Prothrombin and β2-glycoprotein I frequently contribute to antiphospholipid antibody interactions with phospholipids and the generation of abnormal waveform profiles in coagulation assays

2003 ◽  
Vol 90 (08) ◽  
pp. 218-226 ◽  
Author(s):  
Zuowei Su ◽  
Tomonori Izumi ◽  
Thomas Ortel
Keyword(s):  
Prothrombin Time ◽  
Antiphospholipid Antibodies ◽  
Molecular Basis ◽  
Annexin V ◽  
Antiphospholipid Antibody ◽  
Cofactor Binding ◽  
Coagulation Assays ◽  
The Core ◽  
Glycoprotein I ◽  
Antibody Interactions

SummaryTransmittance waveforms are generated during clot formation on photo-optical coagulation analyzers. We previously showed that 61.5% of patients with antiphospholipid antibodies (APLA) exhibited a negative deflection in the pre-coagulation phase of the prothrombin time (PT slope 1). The current studies investigated the ‘molecular basis’ of this abnormal parameter. We found that the negative PT slope 1 is IgG-mediated and is not dependent on the presence of fibrinogen or thrombin activity. We also found that IgG from most of the patients required a specific thromboplastin and the presence of prothrombin or β2-glycoprotein I (β2GPI) to produce an abnormal IgG waveform assay. In addition, the abnormal IgG waveform required cofactor binding to phospholipids when β2GPI was the cofactor, and annexin V could partially block this interaction. In conclusion, these results showed that the interactions of IgG with phospholipids via β2GPI or prothrombin constitute the core mechanisms of the abnormal waveforms.

scholarly journals CLINICAL AND IMMUNOLOGICAL CORRELATIONS IN PATIENTS WITH SYSTEMICLUPUS ERYTHEMATOSUS WITH ANTIPHOSPHOLIPID ANTIBODY SYNDROME

2017 ◽  
Vol 9 (3) ◽  
pp. 7-11 ◽  
Author(s):  
E A Belolipetskaia ◽  
I B Beliaeva ◽  
V I Mazurov ◽  
E A Trofimov ◽  
S V Lapin
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Antiphospholipid Antibodies ◽  
Annexin V ◽  
Anticardiolipin Antibodies ◽  
Antiphospholipid Antibody ◽  
Antiphospholipid Antibody Syndrome ◽  
Systemic Lupus ◽  
Glycoprotein I ◽  
Threefold Increase

Antiphospholipid antibodies (aPL): lupus anticoagulant (LA), anticardiolipin antibodies (aCL) and anti-β2-glycoprotein I antibodies (anti-β2GPI) are found in 12 to 44% of systemic lupus erythematosus (SLE) patients. On average, antiphospholipid antibody syndrome (APS) develops in50% of aPL-positive patients with SLE. The seronegative APS is characterized by the absence of the diagnostic levels of "classical" aPL and by the presence of non-criteria aPL: antibodies against pro- thrombin (aPT), antibodies against annexin V, antibodies against phosphatidylethanoamine (aPE), antibodies to phosphatidylserine/prothrombin complex (aPS-PT) and antibodies against negatively charged phospholipids. The presence of four antibodies (LA + aCT + anti-β2GPI + aPT) is associated with a threefold increase in the risk of thrombosis. The presence of aCL and anti-β2GPI in SLE patients with APS and recurrent thromboses is associated with the HLA dRB1 * 0402.

scholarly journals Epidemiological, clinical and immune factors that influence the persistence of antiphospholipid antibodies in leprosy

2019 ◽  
Vol 59 (1) ◽  
Author(s):  
Sandra Lúcia Euzébio Ribeiro ◽  
Helena Lúcia Alves Pereira ◽  
Antonio Luiz Boechat ◽  
Neusa Pereira Silva ◽  
Emilia Ionue Sato ◽  
...  
Keyword(s):  
Antiphospholipid Antibodies ◽  
Specific Treatment ◽  
Binary Logistic Regression ◽  
Antiphospholipid Antibody ◽  
Antiphospholipid Antibody Syndrome ◽  
Pregnancy Morbidity ◽  
Glycoprotein I ◽  
Leprosy Patients ◽  
Immunological Factors ◽  
Bacterial Index

