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
1  Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
,
Kerstin Sandholm
2  Linnaeus Center for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden
,
Aleksandra Antovic
1  Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
,
Iva Gunnarsson
1  Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
,
Agneta Zickert
1  Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
,
Anna Vikerfors
3  Swedish Medical Products Agency, Uppsala, Sweden
,
Lennart Truedsson
4  Department of Microbiology, Immunology and Glycobiology, Lund University Hospital, Lund, Sweden
,
Maria Bruzelius
5  Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
6  Department of Medicine, Karolinska Institutet, Stockholm, Sweden
,
Bo Nilsson
7  Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
,
Kristina Nilsson-Ekdahl
2  Linnaeus Center for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden
7  Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
,
1  Division 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.

Supplementary Material



Publication History

Received: 08 October 2020

Accepted: 06 January 2021

Publication Date:
07 January 2021 (online)

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