Lupus Anticoagulant Activity Is Frequently Dependent on the Presence of β2-Glycoprotein I

SummaryAntiphospholipid antibodies (aPL) are defined by anticardioli-pin antibody (aCL) ELISA and prolongation of phospholipid dependent coagulation assays (lupus anticoagulant; LAC). For the binding of aCL to cardiolipin a cofactor, β2-glycoprotein I (β2-GPI), is necessary. We have investigated whether the same cofactor is essential for LAC activity. Plasma from 6 LAC positive patients and 3 controls was depleted from β2-GPI by means of affinity chromatography. From the 6 LAC positive plasmas, 4 became LAC negative (tested with dRWT) when β2-GPI was depleted and became positive again when purified β2-GPI (200 μg/ml) was added. A dose response curve showed that addition of 50 μg/ml β2-GPI to β2-GPI deficient patient plasma, led to a positive dRWT. Depletion of, and addition of β2-GPI to plasma from controls had no effect on the dRWT. Measurement of β2-GPI plasma levels in 19 LAC positive patients, 40 LAC negative patients and 15 controls showed no difference in β2-GPI levels.These results show that a combination of aPL and β2-GPI is essential not only for binding to cardiolipin, but also for LAC activity and imply that low β2-GPI levels (<50 μg/ml) can lead to false negative LAC tests. These observations may lead to new insights in the pathophysiological complications associated with aPL.

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Lupus anticoagulant activity of autoimmune antiphospholipid antibodies is dependent upon beta 2-glycoprotein I.

Journal of Clinical Investigation ◽

10.1172/jci115926 ◽

1992 ◽

Vol 90 (3) ◽

pp. 1100-1104 ◽

Cited By ~ 148

Author(s):

R A Roubey ◽

C W Pratt ◽

J P Buyon ◽

J B Winfield

Keyword(s):

Antiphospholipid Antibodies ◽

Lupus Anticoagulant ◽

Anticoagulant Activity ◽

Glycoprotein I ◽

Beta 2

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Correlation between antiphospholipid antibodies that recognize domain I of β2-glycoprotein I and a reduction in the anticoagulant activity of annexin A5

Blood ◽

10.1182/blood-2006-07-030148 ◽

2006 ◽

Vol 109 (4) ◽

pp. 1490-1494 ◽

Cited By ~ 83

Author(s):

Bas de Laat ◽

Xiao-Xuan Wu ◽

Menno van Lummel ◽

Ronald H. W. M. Derksen ◽

Philip G. de Groot ◽

...

Keyword(s):

Antiphospholipid Antibodies ◽

Lupus Anticoagulant ◽

Anticoagulant Activity ◽

Annexin A5 ◽

Anionic Phospholipids ◽

Glycoprotein I ◽

Group A ◽

Group B ◽

Domain I ◽

American Authors

Abstract The paradoxical correlation between thrombosis and the lupus anticoagulant (LAC) effect is an enigmatic feature of the antiphospholipid (aPL) syndrome. The Dutch authors previously reported that thrombosis-related anti–β2-glycoprotein I (β2GPI) antibodies recognize domain I and cause LAC. The American authors reported that aPLs disrupt an anticoagulant annexin A5 (AnxA5) crystal shield. We investigated whether antidomain I antibodies correlate with disruption of AnxA5-anticoagulant activity. We studied a well-characterized group of 33 patients including subgroups with β2GPI-dependent LAC that recognize domain I (n = 11), with β2GPI-independent LAC (n = 12), and lacking LAC (n = 10). The effects on AnxA5-anticoagulant activity were determined with an AnxA5 resistance assay that measures coagulation times with and without AnxA5. Patients with β2GPI-dependent LAC (group A, all with thrombosis) had significantly lower AnxA5-anticoagulant ratios than those with β2GPI-independent LAC (group B, thrombosis n = 4; 157.8% versus 235.6%, P < .001) and those without LAC (group C, thrombosis n = 2; 157.8% versus 232.5%, P < .001). There was no difference in the ratios between groups B and C (P = .92). Plasmas with β2GPI-dependent LAC that recognize domain I displayed significantly increased AnxA5 resistance, suggesting that specifically anti-β2GPI antibodies compete with AnxA5 for anionic phospholipids. These results are consistent with a model in which aPL antibodies may promote thrombosis by interfering with the anticoagulant activity of AnxA5.

