Journal articles on the topic 'Phospholipid antibodies'
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1
Out, HJ, PG de Groot, M. van Vliet, GC de Gast, HK Nieuwenhuis, and RH Derksen. "Antibodies to platelets in patients with anti-phospholipid antibodies." Blood 77, no. 12 (June 15, 1991): 2655–59. http://dx.doi.org/10.1182/blood.v77.12.2655.2655.
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Abstract Binding of anti-phospholipid antibodies to circulating platelets and its consequences on platelet activation and aggregation was investigated in 11 patients with anti-phospholipid antibodies. Seven patients had mild thrombocytopenia. Nine healthy donors served as controls. Binding to platelets was investigated by performing enzyme- linked immunosorbent assays (ELISAs) with phospholipids as antigen on platelet eluates. Platelet activation was measured by flow cytofluorometry using monoclonal antibodies to an activation-specific lysosomal membrane protein. Findings in ELISA were compared with results of a conventional immunofluorescence method to detect platelet autoantibodies. In seven patients antibodies to negatively charged phospholipids were present in platelet eluates. In all thrombocytopenic patients and controls the platelets were not activated and aggregation was not impaired. There was a positive concordance of 50% between the results of immunofluorescence and ELISA. No apparent relation was found between the results of ELISA or immunofluorescence and platelet counts. It is concluded that anti-phospholipid antibodies can bind to circulating platelets. This binding is not associated with measurable aggregation abnormalities nor with platelet activation characterized by exposure of lysosomal membrane proteins. More studies are necessary to determine the exact role of anti-phospholipid antibodies in the pathogenesis of thrombocytopenia and thrombosis.
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Out, HJ, PG de Groot, M. van Vliet, GC de Gast, HK Nieuwenhuis, and RH Derksen. "Antibodies to platelets in patients with anti-phospholipid antibodies." Blood 77, no. 12 (June 15, 1991): 2655–59. http://dx.doi.org/10.1182/blood.v77.12.2655.bloodjournal77122655.
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Binding of anti-phospholipid antibodies to circulating platelets and its consequences on platelet activation and aggregation was investigated in 11 patients with anti-phospholipid antibodies. Seven patients had mild thrombocytopenia. Nine healthy donors served as controls. Binding to platelets was investigated by performing enzyme- linked immunosorbent assays (ELISAs) with phospholipids as antigen on platelet eluates. Platelet activation was measured by flow cytofluorometry using monoclonal antibodies to an activation-specific lysosomal membrane protein. Findings in ELISA were compared with results of a conventional immunofluorescence method to detect platelet autoantibodies. In seven patients antibodies to negatively charged phospholipids were present in platelet eluates. In all thrombocytopenic patients and controls the platelets were not activated and aggregation was not impaired. There was a positive concordance of 50% between the results of immunofluorescence and ELISA. No apparent relation was found between the results of ELISA or immunofluorescence and platelet counts. It is concluded that anti-phospholipid antibodies can bind to circulating platelets. This binding is not associated with measurable aggregation abnormalities nor with platelet activation characterized by exposure of lysosomal membrane proteins. More studies are necessary to determine the exact role of anti-phospholipid antibodies in the pathogenesis of thrombocytopenia and thrombosis.
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Rauch, J., and AS Janoff. "Antibodies against Phospholipids other than Cardiolipin: Potential Roles for Both Phospholipid and Protein." Lupus 5, no. 5 (October 1996): 498–502. http://dx.doi.org/10.1177/096120339600500534.
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Autoantibodies to phospholipids other than cardiolipin have received less attention, to date, than anti-cardiolipin antibodies. This review focuses on these antibodies and potential roles for both phospholipid and protein in their reactivity. We review data in the literature indicating that antibodies to phosphatidylethanolamine and some lupus anticoagulant antibodies recognize phospholipid-binding proteins in association with phospholipid. Kininogens appear to be involved in the binding of antibodies to phosphatidylethanolamine, while phosphatidylserine-binding proteins, such as prothrombin and annexin V, have been implicated in lupus anticoagulant antibody recognition. These proteins bind to phospholipids that normally reside in the inner monolayer of the cell membrane, suggesting that exposure of these lipids is necessary for protein binding and antibody recognition to occur. In contrast, other autoantibodies, in particular those reactive with erythrocytes, appear to be directed at phospholipids that normally occur in the outer membrane leaflet, such as phosphatidylcholine. In summary, there is clearly accumulating evidence that antibodies to phospholipids other than cardiolipin recognize epitopes on phospholipid-binding proteins. It is not clear whether recognition of these epitopes is due to an increase in antigen density or a change in the protein or phospholipid structure, but it is likely that both protein and phospholipid structure play an important role in the in vivo interactions of these antibodies.
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Harris, EN, and SS Pierangeli. "Functional Effects of Anticardiolipin Antibodies." Lupus 5, no. 5 (October 1996): 372–77. http://dx.doi.org/10.1177/096120339600500507.
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The ‘lupus anticoagulant’ phenomenon is the best documented functional effect of antiphospholipid (aPL) antibodies, occurring either by inhibition of the prothrombinase and/or Factor X activation reactions. Understanding the mechanism by which aPL antibodies inhibit phospholipid dependent coagulation reactions may yield important clues about their ‘thrombogenic effects’ in vivo. We conducted a series of studies to determine the specificity, diversity, and mechanism by which aPL antibodies inhibit phospholipid dependent reactions. Results showed that purified immunoglobulins with lupus anticoagulant and anti-cardiolipin activities were absorbed by negatively charged phospholipids and both activities were recovered from the phospholipid-antibody precipitate. Purified aPL antibodies inhibited the prothrombinase reaction in a plasma free system in which β2-glycoprotein 1 (β2-GP1) was absent. Affinity purified aPL antibodies had 25–50 times the inhibitory activity of immunoglobulin preparations. The phospholipid binding proteins, β2-GP1 and placental anticoagulant protein I (PAP I), independently inhibited the prothrombinase reaction, and when these proteins were combined with aPL, inhibition of the prothrombinase reaction was additive. Antibodies of syphilis had no inhibitory effect, partially accounted for by lack of specificity for phosphotidylserine (PS). Although aPL antibodies inhibited the protein C activation reaction, there was no correlation of these activities with inhibition of the prothrombinase reaction. Together, these results show that aPL exert their effects by interaction with negatively charged phospholipids, in particular phosphotidylserine, but lack of correlation between inhibition of the prothrombinase and protein C activation reactions, suggests that the nature of the coagulation protein is also important.
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BRIGHTON, Timothy A., Yan-Ping DAI, Philip J. HOGG, and Colin N. CHESTERMAN. "Microheterogeneity of beta-2 glycoprotein I: implications for binding to anionic phospholipids." Biochemical Journal 340, no. 1 (May 10, 1999): 59–67. http://dx.doi.org/10.1042/bj3400059.
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Considerable interest is currently focused on the interactions of beta-2 glycoprotein I (β2GPI) and anti-phospholipid antibodies with anionic phospholipids in an attempt to understand the association between these antibodies and clinical diseases such as thrombosis. The interactions of β2GPI and anionic phospholipids have only been characterized partially, and the physiological role of this glycoprotein remains uncertain. In this study we have explored in detail the physical and phospholipid-binding characteristics of a number of β2GPI preparations. We have found (i) that perchloric acid-purification methods are damaging to β2GPI during purification, (ii) that the dissociation constants of the various preparations for phosphatidylserine vary between 0.1-2 μM and are considerably weaker than previously reported, (iii) that considerable differences in affinity of the various β2GPI preparations for anionic phospholipids are obtained when comparing anionic phospholipids immobilized to a solid-phase versus phospholipid assembled in unilamellar vesicles, (iv) that the integrity of the fifth domain of β2GPI is important for binding immobilized anionic phospholipid but not especially important in binding vesicular anionic phospholipid, and (v) that β2GPI preparations with differing isoelectric species content bind anionic phospholipids differently, suggesting that varying glycosylation and/or protein polymorphisms impact upon phospholipid binding. These results highlight the importance of assessing the determinants of the interaction of β2GPI with anionic phospholipids assembled in unilamellar vesicles.
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Harris, E. N., A. E. Gharavi, and G. R. V. Hughes. "Anti-phospholipid Antibodies." Clinics in Rheumatic Diseases 11, no. 3 (December 1985): 591–609. http://dx.doi.org/10.1016/s0307-742x(21)00606-8.
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Tincani, A., L. Andreoli, and Y. Shoenfeld. "Anti-phospholipid antibodies." Rheumatology 53, no. 2 (November 27, 2013): 201–2. http://dx.doi.org/10.1093/rheumatology/ket394.
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Deegan, Michael J. "Anti-Phospholipid Antibodies." American Journal of Clinical Pathology 98, no. 4 (October 1, 1992): 390–91. http://dx.doi.org/10.1093/ajcp/98.4.390.
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Mackworth-Young, C. G. "Anti phospholipid antibodies." Current Opinion in Immunology 1, no. 4 (January 1988): 747–52. http://dx.doi.org/10.1016/0952-7915(89)90052-6.
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Banerji, Benoy, and Carl R. Alving. "Antibodies to liposomal phosphatidylserine and phosphatidic acid." Biochemistry and Cell Biology 68, no. 1 (January 1, 1990): 96–101. http://dx.doi.org/10.1139/o90-012.
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Polyclonal antisera to phosphatidylserine or phosphatidic acid were induced in rabbits by injecting liposomes containing phosphatidylserine or phosphatidic acid and lipid A. Adsorption of antisera with liposomes containing different phospholipids revealed that some degree of reactivity with one or more phospholipids other than the immunizing phospholipid was often observed. However, cross-reactivity with other phospholipids was not a universal phenomenon, and one antiserum to phosphatidylserine failed to cross-react (i.e., was not adsorbed) with liposomes containing other phospholipids. All of the antisera were inhibited by soluble phosphorylated haptens (e.g., phosphocholine but not choline), but one of the antisera to phosphatidylserine was inhibited both by phosphoserine and by serine alone. Liposomal membrane composition influenced the activity of antiserum to phosphatidylserine. Regardless of whether unsaturated (beef brain) or saturated (dimyristoyl) phosphatidylserine was used in the immunizing liposomes, the antisera reacted more vigorously with liposomes containing unsaturated than saturated phosphatidylserine. We conclude that liposomes containing lipid A can serve as vehicles for stimulating polyclonal antisera to phosphatidylserine and phosphatidic acid. Although cross-reactivity with certain other phospholipids can be observed, sera from selected animals apparently can exhibit a high degree of specific activity to the immunizing phospholipid antigen.Key words: liposomes, antibodies, phospholipids, phosphatidylserine, phosphatidic acid.
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Salemink, Irene, Ron Blezer, George Willems, Monica Galli, Edouard Bevers, and Theo Lindhout. "Antibodies to β2-Glycoprotein I Associated with Antiphospholipid Syndrome Suppress the Inhibitory Activity of Tissue Factor Pathway Inhibitor." Thrombosis and Haemostasis 84, no. 10 (2000): 653–56. http://dx.doi.org/10.1055/s-0037-1614082.
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SummaryAnionic phospholipid membranes have a dual role in blood coagulation: they are essential for the initiation and propagation as well as for the limitation and termination of the blood coagulation process. Patients with the anti-phospholipid syndrome (APS) carrying antibodies against complexes of anionic phospholipids and plasma proteins, show in vitro inhibited phospholipid dependent coagulation reactions, whereas in vivo the presence of these antibodies is associated with an increased risk of thrombosis. In this study we focussed on the effects of these anti-phospholipid antibodies on the regulation of TF-mediated factor Xa (FXa) generation in plasma. We hypothesized that anti-phospholipid antibodies interfere with the phospholipiddependent inhibition by tissue factor pathway inhibitor (TFPI) of TFinduced coagulation. Indeed, total-IgG, anti-cardiolipin-IgG (aCL) and anti-β2GPI-IgG, isolated from patient plasmas, all stimulated TF-induced FXa generation in normal plasma. This enhanced FXa generation was not observed when the patient’s IgG was depleted of anti-β2GPI-IgG or when normal plasma was depleted of β2GPI or TFPI. Taken together, these data indicate that antibodies to β2GPI, circulating in patients with APS, suppress TFPI-dependent inhibition of TF-induced coagulation, which results in an increased FXa generation.
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Oort, Erica van, Mariëlle Tempelman, Ronald Derksen, Philip de Groot, and Daniëlle Horbach. "The Prevalence of a Non-phospholipid-binding Form of β2-Glycoprotein I in Human Plasma." Thrombosis and Haemostasis 80, no. 11 (1998): 791–97. http://dx.doi.org/10.1055/s-0037-1615360.
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SummaryThe presence of antiphospholipid antibodies (aPL) is strongly correlated with venous and arterial thrombosis, fetal loss and thrombocytopenia. This relation is called the antiphospholipid syndrome (APS). It is well recognized that thrombosis related aPL are not directed against phospholipids alone, but to phospholipid bound plasma proteins like β2-glycoprotein I (β2GPI). aPL that need β2GPI for the binding to negatively charged phospholipids are called anti-β2GPI-antibodies. Recently, a mutation in the gene encoding β2GPI has been described, which results in an amino acid substitution Trp316 into Ser316. This Ser316-β2GPI did not bind to negatively charged phospholipids. Because only phospholipid bound β2GPI is recognized by human anti-β2GPI-antibodies, it might be argued that individuals carrying the Trp316Ser mutation are protected against the development of anti-β2GPI-antibodies.To investigate this hypothesis, the prevalence of the Trp316Ser mutation was measured in 170 systemic lupus erythematosus (SLE) patients and in 18 patients with the primary antiphospholipid syndrome (PAPS) and the mutation was correlated with the presence of anti-β2 GPI-antibodies. In the total patient group 1 homozygous patient and 21 heterozygous patients were found. The allele frequency of the mutation in SLE patients with anti-β2GPI-antibodies (0.063) was comparable to that found in SLE patients without anti-β2-GPI-antibodies (0.062). These results indicate that the heterozygous presence of Trp316Ser mutation does not prevent an individual from developing anti-β2GPI-antibodies. We showed that this can be explained by the concentration of Trp316-β2GPI in heterozygous patients, which is far above the minimal β2GPI level necessary for optimal phospholipid binding. In our single patient homozygous for the Trp316Ser mutation no binding of β2GPI to the phospholipid surface was detected and no anti-β2GPI-antibodies were present in the plasma of this patient.In conclusion, heterozygous Trp316Ser β2GPI persons are not protected against the development of anti-β2GPI-antibodies. To confirm that homozygotes do not develop anti-β2GPI-antibodies a very large population is needed, due to the relatively low prevalence of the mutation.
13
Pengo, V., A. Biasiolo, T. Brocco, S. Tonetto, and A. Ruffatti. "Autoantibodies to Phospholipid-binding Plasma Proteins in Patients with Thrombosis and Phospholipid-reactive Antibodies." Thrombosis and Haemostasis 75, no. 05 (1996): 721–24. http://dx.doi.org/10.1055/s-0038-1650355.
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SummaryAnti-phospholipid (aPL) antibodies are defined as antibodies detected in systems employing phospholipids (PL). This general definition is misleading as it comprises a large group of autoimmune phospholipid-reactive antibodies that are directed against specific phospholipid-binding plasma proteins, such as β2-glycoprotein I (β2GPI) and prothrombin. Definition of phospholipid-reacting antibodies according to the plasma protein against which they are directed appears more appropriate and could be useful in understanding clinical events and pathogenic mechanisms. Using ELISA systems we have studied the presence of antibodies directed against specific phospholipid-binding proteins in a series of 22 patients with thrombosis and phospholipid-reactive antibodies of the IgG isotype. High levels of anti-β2GPI IgG were detected in all 22 patients. Normal values were calculated on the basis of OD values at 405 nm (OD405) obtained for 22 age- and sex-matched healthy subjects (cut off value = 0.401). Levels of anti-β2GPI antibodies were linearly correlated with those of cardiolipin-reactive (aCL) antibodies. Eleven out of 22 patients (50%) had values of anti-prothrombin antibodies exceeding the cut-off value of 0.250. No relationship was found between the levels of anti-β2GPI and anti-prothrombin antibodies. Tests for antibodies against two natural inhibitors of blood coagulation, protein C and protein S, revealed elevated levels of anti-protein C IgG and anti-protein S IgG in 4 and 12 patients, respectively. A highly significant correlation between anti-protein C IgG and anti-protein S IgG values as well as between antibody titers against the two studied natural coagulation inhibitors and anti-prothrombin IgG was found. When comparing patients positive for aCL and presence or absence of a previous thrombotic episode (aCL+/T+ vs aCL+/T-), the positivity of anti-P2GPI IgG was found to be statistically associated with thrombosis. Conversely, among patients with previous thromboembolism with or without aCL (aCL+/T+ vs aCL-/T+) the positivity of anti-β2GPI IgG was strictly associated with the positivity of aCL, thus identifying the aPL antibody syndrome. These data demonstrate that anti-β2GPI antibodies are a marker of “autoimmune” thrombosis. Anti-prothrombin antibodies are not a marker of thrombosis and are closely associated with antibodies to protein C and protein S.
