ARTICLE INFO abstract Aneurysmal Subarachnoid Hemorrhage (aSAH) is a severe form of hemorrhagic stroke resulting from rupture of an intracranial aneurysm. aSAH results in significant primary and secondary neurologic injuries, including hydrocephalus, Delayed Cerebral Ischemia and Cerebral Vasospasm (CV) that leads to chronic neurologic disability. Haptoglobin (Hp) is a naturally-occurring protein that binds to free hemoglobin (Hb) to facilitate its macrophage-based metabolism. In humans, there

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... re three Hp genotypes (Hp1-1, Hp1-2, and Hp2-2) that lead to Hp molecules with different sizes, conformations, and Hbbinding affinities. The prevalence of these three Hp genotypes is variable within different populations. The greatest prevalence of the Hp2-2 genotype exists in native populations from India and Southeast Asia. In observational studies, this Hp2-2 genotype is associated with a two-fold increased risk of CV compared to the Hp1-1 and the Hp1-2 genotypes. To date, no pre-clinical or clinical trials have included this important confounding variable in power analyses, randomization schemes, or post-hoc data analysis. In addition, since the Hp1-2 and the Hp2-2 genotypes exist only in humans, basic science research is routinely conducted only in animals that have only the Hp1-1 genotype, limiting the reliability of these results in humans. Future basic science studies of CV in aSAH should incorporate the different Hp genotypes into animal models, using previouslycreated transgenic models. In addition, future pre-clinical and clinical trials should also account for the effects of the different Hp genotypes in trial design and randomization schemes to minimize the effect of this confounding variable.