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1. Measuring beta‐galactose exposure on platelets: Standardization and healthy reference values

Author

Dominique Lasne, Tiffany Pascreau, Sadyo Darame, Marie‐Charlotte Bourrienne, Peggy Tournoux, Aurélien Philippe, Sara Ziachahabi, Felipe Suarez, Ambroise Marcais, Annabelle Dupont, Cécile V. Denis, Alexandre Kauskot, and Delphine Borgel

Subjects
blood platelets, galactose, N‐acetylneuraminic acid, platelet count, references values, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Abstract Background Correct diagnosis of the cause of thrombocytopenia is crucial for the appropriate management of patients. Hyposialylation/desialylation (characterized by abnormally high β‐galactose exposure) accelerates platelet clearance and can lead to thrombocytopenia. However, the reference range for β‐galactose exposure in healthy individuals has not been defined previously. Objective The objective of the present study was to develop a standardized assay of platelet β‐galactose exposure for implementation in a clinical laboratory. Methods β‐Galactose exposure was measured in platelet‐rich plasma by using flow cytometry and Ricinus communis agglutinin (RCA). A population of 120 healthy adults was recruited to study variability. Results We determined an optimal RCA concentration of 12.5 μg/mL. The measure was stable for up to 4 hours (mean fluorescence intensity [MFI]‐RCA: 1233 ± 329 at 0 hour and 1480 ± 410 at 4 hours). The platelet count did not induce a variation of RCA and the measure of RCA was stable when tested up to 24 hours after blood collection (MFI‐RCA: 1252 ± 434 at day 0 and 1140 ± 297 24 hours after blood sampling). To take into account the platelet size, results should be expressed as RCA/forward scatter ratio. We used the assay to study variability in 120 healthy adults, and we found that the ratio is independent of sex and blood group. Conclusion We defined a normal range in a healthy population and several preanalytical and analytical variables were evaluated, together with positive and negative controls. This assay may assist in the diagnosis of thrombocytopenic diseases linked to changes in β‐galactose exposure.

Published
2020
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2. Antithrombotic potential of a single-domain antibody enhancing the activated protein C-cofactor activity of protein S

Author

Josepha C. Sedzro, Frédéric Adam, Claire Auditeau, Elsa Bianchini, Allan De Carvalho, Ivan Peyron, Sadyo Daramé, Sophie Gandrille, Stella Thomassen, Tilman M. Hackeng, Olivier D. Christophe, Peter J. Lenting, Cécile V. Denis, Delphine Borgel, François Saller, RS: Carim - B01 Blood proteins & engineering, and Biochemie

Subjects
COMPLEX, single-domain antibodies, INHIBITION, Hematology, PROTHROMBINASE, protein C, FACTOR-VA, blood coagulation, DEFICIENCY, FACTOR-XA, Mice, Fibrinolytic Agents, TISSUE FACTOR PATHWAY, MEDIATED CLEAVAGES, BINDING, Animals, Humans, INACTIVATION, protein S, Factor VIIIa, thrombosis
Abstract

BACKGROUND: Protein S (PS) is a natural anticoagulant acting as a cofactor for activated protein C (APC) in the proteolytic inactivation of activated factor V (FVa) and VIII (FVIIIa), but also for tissue factor pathway inhibitor α (TFPIα) in the inhibition of activated factor X (FXa).OBJECTIVE: For therapeutic purposes, we aimed at generating single-domain antibodies (sdAbs) that could specifically modulate the APC-cofactor activity of PS in vivo.METHODS: A llama-derived immune library of sdAbs was generated and screened on recombinant human PS by phage-display. PS binders were tested in a global activated partial thromboplastin time (APTT)-based APC-cofactor activity assay.RESULTS: A PS-specific sdAb (PS003) was found to enhance the APC-cofactor activity of PS in our APTT-based assay, and this enhancing effect was greater for a bivalent form of PS003 (PS003biv). Further characterization of PS003biv demonstrated that PS003biv also enhanced the APC-cofactor activity of PS in a tissue factor (TF)-induced thrombin generation assay and stimulated APC in the inactivation of FVa, but not FVIIIa, in plasma-based assays. Furthermore, PS003biv was directed against the sex hormone-binding globulin (SHBG)-like domain but did not inhibit the binding of PS to C4b-binding protein (C4BP) and did not interfere with the TFPIα-cofactor activity of PS. In mice, PS003biv exerted an antithrombotic effect in a FeCl3 -induced thrombosis model, while not affecting physiological hemostasis in a tail-clip bleeding model.DISCUSSION: Altogether, these results showed that pharmacological enhancement of the APC-cofactor activity of PS through an original anti-PS sdAb might constitute a promising and safe antithrombotic strategy.

Published
2022
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