title: Inhibition of Factor XII-Mediated Activation of Factor XI Provides Protection Against Experimental Acute Ischemic Stroke in Mice.
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.
authors: Department of Biomedical Engineering, Oregon Health & Science University, 3303 SW Bond Ave, Portland, OR 97239, USA; Aronora, LLC, Beaverton, OR 97006, USA.
authors: Philberta Y
authors: PY
authors: Leung
authors: Sawan
authors: S
authors: Hurst
authors: Michelle A
authors: MA
authors: Berny-Lang
authors: Norah G
authors: NG
authors: Verbout
authors: David
authors: D
authors: Gailani
authors: Erik I
authors: EI
authors: Tucker
authors: Ruikang K
authors: RK
authors: Wang
authors: Owen J T
authors: OJ
authors: McCarty
authors: András
authors: A
authors: Gruber
keywords: Factor XI; Hemostasis; Ischemia; Neuroprotection; Thrombolysis
references: JAMA. 1995 Oct 4;274(13):1017-25
references: 7563451
references: Blood. 2009 Jul 9;114(2):235
references: 19589932
references: Blood. 2003 Aug 1;102(3):953-5
references: 12689935
references: Vasc Med. 1998;3(3):257-60
references: 9892520
references: Arterioscler Thromb Vasc Biol. 2009 Dec;29(12):1986-8
references: 19923557
references: Thromb Haemost. 2002 Apr;87(4):774-6
references: 12008966
references: Pharmacotherapy. 2009 Feb;29(2):167-81
references: 19170587
references: Thromb Res. 2011 Nov;128(5):e62-6
references: 21820158
references: Stroke. 2011 Apr;42(4):1116-21
references: 21330626
references: J Thromb Haemost. 2007 Jun;5(6):1106-12
references: 17388803
references: Clin Ther. 1998;20 Suppl B:B18-41
references: 9589829
references: J Exp Med. 2006 Mar 20;203(3):513-8
references: 16533887
references: Eur J Clin Invest. 2012 Feb;42(2):123-9
references: 21707613
references: Blood. 2009 Jul 9;114(2):452-8
references: 19351955
references: Blood. 2010 Nov 25;116(22):4684-92
references: 20807891
references: NeuroRx. 2005 Jul;2(3):396-409
references: 16389304
references: J Clin Invest. 1998 Jan 1;101(1):10-4
references: 9421460
references: Neuroreport. 1999 Jan 18;10(1):107-11
references: 10094143
references: N Engl J Med. 2001 Feb 8;344(6):395-402
references: 11172175
references: Blood. 2010 Nov 11;116(19):3981-9
references: 20634381
references: Eur J Pharmacol. 2007 Sep 10;570(1-3):167-74
references: 17597608
references: Eur Heart J. 2011 Aug;32(16):1968-76, 1976a
references: 21421599
references: J Neurosci. 2011 Jun 8;31(23):8456-63
references: 21653850
references: J Thromb Haemost. 2006 Jul;4(7):1496-501
references: 16839345
references: Stroke. 2011 Jun;42(6):1736-41
references: 21512172
references: J Thromb Haemost. 2009 Jul;7 Suppl 1:84-7
references: 19630775
references: J Thromb Haemost. 2005 Apr;3(4):695-702
references: 15733058
references: Circulation. 2011 Feb 1;123(4):e18-e209
references: 21160056
references: Blood. 2008 Apr 15;111(8):4113-7
references: 18268095
references: J Thromb Haemost. 2009 Jul;7 Suppl 1:79-83
references: 19630774
references: Lancet. 2006 Aug 19;368(9536):694-703
references: 16920475
references: Blood. 2009 Jan 22;113(4):936-44
references: 18945968
references: Cerebrovasc Dis. 2010;29(5):497-502
references: 20299790