Antibody-Mediated Disruption of the Annexin-V Antithrombotic Shield: A New Mechanism for Thrombosis in the Antiphospholipid Syndrome

1999 ◽  
Vol 82 (08) ◽  
pp. 649-655 ◽  
Author(s):  
Xiao-Xuan Wu ◽  
Jacob Rand
Keyword(s):  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Lupus Anticoagulant ◽  
Solid Phase ◽  
Protein Complexes ◽  
Annexin V ◽  
Autoimmune Disorder ◽  
Antigenic Determinants ◽  
Anionic Phospholipid

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.

Antiphospholipid antibody-mediated interference with annexin-V anticoagulant activity

2001 ◽  
Vol 21 (02) ◽  
pp. 50-53 ◽  
Author(s):  
X.-X. Wu ◽  
J. H. Rand
Keyword(s):  
Antiphospholipid Syndrome ◽  
Protein Complexes ◽  
Anticoagulant Activity ◽  
Annexin V ◽  
Phospholipid Bilayer ◽  
Antiphospholipid Antibody ◽  
Anionic Phospholipid ◽  
Anionic Phospholipids ◽  
Coagulation Proteins ◽  
Recurrent Pregnancy Losses

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.

The clinical relevance of isolated lupus anticoagulant positivity in patients with thrombotic antiphospholipid syndrome

2020 ◽  
Author(s):  
Dong-mei Yin ◽  
Philip de Groot ◽  
Marisa Ninivaggi ◽  
Katrien M.J. Devreese ◽  
Bas de Laat
Keyword(s):  
Antiphospholipid Syndrome ◽  
Clinical Relevance ◽  
Antiphospholipid Antibodies ◽  
Odds Ratio ◽  
Lupus Anticoagulant ◽  
Solid Phase ◽  
Control Group ◽  
Domain I ◽  
Normal Controls ◽  
Better Than

Background: Patients positive for three types of antiphospholipid antibodies (aPLs) (triple positivity) have been identified at a high risk for thrombotic events. However, the clinical significance of isolated lupus anticoagulant (LAC) positivity is debated. Objectives: To investigate the clinical relevance of isolated LAC. Patients/Methods 456 patients were enrolled in this study; 66 antiphospholipid syndrome patients and 390 control patients. The control group existed of autoimmune patients (n=91), patients with thrombosis but without aPLs (n=127) and normal controls (n=172). The criteria LAC, anti-cardiolipin (anti-CL) and anti-beta2glycoprotein I (anti-β2GPI) IgG and IgM and the non-criteria IgA anti-CL and anti-β2GPI, anti-domain I (anti-DI) of β2GPI IgG and anti-phosphatidylserine/prothrombin (anti-PS/PT) IgG and IgM were detected according to the ISTH guidelines for solid phase assays. Results: 70 patients were positive for LAC, of which 44 were negative for both anti-β2GPI and anti-CL. We found that isolated LAC proved to be strongly associated with vascular thrombosis (Odds ratio (OR) (95% CI) 7.3 (3.3-16.1)), even better than triple positive samples (OR 4.3 (1.6-12.2)). The titers of the anti-PS/PT IgG and IgM were significantly higher in triple positivity samples compared to samples with isolated LAC positivity. The majority of single LAC positives were anti-PS/PT negative. We observed that LAC positivity was weaker in isolated LAC positive patients compared to LAC activity in triple positive patients. Conclusions: Isolated LAC was highly associated with thrombosis. The presence of anti-PS/PT could not explain LAC positivity in isolated LAC. Isolated LAC showed a weaker LAC activity compared to triple positive patients.

Antiphospholipid Syndrome: Diagnostic Aspects of Lupus Anticoagulants

2001 ◽  
Vol 86 (07) ◽  
pp. 83-91 ◽  
Author(s):  
J. Arnout
Keyword(s):  
Monoclonal Antibodies ◽  
Antiphospholipid Syndrome ◽  
Autoimmune Disorder ◽  
Coagulation Factors ◽  
Laboratory Diagnosis ◽  
Anticardiolipin Antibodies ◽  
Lupus Anticoagulants ◽  
Glycoprotein I ◽  
Antigen Antibody

SummaryAntiphospholipid syndrome (APS) is an autoimmune disorder in which antiphospholipid antibodies (aPL) are thought to be involved in the development of venous and/or arterial thrombosis. APL found in this syndrome are antibodies directed against a variety of phospholipid (PL) binding-proteins of which β2-glycoprotein I (β2GPI) and prothrombin are considered to be the major antigens. Some of these antibodies prolong PL-dependent clotting reactions and are termed lupus anticoagulants (LA). Autoimmune aPL which bind through β2GPI to cardiolipin are called anticardiolipin antibodies (aCL). Clinical studies indicate that LA is a stronger risk factor for thrombosis than aCL. The production of monoclonal antibodies against β2GPI and prothrombin has enabled us to understand the mechanism by which LA prolong coagulation in vitro. LA form bivalent antigen-antibody complexes with increased affinity for PL which compete with coagulation factors for the same catalytic surface. These LA positive monoclonal antibodies may be helpful in further improving the laboratory diagnosis of LA.

