Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis
Standard
Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. / Kleinschnitz, Christoph; Stoll, Guido; Bendszus, Martin; Schuh, Kai; Pauer, Hans-Ulrich; Burfeind, Peter; Renné, Christoph; Gailani, David; Nieswandt, Bernhard; Renné, Thomas.
In: J EXP MED, Vol. 203, No. 3, 20.03.2006, p. 513-8.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis
AU - Kleinschnitz, Christoph
AU - Stoll, Guido
AU - Bendszus, Martin
AU - Schuh, Kai
AU - Pauer, Hans-Ulrich
AU - Burfeind, Peter
AU - Renné, Christoph
AU - Gailani, David
AU - Nieswandt, Bernhard
AU - Renné, Thomas
PY - 2006/3/20
Y1 - 2006/3/20
N2 - Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor-treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases.
AB - Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor-treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases.
KW - Animals
KW - Blood Coagulation Factor Inhibitors
KW - Blood Vessels
KW - Brain Ischemia
KW - Factor XI Deficiency
KW - Factor XII
KW - Factor XII Deficiency
KW - Female
KW - Fibrin
KW - Hemostasis
KW - Male
KW - Mice
KW - Mice, Knockout
KW - Thrombosis
U2 - 10.1084/jem.20052458
DO - 10.1084/jem.20052458
M3 - SCORING: Journal article
C2 - 16533887
VL - 203
SP - 513
EP - 518
JO - J EXP MED
JF - J EXP MED
SN - 0022-1007
IS - 3
ER -