Prothrombin as cofactor for antiphospholipids

Lupus ◽  
1998 ◽  
Vol 7 (2_suppl) ◽  
pp. 37-40 ◽  
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.

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

1999 ◽  
Vol 81 (02) ◽  
pp. 256-258 ◽  
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.

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

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1490-1494 ◽  
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.

Pathological Anti-β2-Glycoprotein I Antibodies Disrupt the Anticoagulant Activity of Annexin A5: A Possible Explanation for the Lupus Anticoagulant Paradox.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 135-135
Author(s):  
Bas de Laat ◽  
Xiao-Xuan Wu ◽  
Menno van Lummel ◽  
Ronald H.W.M. Derksen ◽  
Philip G. de Groot ◽  
...  
Keyword(s):  
Lupus Anticoagulant ◽  
Anticoagulant Activity ◽  
Annexin A5 ◽  
Double Blind Study ◽  
Clotting Time ◽  
Double Blind ◽  
Glycoprotein I ◽  
Group A ◽  
Group B

Abstract One of the most enigmatic features of the antiphospholipid (aPL) syndrome is the paradoxical correlation between thrombosis and the in vitro lupus anticoagulant (LAC) effect. It has recently been shown that only LAC that are due to β2-glycoprotein I (β2GPI) antibodies correlate with thrombosis. It has also been reported that aPL antibodies can disrupt the formation of an anticoagulant crystal shield that is formed by annexin A5 (AnxA5) over phospholipids bilayers. This disruption can be assayed by measuring resistance to AnxA5 anticoagulant activity. We therefore investigated whether the presence of these β2GPI-dependent LACs might correlate with the disruption of AnxA5 anticoagulant activity. We performed a double blind study with 30 patients divided into three groups; Group A: plasma of patients that show a β2GPI-dependent LAC; Group B: plasma of patients that show a β2GPI-independent LAC; Group C: plasma of SLE patients without a LAC. As previously demonstrated, we were able to discriminate between a β2GPI-dependent and a β2GPI-independent LAC by titrating cardiolipin into the plasma sample. A β2GPI-dependent LAC could be normalized by the addition of cardiolipin in contrast to a β2GPI-independent LAC which was prolonged by cardiolipin. To investigate the effects on AnxA5, we performed an APPT-based coagulation assay. In this assay we added AnxA5 to the plasma of patients and measured the prolongation in clotting time. We calculated the ratio of the clotting time divided by the clotting time with AnxA5 added to the plasma (=AnxA5 ratio). This assay represents the resistance against AnxA5 and gives an indication of its effect on the anticoagulant shield formed by AnxA5. Eleven patients displayed a β2GPI-dependent LAC (group A, all thrombosis), that gave an AnxA5 ratio of 151.3% (± SD 14.5). For 9 patients that displayed a β2GPI-independent LAC (group B, thrombosis n=3) we found a ratio of 225.4% (± SD 29.4). Ten patients did not have LAC (group C, thrombosis n=2) that gave a ratio of 219.2% (± SD 31.0). The annexin A5 ratio of group A was significantly lower than the ratio of group B (P=0.0002) and group C (P=0.0001). There was no difference in AnxA5 ratio between group B and group C (P=0.7802). β2GPI-dependent LAC correlate strongly with both thrombosis and AnxA5 resistance. The results therefore suggest that anti-β2GPI antibodies that cause LAC, in contrast to aPL antibodies with other specificities, are capable of disrupting the anticoagulant effect of AnxA5 on phospholipids. The disruption of the AnxA5 anticoagulant shield by LAC-causing anti-β2GPI antibodies may be a mechanism for thrombosis in APS and offers a potential explanation for the LAC paradox. Figure Figure

The Clinical Relevance of Noncriteria Antiphospholipid Antibodies

2017 ◽  
Vol 44 (05) ◽  
pp. 453-457 ◽  
Author(s):  
Giovanni Sanna ◽  
Maria Bertolaccini
Keyword(s):  
Antiphospholipid Syndrome ◽  
Clinical Relevance ◽  
Antiphospholipid Antibodies ◽  
Lupus Anticoagulant ◽  
Clinical Utility ◽  
Diagnostic Value ◽  
Anticardiolipin Antibodies ◽  
Coagulation Cascade ◽  
Glycoprotein I

AbstractWhile lupus anticoagulant (LA), anticardiolipin antibodies (aCL), anti-β2 glycoprotein I (anti-β2GPI) antibodies represent the best available and the most widely used tests in the investigation for antiphospholipid syndrome (APS), evidence gathered in recent years indicates that other antiphospholipid antibodies (aPL) specificities may also play a role in the syndrome. Several autoantibodies have been shown to be complexed with phospholipids other than cardiolipin, or to some domains of β2GPI, or else directed to other proteins of the coagulation cascade, and these have also been proposed to be of relevance to APS, and their diagnostic value and clinical utility are the focus of current research.

