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Biomarkers of Glycocalyx Injury are Associated with Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Case Series Supporting a New Hypothesis

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Abstract

Background

Delayed cerebral ischemia (DCI) contributes to morbidity following aneurysmal subarachnoid hemorrhage; however, its etiology remains poorly understood. DCI is not only a consequence of angiographic vasospasm, but also involves microthrombosis and neuroinflammation, two events with unexplained phenomenology. The vascular endothelial glycocalyx mediates platelet aggregation and endothelial cell-leukocyte interactions and may play an important role in DCI pathogenesis.

Methods

We present a case series in which we conducted multiplex and singlet enzyme-linked immunosorbent assays of endothelial, glycocalyx, inflammatory, and neuroinjury proteins in both CSF and plasma in three patients during active DCI following SAH. Samples were obtained at baseline following surgical repair of SAH, and again at DCI onset. CSF was sampled at the same time points from in situ external ventricular drains.

Results

DCI was associated with significant elevations of soluble markers of endotheliopathy, including vascular adhesion protein-1, soluble fractions of endothelial cell adhesion molecules (CAMs), procoagulant tissue factor, and specific markers of glycocalyx injury, including syndecan-1, and CD44. These phenomena were also associated with an elevation of both circulating and CSF matrix metalloproteinases, which are known to cleave components of the glycocalyx. Elevation of vascular CAM-1 in the CSF with DCI indicated these events were possibly associated with the breakdown of brain microvasculature integrity.

Conclusions

These preliminary data support the hypothesis that glycocalyx injury occurs in SAH, and might contribute to DCI by regulating cerebral microthrombosis and delayed neuroinflammation.

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Acknowledgements

We thank Dr. Marlene Santos for her excellent coordination of sample collection and ongoing study enrollment and Ms. Witty Tse for technical assistance. In accordance with the Department of National Defence policy, the paper was reviewed and approved for submission without modification by the DRDC Publications Office.

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Authors and Affiliations

  1. Clinician-Investigator Program, Department of Anesthesia, University of Toronto, Toronto, ON, Canada

    Josh D. Bell

  2. Defense Research and Development Canada, Toronto Research Centre, Toronto, ON, Canada

    Shawn G. Rhind & Alex P. Di Battista

  3. Division of Critical Care Medicine, Department of Anesthesia, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada

    Andrew J. Baker

  4. Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada

    R. Loch Macdonald & Andrew J. Baker

  5. Division of Neurosurgery, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada

    R. Loch Macdonald

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  1. Josh D. Bell
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  4. R. Loch Macdonald
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Correspondence to Josh D. Bell.

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Conflict of interest

The authors declare that they have no competing interests. Dr. Bell and Dr. Baker report receiving funds from the Physician Services Incorporated Foundation and the Canadian Anesthesiologists Society in collaboration with Ontario’s Anesthesiologists and the Canadian Anesthesia Research Foundation.

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Disclaimer: Opinions expressed or implied in this publication are those of the authors and do not represent the views or policy of the Department of National Defence or the Canadian Armed Forces.

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Supplementary Figure 1

Further evidence of evolving endotheliopathy and glycocalyx damage. A + B) CSF data for MMP-3 and MMP-9 demonstrate these metalloproteinases do not increase with the onset of DCI and that the increase in MMP-1 was specific to that isoform. C) Subarachnoid hemorrhage is associated with a large increase of soluble vascular adhesion protein-1, suggesting breakdown of the endothelium and release of surface receptors, detectable as soluble fragments in plasma. D) SAH is similarly associated with upregulation of soluble CD44, the hyaluronic acid receptor and a critical component of the endothelial glycocalyx. E) Raw data for vascular adhesion protein-1, showing compelling upregulation in all patients studied. F) SAH is associated with increased plasma IL-6 and HMGB1, but the onset of DCI does not change these levels, suggesting the increase in CSF IL-6 likely originates within the brain parenchyma via native or transmigrated immune cells. * = p < 0.05 vs control, ** = p < 0.05 vs. SAH, SAH = subarachnoid hemorrhage, DCI = delayed cerebral ischemia, CSF = cerebrospinal fluid, VAP-1 = vascular adhesion protein-1, MMP = matrix metalloproteinase, IL-6 = interleukin 6, HMGB1 = high-mobility group box 1 (JPEG 713 kb)

Supplementary material 2 (DOCX 14 kb)

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Bell, J.D., Rhind, S.G., Di Battista, A.P. et al. Biomarkers of Glycocalyx Injury are Associated with Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Case Series Supporting a New Hypothesis. Neurocrit Care 26, 339–347 (2017). https://doi.org/10.1007/s12028-016-0357-4

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  • DOI: https://doi.org/10.1007/s12028-016-0357-4

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