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

Tessa Noordermeer; Soumaya Chemlal; Janna J Jansma; Vossa van der Vegte; Roger E G Schutgens; Maarten Limper; Philip G de Groot; Joost C M Meijers; Rolf T Urbanus

doi:10.1016/j.jtha.2023.05.024

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

Tessa Noordermeer, Soumaya Chemlal, Janna J Jansma, Vossa van der Vegte, Roger E G Schutgens, Maarten Limper, Philip G de Groot, Joost C M Meijers, Rolf T Urbanus^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	2509-2518
Number of pages	10
Journal	Journal of thrombosis and haemostasis : JTH
Volume	21
Issue number	9
Early online date	7 Jun 2023
DOIs	https://doi.org/10.1016/j.jtha.2023.05.024
Publication status	Published - Sept 2023

Keywords

activated protein C resistance
antiphospholipid antibodies
lupus anticoagulant
prothrombin
β2-glycoprotein I

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Noordermeer, T., Chemlal, S., Jansma, J. J., van der Vegte, V., Schutgens, R. E. G., Limper, M., de Groot, P. G., Meijers, J. C. M., & Urbanus, R. T. (2023). Anti-β2-glycoprotein I and anti-phosphatidylserine/prothrombin antibodies interfere with cleavage of factor V(a) by activated protein C. Journal of thrombosis and haemostasis : JTH, 21(9), 2509-2518. https://doi.org/10.1016/j.jtha.2023.05.024

@article{91844793f25244679740e4cf015e8742,

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

abstract = "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.",

keywords = "activated protein C resistance, antiphospholipid antibodies, lupus anticoagulant, prothrombin, β2-glycoprotein I",

author = "Tessa Noordermeer and Soumaya Chemlal and Jansma, {Janna J} and {van der Vegte}, Vossa and Schutgens, {Roger E G} and Maarten Limper and {de Groot}, {Philip G} and Meijers, {Joost C M} and Urbanus, {Rolf T}",

note = "Funding Information: Funding information This study was supported by the Netherlands Thrombosis Foundation (grant number 2018-03). Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = sep,

doi = "10.1016/j.jtha.2023.05.024",

language = "English",

volume = "21",

pages = "2509--2518",

journal = "Journal of thrombosis and haemostasis : JTH",

issn = "1538-7933",

publisher = "Wiley-Blackwell",

number = "9",

}

Noordermeer, T, Chemlal, S, Jansma, JJ, van der Vegte, V, Schutgens, REG , Limper, M, de Groot, PG, Meijers, JCM & Urbanus, RT 2023, 'Anti-β2-glycoprotein I and anti-phosphatidylserine/prothrombin antibodies interfere with cleavage of factor V(a) by activated protein C', Journal of thrombosis and haemostasis : JTH, vol. 21, no. 9, pp. 2509-2518. https://doi.org/10.1016/j.jtha.2023.05.024

TY - JOUR

T1 - Anti-β2-glycoprotein I and anti-phosphatidylserine/prothrombin antibodies interfere with cleavage of factor V(a) by activated protein C

AU - Noordermeer, Tessa

AU - Chemlal, Soumaya

AU - Jansma, Janna J

AU - van der Vegte, Vossa

AU - Schutgens, Roger E G

AU - Limper, Maarten

AU - de Groot, Philip G

AU - Meijers, Joost C M

AU - Urbanus, Rolf T

PY - 2023/9

Y1 - 2023/9

N2 - 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.

AB - 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.

KW - activated protein C resistance

KW - antiphospholipid antibodies

KW - lupus anticoagulant

KW - prothrombin

KW - β2-glycoprotein I

UR - http://www.scopus.com/inward/record.url?scp=85162914637&partnerID=8YFLogxK

U2 - 10.1016/j.jtha.2023.05.024

DO - 10.1016/j.jtha.2023.05.024

M3 - Article

C2 - 37290588

SN - 1538-7933

VL - 21

SP - 2509

EP - 2518

JO - Journal of thrombosis and haemostasis : JTH

JF - Journal of thrombosis and haemostasis : JTH

IS - 9

ER -

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

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