The contact system includes factor XII (FXII), factor XI (FXI), prekallikrein (PK) and high-molecular weight kininogen (HK) and has received increased interest as a potential target in immunothrombotic and inflammatory diseases. This system activates two distinct pathways, the intrinsic pathway of coagulation via cleavage of factor IX (FIX) and inflammation via HK cleavage resulting in bradykinin (BK) generation. HK is central to the function of both arms of the system as a substrate for plasma kallikrein (PKa) and critical cofactor which forms interactions with cell receptors and activators. Both FXI and PK circulate in complex with HK and both can be activated by factor XIIa (FXIIa). Reciprocal activation and continuous consumption of PK and FXII is a feature of the contact system. On endothelial cells, PK and FXII become activated but only in the presence of secreted receptor for the globular domain of C1q (gC1qR) and Zn2+ ions. A second mechanism exists on endothelial cells whereby prolylcarboxypeptidase activates the PK-HK complex to generate BK in a FXII independent manner. On platelets, FXI can be cleaved by thrombin, but only in the presence of secreted polyphosphate. This review explores the 3D structure of the contact factors and examines the molecular mechanisms underlying contact activation. We focus on conformational changes that expose cleavage sites and exosites in FXII, PK, and FXI. We also discuss contact factor protein-protein interactions, recognition of polyanions and the role of HK and Zn²⁺ in contact system assembly.
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Review Article|
July 10, 2025
Structure and interactions of the proteins from the contact system Available to Purchase
Jonas Emsley,
University of Nottingham, Nottingham, United Kingdom
* Corresponding Author; email: jonas.emsley@nottingham.ac.uk
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Yujie Ma,
Yujie Ma
University of Nottingham, Nottingham, United Kingdom
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Joost C.M. Meijers
Joost C.M. Meijers
Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
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Blood blood.2024025322.
Article history
Submitted:
September 24, 2024
Revision Received:
May 30, 2025
Accepted:
June 4, 2025
Citation
Jonas Emsley, Yujie Ma, Joost C.M. Meijers; Structure and interactions of the proteins from the contact system. Blood 2025; blood.2024025322. doi: https://doi.org/10.1182/blood.2024025322
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