Letter | Published:

Hyperglycemia-induced cerebral hematoma expansion is mediated by plasma kallikrein

Nature Medicine volume 17, pages 206210 (2011) | Download Citation

Abstract

Hyperglycemia is associated with greater hematoma expansion and poor clinical outcomes after intracerebral hemorrhage. We show that cerebral hematoma expansion triggered by intracerebral infusion of autologous blood is greater in diabetic rats and mice compared to nondiabetic controls and that this augmented expansion is ameliorated by plasma kallikrein (PK) inhibition or deficiency. Intracerebral injection of purified PK augmented hematoma expansion in both diabetic and acutely hyperglycemic rats, whereas injection of bradykinin, plasmin or tissue plasminogen activator did not elicit such a response. This response, which occurs rapidly, was prevented by co-injection of the glycoprotein VI agonist convulxin and was mimicked by glycoprotein VI inhibition or deficiency, implicating an effect of PK on inhibiting platelet aggregation. We show that PK inhibits collagen-induced platelet aggregation by binding collagen, a response enhanced by elevated glucose concentrations. The effect of hyperglycemia on hematoma expansion and PK-mediated inhibition of platelet aggregation could be mimicked by infusing mannitol. These findings suggest that hyperglycemia auguments cerebral hematoma expansion by PK-mediated osmotic-sensitive inhibition of hemostasis.

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Acknowledgements

This work was supported in part by the US National Institutes of Health (grants EY19029, DK36836, HL090132, HL87203 and HL07917) and the American Heart Association (0855905D and 0840043N).

Author information

Author notes

    • Jia Liu
    •  & Ben-Bo Gao

    These authors contributed equally to this work.

Affiliations

  1. Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

    • Jia Liu
    • , Ben-Bo Gao
    • , Allen C Clermont
    •  & Edward P Feener
  2. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Jia Liu
    • , Ben-Bo Gao
    • , Allen C Clermont
    •  & Edward P Feener
  3. Department of Medicine, Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

    • Price Blair
    •  & Robert Flaumenhaft
  4. ActiveSite Pharmaceuticals, Inc., Berkeley, California, USA.

    • Tamie J Chilcote
    •  & Sukanto Sinha

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Contributions

J.L. initiated, designed and conducted most of the experiments and wrote the manuscript. B.-B.G. contributed to the design and performance of animal studies, biochemical analyses, platelet studies and manuscript writing. A.C.C. contributed to animal studies. P.B. and R.F. designed and performed studies using platelet aggregometer and contributed to data interpretation. T.J.C. and S.S. contributed to data interpretation and manuscript editing. E.P.F. designed and supervised the entire study and contributed to manuscript writing.

Competing interests

Tamie J. Chilcote and Sukanto Sinha are employees of and shareholders in ActiveSite Pharmaceuticals, which provided ASP-440. The Joslin Diabetes Center and ActiveSite Pharmaceuticals have submitted a patent application to the US Patent and Trademark Office and the European Patent Office on the methods for treatment of kallikrein-related disorders.

Corresponding author

Correspondence to Edward P Feener.

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DOI

https://doi.org/10.1038/nm.2295

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