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Wu, X. X., and J. H. Rand. "Antiphospholipid antibody-mediated interference with annexin-V anticoagulant activity." Hämostaseologie 21, no. 02 (2001): 50–53. http://dx.doi.org/10.1055/s-0037-1619508.
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SummaryThe antiphospholipid (aPL) syndrome is a disorder in which vascular thrombosis and/or recurrent pregnancy losses occur together with serologic and coagulation evidence for antibodies directed against anionic phospholipid-protein complexes. Evidence has been developed for the idea that thrombosis in this syndrome may result from disruption of the binding of annexin-V to the phospholipids which line the placental and systemic vasculatures. We hypothesize that annexin-V, a protein known to have high affinity for anionic phospholipids, plays a thromboregulatory role at the vascular-blood interface by shielding anionic phospholipids from complexation with coagulation proteins in circulating blood. We propose that the thrombotic manifestations of the antiphospholipid syndrome are due to disruption of this annexin-V shield by antiphospholipid antibodies, thereby resulting in a net increase of thrombogenic phospholipids exposed to circulating blood. The accumulated data from tissue immunohistochemistry, trophoblast and endothelial cell culture studies, coagulation studies using noncellular phospholipids, and competition studies on artificial phospholipid bilayer are consistent with the hypothesis that the interference with the binding of annexin-V to anionic phospholipid surfaces plays an important role in the mechanism of thrombosis and in pregnancy loss in the antiphospholipid syndrome.
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Panarelli, P., M. P. Viola-Magni, and E. Albi. "Antiphosphatidylinositol Antibody in Deep Venous Thrombosis Patients." International Journal of Immunopathology and Pharmacology 16, no. 1 (January 2003): 61–66. http://dx.doi.org/10.1177/039463200301600109.
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Antiphospholipid antibodies are a heterogeneous group of immunoglobulins with specificity for a number of phospholipids, phospholipid-binding proteins and phospholipid-protein complexes. The association between antiphospholipid antibodies and a variety of pathologic disorders, such as arterial and venous thrombosis and recurrent pregnancy loss is recognized as Antiphospholipid Syndrome. The immunoassay currently used to detect antiphospholipid antibodies is the anticardiolipin test. Anticardiolipin antibodies are believed to be polyspecific antibodies that cross-react with all the anionic phospholipids. Therefore, testing only for anticardiolipin antibodies does not always permit detection of all antiphospholipid antibodies, specially when only IgG are evaluated. In a selected population of 74 idiopathic and secondary deep venous thrombosis patients, IgG anticardiolipin, antiphosphatidylinositol and antiphosphatidylserine antibodies were detected by solid-phase immunoassays. Our results show that by testing for each antiphospholipid family, many patients, not evidenced by the standard anticardiolipin assay, were found to be antiphospholipid-positive. The anticardiolipin positive patients have always low, moderate or high levels of antiphospholipid antibodies, suggesting that the antiphospholipid positivity is predictive of anticardiolipin positivity. It should be noted that the patients with only antiphosphatidylinositol positive antibody have a story of nervous system pathology. The meaning of these results is at present under discussion.
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Reddy, Ketha Ravindra, and V. S. Sai Lakshmi. "An Association between Anti-Phospholipid Antibodies and Connective Tissue Diseases." Asian Journal of Medical Research 8, no. 3 (September 2019): DT01—DT03. http://dx.doi.org/10.21276/ajmr.2019.8.3.dt1.
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Kouts, S., M. X. Wang, S. Adelstein, and S. A. Krilis. "Immunization of a rabbit with beta 2-glycoprotein I induces charge-dependent crossreactive antibodies that bind anionic phospholipids and have similar reactivity as autoimmune anti-phospholipid antibodies." Journal of Immunology 155, no. 2 (July 15, 1995): 958–66. http://dx.doi.org/10.4049/jimmunol.155.2.958.
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Abstract A rabbit immunized with beta 2-glycoprotein I (beta 2-GPI) produced Abs that bind to negatively charged phospholipids and to beta 2-GPI. After affinity purification of the Abs to beta 2-GPI, the dual reactivity could still be detected. Adsorption studies with a phosphatidylserine affinity column depleted phospholipid-reactive Abs, but beta 2-GPI reactivity was retained. The same pattern of reactivity was found with culture supernatants from rabbit anti-beta 2-GPI splenocytes fused with an immortalized rabbit cell line. The reactivity to negatively charged phospholipids is likely to involve ionic interactions, as high ionic strength buffers eliminated binding to anionic phospholipids, but not to beta 2-GPI. Affinity-purified anti-phospholipid (aPL) Abs from four of seven autoimmune patients bound anionic phospholipids in the absence of beta 2-GPI. However, in high ionic strength buffer, this binding was abolished in three patients and significantly reduced in the fourth. In contrast, affinity-purified aPL Abs from seven autoimmune patients bound to beta 2-GPI-coated plates, and binding in high ionic strength buffer was reduced only moderately in three patients. Therefore, autoimmune-type aPL Abs display anti-beta 2-GPI reactivity and charge-dependent binding to anionic phospholipids similar to affinity-purified rabbit anti-beta 2-GPI Abs.
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Wu, Xiao-Xuan, and Jacob Rand. "Antibody-Mediated Disruption of the Annexin-V Antithrombotic Shield: A New Mechanism for Thrombosis in the Antiphospholipid Syndrome." Thrombosis and Haemostasis 82, no. 08 (1999): 649–55. http://dx.doi.org/10.1055/s-0037-1615892.
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IntroductionThe antiphospholipid (aPL) syndrome is a condition that manifests in patients as vascular thromboembolism or recurrent pregnancy loss together with laboratory evidence for the presence of antibodies against anionic phospholipid-protein complexes. For a recent comprehensive review, the reader is referred to Hughes et al.1 The syndrome was first proposed to be a distinct entity, called anticardiolipin syndrome, in 1985,2 and was later renamed antiphospholipid syndrome.3 The disorder was classified as “primary” in the absence of a concurrent autoimmune condition, such as systemic lupus erythematosus, or “secondary” in the presence of another such autoimmune disorder. Antiphospholipid antibodies are detected by their reactivity to anionic phospholipids (or protein-phospholipid complexes) in solid phase immunoassays, or by their inhibition of phospholipid-dependent coagulation reactions, known as the “lupus anticoagulant” effect. The ever-expanding, yet still insufficiently integrated, knowledge of this enigmatic disorder makes this area an intriguing subject for investigation.The pathophysiologic mechanism of this syndrome has remained obscure, resulting from the apparent multiplicity of antigenic determinants recognized by the antibodies. In addition, a large number of effects1 have been described for the antibodies in vitro and in cell culture systems. These effects, which include the paradoxical lupus anticoagulant (LAC) phenomenon, are a consequence of the numerous roles played by phospholipids in the hemostasis system and in a multitude of biologic processes. The purpose of this review is to introduce the reader to the current state of knowledge of the role of annexin-V in this disorder.
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Sanmarco, M., and M.-C. Boffa. "Antiphosphatidylethanolamine antibodies and the antiphospholipid syndrome." Lupus 18, no. 10 (August 11, 2009): 920–23. http://dx.doi.org/10.1177/0961203309106920.
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The antiphospholipid antibodies included as laboratory criteria of the antiphospholipid syndrome (APS) are antibodies reacting with anionic phospholipids – anticardiolipin antibodies and lupus anticoagulant – and with β2-glycoprotein I. However, antibodies reacting with phosphatidylethanolamine (aPE), a zwitterionic phospholipid, have also been described to be associated with the main features of APS. The objectives of this review are to describe the characteristics of aPE and to bring attention to recent evidence that aPE are correlated with the main clinical features of APS, notably, in the absence of the laboratory criteria of this syndrome.
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Ernst, J. D. "Epitope mapping of annexin I: antibodies that compete with phospholipids and calcium recognize amino acids 42–99." Biochemical Journal 289, no. 2 (January 15, 1993): 539–42. http://dx.doi.org/10.1042/bj2890539.
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To understand further the structural basis of phospholipid binding by annexin I, three monoclonal antibodies that compete with Ca2+ and phospholipids for binding of annexin I were used to screen an expression library containing fragments of bovine annexin I cDNA. In all, 15 clones were isolated, and all contain overlapping fragments of the cDNA. The smallest unit common to all of the clones encodes amino acids 42-99 of annexin I, representing a portion of the first repeat domain. This demonstrates that recognition of a single domain of annexin I is sufficient to completely block phospholipid binding, and implies that the first repeat may contribute to phospholipid binding by annexin I.
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Shuaib, Ashfaq, Lynn Barklay, Mary Anne Lee, and Oksana Suchowersky. "Migraine and Anti-Phospholipid Antibodies." Headache: The Journal of Head and Face Pain 29, no. 1 (January 1989): 42–45. http://dx.doi.org/10.1111/j.1526-4610.1989.hed2901042.x.
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Carp, H. J. A., and Y. Shoenfeld. "Anti-Phospholipid Antibodies And Infertility." Clinical Reviews in Allergy & Immunology 32, no. 2 (June 30, 2007): 159–61. http://dx.doi.org/10.1007/s12016-007-0010-2.
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NORBERG, RENÉE, J. ERNERUDH, A. HAMSTEN, A. M. UNANDER, and L. ÅRFORS. "Phospholipid Antibodies in Cardiovascular Disease." Acta Medica Scandinavica 221, S715 (April 24, 2009): 93–98. http://dx.doi.org/10.1111/j.0954-6820.1987.tb09908.x.
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Helbert, M., S. Bodger, J. Cavenagh, D. D'Cruz, J. M. Thomas, and P. MacCallum. "Optimising testing for phospholipid antibodies." Journal of Clinical Pathology 54, no. 9 (September 1, 2001): 693–98. http://dx.doi.org/10.1136/jcp.54.9.693.
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Mesa, H. A., B. Lang, M. Schumacher, P. Vaith, and H. H. Peter. "Sneddon's syndrome and phospholipid antibodies." Clinical Rheumatology 12, no. 2 (June 1993): 253–56. http://dx.doi.org/10.1007/bf02231537.
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Galli, M. "Phospholipid inhibitors." Hämostaseologie 31, no. 04 (2011): 243–50. http://dx.doi.org/10.5482/ha-1165.
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SummaryThe antiphospholipid syndrome (APS) is defined by the association of arterial and/or venous thrombosis and/or pregnancy complications with the presence of at least one among the main antiphospholipid antibodies (aPL) (i. e., Lupus anticoagulants, LA, IgG and/ or IgM anticardiolipin antibodies, aCL, IgG and/or IgM antiβ2-glycoprotein I antibodies, aβ2-GPI). Several clinical studies have consistently reported that LA is a stronger risk factor for both arterial and venous thrombosis compared to aCL and aβ2-GPI. In particular, LA activity dependent on the first domain of β2-GPI and triple aPL positivity are associated with the risk of thrombosis and obstetrical complications.Asymptomatic aPL-positive subjects do not require primary thromboprophylaxis. Venous thromboembolism is the most common initial clinical manifestation of APS. To prevent its recurrence indefinite anticoagulation is recommended. Long duration treatment with warfarin or aspirin is used after a first cerebral arterial thrombosis. Low molecular weight heparin (LMWH) with or without aspirin is recommended to reduce the rate of obstetrical complications of APS pregnant women.
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Stewart, M. W., W. S. Etches, A. S. Russell, J. S. Percy, C. A. Johnston, C. K. Chew, and P. A. Gordon. "Detection of Antiphospholipid Antibodies by Flow Cytometry: Rapid Detection of Antibody Isotype and Phospholipid Specificity." Thrombosis and Haemostasis 70, no. 04 (1993): 603–7. http://dx.doi.org/10.1055/s-0038-1649636.
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SummaryLaboratory diagnosis of antiphospholipid antibodies is important in patients with clinical features of the antiphospholipid syndrome, such as thrombosis and fetal loss. We have developed a novel method for the detection of antiphospholipid antibodies using flow cytometry. Anionic phospholipids cardiolipin, phosphatidylserine and phosphatidylinositol are coated onto polystyrene beads of different sizes, allowing detection and semiquantitation of their respective phospholipid antibody isotypes. The results of the flow cytometric method closely correlate those of the standardised anticardiolipin enzyme-linked immunosorbent assay (ELISA), but the method is quicker and is versatile in its ability to detect IgG, IgM and IgA antibody isotypes at the same time. The method promises to be useful in evaluating the significance of phospholipid specificity and antibody isotypes in patients with the antiphospholipid syndrome.
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Rauch, J. "Lupus anticoagulant antibodies: Recognition of phospholipid-binding protein complexes." Lupus 7, no. 2_suppl (February 1998): 29–31. http://dx.doi.org/10.1177/096120339800700207.
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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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Maltseva, L. I., and L. A. Lobova. "Clinical importance of antiphospholipid antibodies in pregnants with mycoplasma and associated infection." Kazan medical journal 82, no. 2 (April 3, 2001): 107–10. http://dx.doi.org/10.17816/kazmj66606.
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The examination of 167 infected pregnants in I and II terms was carried out to reveal the rate of antiphospholi pid antibodies in pregnants with mycoplasma and associated infection. The pathologic level of anti phospholipid antibodies was determined in 21% of the pregnants with micoplasma and associated infection, in 22% of them the anti phospholipid syndrome was revealed. The most severe complications of pregnancy and accompanied extragenital pathology were found in women with anti phospholipid antibodies. During complex therapy the elimination of antibodies accompanying by the positive clinical dynamics of gestational process was found in some pregnants. Various complications of pregnancy which were arrested by timely treatment were found in women with associated mycoplasma infection without anti phospholipid antibodies.lt is concluded that the formation of anti phospholipid antibodies is the part of infectious process in pregnancy.
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Misasi, Roberta, Antonella Capozzi, Agostina Longo, Serena Recalchi, Emanuela Lococo, Cristiano Alessandri, Fabrizio Conti, Guido Valesini, and Maurizio Sorice. "“New” Antigenic Targets and Methodological Approaches for Refining Laboratory Diagnosis of Antiphospholipid Syndrome." Journal of Immunology Research 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/858542.
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Antiphospholipid antibodies (aPLs) are a heterogeneous group of antibodies directed against phospholipids or protein/phospholipid complexes. Currently, aPLs are assessed using either “solid-phase” assays that identify anticardiolipin antibodies and anti-β2-glycoprotein I antibodies or “liquid-phase” assay that identifies lupus anticoagulant. However, in the last few years, “new” antigenic targets and methodological approaches have been employed for refining laboratory diagnosis of antiphospholipid syndrome (APS). In this review the potential diagnostic value of antibodies to domains ofβ2-GPI, prothrombin/phosphatidylserine, vimentin/cardiolipin, protein S, protein C, annexin A2, annexin A5, and phospholipid antigens is discussed. Moreover, new technical approaches, including chemiluminescence, multiline dot assay, and thin layer chromatography (TLC) immunostaining, which utilize different supports for detection of aPL, have been developed. A special focus has been dedicated on “seronegative” APS, that is, those patients with a clinical profile suggestive of APS (thromboses, recurrent miscarriages, or foetal loss), who are persistently negative for the routinely used aPL. Recent findings suggest that, in sera from patients with SN-APS, antibodies may be detected using “new” antigenic targets (mainly vimentin/cardiolipin) or methodological approaches different from traditional techniques (TLC immunostaining). Thus, APS represents a mosaic, in which antibodies against different antigenic targets may be detected thanks to the continuously evolving new technologies.
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Shapoorabadi, Farzaneh Ahmadi, Maryam Sadat Mirbagheri Firoozabad, Neda Habibi, and Giti Emtiazi. "Hemolysis, Platelet Aggregation and Antibacterial Activities of Human Antiphospholipid Antibody." Anti-Infective Agents 18, no. 3 (September 11, 2020): 268–74. http://dx.doi.org/10.2174/2211352517666190613111628.
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Background: Anti-phospholipid antibodies have the potential to become an alternative to conventional antibiotics for humans. The Antiphospholipid Syndrome (APS) is an autoimmune disease where the body’s defense system incorrectly reacts against its own phospholipids. APS is distinct through the existence of venous and arterial thromboses, frequently multiple and recurring fetal losses, commonly accompanied by moderate thrombocytopenia. Anti-phospholipid antibodies include lupus anti-coagulant, anti- cardiolipin, anti-beta 2 glycoprotein 1, and anti-prothrombin antibodies. Methods: In this study, the mechanism of action of Anti-phospholipid antibodies against Klebsiella pneumonia and Staphylococcus aureus was investigated in great detail using a unique combination of imaging and biophysical techniques. Antibacterial activity of antiphospholipid antibodies was detected by a diffusion method and the investigation of the complexity of antibody-antigen was done by spectroscopic examination, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) imaging. Results: There was a profound change in the bacteria treated with healthy and patient serum in the optical microscopic study. In all of the studied fields, bacterial treatment with patient serum immediately induced bacterial swelling and cumulative accumulation of the bacteria while no changes were observed in the healthy serum. Anti-bacterial activities of patient serum were detected on the plate. The result of this study showed that after platelet activation by thrombin and incubation with antiphospholipid antibodies, the platelet was aggregated. The transmission electron microscopy (TEM) image showed that the cell wall of Klebsiella pneumonia and Staphylococcus aureus incubated with antiphospholipid had a bizarre shape and antiphospholipid antibodies bound to bacterial membranes. Conclusion: The data indicated that antiphospholipid antibodies with hemolysis activities have an effect on Gram-positive and negative bacteria and these antibodies have the potential to become antibiotic for human.
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Hu, Yanqing, Charles T. Esmon, and Naomi L. Esmon. "Function of Beta2-GPI in Inhibiting the Oxidized Phospholipids Dependent APC Activity by Antiphospholipid IgG from APS Patients." Blood 108, no. 11 (November 16, 2006): 1612. http://dx.doi.org/10.1182/blood.v108.11.1612.1612.
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Abstract Beta2-GPI (ß2GPI), a plasma glycoprotein with phospholipid-binding properties, is the actual target antigen for autoimmune type antiphospholipid antibodies. Certain groups of these antibodies exert lupus anticoagulant (LA) activity by directly inhibiting the Protein C anticoagulant pathway and associated with an increased risk of thrombotic disease. Our previous studies have shown that the activated protein C (APC) activity and the ability to be inhibited by antiphospholipid antibodies associated with thrombosis are strongly augmented by the presence of Phosphatidyl-ethanolamine (PE) and phospholipid oxidation. In this study, we investigated the relationship between ß2GPI and anti-APC activity by IgG derived from APS patients. IgG from patients with APS syndrome were tested using a modified oxidized PE containing phospholipids dependent dRVVT test, in the presence of APC at concentration of 0.2ug/ml, the clotting times was prolonged to 3 fold of the baseline level, when the anti-phospholipids IgG antibodies added into the system, its showed a significant impact on the APC prolongation clotting times in the presence of ß2GPI. However, no affect was observed on the APC prolongation clotting times in the absence of ß2GPI. To eliminate the possible confounding effect from other plasma component, we investigated the effect on factor Va inactivation by APC in a purified system. As expected, the inhibition was observed only when the B2GPI was present. We also found that the presence of beta2GPI-IgG complex had its strongest effect when Protein S was included. We conclude that ß2GPI is necessary to inhibit the oxidized phospholipids dependent APC activity by IgG antibodies from APS patients. On oxidized lipids surface, ß2GPI -APS IgG complex had its strongest effect on APC activity. This is a potentially important result indicating the functional assay may be more sensitive for pathological antibodies.
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Aleman, Maria M., Siddharth Jindal, Nina Leksa, Robert Peters, and Joe Salas. "Phospholipid-Independent Activity of Fviiia Mimetic Bispecific Antibodies in Plasma." Blood 132, Supplement 1 (November 29, 2018): 2461. http://dx.doi.org/10.1182/blood-2018-99-119226.
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Abstract Introduction: An important coagulation regulatory mechanism is localization of clotting complexes to exposed phosphatidylserine (PS) on cell surfaces. All components of the intrinsic tenase complex (factor (F)VIIIa, FIXa, and FX) bind to PS. FVIIIa mimetic bispecific antibodies are drugs in development for hemophilia A that aim to mimic the cofactor function of FVIIIa by bringing together FIXa and FX to generate FXa. However, these antibodies differ from FVIII in many ways including no requirement of activation and a lack of direct PS binding. Emicizumab is a bispecific antibody currently on the market for hemophilia A patients with inhibitors. It binds to factor FIX, FIXa, FX, and FXa with micromolar affinities in solution. Previously, we have shown that in-house preparations of sequence-identical emicizumab (SI-Emi) showed similar weak affinities to its antigens and similar in vitro activity to published emicizumab results by one-stage clotting, chromogenic FXa generation, and thrombin generation. However, in chromogenic FXa generation using antibody concentrations in the range of the mean steady state plasma concentration of patients on emicizumab prophylaxis [~360 nM, (Oldenburg, et al., NEJM 2017)], SI-Emi maintained 28% of its activity even in the absence of PS-containing phospholipid vesicles. Another FVIIIa mimetic antibody, BS-027125, was discovered by our group and binds with low nanomolar affinity to FIX, FIXa and FX, with no detectable binding to FXa. In one-stage clotting, BS-027125 achieved clot times similar to physiological levels of FVIII, but had poor activity in thrombin generation at these concentrations. Furthermore, it too maintained small amounts of phospholipid-independent activity in chromogenic FXa generation. Given the artificial nature of the chromogenic FXa generation assay, and that activity of prothrombinase is PS-dependent thereby precluding omission of phospholipids from thrombin generation assays, we developed an assay to detect FXa generation in a plasma milieu by FVIIIa mimetic antibodies or FVIII with and without phospholipid vesicles. Methods: FVIIIa mimetic antibodies or recombinant FVIII (rFVIII) were incubated with thrombin for 5 minutes, quenched with hirudin, then spiked into platelet-free congenital hemophilia A plasma treated with additional hirudin. FXIa (to generate FIXa in situ) with and without PC:PE:PS (40:40:20 molar ratio) phospholipid vesicles was added and reactions were triggered with a solution of CaCl2 and fluorogenic FXa substrate (Mes-D-LGR-ANSN(C2H5)2). Substrate cleavage was monitored kinetically on a fluorescent plate reader. Substrate cleavage by FXIa could not be detected, yet another unknown plasma peptidase did cleave substrate at a constant low rate that was background subtracted. Results: In the absence of phospholipid vesicles, SI-Emi maintained 51±3.7% of its FXa generation activity at all concentrations tested (3.8±0.4 versus 8.0±1.1 RFU/min at 333 nM). BS-027125 showed very low activity (0.43±0.12 RFU/min at 50 nM) in the presence of phospholipid vesicles, however, in the absence of phospholipid vesicles, BS-027125 activity was not detectable above baseline. Nearly all rFVIII activity (>99%) was lost in the absence of phospholipid vesicles (0.14±0.04 versus 15.1±1.8 RFU/min at 0.3 IU/mL). Addition of annexin V was sufficient to block all rFVIII activity in the presence or absence of phospholipid vesicles, but could not block SI-Emi activity. Furthermore, addition of rivaroxaban, a direct FXa inhibitor, confirmed that detection of substrate cleavage was due to FXa activity. Conclusions: In the absence of phosphatidylserine-containing phospholipid vesicles, SI-Emi promoted the generation of FXa in plasma triggered with FXIa. The activity of BS-027125 was too low in this assay to clearly determine its phospholipid-independent activity. These results suggest SI-Emi has mis-regulated (PS-independent) procoagulant activity due to a lack of phospholipid localization of the antibody-FIXa-FX complex. Given the weak affinity of SI-Emi for its antigens, the exact mechanism enabling this activity is unclear. Further study of this phenomenon and its relevance to overall thrombin generation and in vivo activity are needed. Disclosures Aleman: Bioverativ, a Sanofi company: Employment. Jindal:Bioverativ, a Sanofi company: Employment. Leksa:Bioverativ a Sanofi company: Employment. Peters:Bioverativ a Sanofi company: Employment, Equity Ownership. Salas:Bioverativ a Sanofi company: Employment, Equity Ownership.
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Petri, M. "Update on anti-phospholipid antibodies in SLE: the Hopkins’ Lupus Cohort." Lupus 19, no. 4 (March 30, 2010): 419–23. http://dx.doi.org/10.1177/0961203309360541.
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Anti-phospholipid antibodies are common in patients in the Hopkins’ Lupus Cohort: 47% have anti-cardiolipin, 32.5% anti-β2-glycoprotein I and 26% lupus anticoagulant (by dRVVT confirmatory testing). Systemic lupus erythematosus patients with the lupus anticoagulant at baseline have a 50% chance of a deep venous thrombosis/pulmonary embolus in the next 20 years. Anti-phospholipid antibodies differ in their association with thrombosis: the lupus anticoagulant is most strongly associated with arterial and venous thrombosis and is the only anti-phospholipid antibody associated with myocardial infarction. Anti-phospholipid antibodies are not associated with atherosclerosis. Lupus (2010) 19, 419—423.
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Amiral, Jean. "Diagnostic Approach of Phospholipid-Dependent Antibodies." Pathophysiology of Haemostasis and Thrombosis 29, no. 2-3 (1999): 135–49. http://dx.doi.org/10.1159/000022494.
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Carreras, L. O., and R. R. Forastiero. "Pathogenic Role Of Antiprotein-Phospholipid Antibodies." Pathophysiology of Haemostasis and Thrombosis 26, no. 4 (1996): 340–57. http://dx.doi.org/10.1159/000217316.
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Kilpatrick, D. C. "ANTI-PHOSPHOLIPID ANTIBODIES AND PREGNANCY WASTAGE." Lancet 328, no. 8513 (October 1986): 980–81. http://dx.doi.org/10.1016/s0140-6736(86)90633-1.
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Out, Henk Jan, Hein W. Bruinse, and Ronald H. W. M. Derksen. "Anti-phospholipid antibodies and pregnancy loss." Human Reproduction 6, no. 6 (July 1991): 889–97. http://dx.doi.org/10.1093/oxfordjournals.humrep.a137446.
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Chedid, Antonio, Kurmanadha R. Chadalawada, Timothy R. Morgan, Thomas E. Moritz, Charles L. Mendenhall, James B. Hammond, Peter W. Emblad, et al. "Phospholipid antibodies in alcoholic liver disease." Hepatology 20, no. 6 (December 1994): 1465–71. http://dx.doi.org/10.1002/hep.1840200614.
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Brandt, John T. "Antibodies to β2-Glycoprotein I Inhibit Phospholipid Dependent Coagulation Reactions." Thrombosis and Haemostasis 70, no. 04 (1993): 598–602. http://dx.doi.org/10.1055/s-0038-1649635.
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SummaryLupus anticoagulants are antibodies that inhibit phospholipid dependent coagulation reactions in vitro. These antibodies are of clinical interest because of their association with a variety of clinical manifestations characterized by microvascular thrombosis. Although these antibodies were originally thought to be directed at negatively charged phospholipid, recent studies have suggested that they may be directed at phospholipid-protein complexes. The effect of antibodies directed against β2-glycoprotein I (β2-GP I, apolipoprotein H) on phospholipid-dependent coagulation reactions has been studied. Polyclonal and monoclonal antibodies to β2-GP I were found to inhibit thrombin generation in a dose dependent manner. Inhibition of thrombin formation was due to specific interaction with β2-GP I. There was no evidence that inhibition was due to crossreactivity with other proteins involved in the prothrombinase complex. These findings document that antibodies directed against β2-GP I can have anticoagulant activity analogous to lupus anticoagulant activity and are consistent with the recent observation of such activity in lupus anticoagulant patient samples.
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Galli, M., G. Finazzi, EM Bevers, and T. Barbui. "Kaolin clotting time and dilute Russell's viper venom time distinguish between prothrombin-dependent and beta 2-glycoprotein I-dependent antiphospholipid antibodies." Blood 86, no. 2 (July 15, 1995): 617–23. http://dx.doi.org/10.1182/blood.v86.2.617.bloodjournal862617.
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Antiphospholipid (aPL) antibodies include anticardiolipin (aCL) and lupus anticoagulant (LA) antibodies. LA antibodies recognize the complex of lipid-bound (human) prothrombin, in this way inhibiting the phospholipid-dependent coagulation reactions, whereas aCL antibodies are directed towards beta 2-glycoprotein I (beta 2-GPI) bound to an anionic lipid surface. According to their behavior in coagulation reactions, we have divided aCL antibodies into two groups: aCL-type A, which inhibit the phospholipid-dependent coagulation reactions because they enhance the binding of beta 2-GPI to the procoagulant phospholipid surface; and aCL-type B antibodies, which are devoid of anticoagulant properties. We report the distinctive laboratory and clinical profiles of 25 patients with well-characterized, phospholipid-dependent inhibitor of coagulation. Fourteen patients had LA antibodies (aCL-type B were concomitantly present in 10 cases, while in the other four, aCL titer was normal), and the other 11 had aCL-type A antibodies. The laboratory evaluation of the two groups showed the dilute Russell viper venom time (dRVVT) to be the most abnormal coagulation test in the aCL- type A-positive group, whereas the kaolin clotting time (KCT) was the most abnormal assay in the LA-positive group. In fact, the ratios of the coagulation times of patient plasma over normal pooled plasma (mean +/- standard deviation) for LA versus aCL-type A antibodies were 1.48 +/- 0.27 versus 2.20 +/- 0.42, P = .0001, and 2.22 +/- 0.42 versus 1.50 +/- 0.42, P = .0003, for the dRVVT and KCT, respectively. No differences were observed either in the ratios of the activated partial thromboplastin times and the prothrombin times or the plasma levels of beta 2-GPI and prothrombin. Conversely, aCL titers were significantly higher in aCL-type A-positive patients (147 +/- 44 U) than in the LA- positive group (61 +/- 55 U; P = .0003). We ruled out the possibility that platelet contamination of plasma could account for the observed coagulation profiles, as the two patterns were reproduced in platelet- free plasma. In addition, we performed clotting tests in plasma in the presence of phospholipids and calcium after addition of factor IXa or factor Xa. The assay performed with factor Xa was more sensitive to the presence of aCL-type A antibodies, while the assay performed with factor IXa was preferentially sensitive to LA-containing plasmas, supporting the earlier findings with the dRVVT and KCT assays.(ABSTRACT TRUNCATED AT 400 WORDS)
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Umeda, M., K. Igarashi, K. S. Nam, and K. Inoue. "Effective production of monoclonal antibodies against phosphatidylserine: stereo-specific recognition of phosphatidylserine by monoclonal antibody." Journal of Immunology 143, no. 7 (October 1, 1989): 2273–79. http://dx.doi.org/10.4049/jimmunol.143.7.2273.
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Abstract A system based on the direct immunization of phospholipid Ag into mouse spleen has been used to produce mAb against phosphatidylserine (PS). mAb that bind to PS but not to phosphatidylcholine were selected. Remarkable frequency of the production of mAb against PS was observed with the immunization protocol. The mAb exhibited three distinct reactivity profiles ranging from highly specific to broadly cross-reactive. Among 61 hybridomas, 15 mAb were established for further analysis. The reactivities of three typical mAb, designated PS4A7, PS3A, and PSC8, are described. PS4A7 is highly specific to PS and no cross-reaction with other acidic phospholipids was observed. In the experiments using PS derivatives with a modified polar head group, PS4A7 was shown to bind to 1,2-diacyl-sn-glycero-3-phospho-L-serine (PS) but not to 1,2-diacyl-sn-glycero-3-phospho-D-serine or 1,2-diacyl-sn-glycero-3-phospho-L-homoserine, indicating that the antibody recognizes the stereo-specific configuration of serine residue in PS. PS3A binds to both PS and phosphatidylethanolamine, whereas no cross-reaction with other acidic phospholipids was observed. The analysis using the derivatives of PS and phosphatidylethanolamine shows that the antibody recognizes the amino group of the phospholipid Ag and cannot distinguish the conformational structure of serine residue in PS. PSC8 represents the family of mAb that cross-react considerably with other acidic phospholipids.
