IgG reactivity to phospholipid-bound β2-glycoprotein I is the main determinant of the fraction of lupus anticoagulant activity quenched by addition of hexagonal (II) phase phospholipid in patients with the clinical suspicion of antiphospholipid-antibody syndrome

Omid Safa, Luciano Crippa, Patrizia Della Valle, Maria Grazia Sabbadini, Silvana Vigano D'Angelo, Armando D'Angelo

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Abstract

Background and Objective. Autoantibodies to β2-glycoprotein 1 (β2- GPI) and/or prothrombin (FII) have been involved in the expression of lupus anticoagulant (LA) activity, an in vitro phenomenon associated with an increased risk of arterial and/or venous thromboembolic events. However, LA activity sustained by anti-FII antibodies has a much weaker association with thrombosis than LA activity sustained by anti-β2GPI antibodies. Because assays aimed at detecting LA. activity are now commercially available, we evaluated the relative sensitivity to antI-FII and anti-β2-GPI antibodies of a commercial LA assay in a consecutive series of patients with the clinical suspicion of anti-phospholipid antibody (APA) syndrome. Design and Methods. One hundred and ten consecutive patients with the clinical suspicion of APA syndrome (primary in 39) and 36 healthy controls were evaluated for the presence of LA activity (LA, Staclot®, Stago), anticardiolipin antibodies (Quanta Lite aCL IgG, IgM, Inova Diagnostics), and IgG binding to solid-phase and/or phospholipid (PL)-bound β2-GPI and FII by ELISA assays developed and optimized in our laboratory. Odds ratios for the association of IgG binding activity with LA and the aCL IgG status were calculated. In LA patients, dependency of LA potency (as assessed by clotting time prolongation in absence or presence of hexagonal phospholipid) on autoantibody titers was analyzed by the generalized linear model. Total IgG fractions were purified from selected patients to evaluate their ability to inhibit prothrombin activation at low FII concentration. Results. Anticardiolipln antibodies (aCL) of the IgG or IgM type were found in 64 and 23 patients and LA activity in 49 patients. Anti-β2-GPI and anti-FII (solid-phase and PL-bound) IgG titers exceeding by more than 3 standard deviations the mean values observed in control subjects were found in 46 and 47 patients and in 56 and 30 patients respectively, with the highest titers detected in the subgroup of patients with both LA and aCL IgG. The relative risk of LA for patients free of anti-FII and/or anti-β2-GPI IgG was 0.03 after stratification for the aCL IgG status. Antiβ2-GPI (solid-phase and-PL-bound) IgG (RR 34.4 and 12.6) and anti-FII (solid-phase) IgG (RR 6.33) were all associated with LA activity. However, when taking into account co-existence of anti-FII and anti-β2-GPI IgG in the same patients, the relative risk of LA for patients with isolated anti-FII IgG (solid-phase and/or PL-bound) was 0.50, whereas it ranged from 4.24 to 8.70 for all the antibody combinations including antiβ2-GPI IgG. Anti-β2-GPI (PL-bound) and aCL IgG titers were the only significant predictors of LA potency determined in the absence of phospholipid (anti-β2GPI IgG) or presence of hexagonal phospholipid (aCL IgG). Total IgG fractions purified from 12 patients (6 with anti-FII IgG) did not significantly Inhibit factor II activity up to a 150-fold molar excess. Interpretation and Conclusions. These results highlight the high prevalence of anti-FII and anti-β2-GPI IgG in patients with the clinical suspicion of APA syndrome and particularly in the subgroup of patients with LA activity. The fraction of LA activity which can be quenched by addition of hexagonal phospholipid is, however, only dependent on IgG directed to PL-bound β2- GPI. Other antibodies associated with anticardiolipin IgG may explain residual clotting time prolongation observed in the presence of hexagonal phospholipid.

