Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury

Akeret, Kevin; Buzzi, Raphael M; Schaer, Christian A.; Thomson, Bart R.; Vallelian, Florence; Wang, S.; Willms, Jan; Sebök, Martina; Held, Ulrike; Deuel, Johanna; Humar, Rok; Regli, Luca; Keller, E.; Hugelshofer, Michael; Schaer, Dominik J.

doi:10.1016/j.bas.2021.100310

Cited by 5 publications

(16 citation statements)

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“…Moreover, haptoglobin co-infusion seems to prevent these microvascular changes. These findings further support the therapeutic concept of intracerebroventricular haptoglobin administration as strategy to target CSF-Hb toxicity after aSAH 5 , which is planned to be translated into clinical studies in the near future.…”

Section: Discussionsupporting

confidence: 64%

“…This could partially explain the clinical observation of occurrence of SAH-SBI in absence of angiographic vasospasm 22 , and presence of vasospasm when SAH-SBI is absent 23 . A previous clinical study 5 showed strong evidence for a positive association between the occurrence of SAH-SBI and daily measured CSF-Hb concentrations. Future research should be scoped towards relating quantitative BOLD-CVR measurements in aSAH patients to CSF-Hb concentration and the clinical presentation of SAH-SBI.…”

Section: Discussionmentioning

confidence: 83%

“…Three main components of SAH-SBI are identified: 1. angiographic vasospasm in large cerebral arteries (aVSP); 2. radiologically diagnosed delayed cerebral ischemia; and 3. clinically evident delayed ischemic neurologic deficits. SAH-SBI is a complex process and recent evidence indicates that one of the main drivers may be the acute toxicity of cell-free hemoglobin in the cerebrospinal fluid (CSF-Hb) 5 .…”

Section: Introductionmentioning

confidence: 99%

“…The pathophysiology is believed to involve the gradual lysis of erythrocytes in the subarachnoid space, thereby releasing large amounts of Hb 5,6 , causing direct oxidative tissue injury 7,8 and interaction with nitric oxide (NO) signaling in the arterial vessel wall, resulting in cerebrovascular disruption 9,10 . Recent findings from our group 10 and others 11 suggest that scavenging of CSF-Hb by haptoglobin mitigates these negative effects by preventing CSF-Hb tissue penetration, thus maintaining NO signaling.…”

Section: Introductionmentioning

confidence: 99%

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Blood oxygenation-level dependent cerebrovascular reactivity imaging as strategy to monitor CSF-hemoglobin toxicity

Thomson

Richter

Akeret

et al. 2022

Preprint

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Purpose Cell-free hemoglobin in the cerebrospinal fluid (CSF-Hb) may be one of the main drivers of secondary brain injury after aneurysmal subarachnoid hemorrhage. Haptoglobin scavenging of CSF-Hb has been shown to mitigate cerebrovascular disruption. Using digital subtraction angiography (DSA) and blood oxygenation-level dependent cerebrovascular reactivity imaging (BOLD-CVR) the aim was to assess the acute toxic effect of CSF-Hb on cerebral blood flow and autoregulation, as well as to test the protective effects of haptoglobin. Methods DSA imaging was performed in eight anesthetized and ventilated sheep (mean weight: 80.4 kg) at baseline, 15, 30, 45 and 60 minutes after infusion of hemoglobin (Hb) or co-infusion with haptoglobin (Hb:Haptoglobin) into the left lateral ventricle. Additionally, 10 ventilated sheep (mean weight: 79.8 kg) underwent BOLD-CVR imaging to assess the cerebrovascular reserve capacity. Results DSA imaging did not show a difference in mean transit time or cerebral blood flow. Whole-brain BOLD-CVR compared to baseline decreased more in the Hb group after 15 minutes (Hb vs Hb:Haptoglobin: -0.03 +/- 0.01 vs -0.01 +/- 0.02) and remained diminished compared to Hb:Haptoglobin group after 30 minutes (Hb vs Hb:Haptoglobin: -0.03 +/- 0.01 vs 0.0 +/- 0.01), 45 minutes (Hb vs Hb:Haptoglobin: -0.03 +/- 0.01 vs 0.01 +/- 0.02) and 60 minutes (Hb vs Hb:Haptoglobin: -0.03 +/- 0.02 vs 0.01 +/- 0.01). Conclusion It is demonstrated that CSF-Hb toxicity leads to rapid cerebrovascular reactivity impairment, which is blunted by haptoglobin co-infusion. BOLD-CVR may therefore be further evaluated as a monitoring strategy for CSF-Hb toxicity after aSAH.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Blood oxygenation-level dependent cerebrovascular reactivity imaging as strategy to monitor CSF-hemoglobin toxicity

Thomson

Richter

Akeret

et al. 2022

Preprint

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“…Prevention and treatment of secondary brain injury in patients with aneurysmal subarachnoid hemorrhage (aSAH) represents another opportunity for scavenger protein-based therapeutics outside the classical hemolysis field. In aSAH patients, the decomposition of the blood clot generates cell-free Hb in the cerebral spinal fluid (CSF) and concurrence of cerebral vasospasm, ischemia, and secondary brain injury with high CSF-Hb has been described in approximately one-third of aSAH patients 13,97 . Preclinical evidence demonstrated that CSF-Hb causes cerebral vasospasm and potentially toxic neuronal exposures 13,97,98 .…”

Section: Therapeutic Potential Of Haptoglobin and Hemopexinmentioning

confidence: 99%

Hemolysis, free hemoglobin toxicity, and scavenger protein therapeutics

Vallelian

Buehler

Schaer

2022

Blood

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During hemolysis, erythrophagocytes dispose damaged red blood cells. This prevents the extracellular release of hemoglobin, detoxifies heme, and recycles iron in a linked metabolic pathway. Complementary to this process, haptoglobin and hemopexin scavenge and shuttle the red blood cell toxins hemoglobin and heme to cellular clearance. Pathological hemolysis outpaces macrophage capacity and scavenger synthesis across a diversity of diseases. This imbalance leads to hemoglobin-driven disease progression. To meet a void in treatment options, scavenger protein-based therapeutics are in clinical development.

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Rethinking the initial changes in subarachnoid haemorrhage: Focusing on real-time metabolism during early brain injury

Chen¹,

Galea²,

Macdonald³

et al. 2022

eBioMedicine

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Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury

Cited by 5 publications

References 0 publications

Blood oxygenation-level dependent cerebrovascular reactivity imaging as strategy to monitor CSF-hemoglobin toxicity

Blood oxygenation-level dependent cerebrovascular reactivity imaging as strategy to monitor CSF-hemoglobin toxicity

Hemolysis, free hemoglobin toxicity, and scavenger protein therapeutics

Rethinking the initial changes in subarachnoid haemorrhage: Focusing on real-time metabolism during early brain injury

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