Single-chain factor XII: a new form of activated factor XII

Abstract

Purpose Exposure of blood to foreign surfaces induces reciprocal conversion of the plasma proteins factor XII (fXII) and plasma prekallikrein (PPK) to the proteases α-fXIIa and α-kallikrein. This process, called contact activation, has a range of effects on host defense mechanisms, including promoting coagulation. The nature of the triggering mechanism for contact activation is debated. One hypothesis predicts that fXII has protease activity, either intrinsically or upon surface-binding, that initiates contact activation. We tested this by assessing the proteolytic activity of a recombinant fXII variant that cannot be converted to α-fXIIa. Recent findings The proteolytic activity of fXII-T (for “triple” mutant), a variant with alanine substitutions for arginine at activation cleavage sites (Arg334, Arg344, and Arg353) was tested with known α-fXIIa substrates. FXII-T activates PPK in solution, and the reaction is enhanced by polyphosphate, an inducer of contact activation released from platelets. In the presence of polyphosphate, fXII-T converts fXII to α-fXIIa, and also converts the coagulation protein factor XI to its active form. Summary The findings support the hypothesis that contact activation is initiated through activity intrinsic to single-chain fXII, and indicate that pre-existing α-fXIIa is not required for induction of contact activation.

Antibody inhibition of contact factor XII reduces platelet deposition in a model of extracorporeal membrane oxygenator perfusion in nonhuman primates

“…Concomitantly, α‐FXIIa activates the zymogen PK to α‐kallikrein, which then converts additional FXII to α‐FXIIa. β‐FXIIa can activate components of the complement system and as part of the kallikrein‐kinin system cleaves the cofactor HK to liberate the potent systemic vasoregulatory and proinflammatory molecule bradykinin . Thus, contact activation initiates both prothrombotic and proinflammatory processes …”

“…β-FXIIa can activate components of the complement system and as part of the kallikrein-kinin system cleaves the cofactor HK to liberate the potent systemic vasoregulatory and proinflammatory molecule bradykinin. 17 Thus, contact activation initiates both prothrombotic and proinflammatory processes. 18 Contact activation of plasma drives thrombin formation in the activated partial thromboplastin time (aPTT) assay in vitro.…”

Targeting the Contact Pathway of Coagulation for the Prevention and Management of Medical Device-Associated Thrombosis

“…Although the binding partners for FXII KNG have not been identified, available data point to residues in the FN2 domain, thus exposing the cleavage site of FXII requisite for activation. 42 46…”

“…Although the binding partners for FXII KNG have not been identified, available data point to residues in the FN2 domain, thus exposing the cleavage site of FXII requisite for activation. 42,46 In this "open" conformation, surface-bound FXII is now able to rapidly undergo autocatalytic activation or activation by proteases such as kallikrein. 42 Once activated by the surface, FXIIa then initiates coagulation by activating FXI, leading to downstream thrombin generation.…”

Factor XII-Driven Inflammatory Reactions with Implications for Anaphylaxis

“…The catalytic domain is located within the C-terminal light chain of the protease. In humans, single-chain (sc)FXII has measurable, although much lower, proteolytic activity than complete FXIIa and its potential importance in vivo remains to be shown ( 10 ). FXIIa initiates the intrinsic coagulation cascade, which leads to the generation of thrombin and fibrin to produce clots in the blood ( 11 ).…”