Original languageEnglish
Pages (from-to)829-838
Number of pages10
JournalHaematologica
Volume84
Issue number9
Publication statusPublished - Sep 1999

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Lupus Coagulation Inhibitor
Antiphospholipid Syndrome
Phospholipids
Glycoproteins
Immunoglobulin G
Antibodies
Prothrombin
Autoantibodies
Immunoglobulin M
Anti-Idiotypic Antibodies
Anticardiolipin Antibodies

Keywords

  • Anti-prothrombin IgG
  • Anticardiolipin antibodies
  • APA-syndrome
  • Lupus anticoagulants, anti-β-glycoprotein I IgG
  • Thrombosis

ASJC Scopus subject areas

  • Hematology

Cite this

@article{4d779bdc0f2042578577788af221435c,
title = "IgG reactivity to phospholipid-bound β2-glycoprotein I is the main determinant of the fraction of lupus anticoagulant activity quenched by addition of hexagonal (II) phase phospholipid in patients with the clinical suspicion of antiphospholipid-antibody syndrome",
abstract = "Background and Objective. Autoantibodies to β2-glycoprotein 1 (β2- GPI) and/or prothrombin (FII) have been involved in the expression of lupus anticoagulant (LA) activity, an in vitro phenomenon associated with an increased risk of arterial and/or venous thromboembolic events. However, LA activity sustained by anti-FII antibodies has a much weaker association with thrombosis than LA activity sustained by anti-β2GPI antibodies. Because assays aimed at detecting LA. activity are now commercially available, we evaluated the relative sensitivity to antI-FII and anti-β2-GPI antibodies of a commercial LA assay in a consecutive series of patients with the clinical suspicion of anti-phospholipid antibody (APA) syndrome. Design and Methods. One hundred and ten consecutive patients with the clinical suspicion of APA syndrome (primary in 39) and 36 healthy controls were evaluated for the presence of LA activity (LA, Staclot{\circledR}, Stago), anticardiolipin antibodies (Quanta Lite aCL IgG, IgM, Inova Diagnostics), and IgG binding to solid-phase and/or phospholipid (PL)-bound β2-GPI and FII by ELISA assays developed and optimized in our laboratory. Odds ratios for the association of IgG binding activity with LA and the aCL IgG status were calculated. In LA patients, dependency of LA potency (as assessed by clotting time prolongation in absence or presence of hexagonal phospholipid) on autoantibody titers was analyzed by the generalized linear model. Total IgG fractions were purified from selected patients to evaluate their ability to inhibit prothrombin activation at low FII concentration. Results. Anticardiolipln antibodies (aCL) of the IgG or IgM type were found in 64 and 23 patients and LA activity in 49 patients. Anti-β2-GPI and anti-FII (solid-phase and PL-bound) IgG titers exceeding by more than 3 standard deviations the mean values observed in control subjects were found in 46 and 47 patients and in 56 and 30 patients respectively, with the highest titers detected in the subgroup of patients with both LA and aCL IgG. The relative risk of LA for patients free of anti-FII and/or anti-β2-GPI IgG was 0.03 after stratification for the aCL IgG status. Antiβ2-GPI (solid-phase and-PL-bound) IgG (RR 34.4 and 12.6) and anti-FII (solid-phase) IgG (RR 6.33) were all associated with LA activity. However, when taking into account co-existence of anti-FII and anti-β2-GPI IgG in the same patients, the relative risk of LA for patients with isolated anti-FII IgG (solid-phase and/or PL-bound) was 0.50, whereas it ranged from 4.24 to 8.70 for all the antibody combinations including antiβ2-GPI IgG. Anti-β2-GPI (PL-bound) and aCL IgG titers were the only significant predictors of LA potency determined in the absence of phospholipid (anti-β2GPI IgG) or presence of hexagonal phospholipid (aCL IgG). Total IgG fractions purified from 12 patients (6 with anti-FII IgG) did not significantly Inhibit factor II activity up to a 150-fold molar excess. Interpretation and Conclusions. These results highlight the high prevalence of anti-FII and anti-β2-GPI IgG in patients with the clinical suspicion of APA syndrome and particularly in the subgroup of patients with LA activity. The fraction of LA activity which can be quenched by addition of hexagonal phospholipid is, however, only dependent on IgG directed to PL-bound β2- GPI. Other antibodies associated with anticardiolipin IgG may explain residual clotting time prolongation observed in the presence of hexagonal phospholipid.",
keywords = "Anti-prothrombin IgG, Anticardiolipin antibodies, APA-syndrome, Lupus anticoagulants, anti-β-glycoprotein I IgG, Thrombosis",
author = "Omid Safa and Luciano Crippa and {Della Valle}, Patrizia and Sabbadini, {Maria Grazia} and {Vigano D'Angelo}, Silvana and Armando D'Angelo",
year = "1999",
month = "9",
language = "English",
volume = "84",
pages = "829--838",
journal = "Haematologica",
issn = "0390-6078",
publisher = "NLM (Medline)",
number = "9",

