The plasma contact system, a protease cascade at the nexus of inflammation, coagulation and immunity

Abstract

The contact system is a potent procoagulant and proinflammatory plasma protease cascade that is initiated by binding ("contact")-induced, auto-activation of factor XII zymogen. Formed active serine protease FXIIa then cleaves plasma prekallikrein to kallikrein that in turn liberates the mediator bradykinin from its precursor high molecular weight kininogen. Bradykinin induces inflammation with implications for host defense and innate immunity. FXIIa also triggers the intrinsic pathway of coagulation that has been shown to critically contribute to thrombosis. Vice versa, FXII deficiency impairs thrombosis in animal models without inducing abnormal excessive bleeding. Recent work has established the FXIIa-driven contact system as promising target for anticoagulant and anti-inflammatory drugs. This review focuses on the biochemistry of the contact system, its regulation by endogenous and exogenous inhibitors, and roles in disease states. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.

Proteases: Pivot Points in Functional Proteomics

“…The proteases of the contact pathway play a role in inflammatory and immune processes as well as in maintaining hemostasis [102]. Kallikrein cleaves high molecular weight kininogen to the pro-inflammatory bradykinin.…”

“…Several bacterial, viral, protozoan and fungal proteases trigger inflammation by activating the intrinsic coagulation pathway [102], or act as procoagulants by non-canonical, direct activation of prothrombin [179]. Large panels of small-molecule inhibitors of the proteasome in pathogenic organisms are currently being screened for potential therapeutic benefit and minimal toxicity toward the cellular machinery of the host [180].…”

Contact activation‐induced complex formation between complement factor H and coagulation factor XIIa

“…The role of coagulation factor XII (FXII) in the interplay between the coagulation and the complement system has been suggested since the early 1980s . FXII is primarily produced in the liver by hepatocytes and further secreted and present in plasma as an 80 kDa single‐chain zymogen at a concentration of ~30 μg/mL . Upon binding of negatively charged surfaces, lipophilic surfaces or binding toward zinc ions, FXII is either auto‐ or proteolytically activated by the two downstream serine proteases, kallikrein and plasmin, that cleave the Arg353‐Val354 bond, thereby producing a two‐chain molecule (α‐FXIIa) consisting of a disulphide‐linked heavy and a light chain of 353 and 243 amino acids, respectively .…”

Differential processing of high‐molecular‐weight kininogen during normal pregnancy

“…HK is detectable in porcine endometrium and human placenta . HK and its D5 peptides are implicated in the regulation of diverse functions relevant to normal pregnancy and PE pathogenesis including blood pressure regulation, smooth muscle contraction, coagulation, angiogenesis, immune response, immunity, and endothelial cell migration, proliferation, and apoptosis . HK is highly concentrated in the female reproductive tract and may be an important regulator of placental vascularization and nutrient transport to the fetus …”

“…17,19 HK and its D5 peptides are implicated in the regulation of diverse functions relevant to normal pregnancy and PE pathogenesis including blood pressure regulation, smooth muscle contraction, coagulation, angiogenesis, immune response, immunity, and endothelial cell migration, proliferation, and apoptosis. 11,20,21 HK is highly concentrated in the female reproductive tract and may be an important regulator of placental vascularization and nutrient transport to the fetus. 22 Previous biomarker studies compared HK protein and/or HKderived peptide levels in normal and hypertensive pregnancies, but interpretation of the results is confounded by differing methodologies and a lack of knowledge regarding kininogen dynamics in the course of normal pregnancy.…”