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

Giorgia Grosso; Kerstin Sandholm; Aleksandra Antovic; Iva Gunnarsson; Agneta Zickert; Anna Vikerfors; Lennart Truedsson; Maria Bruzelius; Bo Nilsson; Kristina Nilsson-Ekdahl; Elisabet Svenungsson

doi:10.1055/a-1347-5655

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2021; 121(10): 1299-1309
DOI: 10.1055/a-1347-5655

Coagulation and Fibrinolysis

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

Giorgia Grosso

¹Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

,

Kerstin Sandholm

²Linnaeus Center for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden

,

Aleksandra Antovic

¹Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

,

Iva Gunnarsson

¹Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

,

Agneta Zickert

¹Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

,

Anna Vikerfors

³Swedish Medical Products Agency, Uppsala, Sweden

,

Lennart Truedsson

⁴Department of Microbiology, Immunology and Glycobiology, Lund University Hospital, Lund, Sweden

,

Maria Bruzelius

⁵Department of Haematology, Karolinska University Hospital, Stockholm, Sweden

⁶Department of Medicine, Karolinska Institutet, Stockholm, Sweden

,

Bo Nilsson

⁷Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

,

Kristina Nilsson-Ekdahl

²Linnaeus Center for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden

⁷Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

,

Elisabet Svenungsson

¹Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

› Author Affiliations

Abstract

Background Low levels of total C4b-binding protein (C4BPt), a circulating inhibitor of the classical/lectin complement pathways, were observed in patients with antiphospholipid antibodies (aPLs) and during warfarin treatment.

Objectives To investigate the associations between aPL and C4BPt in patients with persistently positive (++) aPL, with/without clinical manifestations and systemic lupus erythematosus (SLE), and in controls. Furthermore, we explored the impact of anticoagulation on C4BPt and in relation to complement activation.

Methods In a cross-sectional design we investigated defined subgroups: primary (p) antiphospholipid syndrome (APS, N = 67), aPL++ individuals without clinical manifestations (aPL carriers, N = 15), SLE-aPL++ (N = 118, among them, secondary [s] APS, N = 56), aPL negative (−) SLE (SLE-aPL−, N = 291), and 322 controls. Clinical characteristics, including treatment, were tabulated. C4BPt was determined with a magnetic bead method. Complement proteins (C1q, C2, C3, C4, C3a, C3dg, sC5b-9, factor I [FI]) were measured. A mediation analysis was performed to decompose the total effect of aPL++ on C4BPt into the direct and indirect effects of aPL++ through warfarin.

Results Overall, C4BPt is 20% decreased in aPL++ patients, regardless of SLE, APS, clinical manifestations, and aPL profile. C4BPt levels associate positively with complement proteins C1q, C2, C3, and C4, and negatively with complement activation product C3dg. In the SLE group, warfarin treatment contributes to approximately half of the C4BPt reduction (9%)

Conclusion Both aPLs and warfarin are associated with C4BPt reduction. Complement activation in aPL++ patients may partly be explained by impaired inhibition through depressed C4BPt levels. Further studies are needed to understand the clinical implications.

Keywords

complement - antiphospholipid antibodies - coagulation

Full Text

References

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