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

被引：6
作者：
Noordermeer, Tessa [1 ,2 ]
Chemlal, Soumaya [1 ,2 ]
Jansma, Janna J. [1 ,2 ]
van der Vegte, Vossa [1 ,2 ]
Schutgens, Roger E. G. [1 ]
Limper, Maarten [3 ]
de Groot, Philip G. [4 ]
Meijers, Joost C. M. [5 ,6 ]
Urbanus, Rolf T. [1 ,2 ,7 ]
机构：
[1] Univ Utrecht, Univ Med Ctr Utrecht, Ctr Benign Haematol Thrombosis & Haemostasis, Van Creveldklin, Utrecht, Netherlands
[2] Univ Med Ctr Utrecht, Circulatory Hlth Res Ctr, Utrecht, Netherlands
[3] Univ Utrecht, Univ Med Ctr Utrecht, Dept Rheumatol & Clin Immunol, Utrecht, Netherlands
[4] Synapse Res Inst, Maastricht, Netherlands
[5] Sanquin Res, Dept Mol Hematol, Amsterdam, Netherlands
[6] Univ Amsterdam, Amsterdam UMC, Dept Expt Vasc Med, Amsterdam, Netherlands
[7] Univ Med Ctr Utrecht, Ctr Benign Hematol Thrombosis & Hemostasis, Van Creveldklin, Room C01 428,POB 85500, NL-3508 GA Utrecht, Netherlands
来源：
JOURNAL OF THROMBOSIS AND HAEMOSTASIS | 2023年 / 21卷 / 09期
关键词：
activated protein C resistance; antiphospholipid antibodies; 82-glycoprotein I; lupus anticoagulant; prothrombin; LUPUS ANTICOAGULANT ACTIVITY; FACTOR-V; ANTIPHOSPHOLIPID ANTIBODIES; BETA(2)-GLYCOPROTEIN I; THROMBIN GENERATION; VENOUS THROMBOSIS; IGG ANTIBODIES; RISK-FACTORS; DOMAIN-I; RESISTANCE;
D O I：
10.1016/j.jtha.2023.05.024
中图分类号：
R5 [内科学];
学科分类号：
1002 ; 100201 ;
摘要：
Background: The acquired thrombotic risk factor known as lupus anticoagulant (LA) interferes with laboratory clotting assays and can be caused by autoantibodies against & beta;2-glycoprotein I (& beta;2GPI) 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 & beta;2GPI and prothrombin cause APC resistance is currently unclear.Objectives: To investigate how anti-& beta;2GPI and antiphosphatidylserine/prothrombin (PS/PT) antibodies induce APC resistance.Methods: The effects of anti-& beta;2GPI 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-& beta;2GPI or antiPS/PT antibodies and in normal plasma spiked with monoclonal anti-& beta;2GPI or anti-PS/ PT antibodies with LA activity. Analysis of factor (F)V cleavage patterns after APC incubation indicated that anti-& beta;2GPI 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-& beta;2GPI 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-& beta;2GPI 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.
引用
收藏
页码：2509 / 2518
页数：10
相关论文
共 52 条
  • [1] BEVERS EM, 1991, THROMB HAEMOSTASIS, V66, P629
  • [2] The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial thromboembolism in patients with systemic lupus erythematosus
    Brouwer, JLR
    Bijl, M
    Veeger, NJGM
    Kluin-Nelemans, HC
    van der Meer, J
    [J]. BLOOD, 2004, 104 (01) : 143 - 148
  • [3] The Significance of Anti-Beta-2-Glycoprotein I Antibodies in Antiphospholipid Syndrome
    Brusch, Anna
    [J]. ANTIBODIES, 2016, 5 (02)
  • [4] Tetra positive thrombotic antiphospholipid syndrome: Major contribution of anti-phosphatidyl-serine/prothrombin antibodies to lupus anticoagulant activity
    Cattini, Maria Grazia
    Bison, Elisa
    Pontara, Elena
    Cheng, Chunyan
    Denas, Gentian
    Pengo, Vittorio
    [J]. JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2020, 18 (05) : 1124 - 1132
  • [5] Regulation of blood coagulation by the protein C anticoagulant pathway -: Novel insights into structure-function relationships and molecular recognition
    Dahlbäck, B
    Villoutreix, BO
    [J]. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2005, 25 (07) : 1311 - 1320
  • [6] IgG antibodies that recognize epitope Gly40-Arg43 in domain I of β2-glycoprotein I cause LAC, and their presence correlates strongly with thrombosis
    de Laat, B
    Derksen, RHWM
    Urbanus, RT
    de Groot, PG
    [J]. BLOOD, 2005, 105 (04) : 1540 - 1545
  • [7] Correlation between the potency of a beta2-glycoprotein I-dependent lupus anticoagulant and the level of resistance to activated protein C
    de Laat, Bas
    Eckmann, Carel M.
    van Schagen, Marlies
    Meijer, Alexander B.
    Mertens, Koen
    van Mourik, Jan A.
    [J]. BLOOD COAGULATION & FIBRINOLYSIS, 2008, 19 (08) : 757 - 764
  • [8] A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis
    de Visser, MCH
    Rosendaal, FR
    Bertina, RM
    [J]. BLOOD, 1999, 93 (04) : 1271 - 1276
  • [9] Patient-derived monoclonal antibodies directed towards beta2 glycoprotein-1 display lupus anticoagulant activity
    Dienava-Verdoold, I.
    Boon-Spijker, M. G.
    de Groot, P. G.
    Brinkman, H. J. M.
    Voorberg, J.
    Mertens, K.
    Derksen, R. H. W. M.
    de Laat, B.
    [J]. JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2011, 9 (04) : 738 - 747
  • [10] Resistance to activated protein C: Role in venous and arterial thrombosis
    Emmerich, J
    AlhencGelas, M
    Aiach, M
    Fiessinger, JN
    [J]. BIOMEDICINE & PHARMACOTHERAPY, 1996, 50 (6-7) : 254 - 260
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