Processing of Factor XII during Inflammatory Reactions

Abstract

The contact system was originally identified as an obsolete part of the coagulation system, but it has been repeatedly implicated in inflammatory states, such as infection, as well as in allergic- and chronic inflammatory disease. Under these conditions, there is surprisingly little evidence that factor XII (FXII) acts as a coagulation factor, and its activity appears to be mainly directed toward activation of the kallikrein–kinin system. The contact system factors interact with pathogens as well as cells of the (innate) immune system on several levels. Among others, these cells may provide negatively charged surfaces that contribute to contact activation as well as release enzymes that feed into this system. Furthermore, cellular receptors have been identified that bind contact factors at sites of inflammation. Based on the accumulated evidence, we propose a model for enzymatic crosstalk between inflammatory cells and the plasma contact system. During these reactions, FXII is enzymatically cleaved by non-contact system enzymes. This generates unactivated FXII fragments that can subsequently be rapidly activated in the fluid phase. The resulting enzyme lacks procoagulant properties, but retains its pro-inflammatory characteristic as a prekallikrein activator.

The coagulation system in host defense

“…Studies proposed that depending on the mode of activation, FXII can either trigger blood coagulation via activation of FXI or activate the kallikrein‐kinin system (KKS). When FXII is bound to an activating surface, the classic activation, FXII is cleaved and activated by plasma prekallikrein/kallikrein in complexing with high molecular weight kininogen (HK) which subsequently leads to FXIa generation . In addition, enveloped viruses were shown to enhance intrinsic pathway activation in vitro .…”

“…In addition, enveloped viruses were shown to enhance intrinsic pathway activation in vitro . However, FXII can also be activated by an alternative mechanism via proteases, including elastase and plasmin . Certain bacteria were shown to express specific LPS, polyphosphates, elastase, or plasminogen activators to trigger bradykinin production via FXII activation .…”

Factor XII truncation accelerates activation in solution

“…These experiments suggest that the activating cleavage site after R353 is shielded from cleavage. These findings indicate a two-step mechanism in which FXII-T309K is first truncated, exposing R353 for subsequent cleavage by PKa, as we previously proposed [15]. 3 The proline-rich region of FXII contains naturally occurring cleavage sites for a variety of enzymes, including neutrophil elastase and cathepsin K. These enzymes are unable to directly activate FXII.…”

Hereditary angioedema: the plasma contact system out of control: reply

“…However, neither paper definitively demonstrates that bradykinin is a critical disease mediator in human FXII-HAE patients during a real-world angioedema attack. Fortunately, recent clinical studies have demonstrated that this is most probably the case: both infusion of additional C1INH and B2R inhibition are therapeutic in FXII-HAE patients [7].In our review, we propose that plasmin makes a significant contribution to bradykinin C1INH-HAE and FXII-HAE; firstly, levels of plasmin-a2-antiplasmin complexes are elevated during swelling attacks [8,9]. Secondly, there is a growing body of biochemical evidence for a role of plasmin as activator of the contact system [6,10,11] More convincingly, there good clinical experience with tranexamic acid as a maintenance therapy in both forms of HAE [7,12,13], and even in patients with (H)AE of unknown origin [14].…”

“…In our review, we propose that plasmin makes a significant contribution to bradykinin C1INH-HAE and FXII-HAE; firstly, levels of plasmin-a2-antiplasmin complexes are elevated during swelling attacks [8,9]. Secondly, there is a growing body of biochemical evidence for a role of plasmin as activator of the contact system [6,10,11] More convincingly, there good clinical experience with tranexamic acid as a maintenance therapy in both forms of HAE [7,12,13], and even in patients with (H)AE of unknown origin [14].…”