Why do we want to know how factor XII levels are modulated?

Abstract

New interest in factor XII has been found due to the fact that its murine knockout animal is protected from arterial thrombosis in several models (1,2). The mechanism(s) for these observations have not been precisely described. However, several investigators have shown that factor XII converting to factor XIIa presumably by autoactivation on surfaces such as platelet polysomes, expressed RNA, exposed vascular collagen, and/or aggregated protein contributes to developing thrombus (3-6). Since factor XII participates in the size of an induced-clot formation it has a role in thrombosis. This activity describes for the first time an in vivo pathophysiologic event contributed to by factor XII/XIIa.It is known from the observations of Ratnoff and others that factor XII is essential for surface activated blood coagulation reactions (7). Recognition that factor XII initiates test-tube blood coagulations was the basis for the waterfall hypothesis for the blood coagulation system (8). However, factor XII deficient patients do not have a bleeding defect even though their surfaceactivated blood coagulation tests are prolonged. Thus, factor XII is not a hemostatic protein.The dichotomy of factor XII being needed for normal blood coagulation tests, but not hemostasis has confused this field for decades. Now that it is generally agreed that tissue factor is the physiologic initiator of blood coagulation leading to hemostasis, the contact activation system needs to be redefined (9,10). Contact activation mechanisms explain how common blood coagulations tests like the activated partial thromboplastin time (APTT) or activated coagulation time (ACT) which are performed on millions of patients annually work. The molecular mechanism for factor XII autoactivation still is not known. Factor XII autoactivation at the molecular level occurs by imposing specific orientation and ordering on the adsorbed protein molecules on sum frequency generation vibrational spectroscopy (11). Alternatively, factor XII in vivo may be activated by contact as described above with various biologic substances in developing thrombus or secondary to formed plasma kallikrein, its only known enzyme activator.The kinetics of factor XII activation by plasma kallikrein (K m =11 µM) is similar to factor XIIa activation of prekallikrein (K m =2.4 µM). However, the K m of prekallikrein activation in vivo by its endothelial cell membrane expressed serine protease, prolylcarboxypeptidase, is 9 nM (12). These latter kinetic data suggest that physiologic factor XII activation is secondary to plasma kallikrein formation. However, it has yet to be shown if prolylcarboxypeptidase is important for in vivo prekallikrein activation for factor XII activation. Although C1 inhibitor deficient mice have angioedema, indicating higher constitutive bradykinin formation from

The Coagulation Factor XIIa Inhibitor rHA-Infestin-4 Improves Outcome after Cerebral Ischemia/Reperfusion Injury in Rats

“…Based on a new concept, FXII seems to be relevant for thrombosis but not for physiological coagulation processes in vivo [ 15 – 17 ]; making FXII the ideal target for a safe treatment approach in stroke. In line with multiple other reports on FXII-deficient humans [ 60 , 61 ] and FXII-deficient [ 18 , 19 ] or -inhibited animals [ 17 ], we did not find any evidence for an increased bleeding tendency of rHA-Infestin-4 treatment in this study and recent studies in murine models of silent brain ischemia [ 41 ], further emphasizing the opportunity for a safe treatment approach using FXIIa inhibitors.…”