}

TY - JOUR

T1 - IgG reactivity to phospholipid-bound β2-glycoprotein I is the main determinant of the fraction of lupus anticoagulant activity quenched by addition of hexagonal (II) phase phospholipid in patients with the clinical suspicion of antiphospholipid-antibody syndrome

AU - Safa, Omid

AU - Crippa, Luciano

AU - Della Valle, Patrizia

AU - Sabbadini, Maria Grazia

AU - Vigano D'Angelo, Silvana

AU - D'Angelo, Armando

PY - 1999/9

Y1 - 1999/9

N2 - Background and Objective. Autoantibodies to β2-glycoprotein 1 (β2- GPI) and/or prothrombin (FII) have been involved in the expression of lupus anticoagulant (LA) activity, an in vitro phenomenon associated with an increased risk of arterial and/or venous thromboembolic events. However, LA activity sustained by anti-FII antibodies has a much weaker association with thrombosis than LA activity sustained by anti-β2GPI antibodies. Because assays aimed at detecting LA. activity are now commercially available, we evaluated the relative sensitivity to antI-FII and anti-β2-GPI antibodies of a commercial LA assay in a consecutive series of patients with the clinical suspicion of anti-phospholipid antibody (APA) syndrome. Design and Methods. One hundred and ten consecutive patients with the clinical suspicion of APA syndrome (primary in 39) and 36 healthy controls were evaluated for the presence of LA activity (LA, Staclot®, Stago), anticardiolipin antibodies (Quanta Lite aCL IgG, IgM, Inova Diagnostics), and IgG binding to solid-phase and/or phospholipid (PL)-bound β2-GPI and FII by ELISA assays developed and optimized in our laboratory. Odds ratios for the association of IgG binding activity with LA and the aCL IgG status were calculated. In LA patients, dependency of LA potency (as assessed by clotting time prolongation in absence or presence of hexagonal phospholipid) on autoantibody titers was analyzed by the generalized linear model. Total IgG fractions were purified from selected patients to evaluate their ability to inhibit prothrombin activation at low FII concentration. Results. Anticardiolipln antibodies (aCL) of the IgG or IgM type were found in 64 and 23 patients and LA activity in 49 patients. Anti-β2-GPI and anti-FII (solid-phase and PL-bound) IgG titers exceeding by more than 3 standard deviations the mean values observed in control subjects were found in 46 and 47 patients and in 56 and 30 patients respectively, with the highest titers detected in the subgroup of patients with both LA and aCL IgG. The relative risk of LA for patients free of anti-FII and/or anti-β2-GPI IgG was 0.03 after stratification for the aCL IgG status. Antiβ2-GPI (solid-phase and-PL-bound) IgG (RR 34.4 and 12.6) and anti-FII (solid-phase) IgG (RR 6.33) were all associated with LA activity. However, when taking into account co-existence of anti-FII and anti-β2-GPI IgG in the same patients, the relative risk of LA for patients with isolated anti-FII IgG (solid-phase and/or PL-bound) was 0.50, whereas it ranged from 4.24 to 8.70 for all the antibody combinations including antiβ2-GPI IgG. Anti-β2-GPI (PL-bound) and aCL IgG titers were the only significant predictors of LA potency determined in the absence of phospholipid (anti-β2GPI IgG) or presence of hexagonal phospholipid (aCL IgG). Total IgG fractions purified from 12 patients (6 with anti-FII IgG) did not significantly Inhibit factor II activity up to a 150-fold molar excess. Interpretation and Conclusions. These results highlight the high prevalence of anti-FII and anti-β2-GPI IgG in patients with the clinical suspicion of APA syndrome and particularly in the subgroup of patients with LA activity. The fraction of LA activity which can be quenched by addition of hexagonal phospholipid is, however, only dependent on IgG directed to PL-bound β2- GPI. Other antibodies associated with anticardiolipin IgG may explain residual clotting time prolongation observed in the presence of hexagonal phospholipid.