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

1992 ◽  
Vol 67 (05) ◽  
pp. 499-502 ◽  
Author(s):  
Janine D Oostin ◽  
Ronald H W M Derksen ◽  
H Tanja I Entjes ◽  
Bonno N Bouma ◽  
Philip G de Groot
Keyword(s):  
Dose Response ◽  
Plasma Levels ◽  
Antiphospholipid Antibodies ◽  
Lupus Anticoagulant ◽  
Response Curve ◽  
Anticoagulant Activity ◽  
False Negative ◽  
Coagulation Assays ◽  
Glycoprotein I ◽  
Deficient Patient

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.

Heterogeneity of Lupus Anticoagulant (LA) Antibodies: LA Activity in Dilute Russell’s Viper Venom Time and Dilute Kaolin Clotting Time Detect Different Populations of Antibodies in Patients with the “Antiphospholipid” Syndrome

1998 ◽  
Vol 80 (08) ◽  
pp. 250-257 ◽  
Author(s):  
David Kandiah ◽  
Steven Krilis
Keyword(s):  
Lupus Anticoagulant ◽  
Protein C ◽  
Solid Phase ◽  
Clotting Time ◽  
Chromatographic Techniques ◽  
Differential Reactivity ◽  
Phospholipid Liposomes ◽  
Different Populations ◽  
Russell’S Viper ◽  
Kaolin Clotting Time

Summary“Antiphospholipid” (aPL) antibodies comprise two main groups of antibodies, lupus anticoagulant (LA) antibodies and “anticardiolipin” (aCL) antibodies which can be separated by certain chromatographic techniques. In this study we analysed the plasma of 10 patients with aPL antibodies, and were able to demonstrate that in four patients with both clotting test reactivities, the dilute Russell’s Viper Venom Time (dRVVT) activity can be separated from the dilute Kaolin Clotting Time (dKCT) reactivity by using a polyacrylamide-immobilised phosphatidylserine column but not with phospholipid liposomes. The differential reactivity of the autoantibodies in this patient population is not due to binding to β2GPI, prothrombin or protein C in solid-phase immunoassays. Hence LA antibodies detected in different phospholipid-dependent clotting tests detect different populations of antibodies in some APS patients and the routine detection of LA antibodies should be performed with at least two clotting tests looking at different coagulation reactions.

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

1993 ◽  
Vol 46 (7) ◽  
pp. 665-667 ◽  
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

Detection of Lupus-Like Anticoagulants by an Enzyme-Linked Immunosorbent Assay Using a Partial Thromboplastin as Antigen; A Comparative Study

1990 ◽  
Vol 64 (01) ◽  
pp. 026-031 ◽  
Author(s):  
J Arnout ◽  
E Huybrechts ◽  
M Vanrusselt ◽  
C Falcon ◽  
J Vermylen
Keyword(s):  
Antiphospholipid Antibodies ◽  
Lupus Anticoagulant ◽  
Activated Partial Thromboplastin Time ◽  
The Other ◽  
Quantitative Detection ◽  
Enzyme Linked Immunosorbent Assay ◽  
Clotting Time ◽  
Coagulation Tests ◽  
Tissue Thromboplastin ◽  
Kaolin Clotting Time

SummaryClotting assays allow qualitative rather than quantitative detection of the lupus anticoagulant. We have therefore studied the usefulness of an ELISA using a commercial partial thromboplastin, Thrombofax, oS antigen; the results obtained on 146 selected patient plasmas were compared to the results of coagulation tests (kaolin clotting time, tissue thromboplastin inhibition test, activated partial thromboplastin time) and of ELISAs using cardiolipin or phosphatidylserine as antigen. While satisfactory agreement was found within the group of coagulation tests or that of ELISAs, only a moderate agreement was obtained between clotting tests and ELISAs, the best being with the partial thromboplastin ELISA using low plasma dilutions. The study further indicates that ELISA techniques cannot entirely replace coagulation tests for the detection of a lupus anticoagulant, even when a partial thromboplastin is used as antigen. On the other hand, coagulation tests are less sensitive than ELISAs for the detection of antiphospholipid antibodies.

Lupus anticoagulant antibodies: Recognition of phospholipid-binding protein complexes

Lupus ◽  
1998 ◽  
Vol 7 (2_suppl) ◽  
pp. 29-31 ◽  
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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