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Rand, Jacob H., Xiao-Xuan Wu, Harry A. M. Andree, J. B. Alexander Ross, Elena Rusinova, Mayra G. Gascon-Lema, Cesare Calandri, and Peter C. Harpel. "Antiphospholipid Antibodies Accelerate Plasma Coagulation by Inhibiting Annexin-V Binding to Phospholipids: A “Lupus Procoagulant” Phenomenon." Blood 92, no. 5 (September 1, 1998): 1652–60. http://dx.doi.org/10.1182/blood.v92.5.1652.
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Abstract The antiphospholipid syndrome is a thrombophilic condition marked by antibodies that recognize anionic phospholipid-protein cofactor complexes. We recently reported that exposure to IgG fractions from antiphospholipid patients reduces the level of annexin-V, a phospholipid-binding anticoagulant protein, on cultured trophoblasts and endothelial cells and accelerates coagulation of plasma exposed to these cells. Therefore, we asked whether antiphospholipid antibodies might directly reduce annexin-V binding to noncellular phospholipid substrates. Using ellipsometry, we found that antiphospholipid IgGs reduce the quantity of annexin-V bound to phospholipid bilayers; this reduction is dependent on the presence of β2-glycoprotein I. Also, exposure to plasmas containing antiphospholipid antibodies reduces annexin-V binding to phosphatidyl serine-coated microtiter plates, frozen thawed washed platelets, activated partial thromboplastin time (aPTT) reagent and prothrombin time reagent and reduces the anticoagulant effect of the protein. These studies show that antiphospholipid antibodies interfere with the binding of annexin-V to anionic phospholipid and with its anticoagulant activity. This acceleration of coagulation, due to reduced binding of annexin V, stands in marked contrast to the “lupus anticoagulant effect” previously described in these patients. These results are the first direct demonstration of the displacement of annexin-V and the consequent acceleration of coagulation on noncellular phospholipid surfaces by antiphospholipid antibodies. © 1998 by The American Society of Hematology.
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Rand, Jacob H., Xiao-Xuan Wu, Harry A. M. Andree, J. B. Alexander Ross, Elena Rusinova, Mayra G. Gascon-Lema, Cesare Calandri, and Peter C. Harpel. "Antiphospholipid Antibodies Accelerate Plasma Coagulation by Inhibiting Annexin-V Binding to Phospholipids: A “Lupus Procoagulant” Phenomenon." Blood 92, no. 5 (September 1, 1998): 1652–60. http://dx.doi.org/10.1182/blood.v92.5.1652.417k21_1652_1660.
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The antiphospholipid syndrome is a thrombophilic condition marked by antibodies that recognize anionic phospholipid-protein cofactor complexes. We recently reported that exposure to IgG fractions from antiphospholipid patients reduces the level of annexin-V, a phospholipid-binding anticoagulant protein, on cultured trophoblasts and endothelial cells and accelerates coagulation of plasma exposed to these cells. Therefore, we asked whether antiphospholipid antibodies might directly reduce annexin-V binding to noncellular phospholipid substrates. Using ellipsometry, we found that antiphospholipid IgGs reduce the quantity of annexin-V bound to phospholipid bilayers; this reduction is dependent on the presence of β2-glycoprotein I. Also, exposure to plasmas containing antiphospholipid antibodies reduces annexin-V binding to phosphatidyl serine-coated microtiter plates, frozen thawed washed platelets, activated partial thromboplastin time (aPTT) reagent and prothrombin time reagent and reduces the anticoagulant effect of the protein. These studies show that antiphospholipid antibodies interfere with the binding of annexin-V to anionic phospholipid and with its anticoagulant activity. This acceleration of coagulation, due to reduced binding of annexin V, stands in marked contrast to the “lupus anticoagulant effect” previously described in these patients. These results are the first direct demonstration of the displacement of annexin-V and the consequent acceleration of coagulation on noncellular phospholipid surfaces by antiphospholipid antibodies. © 1998 by The American Society of Hematology.
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Rand, JH, X.-X. Wu, AS Quinn, and DJ Taatjes. "The annexin A5-mediated pathogenic mechanism in the antiphospholipid syndrome: role in pregnancy losses and thrombosis." Lupus 19, no. 4 (March 30, 2010): 460–69. http://dx.doi.org/10.1177/0961203310361485.
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Annexin A5 (AnxA5) binds to phospholipid bilayers, forming two-dimensional crystals that block the phospholipids from availability for coagulation enzyme reactions. Antiphospholipid (aPL) antibodies cause gaps in the ordered crystallization of AnxA5 which expose phospholipids and thereby accelerate blood coagulation reactions. The aPL antibody-mediated disruption of AnxA5 crystallization has been confirmed on artificial phospholipid bilayers and on cell membranes including endothelial cells, placental trophoblasts and platelets. Recently, we reported that hydroxychloroquine, a synthetic antimalarial drug, can reverse this antibody-mediated process through two mechanisms: (1) by inhibiting the formation of aPL IgG-β2glycoprotein I complexes; and (2) by promoting the formation of a second layer of AnxA5 crystal ‘patches’ over areas where the immune complexes had disrupted AnxA5 crystallization. In another translational application, we have developed a mechanistic assay that reports resistance to AnxA5 anticoagulant activity in plasmas of patients with aPL antibodies. AnxA5 resistance may identify a subset of aPL syndrome patients for whom this is a mechanism for pregnancy losses and thrombosis. The elucidation of aPL-mediated mechanisms for thrombosis and pregnancy complications may open new paths towards addressing this disorder with targeted treatments and mechanistic assays.
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Gharavi, Azzudin E., Silvia S. Pierangeli, Margaret Colden-Stanfield, Xiao Wei Liu, Ricardo G. Espinola, and E. Nigel Harris. "GDKV-Induced Antiphospholipid Antibodies Enhance Thrombosis and Activate Endothelial Cells In Vivo and In Vitro." Journal of Immunology 163, no. 5 (September 1, 1999): 2922–27. http://dx.doi.org/10.4049/jimmunol.163.5.2922.
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Abstract Antiphospholipid (aPL) Abs are associated with thrombosis, pregnancy loss, and thrombocytopenia in patients with systemic lupus erythematosus or primary antiphospholipid syndrome (APS). β2-Glycoprotein I (β2GPI), a phospholipid-binding serum protein, is involved in aPL binding to phospholipids. aPL can be generated in mice by immunization with β2GPI, and these Abs are thrombogenic and cause pregnancy loss in mice. The objective of this study is to determine whether aPL induced by immunization with the phospholipid-binding site of β2GPI are thrombogenic and whether they activate endothelial cells (EC) in vivo and in vitro. Murine monoclonal aPL were generated from spleen cells of a mouse immunized with GDKV, a synthetic 15-aa peptide spanning Gly274–Cys288 in the fifth domain of human β2GPI, which represents the phospholipid-binding site of β2GPI. The Abs generated had aPL and anti-β2GPI activities. The effect of these Abs on thrombus formation and on EC activation in vivo was determined using a mouse model of thrombosis and microcirculation that enables examination of the adhesion of leukocyte to EC as an indication of EC activation as well as adhesion molecule expression using in vitro ELISA analysis. Mice injected with this monoclonal aPL showed a significant increase in leukocyte sticking and also produced larger thrombi that persisted longer. Exposure to GDKV-induced aPL for 4 h significantly increased surface Ag expression of E-selectin, ICAM-1, and VCAM-1. These data indicate that aPL induced by immunization with the phospholipid binding site of β2GPI are thrombogenic and activate endothelial cells.