AB - Background and Objective. Autoantibodies to β2-glycoprotein 1 (β2- GPI) and/or prothrombin (FII) have been involved in the expression of lupus anticoagulant (LA) activity, an in vitro phenomenon associated with an increased risk of arterial and/or venous thromboembolic events. However, LA activity sustained by anti-FII antibodies has a much weaker association with thrombosis than LA activity sustained by anti-β2GPI antibodies. Because assays aimed at detecting LA. activity are now commercially available, we evaluated the relative sensitivity to antI-FII and anti-β2-GPI antibodies of a commercial LA assay in a consecutive series of patients with the clinical suspicion of anti-phospholipid antibody (APA) syndrome. Design and Methods. One hundred and ten consecutive patients with the clinical suspicion of APA syndrome (primary in 39) and 36 healthy controls were evaluated for the presence of LA activity (LA, Staclot®, Stago), anticardiolipin antibodies (Quanta Lite aCL IgG, IgM, Inova Diagnostics), and IgG binding to solid-phase and/or phospholipid (PL)-bound β2-GPI and FII by ELISA assays developed and optimized in our laboratory. Odds ratios for the association of IgG binding activity with LA and the aCL IgG status were calculated. In LA patients, dependency of LA potency (as assessed by clotting time prolongation in absence or presence of hexagonal phospholipid) on autoantibody titers was analyzed by the generalized linear model. Total IgG fractions were purified from selected patients to evaluate their ability to inhibit prothrombin activation at low FII concentration. Results. Anticardiolipln antibodies (aCL) of the IgG or IgM type were found in 64 and 23 patients and LA activity in 49 patients. Anti-β2-GPI and anti-FII (solid-phase and PL-bound) IgG titers exceeding by more than 3 standard deviations the mean values observed in control subjects were found in 46 and 47 patients and in 56 and 30 patients respectively, with the highest titers detected in the subgroup of patients with both LA and aCL IgG. The relative risk of LA for patients free of anti-FII and/or anti-β2-GPI IgG was 0.03 after stratification for the aCL IgG status. Antiβ2-GPI (solid-phase and-PL-bound) IgG (RR 34.4 and 12.6) and anti-FII (solid-phase) IgG (RR 6.33) were all associated with LA activity. However, when taking into account co-existence of anti-FII and anti-β2-GPI IgG in the same patients, the relative risk of LA for patients with isolated anti-FII IgG (solid-phase and/or PL-bound) was 0.50, whereas it ranged from 4.24 to 8.70 for all the antibody combinations including antiβ2-GPI IgG. Anti-β2-GPI (PL-bound) and aCL IgG titers were the only significant predictors of LA potency determined in the absence of phospholipid (anti-β2GPI IgG) or presence of hexagonal phospholipid (aCL IgG). Total IgG fractions purified from 12 patients (6 with anti-FII IgG) did not significantly Inhibit factor II activity up to a 150-fold molar excess. Interpretation and Conclusions. These results highlight the high prevalence of anti-FII and anti-β2-GPI IgG in patients with the clinical suspicion of APA syndrome and particularly in the subgroup of patients with LA activity. The fraction of LA activity which can be quenched by addition of hexagonal phospholipid is, however, only dependent on IgG directed to PL-bound β2- GPI. Other antibodies associated with anticardiolipin IgG may explain residual clotting time prolongation observed in the presence of hexagonal phospholipid.

KW - Anti-prothrombin IgG

KW - Anticardiolipin antibodies

KW - APA-syndrome

KW - Lupus anticoagulants, anti-β-glycoprotein I IgG

KW - Thrombosis

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VL - 84

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JO - Haematologica

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