The antiphospholipid (antibody) syndrome

2011 ◽  
pp. 343-352
Author(s):  
Alan J. Hakim ◽  
Gavin P.R. Clunie ◽  
Inam Haq
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Diseases ◽  
Venous Thrombosis ◽  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Lupus Anticoagulant ◽  
Antiphospholipid Antibody ◽  
Antiphospholipid Antibody Syndrome ◽  
Systemic Lupus ◽  
Pregnancy Morbidity

Introduction 344 Epidemiology and pathology 345 Clinical features of antiphospholipid syndrome 346 Treatment of antiphospholipid syndrome 348 Catastrophic antiphospholipid syndrome 350 The antiphospholipid syndrome (APS) was first described in the 1980s and comprises arterial and venous thrombosis with or without pregnancy morbidity in the presence of anticardiolipin (ACL) antibodies or the lupus anticoagulant (LAC). It can be primary, or secondary to other autoimmune diseases, most commonly systemic lupus erythematosus (SLE) (...

Pathophysiology of Anti-PL Syndrome in Thrombosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-45-SCI-45
Author(s):  
Jacob H. Rand
Keyword(s):  
Endothelial Cells ◽  
Lupus Erythematosus ◽  
Vascular Endothelial Cells ◽  
Anticoagulant Activity ◽  
Maternal Blood ◽  
Bleeding Complications ◽  
Target Cells ◽  
Anionic Phospholipid ◽  
Thrombotic Disorder

Abstract Abstract SCI-45 The antiphospholipid (aPL) syndrome (APS) is an enigmatic autoimmune thrombotic disorder that was initially identified through astute clinical observations and the development of a quantitative test for aPL antibodies. The condition is marked by 2 types of assays: 1) immunoassays that were derived from the “biologic false positive syphilis” test and 2) coagulation assays that detect “lupus anticoagulants” (LAs), which are inhibitors of phospholipid-dependent coagulation reactions. The most recent consensus investigational criteria for diagnosing APS require that patients have evidence for thrombosis and/or pregnancy complications attributable to placental insufficiency and also laboratory evidence for persistent (aPL) antibodies, detected by high levels of IgG or IgM antibodies against cardiolipin and β2-glycoprotein I (β2GPI) and/or through abnormal LA assays. The thrombotic disorder requires long term anticoagulant treatment, which is accompanied by the risk of bleeding complications. Several mechanisms have been postulated and can be classified as involving: 1) aPL antibody-mediated inhibition of endogenous anticoagulant mechanisms; 2) aPL antibody-triggered signaling events on target cells (vascular endothelial cells, monocytes, platelets and trophoblasts) that promote proadhesive and prothrombotic phenotypes; and 3) aPL antibody-mediated complement activation. At present, it appears that the APS diagnostic entity actually includes several distinct subsets that reflect the actions of heterogeneous antibodies directed against different epitopes of phospholipid-binding proteins which then may yield different clinical sequelae. We have accumulated significant data indicating that a major one of these mechanisms involves aPL antibody-mediated disruption of annexin A5 (AnxA5) activity. AnxA5 is a potent anticoagulant protein whose anticoagulant properties are a consequence of its high affinity for anionic phospholipid. The protein forms 2-dimensional crystals on phospholipid surfaces that shield the phospholipids from availability for coagulation reactions. AnxA5 appears to play a thrombomodulatory role on the surfaces of cells lining the placental and systemic vasculatures. It is highly expressed on the apical membranes of placental syncytiotrophoblasts, the location where maternal blood interfaces with fetal cells. aPL antibody-antigen complexes disrupt the ordered crystallization of AnxA5, displace the protein from phospholipid membrane surfaces and thereby accelerate coagulation reactions. This effect of the antibodies has been demonstrated on artificial bilayers, on cultured trophoblasts and on endothelial cells and platelets. This disruption has been appears to be a consequence of aPL antibodies that recognize a specific epitope within domain I of β2GPI, the key antigen recognized by aPL antibodies. Based upon these data, we developed a novel clinical assay “the AnxA5 resistance (A5R) test” to identify patients who have antibodies that interfere with the anticoagulant activity of AnxA5. Initial studies indicate that a large proportion of APS patients have evidence for A5R. It therefore appears possible that measurement for A5R may provide a mechanistic assay for APS. We are also developing treatments to target this mechanism and protect AnxA5 from antibody-mediated disruption which may open novel nonanticoagulant approaches to treating APS. Disclosures Off Label Use: The presentation will include research on in vitro effects of hydroxychloroquine; the drug is not FDA approved for the treatment of patients with antiphospholipid syndrome who do not also have concurrent systemic lupus erythematosus or rheumatoid arthritis.

