Anti-β2-glycoprotein I and anti-phosphatidylserine/prothrombin antibodies interfere with cleavage of factor V(a) by activated protein C.

Autor:	Noordermeer T; Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Circulatory Health Research Center, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: https://twitter.com/Tessa_Noorder., Chemlal S; Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Circulatory Health Research Center, University Medical Center Utrecht, Utrecht, the Netherlands., Jansma JJ; Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Circulatory Health Research Center, University Medical Center Utrecht, Utrecht, the Netherlands., van der Vegte V; Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Circulatory Health Research Center, University Medical Center Utrecht, Utrecht, the Netherlands., Schutgens REG; Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Limper M; Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., de Groot PG; Synapse Research Institute, Maastricht, the Netherlands., Meijers JCM; Department of Molecular Hematology, Sanquin Research, Amsterdam, the Netherlands; Department of Experimental Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands., Urbanus RT; Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Circulatory Health Research Center, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: r.t.urbanus@umcutrecht.nl.
Jazyk:	angličtina
Zdroj:	Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2023 Sep; Vol. 21 (9), pp. 2509-2518. Date of Electronic Publication: 2023 Jun 07.
DOI:	10.1016/j.jtha.2023.05.024
Abstrakt:	Background: The acquired thrombotic risk factor known as lupus anticoagulant (LA) interferes with laboratory clotting assays and can be caused by autoantibodies against β2-glycoprotein I (β2GPI) and prothrombin. LA is associated with activated protein C (APC) resistance, which might contribute to thrombotic risk in patients with antiphospholipid syndrome. How antibodies against β2GPI and prothrombin cause APC resistance is currently unclear. Objectives: To investigate how anti-β2GPI and antiphosphatidylserine/prothrombin (PS/PT) antibodies induce APC resistance. Methods: The effects of anti-β2GPI and anti-PS/PT antibodies on APC resistance were studied in plasma (of patients with antiphospholipid syndrome) and with purified coagulation factors and antibodies. Results: APC resistance was observed in LA-positive patients with anti-β2GPI or anti-PS/PT antibodies and in normal plasma spiked with monoclonal anti-β2GPI or anti-PS/PT antibodies with LA activity. Analysis of factor (F)V cleavage patterns after APC incubation indicated that anti-β2GPI antibodies attenuated APC-mediated FV cleavage at R506 and R306. APC-mediated cleavage at R506 is required for FV cofactor activity during inactivation of FVIIIa. Assays with purified coagulation factors confirmed that anti-β2GPI antibodies interfered with the cofactor function of FV during FVIIIa inactivation but not with FVa inactivation. Anti-PS/PT antibodies attenuated APC-mediated FVa and FVIIIa inactivation. Analysis of FV(a) cleavage patterns after APC incubation indicated that anti-PS/PT antibodies interfere with APC-mediated cleavage of FV at positions R506 and R306. Conclusion: Anti-β2GPI antibodies with LA activity contribute to a procoagulant state by causing APC resistance via interference with the cofactor function of FV during FVIIIa inactivation. LA-causing anti-PS/PT antibodies interfere with the anticoagulant function of APC by preventing FV(a) cleavage. Competing Interests: Declaration of competing interests There are no competing interests to disclose. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu