The intrinsic pathway of coagulation: a target for treating thromboembolic disease?
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.
Gailani
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Department of Pathology, Vanderbilt University, Nashville, TN, USA. dave.gailani@vanderbilt.edu
Renné
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D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology*; D004195:Disease Models, Animal; D005172:Factor XI / Q000502:physiology; D005174:Factor XII / Q000502:physiology; D006801:Humans; D051379:Mice; D008955:Models, Cardiovascular; D013923:Thromboembolism / Q000097:blood* / Q000188:drug therapy*; D013925:Thromboplastin / Q000502:physiology
D000925:Anticoagulants; D005174:Factor XII; D005172:Factor XI; D013925:Thromboplastin