scholarly journals Practical approaches to laboratory assessment of risk of reсcurent thrombosis in antiphospholipid syndrome

2020 ◽  
Vol 4 (35) ◽  
pp. 16-22
Author(s):  
O. Yu. Tkachenko ◽  
S. V. Lapin ◽  
A. V. Mazing ◽  
V. L. Emanuel
Keyword(s):  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Protein Complexes ◽  
Systemic Disease ◽  
Simultaneous Detection ◽  
Laboratory Assessment ◽  
Heterogenous Group ◽  
Healthy Young People ◽  
Diagnostic Indicator

Antiphospholipid antibodies (aPLs) are a heterogenous group of auto‑ antibodies that interact with phospholipids (PL), phospholipid‑protein complexes and phospholipid‑binding proteins. aPLs are pathogenic and associated with the development of thrombosis and pregnancy pathology. The detection of aPLs as a diagnostic indicator is included in the criteria for antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) SLISS 2012. Also, aPLs is found in patients with other autoimmune, infectious diseases and cancer, in 10–12 % of elderly and 1–5 % healthy young people, but do not lead to the development of thrombosis and/or miscarriage. Simultaneous detection of aPLs with different tests indicate bad prognosis and a higher risk of clinical manifestation of APS. Triple positivity for classical markers of disease is found in patients with oncoming thrombosis. Another concept is the Global APS Score (GAPSS) that also takes into account the aPL profile as well as conventional cardiovascular risk factor and also some autoantibodies found in systemic disease. Currently, enzyme‑linked immunosorbent analysis (ELISA) are most widely used test for detection of aPLs. The advantage of new methods for detecting aPLs is to improve the parameters of sorption of antigens, automation, multiplex approach. Thus, new techniques can serve as a tool for the detection of aPLs and contribute to improving the quality of diagnosis of autoimmune diseases.

scholarly journals Protein antigens of the RNA-protein complexes detected by anti-SM and anti-RNP antibodies found in serum of patients with systemic lupus erythematosus and related disorders.

1982 ◽  
Vol 156 (5) ◽  
pp. 1475-1485 ◽  
Author(s):  
G E Conner ◽  
D Nelson ◽  
R Wisniewolski ◽  
R G Lahita ◽  
G Blobel ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Protein Complexes ◽  
The Other ◽  
Antigenic Determinants ◽  
Protein Antigens ◽  
Systemic Lupus ◽  
Banding Patterns ◽  
Rna Protein Complexes ◽  
Different Tissues

Evidence has been obtained previously indicating that the antigens reacting with the anti-Sm and anti-RNP sera are present as a large complex, and similar protein bands are obtained with both types of sera. Inthe present study, it proved possible to break up this complex using SDS treatment before immunoprecipitation. After such treatment, different protein bands were immunoprecipitated by the two antisera; Sm determinants resided, at least partially, in a 19-kd protein. Sequential immunoprecipitation with and without prior SDS treatment provided further evidence for these specificities and suggested that two classes of particles exist in different tissues, one containing proteins immunoreactive with the Sn and RNP antisera and the other containing proteins immunoreactive only with the Sm antisera. The latter particle contained all the bands seen with the first type except for the absence of the 19-kd band. Nitrocellulose blot analyses confirmed the assignment of the 25- and 16-kd polypeptides to Sm antigenic determinants; analyses for RNP proved les informative by this technique. Some differences in the banding patterns were obtained using cells from different species: the 25-kd Sm band was usually double in human cells and single in rat and rabbit tissue. Methods of extraction also caused some differences which was especially true for the rabbit thymus extract widely used for Sm and RNP studies. Additional immunoreactive bands at 68 and 70 kd also were detected when the Sm and RNP antisera were used in nitrocellulose blot analyses. Furthermore, evidence was obtained for a number of other antibodies in lupus sera which have not as yet been detected by serological methods.

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