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Baidoun, Firas, Rommy Issa, Robert Ali, and Bashar Al-Turk. "Acute Unilateral Blindness from Superior Ophthalmic Vein Thrombosis: A Rare Presentation of Nephrotic Syndrome from Class IV Lupus Nephritis in the Absence of Antiphospholipid or Anticardiolipin Syndrome." Case Reports in Hematology 2015 (2015): 1–3. http://dx.doi.org/10.1155/2015/413975.
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Patients with systemic lupus erythematosus (SLE) are at high risk of arterial and venous thrombosis secondary to anti-phospholipid antibodies. Herein, we are presenting an interesting case of venous thrombosis in a patient with SLE in the absence of anti-phospholipid antibodies.
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Sorice, M., P. Arcieri, T. Griggi, A. Circella, R. Misasi, L. Lenti, G. D. Di Nucci, and G. Mariani. "Inhibition of Protein S by Autoantibodies in Patients with Acquired Protein S Deficiency." Thrombosis and Haemostasis 75, no. 04 (1996): 555–59. http://dx.doi.org/10.1055/s-0038-1650320.
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SummaryThis study was undertaken to analyze antibodies to protein S (PS) in patients with an acquired PS deficiency. Plasma from symptomatic patients with acquired (n = 14) or congenital (n = 10) PS deficiency and 10 healthy donors was screened for PS antibodies by immunoblotting and for anti-phospholipid antibodies. PS antibodies (IgG) were detected in five of the patients with acquired PS deficiency. These antibodies belonged to the G1 and G4 immunoglobulin subclasses. IgG fractions from the same 5 patients were shown to inhibit PS activity. The inhibition of PS activity by the 5 IgG fractions was shown to be time-and dose-dependent and was abolished following incubation with purified PS, while no effect was found after absorption with cardiolipin micelles. In addition, anticardiolipin monoclonal or human purified antibodies, failed to exert significant PS inhibition. These findings demonstrate that anti-PS antibodies are able to inhibit PS activity and that this is independent of anti-phospholipid antibodies. Given the clinical features of the patients, these antibodies should be regarded as an expression of the broad autoimmune syndrome involving the phospholipid-binding plasma proteins.
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Bizzaro, Nicola, Elio Tonutti, Danilo Villalta, Marilina Tampoia, and Renato Tozzoli. "Prevalence and Clinical Correlation of Anti-Phospholipid–Binding Protein Antibodies in Anticardiolipin-Negative Patients With Systemic Lupus Erythematosus and Women With Unexplained Recurrent Miscarriages." Archives of Pathology & Laboratory Medicine 129, no. 1 (January 1, 2005): 61–68. http://dx.doi.org/10.5858/2005-129-61-paccoa.
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Abstract Context.—Anti-phospholipid antibodies (aPL) are a heterogeneous group of autoantibodies, the presence of which is associated with thrombotic events and miscarriage. Objective.—To establish whether antibodies directed against phospholipid-binding plasma proteins such as β2-glycoprotein I (β2GPI), prothrombin (PT), and annexin V (Anx V) constitute a risk factor for thromboembolism in patients with systemic lupus erythematosus (SLE) and for miscarriage in women with recurrent pregnancy loss (RPL), independently of the presence of the classic anticardiolipin (aCL) antibodies, and whether their determination together with that of aCL would help to increase the diagnostic sensitivity of aPL tests. Design.—The prevalence of various antibodies directed toward phospholipids (CL and other anionic phospholipids [APL]) and phospholipid-binding proteins (β2GPI, PT, and Anx V) was determined by immunoenzymatic methods in 311 serum samples. Patients.—Twenty-five patients with aCL-positive primary anti-phospholipid syndrome (pAPS); 89 patients with SLE, 23 of whom had thrombotic complications (SLE/APS) and 66 of whom had no thrombosis; and 77 women with unexplained recurrent pregnancy loss comprised our study group. One hundred twenty healthy subjects matched for age and sex were studied as the control group. Results.—Immunoglobulin (Ig) G and/or IgM aAPL, anti-β2GPI, anti-PT, and IgG anti-Anx V antibodies were detected in 25 (100%), 20 (80%), 15 (60%), and 6 (24%), respectively, of the 25 aCL-positive pAPS patients; IgG and/or IgM aCL, aAPL, anti-β2GPI, anti-PT, and IgG anti-Anx V antibodies were detected in 33 (37%), 42 (47%), 31 (35%), 40 (45%), and 12 (13%) of the 89 SLE patients, respectively. Of the 56 SLE patients who proved to be aCL negative, anti-β2GPI was present in 3 patients (5%), anti-PT in 13 (23%) patients, and anti-Anx V in 5 (9%) patients. In the subset of 23 SLE/APS patients, IgG anti-PT prevalence was higher than that of the other autoantibodies (87% vs 70% aCL, 66% aAPL, 57% anti-β2GPI, and 4% anti-Anx V), and in 26% of cases, IgG anti-PT was the only antibody present. Anti-PT had a slightly lower specificity than aCL (46% vs 49%); however, the occurrence of both antibodies brought the specificity to 92.4%. The highest risk for thrombosis in SLE patients was associated with the presence of IgG anti-PT antibody (odds ratio [OR] 15.3, P < .001, vs 6.5 aCL, 3.5 aAPL, 3.4 anti-β2GPI, 0.2 anti-Anx V). Fifty-one of the 77 women with recurrent pregnancy loss were negative for all antibodies investigated; the prevalence of IgG and/or IgM aCL, aAPL, anti-β2GPI, anti-PT, and IgG anti-Anx V antibodies was 6% (5), 12% (9), 6% (5), 16% (12), and 17% (13), respectively. Of the 67 aCL-negative women, none had anti-β2GPI antibodies, 7 (11%) were anti-PT positive, and 13 (19%) were anti-Anx V positive. In the subgroup of 26 recurrent pregnancy loss patients who had at least one antibody, anti-Anx V was present in 50% of cases (in 42% as the sole antibody) and was the only antibody significantly associated with miscarriage (P = .02). Conclusions.—The results of this study indicate that it is useful to measure anti-PT antibodies in addition to the more widely used aCL and anti-β2GPI antibodies in the prognostic evaluation of SLE patients for the risk of thrombosis, and the results also confirm that anti-Anx V antibodies may play an important role in recurrent pregnancy loss.
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Shi, W., BH Chong, and CN Chesterman. "Beta 2-glycoprotein I is a requirement for anticardiolipin antibodies binding to activated platelets: differences with lupus anticoagulants." Blood 81, no. 5 (March 1, 1993): 1255–62. http://dx.doi.org/10.1182/blood.v81.5.1255.1255.
Full textAbstract:
Abstract Antiphospholipid (aPL) antibodies are of major interest not only because the lupus anticoagulant (LA) causes an inhibition of in vitro blood coagulation, but also because the presence of aPL antibodies confers a risk of thrombosis. The inhibition of in vitro phospholipid- dependent coagulation (LA) is thought to be caused by the binding of LA to procoagulant phospholipid surfaces, thus impeding the clotting process. Another class of aPL antibodies are those originally described to be directed against negatively charged phospholipids, in particular cardiolipin (ACA). ACA are usually directed against a complex antigen consisting of negatively charged phospholipid and a plasma protein, beta 2-glycoprotein I (beta 2-GPI). Further, there is antibody heterogeneity even within individual patients so that ACA and LA are separable using physicochemical techniques such as ion exchange chromatography and chromatofocusing. Using such techniques we have enriched Ig fractions for LA and ACA from two patient plasmas. The majority of Ig with LA activity had a pI of 7.2 to 7.3 whereas ACA had a pI of 5.0 to 5.2. Using these enriched fractions labeled with [125I]- iodine we have shown that LA binds to platelets in a specific and saturable manner. Binding is dependent on thrombin activation. [125I]- ACA behaves differently. Like LA, binding is specific and dependent on thrombin activation but in this case requires the presence of beta 2- GPI. ACA, in the presence of beta 2-GPI, competes for binding with LA suggesting the same or contiguous site. There is no cross-reactivity of these antibodies with GPIIb/IIIa and the most likely binding site is phospholipid. In neither case does LA nor ACA have an effect on thrombin-induced release of serotonin or beta-thromboglobulin nor do they affect platelet aggregation induced by a number of agonists. This antibody binding may play an etiological role in thrombocytopenia associated with aPL, but does not explain thrombosis on the basis of hyperaggregability or increased platelet release.