High molecular weight kininogen interactions with the homologs prekallikrein and factor XI: importance to surface-induced coagulation

Mohammed, Bassem M; Sun, Mao-Fu; Cheng, Qiufang; Litvak, Maxim; McCrae, Keith R; Emsley, Jonas; McCarty, Owen J T; Gailani, David

Abstract

Background: In plasma, high molecular weight kininogen (HK) is either free or bound to prekallikrein (PK) or factor (F) XI (FXI). During contact activation, HK is thought to anchor PK and FXI to surfaces, facilitating their conversion to the proteases plasma kallikrein and FXIa. Mice lacking HK have normal hemostasis but are resistant to injury-induced arterial thrombosis. Objectives: To identify amino acids on the HK-D6 domain involved in PK and FXI binding and study the importance of the HK–PK and HK–FXI interactions to coagulation. Methods: Twenty-four HK variants with alanine replacements spanning residues 542-613 were tested in PK/FXI binding and activated partial thromboplastin time clotting assays. Surface-induced FXI and PK activation in plasma were studied in the presence or absence of HK. Kng1-/- mice lacking HK were supplemented with human or murine HK and tested in an arterial thrombosis model. Results: Overlapping binding sites for PK and FXI were identified in the HK-D6 domain. HK variants with defects only in FXI binding corrected the activated partial thromboplastin time of HK-deficient plasma poorly compared to a variant defective only in PK-binding. In plasma, HK deficiency appeared to have a greater deleterious effect on FXI activation than PK activation. Human HK corrected the defect in arterial thrombus formation in HK-deficient mice poorly due to a specific defect in binding to mouse FXI. Conclusion: Clinical observations indicate FXI is required for hemostasis, while HK is not. Yet, the HK–FXI interaction is required for contact activation-induced clotting in vitro and in vivo suggesting an important role in thrombosis and perhaps other FXI-related activities.

Citation

Mohammed, B. M., Sun, M.-F., Cheng, Q., Litvak, M., McCrae, K. R., Emsley, J., McCarty, O. J. T., & Gailani, D. (2024). High molecular weight kininogen interactions with the homologs prekallikrein and factor XI: importance to surface-induced coagulation. Journal of Thrombosis and Haemostasis, 22(1), 225-237. https://doi.org/10.1016/j.jtha.2023.09.027

• Journal Article Type: Article
• Acceptance Date: Sep 27, 2023
• Online Publication Date: Oct 9, 2023
• Publication Date: 2024-01
• Deposit Date: Dec 13, 2023
• Publicly Available Date: Oct 10, 2024
• Journal: Journal of Thrombosis and Haemostasis
• Print ISSN: 1538-7933
• Electronic ISSN: 1538-7836
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 22
• Issue: 1
• Pages: 225-237
• DOI: https://doi.org/10.1016/j.jtha.2023.09.027
• Keywords: Prekallikrein, Factor XII, thrombosis, High-molecular-weight Kininogen, Factor XI
• Public URL: https://nottingham-repository.worktribe.com/output/26791350
• Publisher URL: https://www.sciencedirect.com/science/article/abs/pii/S1538783623007298?via%3Dihub