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Prothrombin as cofactor for antiphospholipids

Lupus ◽

10.1177/096120339800700209 ◽

1998 ◽

Vol 7 (2_suppl) ◽

pp. 37-40 ◽

Cited By ~ 19

Author(s):

M Galli ◽

T Barbui

Keyword(s):

Clinical Relevance ◽

Antiphospholipid Antibodies ◽

Lupus Anticoagulant ◽

Anticoagulant Activity ◽

Low Risk ◽

Immune Recognition ◽

Clotting Time ◽

Glycoprotein I ◽

Russell’S Viper ◽

Kaolin Clotting Time

Prothrombin is a common antigenic target of antiphospholipid antibodies, since anti-prothrombin antibodies are detected in about 50-90% of the patients. To allow proper immune recognition, prothrombin must be adsorbed on suitable anionic surfaces. The epitope(s) have not yet been identified: the majority of anti-prothrombin antibodies appear to be of poly- or oligoclonal nature. Anti-prothrombin antibodies, either alone or in combination with anti-β2-glycoprotein I antibodies, are responsible for the lupus anticoagulant activity of about 75% of the cases of phospholipid-dependent inhibitors of coagulation. The two antibodies may be discriminated by means of specific coagulation profiles generated by the comparison of the ratio of the Kaolin Clotting Time (KCT) and the dilute Russell's Viper Venom Time (dRVVT): the KCT profile, which mainly reflects the presence of anti-prothrombin antibodies and the dRVVT profile, which is mostly associated with anti-β2-glycoprotein I antibodies. This distinction, although somewhat artificial, may be clinically useful, since the KCT profile identifies patients at low risk to develop thrombosis. Similarly, most of the studies that measured anti-prothrombin antibodies by ELISA failed to find a significant association with thrombosis. In conclusion, the clinical relevance of these antibodies has not yet been established.

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Lupus anticoagulant activity of some antiphospholipid antibodies against phospholipid bound beta 2 glycoprotein I.

Journal of Clinical Pathology ◽

10.1136/jcp.46.7.665 ◽

1993 ◽

Vol 46 (7) ◽

pp. 665-667 ◽

Cited By ~ 11

Author(s):

D M Keeling ◽

A J Wilson ◽

I J Mackie ◽

D A Isenberg ◽

S J Machin

Keyword(s):

Antiphospholipid Antibodies ◽

Lupus Anticoagulant ◽

Anticoagulant Activity ◽

Glycoprotein I ◽

Beta 2

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Lupus anticoagulant antibodies: Recognition of phospholipid-binding protein complexes

Lupus ◽

10.1177/096120339800700207 ◽

1998 ◽

Vol 7 (2_suppl) ◽

pp. 29-31 ◽

Cited By ~ 15

Author(s):

J Rauch

Keyword(s):

Antiphospholipid Antibodies ◽

Lupus Anticoagulant ◽

Binding Proteins ◽

Protein Complexes ◽

Binding Protein ◽

Anticoagulant Activity ◽

Annexin V ◽

Antibody Activity ◽

Phospholipid Binding ◽

Glycoprotein I

Lupus anticoagulant antibodies form a heterogeneous group of antiphospholipid antibodies with rather poorly defined antigens. The role that phospholipid-binding proteins play in lupus anticoagulant antibody activity is a subject of current investigation. Several candidate proteins have been proposed, including β2-glycoprotein I (β2GPI), prothrombin, and annexin V. As β2GPI-dependent lupus anticoagulants will be reviewed elsewhere in this issue, this paper will focus on the involvement of prothrombin and annexin V in lupus anticoagulant activity. Evidence for a role for these proteins in the reactivity and induction of lupus anticoagulant antibodies will be discussed, as well as an apparent requirement for both phospholipid and phospholipid-binding protein. The data presented here suggest that some lupus anticoagulant antibodies recognize and may be induced by complexes of phospholipid and phospholipid-binding proteins, in particular, phospholipid and prothrombin or annexin V.

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Lupus anticoagulant activity of some antiphospholipid antibodies against phospholipid bound 2 glycoprotein I

Journal of Clinical Pathology ◽

10.1136/jcp.46.10.976-b ◽

1993 ◽

Vol 46 (10) ◽

pp. 976-976

Keyword(s):

Antiphospholipid Antibodies ◽

Lupus Anticoagulant ◽

Anticoagulant Activity ◽

Glycoprotein I

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Synchronized Inhibition of the Phospholipid Mediated Autoactivation of Factor XII in Plasma by β2-glycoprotein I and Anti-β2-glycoprotein I

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653871 ◽

1995 ◽

Vol 73 (05) ◽

pp. 798-804 ◽

Cited By ~ 48

Author(s):

Inger Schousboe ◽

Margit Søe Rasmussen

Keyword(s):

