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

AI Article Synopsis

  • High molecular weight kininogen (HK) aids in the binding of prekallikrein (PK) and factor XI (FXI) during blood clotting, although mice lacking HK still maintain normal blood clotting but are resistant to thrombosis.
  • Research focused on identifying specific amino acids in the HK-D6 domain that are crucial for binding with PK and FXI, using various HK variants in binding and clotting assays.
  • Findings indicated that while FXI is vital for blood clotting, the interaction with HK is essential for activating clotting processes, emphasizing HK's role in thrombosis and FXI-related functions despite HK not being required for overall hemostasis.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841474PMC
http://dx.doi.org/10.1016/j.jtha.2023.09.027DOI Listing

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