The Complex Relationship between C4b-Binding Protein, Warfarin, and Antiphospholipid Antibodies

Area of Science:

• Immunology
• Rheumatology
• Complement System Biology

Background:

• Low levels of total C4b-binding protein (C4BPt), a key inhibitor of complement pathways, are observed in patients with antiphospholipid antibodies (aPLs).
• Warfarin treatment has also been associated with reduced C4BPt levels.

Purpose of the Study:

• To investigate the association between aPLs and C4BPt levels in patients with persistently positive aPLs, with or without clinical manifestations and systemic lupus erythematosus (SLE).
• To explore the impact of anticoagulation (warfarin) on C4BPt levels and its relation to complement activation.

Main Methods:

• A cross-sectional study involving patients with primary antiphospholipid syndrome (APS), aPL carriers, SLE patients with aPLs (SLE-aPL++), SLE patients without aPLs (SLE-aPL-), and controls.
• Measurement of C4BPt levels using a magnetic bead method and quantification of various complement proteins and activation products.
• Mediation analysis to assess the direct and indirect effects of aPLs on C4BPt through warfarin treatment.

Main Results:

• C4BPt levels were decreased by 20% in aPL++ patients, irrespective of SLE, APS, or clinical manifestations.
• C4BPt levels positively correlated with complement proteins (C1q, C2, C3, C4) and negatively with a complement activation product (C3dg).
• In SLE patients, warfarin treatment accounted for approximately half of the observed C4BPt reduction (9%).

Conclusions:

• Both antiphospholipid antibodies (aPLs) and warfarin are independently associated with reduced C4BPt levels.
• Impaired complement inhibition due to lower C4BPt may partly explain complement activation observed in aPL++ patients.
• Further research is necessary to elucidate the clinical implications of these findings.