The intrinsic pathway of coagulation: a target for treating thromboembolic disease?

Abstract

Summary. 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.

New insights into the mechanisms of venous thrombosis

“…[39][40][41][42]. Under pathological conditions, tissue New insights into the mechanisms of venous thrombosis factor (TF) is expressed on circulating leukocytes and possibly activated endothelial cells (40).…”

Factor XIIa Inhibitor Recombinant Human Albumin Infestin-4 Abolishes Occlusive Arterial Thrombus Formation Without Affecting Bleeding

“…2,3 Clot formation through the extrinsic pathway occurs when tissue factor comes into contact with activated coagulation factor VII (FVIIa). 4 According to the original assumption, the intrinsic pathway is initiated when coagulation factor XII (FXII) becomes activated on a charged surface, 5 followed by successive activation of factor XI (FXI) and factor IX. This contact activation process serves as the basis of the activated partial thromboplastin time (aPTT), a method widely used to determine overall plasma coagulation in clinical practice.…”

Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis

“…Activation of the contact protease factor XII (FXII) on negatively charged surfaces, including bacterial components, activates prekallikrein and factor XI (FXI) in terrestrial mammals, 4 which results in thrombin generation through the intrinsic coagulation pathway, activation of the complement system, and release of the inflammatory peptide bradykinin from high-molecular-weight kininogen. 5,6 Although the contact proteases appear to play a significant prothrombotic role as part of the intrinsic coagulation pathway, the importance of contact system activation in infection-related hostresponse remains uncertain.…”

“…Activation of the contact protease factor XII (FXII) on negatively charged surfaces, including bacterial components, activates prekallikrein and factor XI (FXI) in terrestrial mammals, 4 which results in thrombin generation through the intrinsic coagulation pathway, activation of the complement system, and release of the inflammatory peptide bradykinin from high-molecular-weight kininogen. 5,6 Although the contact proteases appear to play a significant prothrombotic role as part of the intrinsic coagulation pathway, the importance of contact system activation in infection-related hostresponse remains uncertain.Most persons with inherited contact protease deficiencies, including FXII and its substrate prekallikrein, do not have an obvious abnormal phenotype and have normal hemostasis. 7-9 FXI deficiency (hemophilia C) is associated with excessive traumainduced bleeding in a subset of affected persons, 10,11 indicating that FXI can contribute to normal hemostasis.…”