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- Title
Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm.
- Authors
Hugelshofer, Michael; Buzzi, Raphael M.; Schaer, Christian A.; Richter, Henning; Akeret, Kevin; Anagnostakou, Vania; Mahmoudi, Leila; Vaccani, Raphael; Vallelian, Florence; Deuel, Jeremy W.; Kronen, Peter W.; Kulcsar, Zsolt; Regli, Luca; Jin Hyen Baek; Pires, Ivan S.; Palmer, Andre F.; Dennler, Matthias; Humar, Rok; Buehler, Paul W.; Kircher, Patrick R.
- Abstract
Delayed ischemic neurological deficit (DIND) is a major driver of adverse outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH), defining an unmet need for therapeutic development. Cell-free hemoglobin that is released from erythrocytes into the cerebrospinal fluid (CSF) is suggested to cause vasoconstriction and neuronal toxicity, and correlates with the occurrence of DIND. Cell-free hemoglobin in the CSF of patients with aSAH disrupted dilatory NO signaling ex vivo in cerebral arteries, which shifted vascular tone balance from dilation to constriction. We found that selective removal of hemoglobin from patient CSF with a haptoglobin-affinity column or its sequestration in a soluble hemoglobin-haptoglobin complex was sufficient to restore physiological vascular responses. In a sheep model, administration of haptoglobin into the CSF inhibited hemoglobin-induced cerebral vasospasm and preserved vascular NO signaling. We identified 2 pathways of hemoglobin delocalization from CSF into the brain parenchyma and into the NO-sensitive compartment of small cerebral arteries. Both pathways were critical for hemoglobin toxicity and were interrupted by the large hemoglobin-haptoglobin complex that inhibited spatial requirements for hemoglobin reactions with NO in tissues. Collectively, our data show that compartmentalization of hemoglobin by haptoglobin provides a novel framework for innovation aimed at reducing hemoglobin-driven neurological damage after subarachnoid bleeding.
- Subjects
CEREBRAL vasospasm; SUBARACHNOID space; CEREBROSPINAL fluid; CEREBRAL arteries; SUBARACHNOID hemorrhage
- Publication
Journal of Clinical Investigation, 2019, Vol 129, Issue 12, p5219
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI130630