Pharmacological regulation of factor XII activation may be a new target to control pathological coagulation.
FXII was identified 50 years ago as a coagulation protein in the intrinsic pathway of blood coagulation as FXII deficient patients had marked prolongation of the in vitro surface-activated coagulation time. However, series of investigations have convincingly shown that FXII has no role in normal hemostasis. Recently, experimentally induced thrombosis in factor XII-knockout mice has provided evidence that factor XII (FXII) deficient mice are protected against ischemic brain injury after obstructive clot formation. Based on these experiments it has, therefore, been suggested, that blocking of FXII could be a unique target to prevent obstructive clot formation in arterial thrombosis without side effect of increased bleeding. FXII deficiency has, however, not convincingly been shown to protect against arterial thrombosis in humans. The target mentioned above may either be an inhibition of FXII activation or an inhibition of its proteolytic activity. FXII is a zymogen of the proteolytic enzyme, FXIIa, the substrates of which are factor XI and prekallikrein. Thus, FXIIa is not only involved in the activation of the coagulation system, but is also associated with the kallikrein/kinin system. The activation of the latter is deeply involved in inflammation and pain sensation. Furthermore, FXIIa binds to endothelial cells and to the extracellular matrix, indicating a role in vascular repair. Therefore, a complete evaluation of all these properties of FXII and FXIIa has to be considered when formulating a strategy for blocking FXII activation.
Schousboe
Inger
I
Department of Biomedical Sciences, Heart and Circulatory Research Section, The Panum Institute, University of Copenhagen, Blegdamsvej 3C, DK-2200 Copenhagen, Denmark. schousboe@imbg.ku.dk
D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism*; D005174:Factor XII / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D011110:Polymorphism, Genetic
D005174:Factor XII