Abstract

ABSTRACT: Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to 
middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal 
haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global 
consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation 
of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free 
hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. 
Haptoglobin is the body’s first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation 
of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse 
and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and 
biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique 
challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early 
input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the 
Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling 
were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to 
play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, 
there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase 
trial. The highest research priorities were related to confirming haptoglobin’s anticipated safety, individualized versus standard 
dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight 
the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early 
input from clinical disciplines on a global scale during the early stages of clinical translation.