Cross-Talk between the Complement Pathway and the Contact Activation System of Coagulation: Activated Factor XI...

Area of Science:

• Biochemistry
• Immunology
• Hematology

Background:

• Complement factor H (CFH) regulates the alternative complement pathway.
• Coagulation factor XI (FXI) is structurally related to CFH.
• Cross-talk between FXI and complement activation is suggested by prior studies.

Purpose of the Study:

• To investigate the direct interaction between FXI/FXIa and CFH.
• To determine if FXIa can inhibit CFH activity.
• To elucidate the molecular link between coagulation and complement systems.

Main Methods:

• In vitro assays measuring CFH cleavage by FXIa.
• Functional assays assessing CFH cofactor activity (C3b cleavage, C3bBb decay).
• Analysis of CFH binding to endothelial cells and platelet secretomes.
• Plasma and serum assays to evaluate FXIa-mediated CFH cleavage and complement activation.

Main Results:

• FXIa cleaves CFH at R341/R342 bonds, neutralizing its activity.
• FXIa reduces CFH's ability to enhance C3b cleavage and C3bBb decay.
• FXIa diminishes CFH binding to endothelial cells and its presence in platelet secretomes.
• FXIa generation in plasma leads to CFH cleavage and reduced C3b cleavage in serum.
• CFH inhibits FXI activation by thrombin and FXIIa.

Conclusions:

• FXIa directly interacts with and inactivates CFH, enhancing complement system activity.
• A novel molecular link exists between the contact pathway of coagulation and the complement system.
• FXIa generation potentiates the immune response by upregulating complement activation.