LAUSR

Introduction: Perihematomal edema in intracranial hemorrhage (ICH) is influenced by free hemoglobin clearance and inflammation. Serum Haptoglobin (Hp) binds free hemoglobin, affecting clearance as well as free radical production, resulting in inflammation. Of the three phenotypes of Haptoglobin, Hp 1-1 has the greatest effect on free hemoglobin clearance. We hypothesized that individuals with the Hp 1-1 phenotype have different rates of early perihematomal edema formation as compared to those with Hp 2-1 and Hp 2-2. Methods: We determined Hp phenotype, ICH volume, and rate of early change in perihematomal volume (ePHE) in participants from three prospectively collected ICH cohorts; Johns Hopkins University hospital (JHH), Massachusetts General Hospital (MGH), and the MISTIE III trial. The association of Hp phenotypes 1-1, 2-1, 2-2, with ePHE, while controlling for key clinical characteristics was analyzed using a multivariate model. Findings: 166 participants, 57 from JHH, 30 from MGH, and 79 from the MISTIE III trial were included: 73 (44%) female, 41(25%) African Americans, 34 (20%) diabetics, 133 (80%) with hypertension, and 75 (45%) active smokers. There were 15 subjects with Hp phenotype 1-1, 86 with 2-1 and 65 with 2-2. In the adjusted analysis, controlling for race, diabetes, hypertension, smoking status, and change in intracranial hemorrhage volume over time (cc/hr), Hp 1-1 had a significantly increased estimated mean rate of ePHE at 1·15, (95% CI 0·58-1·71) as compared to all other Hp 2-1 or Hp 2-2 containing phenotypes (0·30, 95% CI 0·06-0·54; 0.29 95% CI 0·02-0·56). Neither mortality nor discharge mRS differed between Hp phenotypes. Interpretation: Haptoglobin phenotype is associated with ePHE. Hp 1-1 significantly increased mean rate of ePHE suggests that haptoglobin phenotype may be a key player in understanding the multiphasic progression of PHE in sICH, which may help identify windows for targeted interventions to improve clinical outcomes. Conclusion: In our adjusted models, patients with the Haptoglobin 1-1 phenotype had an increased rate of ePHE formation within the first 96 hours. The Hp 1-1 phenotype may increase perihematomal progression in sICH. A larger prospective observational study is warranted.