Abstract Introduction Antiphospholipid antibodies (aPL) are described in individuals with leprosy without the clinical features of antiphospholipid antibody syndrome (APS), a condition involving thromboembolic phenomena. We have described the persistence of these antibodies for over 5 years in patients with leprosy after specific treatment. Objectives To determine whether epidemiological, clinical and immunological factors played a role in the long-term persistence of aPL antibodies in leprosy patients after multidrug therapy (MDT) had finished. Methods The study sample consisted of 38 patients with a diagnosis of leprosy being followed up at the Dermatology and Venereology Outpatient Department at the Alfredo da Matta Foundation (FUAM) in Manaus, AM. ELISA was used to detect anticardiolipin (aCL) and anti-β2 glycoprotein I (anti-β2GPI) antibodies. Patients were reassessed on average of 5 years after specific treatment for the disease (MDT) had been completed. Results Persistence of aPL antibodies among the 38 leprosy patients was 84% (32/38), and all had the IgM isotype. Mean age was 48.1 ± 15.9 years, and 23 (72.0%) were male. The lepromatous form (LL) of leprosy was the most common (n = 16, 50%). Reactional episodes were observed in three patients (9.4%). Eighteen (47.37%) were still taking medication (prednisone and/or thalidomide). Mean IgM levels were 64 U/mL for aCL and 62 U/mL for anti-β2GPI. In the multivariate binary logistic regression the following variables showed a significant association: age (p = 0.045, OR = 0.91 and CI 95% 0.82–0.98), LL clinical presention (p = 0.034; OR = 0.02 and CI 95% = 0.0–0.76) and bacterial index (p = 0.044; OR = 2.74 and CI 95% = 1.03–7.33). We did not find association between prednisone or thalidomide doses and positivity for aPL (p = 0.504 and p = 0.670, respectively). No differences in the variables vascular thrombosis, pregnancy morbidity, diabetes, smoking and alcoholism were found between aPL-positive and aPL-negative patients. Conclusion Persistence of positivity for aPL antibodies was influenced by age, clinical presentation and bacterial index. However, further studies are needed to elucidate the reason for this persistence, the role played by aPL antibodies in the disease and the B cell lineages responsible for generation of these antibodies.

Annexin V antibodies in multiple sclerosis and SLE/APS

Open Medicine ◽  
2013 ◽  
Vol 8 (2) ◽  
pp. 225-228
Author(s):  
Marta Baleva ◽  
Detelina Stoilova ◽  
Petko Shotekov ◽  
Krasimir Nikolov
Keyword(s):  
Multiple Sclerosis ◽  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Antiphospholipid Antibodies ◽  
Annexin V ◽  
Serum Levels ◽  
Organ Damage ◽  
Systemic Lupus ◽  
Pathogenic Role ◽  
Glycoprotein I

AbstractMultiple sclerosis (MS) is an autoimmune disease with unclear etiopathogenesis. Some MS patients have anticardiolipin (ACL), anti-beta-2-glycoprotein-I (B2GPI) and anti-annexin V (AnV) antibodies. These antibodies can also be found in systemic lupus erythematosus with antiphospholipid syndrome (SLE/APS). The aim of our study was to compare the levels of ACL, B2GPI and AnV antibodies in MS and SLE/APS. Materials and methods: We investigated serum levels of IgG and IgM ACL, B2GPI and AnV in 21 MS patients, 30 SLE/APS patients and 30 controls using ELISA. Results: Mean levels of IgM and IgG ACL and B2GPI in MS were comparable with controls and lower than SLE/APS (p<0.05). Mean levels of IgM AnV in MS were higher compared to SLE/APS and controls (p<0.05); mean levels of IgG AnV in MS were higher than normal but similar to SLE/APS (p>0.05). Discussion: The results show that MS with negative “classic” autoantibodies (ACL and B2GPI) and without clinical data for antiphospholipid syndrome may have other positive antiphospholipid antibodies, such as AnV. Larger studies are needed to clarify whether AnV are epiphenomenon of the vascular and organ damage or they play a pathogenic role in the development of MS.

Non β2-Glycoprotein I Cofactors for Antiphospholipid Antibodies

Lupus ◽  
1996 ◽  
Vol 5 (5) ◽  
pp. 388-392 ◽  
Author(s):  
M Galli
Keyword(s):  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Protein C ◽  
Activated Protein C ◽  
Clinical Manifestations ◽  
Annexin V ◽  
Protein S ◽  
Thromboembolic Events ◽  
Glycoprotein I ◽  
Recurrent Abortions

