Translational Stroke Research

, Volume 3, Issue 3, pp 381–389 | Cite as

Inhibition of Factor XII-Mediated Activation of Factor XI Provides Protection Against Experimental Acute Ischemic Stroke in Mice

  • Philberta Y. Leung
  • Sawan Hurst
  • Michelle A. Berny-Lang
  • Norah G. Verbout
  • David Gailani
  • Erik I. Tucker
  • Ruikang K. Wang
  • Owen J. T. McCarty
  • András Gruber
Original Article
First Online:
Received:
Revised:
Accepted:

Abstract

Blood coagulation factor XI (FXI) is an established risk factor for acute ischemic stroke (AIS) and thrombosis, but is also needed for normal hemostasis. Contact factor XII (FXII), an upstream activator of FXI, also contributes to experimental stroke, but is not required for hemostasis. We investigated whether selectively inhibiting FXII-mediated FXI activation, while leaving other FXI and FXII functions intact, could improve the outcome of experimental AIS in mice. Twenty-four hours before induction of AIS by placement of a filament into the internal carotid artery for 60 min, mice were anticoagulated with an antibody directed against the apple 2 domain of FXI. This antibody selectively reduces the prothrombotic activation of FXI by FXIIa but does not affect activated FXI or hemostatic activation of FXI by thrombin, thus leaving hemostasis intact in mice and primates. In this model of AIS/reperfusion injury, mice that received the antibody before AIS displayed less ischemic damage, manifested as reduced cerebral infarction and fibrin deposition (thrombosis), increased cortical reperfusion, and improved neurological behavior. Further, the antibody-anticoagulated mice had no detectable hemostasis impairment. Consistent with the neuroprotective phenotype of FXII-deficient mice, our data suggest that a single molecular event, FXII-mediated FXI activation, contributes to the development of experimental AIS.

Keywords

Factor XI Ischemia Neuroprotection Thrombolysis Hemostasis 
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Notes

Acknowledgments

Supportive discussions with Dr. Joseph Aslan and technical support from Jiaqing Pang are gratefully acknowledged.

Sources of Funding

This work was supported in part by NIH grants HL 101972 (O.J.T.M. and A.G.), HL 095315 (A.G. and E.I.T.), and by an unrestricted grant from Bayer Healthcare (E.I.T. and A.G.).

Conflicts of Interest

Oregon Health & Science University (OHSU) and Vanderbilt University have been seeking patent protection for the monoclonal antibody 14E11 that has been out-licensed to Aronora, LLC, an Oregon company, and these institutions. The authors AG, DG, PYL, EIT, and NGV have a potential financial interest in its commercial development.

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Philberta Y. Leung
    • 1
    • 2
  • Sawan Hurst
    • 1
  • Michelle A. Berny-Lang
    • 1
  • Norah G. Verbout
    • 1
    • 2
  • David Gailani
    • 4
  • Erik I. Tucker
    • 1
    • 2
  • Ruikang K. Wang
    • 3
  • Owen J. T. McCarty
    • 1
    • 5
  • András Gruber
    • 1
    • 6
  1. 1.Department of Biomedical EngineeringOregon Health & Science UniversityPortlandUSA
  2. 2.Aronora, LLCBeavertonUSA
  3. 3.Department of BioengineeringUniversity of WashingtonSeattleUSA
  4. 4.Departments of Pathology and MedicineVanderbilt UniversityNashvilleUSA
  5. 5.Department of Cell and Developmental BiologyOregon Health & Science UniversityPortlandUSA
  6. 6.Department of MedicineOregon Health & Science UniversityPortlandUSA

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