Although the physiological role of factor XII in haemostasis is debated, as congenital factor XII deficiency does not result in any type of bleeding diathesis [25, 26], it is however clear that factor XII has a great impact on coagulation during the contact between blood and artificial materials. Factor XII activation has for a long time been thought to exclusively undergo autoactivation on surfaces exposing a negative net charge (anionic surfaces). However, after the recent work of Zhuo et al. [27, 28] it is evident that autoactivation also can occur on hydrophobic surfaces, but only in neat factor XII buffer solutions. It has been hypothesized that factor XII in plasma is competitively excluded from hydrophobic surfaces by other proteins with higher affinity to the surface, a process that has been named “adsorption-dilution effect” . Although this was an interesting discovery, it has no real impact on blood compatibility testing of biomaterials under physiological conditions. Blood contact will always entail competitive adsorption between the many plasma proteins, and contact activation of factor XII in plasma will therefore only occur at negatively charged hydrophilic surfaces. The underlying mechanism facilitating the conversion of the inactive zymogen factor XII to the active enzyme factor XIIa on anionic surfaces, independent on other enzymatic activity, is still not very well understood, but it is suggested to be facilitated by conformational changes in the protein structure upon surface adsorption [30, 31]. After initiation by factor XII the contact activation is effectively amplified by the presence of prekallikrein and HMWK. Prekallikrein is located at the anionic surface when bound to its surface binding cofactor HMWK. The co-localization of prekallikrein with factor XIIa on the surface facilitates the cleavage of prekallikrein to kallikrein, which then can participate in reciprocal activation of factor XII. The intrinsic pathway is from factor XII propagated downstream by activation of factor XI, which also is colocalized to the surface by HMWK (reviewed in ). The mechanisms of contact activation are presented in Figure 3. Contact activation in plasma by a hydrophilic glass surface will lead to fibrin formation in a matter of minutes.
Figure 3. The initiation of the intrinsic pathway through autoactivation of factor XII (contact activation) at a biomaterial surface.
Factor XII activation is accelerated by feedback activation of kallikrein. High molecular weight kininogen functions as a cofactor
for kallikrein and factor XI by facilitating the binding to surfaces. White arrow indicates autoactivation of factor XII (FXII).