The Antiphospholipid Syndrome is defined by the association between peculiar clinical manifestations, namely arterial and/or venous thrombosis, recurrent abortions and thrombocytopenia, and the antiphospholipid antibodies. These antibodies are directed to plasma proteins bound to anionic phospholipids or other anionic surfaces: so far, β2-glycoprotein I is the best known and characterized antiphospholipid ‘cofactor’ ( this issue is specifically treated in other parts of this journal). In recent years, such a role has been reported also for prothrombin, activated Protein C, Protein S, Annexin V, Thrombomodulin, high- and low-molecular weight kininogens. Anti-prothrombin antibodies are detected in approximately 50% of the antiphospholipid-positive patients; conversely, limited data are available regarding the prevalence the other antibodies. ‘Cofactors' are necessary for the expression of both the immunological and the functional properties of their respective antiphospholipid antibodies. In particular, the recognition of the calcium-mediated prothrombin/lipid complex by anti-prothrombin antibodies hampers prothrombin activation, thus causing the prolongation of the phospholipid-dependent coagulation reactions. The interaction between antiphospholipid antibodies and natural inhibitors of coagulation such as activated Protein C, its non-enzymatic accessory protein Protein S or Thrombomodulin might increase the risk to develop thromboembolic events. Similarly, the presence of antibodies to surface-bound Annexin V has been hypothesized to play a role in recurrent abortions and fetal deaths. However, to clearly establish whether and which antiphospholipid antibodies represent risk factors for the thromboembolic events of the antiphospholipid syndrome, further studies of their behaviour and properties as well as the identification and characterization of (possibly) other antibodies are required.

116. TROPHOBLAST ANTIPHOSPHOLIPID ANTIBODY INTERNALISATION BY A β2 GLYCOPROTEIN I-ANIONIC PHOSPHOLIPID-MEGALIN COMPLEX

2010 ◽  
Vol 22 (9) ◽  
pp. 34
Author(s):  
C. A. Viall ◽  
L. W. Chamley ◽  
Q. Chen
Keyword(s):  
Antiphospholipid Antibodies ◽  
Recurrent Miscarriage ◽  
First Trimester ◽  
Antiphospholipid Antibody ◽  
Anionic Phospholipid ◽  
Anionic Phospholipids ◽  
Glycoprotein I ◽  
Increased Risk ◽  
Dependent Mechanism ◽  
Risk Of Preeclampsia

Women with antiphospholipid antibodies (aPL) are at an increased risk of preeclampsia, recurrent miscarriage, stillbirth and intrauterine growth restriction. Antiphospholipid antibodies may predispose to these pathologies by damaging the placenta, although exactly how is not understood. Recently, a novel pathogenic mechanism was suggested by work which showed that aPL are specifically internalised by placental trophoblasts where they caused aberrant trophoblast death. Internalisation may occur via an endocytic receptor called megalin in a process that seems to involve at least one of the two components of the antigen for aPL, the anionic phospholipid-binding protein β2 glycoprotein I (β2GPI). However, whether internalisation is also dependent upon anionic phospholipids is unknown. Identifying the receptor pathway responsible for aPL internalisation may provide insight into the pathogenesis of aPL in the placenta. To investigate the process of aPL internalisation, first trimester placental explants were cultured with fluorescently-labeled monoclonal aPL, or a control antibody and/or β2GPI or acetylated β2GPI, which can not bind anionic phospholipids. The explants were then sectioned and the localisation of the aPL, β2GPI, or acetylated β2GPI was determined by confocal microscopy. The localisation of megalin expression in placental explants was determined by immunohistochemistry. Megalin was expressed throughout the syncytiotrophoblast but more strongly in some regions. After an overnight incubation, both aPL and β2GPI, but not control antibodies were co-localised in the cytoplasm of the syncytiotrophoblast. Acetylated β2GPI was not internalised and partially blocked aPL uptake. These results suggest that aPL are internalised into the synctiotrophoblast by a receptor-dependent mechanism involving β2GPI, anionic phospholipids and megalin. This work forms the first step to understanding how aPL are internalised by trophoblasts. Further investigation of this mechanism and the subsequent intracellular effects of aPL may lead to a new therapeutic strategy for aPL-positive pregnant women by preventing the pathogenic effect of aPL on the placenta.

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.

