Effect of recombinant ADAMTS-13 on microthrombosis and brain injury after experimental subarachnoid hemorrhage

Authors

  • M. D. I. Vergouwen,

    Corresponding author
    1. Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
    2. Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
    • Correspondence: Mervyn D.I. Vergouwen, Department of Neurology and Neurosurgery, Room G03-228, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.

      Tel.: +31 88 7550455; fax: +31 30 2542100.

      E-mail: M.D.I.Vergouwen@umcutrecht.nl

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  • V. L. Knaup,

    1. Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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  • J. J. T. H. Roelofs,

    1. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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  • O. J. de Boer,

    1. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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  • J. C. M. Meijers

    1. Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
    2. Department of Plasma Proteins, Sanquin-AMC Landsteiner Laboratory, Amsterdam, the Netherlands
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  • Manuscript handled by: P. de Moerloose
  • Final decision: P. H. Reitsma, 23 March 2014

Summary

Background

A common complication after aneurysmal subarachnoid hemorrhage (SAH) is delayed cerebral ischemia (DCI), which is associated with vasospasm and other mechanisms such as microthrombosis. ADAMTS-13 activity plays a role in the prevention of thrombus formation in the cerebral microvasculature. Previously, we observed that patients with DCI have lower levels of ADAMTS-13.

Objectives

To examine whether recombinant human ADAMTS-13 (rADAMTS-13) reduces cerebral microthrombus formation and brain injury in an experimental mouse model of SAH including wild-type and ADAMTS-13−/− mice.

Methods

Experimental SAH was induced with the prechiasmatic blood injection model. The following experimental groups were investigated: (i) C57BL/6J mice (n = 10); (ii) C57BL/6J mice (n = 10) treated with rADAMTS-13 20 min after SAH; (iii) ADAMTS-13−/− mice (n = 10); and (iv) ADAMTS-13−/− mice (n = 10) treated with rADAMTS-13 20 min after SAH. Mice were killed at 48 h. Results are presented as means with standard errors of the mean.

Results

Infusion with rADAMTS-13 reduced the extent of microthrombosis by ~ 50% in both wild-type mice (mean fibrinogen area: 0.28% ± 0.09% vs. 0.15% ± 0.04%; P = 0.20) and ADAMTS-13−/− mice (mean fibrinogen area: 0.32% ± 0.05% vs. 0.16% ± 0.03%; P = 0.016). In addition, rADAMTS-13 reduced brain injury by > 60% in both wild-type mice (mean microglia area: 0.65% ± 0.18% vs. 0.18% ± 0.04%; P = 0.013) and ADAMTS-13−/− mice (mean microglia area: 1.24% ± 0.36% vs. 0.42% ± 0.13%; P = 0.077).

Conclusions

Our results support the further study of rADAMTS-13 as a treatment option for the prevention of microthrombosis and brain injury after SAH.

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