scholarly journals AB1240 C4B BINDING PROTEIN AND WARFARIN IN THE ANTIPHOSPHOLIPID SYNDROME

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1911.2-1911
Author(s):  
G. Grosso ◽  
K. Sandholm ◽  
I. Gunnarsson ◽  
A. Zickert ◽  
A. Vikerfors ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Mediation Analysis ◽  
Binding Protein ◽  
Protein A ◽  
Protein S ◽  
Protein Isoforms ◽  
Type I ◽  
Complement Inhibitor ◽  
Warfarin Treatment ◽  
The Impact

Background:Complement plays a role in the Antiphospholipid Syndrome (APS). C4b Binding Protein (C4BP) is a complement inhibitor with anticoagulant function (1). It belongs to the same protein family as β2GPI, the main antigen in APS. Its main isoform is bound to protein S in the circulation. Levels of both protein S and C4BP are known to be reduced by warfarin treatment (2) as well as by aPL, directly and indirectly.Objectives:To investigate the levels of C4BP in primary (p) and secondary (s) APS, also considering warfarin treatment.Methods:The total amount of C4BP (C4BPt) was measured by using magnetic carboxylated microspheres which were coupled with a monoclonal antibody against the α-chain of human-C4BP to capture the antigen. To detect C4BPt the same antibody was used, biotinylated. The binding of biotinylated antibodies was detected by streptavidin-phycoerythrin and data were collected using a MAGPIX Multiplex Reader. Using independent t-test, we compared C4BP in 118 SLE patients with repeated positivity for Antiphospholipid antibodies (aPL) (39/118 on warfarin), 291 aPL negative SLE patients (16/291 on warfarin), 67 pAPS (33/67 on warfarin), and 322 controls (none on warfarin). We then performed an interaction and a mediation analysis (3) in the SLE group to study the impact of warfarin on C4BP levels: since warfarin is mostly prescribed to aPL+ patients, it is considered a mediator in the reducing effect of aPL on C4BP. Therefore we compared individuals exposed and non-exposed to the presence of aPL with or without the mediator warfarin and calculated the percentage of reduction in C4BP that could be attributed to aPL or warfarin.Results:Overall C4BP is 20% reduced in aPL+ patients (fig 1), independently of SLE, past thrombotic events and nephritis. Warfarin treated patients have lower levels of C4BP (fig 2). According to mediation analysis 11% of C4BP reduction is due to aPL and 9% to warfarin.Figure 1.C4BP in different subgroups (67 pAPS, 118 SLEaPL+, 291 SLEaPL-, 322 controls)Figure 2.C4BP in 67 pAPS patients, 33/67 on warfarinConclusion:Both aPL and warfarin decrease levels of C4BP, a complement and coagulation regulator. Reduction of this complement inhibitor could contribute to complement activation and thrombosis in APS. Our results raise new questions regarding the effects of warfarin treatment on complement and coagulation in APS.References:[1]Dahlbäck B. C4b-binding protein: a forgotten factor in thrombosis and hemostasis. Seminars in thrombosis and hemostasis 2011; 37(4): 355.[2]Zöller B, García de Frutos P, Dahlbäck B. Evaluation of the relationship between protein S and C4b-binding protein isoforms in hereditary protein S deficiency demonstrating type I and type III deficiencies to be phenotypic variants of the same genetic disease. Blood 1995; 85(12): 3524.[3]Vanderweele TJ, Vansteelandt S. Conceptual issues concerning mediation, interventions and composition. Statistics and Its Interface 2009; 2(4): 457-68.Disclaimer:AV is employed at the Swedish Medical Products Agency, the views expressed in this paper are the personal views of the authors and not necessarily the views of the Governement AgencyAcknowledgments:Thanks to the Biostatistics Core Facility, Karolinska UniversityDisclosure of Interests:None declared

scholarly journals Vitamin K-dependent protein S is similar to rat androgen-binding protein

1987 ◽  
Vol 243 (1) ◽  
pp. 293-296 ◽  
Author(s):  
M E Baker ◽  
F S French ◽  
D R Joseph
Keyword(s):  
Vitamin K ◽  
Binding Protein ◽  
Protein A ◽  
Serine Proteinase ◽  
Protein S ◽  
Clotting Factors ◽  
The Family ◽  
Androgen Binding Protein ◽  
Dependent Protein ◽  
Androgen Binding

Vitamin K-dependent protein S belongs to the family of clotting factors (e.g. Factors IX and X, and protein C). Unlike the other clotting factors, the C-terminal half (residues 250-634) of protein S is not a serine proteinase. In fact, the function of residues 250-634 of protein S is unknown. By using computer programs designed to detect evolutionary relationships between proteins, we find that this part of protein S is similar to rat androgen-binding protein, a protein produced and secreted by testicular Sertoli cells. The homology between protein S and androgen-binding protein suggests new approaches for elucidating their functions.

