematoma expansion (adjusted odds ratio per -1 g/dL hemoglobin decrement, 1.10 [95% CI, 1.02-1.19]) and poor 3-month clinical outcomes (adjusted odds ratio per -1 g/dL hemoglobin decrement, 1.11 [95% CI, 1.03-1.21]). Similar relationships were seen with poor 6- and 12-month outcomes. In our animal model, anemic mice had significantly greater ICH lesion expansion, 24-hour lesion volumes, and greater mortality, as compared with nonanemic mice. Conclusions: These results, in a human cohort and a mouse model, provide novel evidence suggesting that anemia has causal roles in hematoma expansion and poor ICH outcomes. Additional studies are required to clarify whether correcting anemia can improve these outcomes.