TY - JOUR
T1 - Inhibition of Factor XII-Mediated Activation of Factor XI Provides Protection Against Experimental Acute Ischemic Stroke in Mice
AU - Leung, Philberta Y.
AU - Hurst, Sawan
AU - Berny-Lang, Michelle A.
AU - Verbout, Norah G.
AU - Gailani, David
AU - Tucker, Erik I.
AU - Wang, Ruikang K.
AU - McCarty, Owen J.T.
AU - Gruber, András
N1 - Funding Information:
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.).
PY - 2012/9
Y1 - 2012/9
N2 - 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.
AB - 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.
KW - Factor XI
KW - Hemostasis
KW - Ischemia
KW - Neuroprotection
KW - Thrombolysis
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U2 - 10.1007/s12975-012-0186-5
DO - 10.1007/s12975-012-0186-5
M3 - Article
C2 - 23634198
AN - SCOPUS:84865794214
SN - 1868-4483
VL - 3
SP - 381
EP - 389
JO - Translational Stroke Research
JF - Translational Stroke Research
IS - 3
ER -