Possible Role for Increased C4b-Binding-Protein Level in Acquired Protein S Deficiency in Type I Diabetes

Diabetes ◽  
1990 ◽  
Vol 39 (4) ◽  
pp. 447-449 ◽  
Author(s):  
A. Ceriello ◽  
D. Giugliano ◽  
A. Quatraro ◽  
E. Marchi ◽  
M. Barbanti ◽  
...  
Keyword(s):  
Protein Level ◽  
Type I Diabetes ◽  
Binding Protein ◽  
Protein S ◽  
Type I ◽  
Protein S Deficiency ◽  
S Deficiency

The complex relationship between C4b Binding Protein, warfarin and antiphospholipid antibodies

2021 ◽  
Author(s):  
Giorgia Grosso ◽  
Kerstin Sandholm ◽  
Aleksandra M Antovic ◽  
Iva Gunnarsson ◽  
Agneta Zickert ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Complement Activation ◽  
Antiphospholipid Antibodies ◽  
Binding Protein ◽  
Clinical Manifestations ◽  
Magnetic Bead ◽  
Cross Sectional ◽  
Complement Proteins ◽  
Warfarin Treatment ◽  
The Impact

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 (aPL) 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) 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 SLE, APS, clinical manifestations and aPL profile. C4BPt levels associate positively with complement proteins C1q, C2, C3, 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 antiphospholipid antibodies 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 implication

Possible role for increased C4b-binding-protein level in acquired protein S deficiency in type I diabetes

Diabetes ◽  
1990 ◽  
Vol 39 (4) ◽  
pp. 447-449 ◽  
Author(s):  
A. Ceriello ◽  
D. Giugliano ◽  
A. Quatraro ◽  
E. Marchi ◽  
M. Barbanti ◽  
...  
Keyword(s):  
Protein Level ◽  
Type I Diabetes ◽  
Binding Protein ◽  
Protein S ◽  
Type I ◽  
Protein S Deficiency ◽  
S Deficiency

scholarly journals Causal Mediation Analysis with Multiple Causally Ordered and Non-ordered Mediators based on Summarized Genetic Data

2021 ◽  
Author(s):  
Lei Hou ◽  
Yuanyuan Yu ◽  
Xiaoru Sun ◽  
Xinhui Liu ◽  
Yifan Yu ◽  
...  
Keyword(s):  
Mediation Analysis ◽  
Genetic Data ◽  
Type I ◽  
Finite Sample ◽  
Mediation Effects ◽  
Causal Mediation ◽  
Causal Pathways ◽  
Causal Pathway ◽  
Causal Mediation Analysis ◽  
The Impact

Causal mediation analysis aims to investigate the mechanism linking an exposure and an outcome. Dealing with the impact of unobserved confounders among the exposure, mediator and outcome has always been an issue of great concern. Moreover, when multiple mediators exist, this causal pathway intertwines with other causal pathways, making it more difficult to estimate of path-specific effects (PSEs). In this article, we propose a method (PSE-MR) to identify and estimate PSEs of an exposure on an outcome through multiple causally ordered and non-ordered mediators using Mendelian Randomization, when there are unmeasured confounders among the exposure, mediators and outcome. Additionally, PSE-MR can be used when pleiotropy exists, and can be implemented using only summarized genetic data. We also conducted simulations to evaluate the finite sample performances of our proposed estimators in different scenarios. The results show that the causal estimates of PSEs are almost unbiased with good coverage and Type I error properties. We illustrate the utility of our method through a study of exploring the mediation effects of lipids in the causal pathways from body mass index to cardiovascular disease.

scholarly journals An abnormal plasma distribution of protein S occurs in functional protein S deficiency

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 504-508 ◽  
Author(s):  
PC Comp ◽  
D Doray ◽  
D Patton ◽  
CT Esmon
Keyword(s):  
Binding Protein ◽  
Activated Protein C ◽  
Protein S ◽  
Free Form ◽  
Functional Assay ◽  
Type I ◽  
Protein S Deficiency ◽  
Functional Protein ◽  
S Deficiency ◽  
Disease Protein

Protein S is a natural anticoagulant present in the plasma that serves as a cofactor for activated protein C. Patients deficient in protein S are subject to recurrent venous thrombotic disease. Protein S deficiency differs from other plasma protein deficiencies in that deficient patients often have normal or only mildly reduced levels of protein S in their plasma as detected by conventional immunologic methods but have markedly reduced functional protein S levels. This apparent discrepancy is due to the presence of two forms of protein S in plasma. The protein S is present free and in a complex with C4b- binding protein. The free form is functionally active, whereas the bound form is not. Examination by crossed immunoelectrophoresis of 31 functionally protein S-deficient individuals from seven families reveals that 29 of the 31 have all or most of their protein S complexed to C4b-binding protein with little or no free protein and have correspondingly low levels of protein S functional activity (type I deficiency). Two related protein S-deficient individuals show a different type of distribution with little or no protein S, either bound or free (type II deficiency). The detection and classification of protein S-deficient individuals requires the application of both a functional assay and an assessment of protein S distribution between bound and free forms.

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