The intrinsic pathway of coagulation a target for treating thromboembolic disease?
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The intrinsic pathway of coagulation a target for treating thromboembolic disease? / Gailani, D; Renné, T.
In: J THROMB HAEMOST, Vol. 5, No. 6, 01.06.2007, p. 1106-12.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The intrinsic pathway of coagulation a target for treating thromboembolic disease?
AU - Gailani, D
AU - Renné, T
PY - 2007/6/1
Y1 - 2007/6/1
N2 - The classic intrinsic pathway of coagulation is triggered by contact activation of the plasma protease factor (F)XII, followed by sequential proteolytic activation of FX1 and FIX. While a key mechanism for initiating coagulation in some clinically useful in vitro assays, the absence of abnormal bleeding associated with congenital FXII deficiency indicates that the intrinsic pathway is not important for normal blood coagulation in vivo. However, recent work with mice lacking FXII or FXI suggest that these proteases make important contributions to formation of pathologic intravascular thrombi. In models of arterial injury, FXII or FXI null mice are protected from formation of platelet rich occlusive thrombi to a degree similar to that seen in FIX deficient mice (a model for the severe bleeding disorder hemophilia B) or to wild type mice treated with high dose heparin. FXII or FXI deficiency does not appear to prevent the initiation of thrombus formation in these models, but instead causes significant thrombus instability that prevents occlusion of the vessel. These findings raise the possibility that a pathway similar or identical to the intrinsic pathway may operate in vivo under some circumstances. Furthermore, the disproportionate importance of FXII and FXI to occlusive thrombus formation compared to normal hemostasis makes these proteases attractive candidates for therapeutic inhibitors to treat or prevent thromboembolic disorders.
AB - The classic intrinsic pathway of coagulation is triggered by contact activation of the plasma protease factor (F)XII, followed by sequential proteolytic activation of FX1 and FIX. While a key mechanism for initiating coagulation in some clinically useful in vitro assays, the absence of abnormal bleeding associated with congenital FXII deficiency indicates that the intrinsic pathway is not important for normal blood coagulation in vivo. However, recent work with mice lacking FXII or FXI suggest that these proteases make important contributions to formation of pathologic intravascular thrombi. In models of arterial injury, FXII or FXI null mice are protected from formation of platelet rich occlusive thrombi to a degree similar to that seen in FIX deficient mice (a model for the severe bleeding disorder hemophilia B) or to wild type mice treated with high dose heparin. FXII or FXI deficiency does not appear to prevent the initiation of thrombus formation in these models, but instead causes significant thrombus instability that prevents occlusion of the vessel. These findings raise the possibility that a pathway similar or identical to the intrinsic pathway may operate in vivo under some circumstances. Furthermore, the disproportionate importance of FXII and FXI to occlusive thrombus formation compared to normal hemostasis makes these proteases attractive candidates for therapeutic inhibitors to treat or prevent thromboembolic disorders.
KW - Animals
KW - Anticoagulants
KW - Blood Coagulation
KW - Disease Models, Animal
KW - Factor XI
KW - Factor XII
KW - Humans
KW - Mice
KW - Models, Cardiovascular
KW - Thromboembolism
KW - Thromboplastin
U2 - 10.1111/j.1538-7836.2007.02446.x
DO - 10.1111/j.1538-7836.2007.02446.x
M3 - SCORING: Journal article
C2 - 17388803
VL - 5
SP - 1106
EP - 1112
JO - J THROMB HAEMOST
JF - J THROMB HAEMOST
SN - 1538-7933
IS - 6
ER -