Haptoglobin Treatment for Aneurysmal Subarachnoid Hemorrhage: Review and Expert Consensus on Clinical Translation

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.

The Haptoglobin Response after Aneurysmal Subarachnoid Haemorrhage

“…The likely reason our study did not find an association between Hp phenotype and clinical outcomes is because of a marked Hp deficit in the CNS, which is well recognised in the literature [19]. With intrathecal administration, CSF Hp levels will be higher, and functional differences between Hp phenotypes may become apparent [26]. Therefore, intrathecal haptoglobin administration has therapeutic potential.…”

“…An individual can have one of three genotypes: HP1-1 homozygote, HP2-1 heterozygote, and HP2-2 homozygote. The different Hp types bind haemoglobin with identical affinities but may have functional differences related to haemoglobin-binding capacity, protection against haemoglobin-induced neurotoxicity, binding of complexes to CD163, subsequent endocytosis, and the ability to generate antiinflammatory responses [23,26]. Consequently, Hp turnover and function across different Hp phenotypes is a topic of significant interest.…”

All Three Supersystems—Nervous, Vascular, and Immune—Contribute to the Cortical Infarcts After Subarachnoid Hemorrhage

“…Whether they are harmless, or cause infarcts, most likely depends on whether the complex neuroglial, neurovascular, and neuroimmunological regulatory circuits that normally protect the cortex and allow rapid repolarization after SD are locally disrupted by red blood cell products. Possible treatment targets are not only an improved elimination of the triggering agent (i.e., the extravascular blood [206][207][208][209][210][211]), and other conditions that may contribute to SD, but also a correction of the dysfunctional regulatory circuits that are downstream of SD and render it truly dangerous. If these regulatory circuits are no longer able to rescue the neurons from the SD state, they will inevitably perish.…”

Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance

“…Given its chemistry, the oxidant heme has the potential to broadly activate NRF2 across cell types and tissues ( 57 ). However, physiological mechanisms, such as hemoglobin coordination and packaging within the RBC membrane, RBC antioxidant metabolites, and extracellular scavenger proteins, effectively shield tissue environments against oxidative impact from heme ( 31 , 57 , 58 ). Instead, the hemorrhage-triggered wound healing response recruits macrophages ( 59 ), which have the unique ability to recognize and ingest damaged RBCs and heme-protein complexes ( 60 ), allowing them to shuttle heme toward a system capable of safely degrading and reutilizing its components ( 61 ).…”