Lupus Erythematosus ◽

Lupus Anticoagulant ◽

Response Curve ◽

Inhibitory Effect ◽

Factor Xii ◽

High Antibody ◽

Contact Activation ◽

Maximal Inhibition ◽

Lupus Anticoagulants ◽

Glycoprotein I

SummaryLupus anticoagulants are a group of antibodies commonly found in patients with autoimmune diseases such as systemic lupus erythematosus. Lupus anticoagulants inhibit phospholipid dependent coagulation and may bind to negatively charged phospholipids. Recent studies have suggested an association between anti-β2-glycoprotein I and a lupus anticoagulant, whose activity is frequently dependent on the presence of β2-glycoprotein I. Based on these observations, the effect of anti-β2-glycoprotein I on the autoactivation of factor XII in plasma was investigated. Autoactivation initiated by the presence of negatively charged phospholipids, but not by sulfatide, was strongly inhibited by immunoaffinity purified anti-β2-glycoprotein I. The dose-response curve of anti-β2-gly coprotein I was identical with that of a precipitating antibody, showing no inhibition at low and high antibody dilutions and maximal inhibition at an intermediate dilution. At high antibody concentrations, an increased rate of factor Xlla activation was observed. This increase was of the same magnitude as the decreased rate observed in plasma supplemented with the same amount of β2-glycoprotein I as in the plasma itself. This confirms the inhibitory effect of β2-GP-I on the contact activation and shows that inhibition is effective on the autoactivation of factor XII in plasma. The inhibitory action of β2-glycoprotein I was independent of the inhibition caused by the anti- β2-glycoprotein I/β2-glycoprotein I complex suggesting a synchronized inhibition of factor XII autoactivation by β2-glycoprotein I and anti-β2-gly coprotein I. The inhibition caused by the antibody is suggested to be caused by a reduced availability of negatively charged phospholipids due to the binding of the anti-β2- GP-I/β2-GP-I complex. This complex may be a lupus anticoagulant.

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dRVVT Is more Sensitive than KCT or TTI for Detecting Lupus Anticoagulant Activity of Anti-β2-glycoprotein I Autoantibodies

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614453 ◽

1999 ◽

Vol 81 (02) ◽

pp. 256-258 ◽

Cited By ~ 53

Author(s):

A. Biasiolo ◽

P. Rampazzo ◽

T. Brocco ◽

V. Pengo

Keyword(s):

Lupus Anticoagulant ◽

Anticoagulant Activity ◽

Test System ◽

Clotting Time ◽

Lupus Anticoagulants ◽

Glycoprotein I ◽

Tissue Thromboplastin ◽

The Mean ◽

Kaolin Clotting Time ◽

Antibody Preparations

SummaryAnti-β2-glycoprotein I (β2-GPI) antibodies behave as classical Lupus Anticoagulants (LA), as they inhibit phospholipid-dependent coagulation reactions and their activity disappears in the presence of excess exogenous phospholipids (PLs). We have recently shown that a certain amount of PLs in the dilute Russell Viper Venom Time (dRVVT) test system is required to express LA activity of anti β2-GPI antibodies. We have now extended this observation to two other tests, i.e., Kaolin Clotting Time (KCT) in which PLs are not added, and Tissue Thromboplastin Inhibition test (TTI) in which PLs are extremely diluted. In fact, affinity-purified antibody preparations from 5 patients with antiphospholipid syndrome did not express or only weakly expressed anticoagulant activity in both tests; the mean ratios of coagulation times obtained with purified antibodies and that of control buffer were 1.11 and 1.0 for KCT and TTI, respectively. On the contrary, the mean ratios in dRVVT were 1.31 and 1.49 at a PLs dilution of 1:8 and 1:64, respectively. Therefore, the presence of LA activity due to autoantibodies to β2-GPI is characterized by a positive dRVVT and negative or only weakly positive KCT and TTI.

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Hemostasis system and immunomorphologic state of placenta under presence of antiphospholipid antibodies in plasma with consideration of their class and pregnancy outcome

Journal of obstetrics and women s diseases ◽

10.17816/jowd86971 ◽

2004 ◽

Vol 53 (1) ◽

pp. 22-26

Author(s):

N. G. Kosheleva ◽

L. В. Zubzhitskaia ◽

О. N. Arzhanova ◽

О. V. Tyshkevich ◽

Y. Gromyko ◽

...

Keyword(s):

Pregnancy Outcome ◽

Antiphospholipid Antibodies ◽

Lupus Anticoagulant ◽

Recurrent Miscarriage ◽

Anticardiolipin Antibodies ◽

Research Groups ◽

Hemostasis System ◽

Autoimmune Antibodies ◽

Glycoprotein I ◽

Tissue Damages

The present study was undertaken to investigate hemostasis system of 197 women with recurrent miscarriage: Analysis placentas by immunomorphology are studied of 41 women and of 52 women with autoimmune antibodies to 2-glycoprotein-I (2-GPI) in placenta. There was exposed hyperactivation platelets blood of all women with antiphospholipid antibodies irrespective of groups with significantly was increased at the beginning of pregnancy and progressed with growing gestation. As result of investigation it is determined certain connection between outcome of pregnancy and activation degree platelets blood in vasculars. Was found absence influence anticardiolipin antibodies (aCL) on plasmocoagulative link hemostasis. The circulation of lupus anticoagulant (LA) was accompanied indication of hypercoagulation. In all research groups was determined significant oppression of fibrinolisis. Analysis placentas by immunomorphology was determined significantly tissue damages with LA and 2-GPI-dependent aCL.

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