Antiphospholipid Antibodies

2002 ◽  
Vol 126 (11) ◽  
pp. 1424-1429
Author(s):  
Douglas A. Triplett
Keyword(s):  
Antiphospholipid Antibodies ◽  
Medical Literature ◽  
Data Extraction ◽  
Annexin V ◽  
Protein S ◽  
Thromboembolic Events ◽  
Cellular Membranes ◽  
Lupus Anticoagulants ◽  
Glycoprotein I ◽  
Wide Range

Abstract Objective.—To review the role of lupus anticoagulants in the pathogenesis of both venous and arterial thromboembolic events, as well as in recurrent spontaneous abortions. The pathophysiology of lupus anticoagulants and associated antiphospholipid antibodies (eg, anticardiolipin antibodies) is also discussed. Data Sources.—Review of the recent medical literature. Data Extraction and Synthesis.—Key articles in the recent medical literature dealing with lupus anticoagulants and their role in pathogenesis of thromboembolic events were reviewed. Plasma proteins that have an affinity for binding to “perturbed cellular membranes” have been identified as the antigenic targets for antiphospholipid antibodies. Thus, the concept of antiphospholipid antibodies needs to be reevaluated. Perhaps a better term is antiprotein-phospholipid antibodies. The principal antigenic protein targets are β2-glycoprotein I, prothrombin, and a wide range of additional proteins that interact with activated cellular membranes, including protein C, protein S, annexin V, etc. Most research reported in the literature has focused on β2-glycoprotein I and human prothrombin.

Standardization of Antiphospholipid Antibody Testing—Historical Perspectives and Ongoing Initiatives

2014 ◽  
Vol 40 (02) ◽  
pp. 172-177 ◽  
Author(s):  
Rohan Willis ◽  
Gabriella Lakos ◽  
E. Harris
Keyword(s):  
Clinical Significance ◽  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Task Force ◽  
Anticardiolipin Antibodies ◽  
Antiphospholipid Antibody ◽  
Antibody Testing ◽  
Historical Perspectives ◽  
The Past ◽  
Glycoprotein I

The measurement of antiphospholipid antibodies (aPL) has been an important aspect of antiphospholipid syndrome (APS) characterization since the disease was first described in the 1980s. Despite significant efforts geared toward the standardization of immunoassays that measure anticardiolipin antibodies and anti-β2-glycoprotein I spanning three decades, there are still reports of significant interassay and interlaboratory variation in the results of these assays. At the recent 13th International Congress on Antiphospholipid Antibodies (APLA 2010, April 13–16, 2010, Galveston, TX), a task force composed of internationally recognized experts in the field of APS was formed to address these issues. In this review, we discuss approaches that have been used in the past to achieve harmonization among aPL immunoassays as well as the ongoing efforts of the APLA task force. Our review also highlights the importance of cutoff determination in aPL assays and the clinical significance of positive aPL results of varying magnitudes.

Antiphospholipid Antibody Syndrome

2011 ◽  
Vol 135 (9) ◽  
pp. 1092-1096 ◽  
Author(s):  
Nikhil A Sangle ◽  
Kristi J Smock
Keyword(s):  
Antiphospholipid Antibodies ◽  
Lupus Anticoagulant ◽  
Protein Complexes ◽  
Anticardiolipin Antibodies ◽  
Clinical Aspects ◽  
Antiphospholipid Antibody ◽  
Antiphospholipid Antibody Syndrome ◽  
Pregnancy Morbidity ◽  
Glycoprotein I ◽  
Laboratory Results

Antiphospholipid antibodies are directed against phospholipid-protein complexes and include lupus anticoagulant, anticardiolipin antibodies, and anti–beta-2 glycoprotein I antibodies. Antiphospholipid antibody syndrome is a common cause of acquired thrombophilia and is characterized by venous or arterial thromboembolism or pregnancy morbidity and the presence of antiphospholipid antibodies. Antibodies should be demonstrable on at least 2 occasions separated by 12 weeks. Heterogeneity of the autoantibodies and absence of gold standard assays makes interpretation of laboratory results a challenge for both laboratorians and clinicians. This review discusses the key laboratory and clinical aspects of antiphospholipid antibody syndrome. Particular focus is given to lupus anticoagulant detection, in view of recently updated laboratory guidelines.

Current concepts on the pathogenesis of the antiphospholipid syndrome

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 422-430 ◽  
Author(s):  
Bill Giannakopoulos ◽  
Freda Passam ◽  
Soheila Rahgozar ◽  
Steven A. Krilis
Keyword(s):  
Experimental Evidence ◽  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Clinical Manifestations ◽  
Fetal Loss ◽  
Peripheral Tolerance ◽  
The Core ◽  
Glycoprotein I ◽  
Antigenic Targets ◽  
Acquired Thrombophilia

Abstract The antiphospholipid syndrome (APS) is an important cause of acquired thrombophilia. It is characterized by the core clinical manifestations of thrombosis, either venous or arterial, and in women it can also be associated with recurrent fetal loss. The detection of persistently elevated levels of antiphospholipid antibodies (aPL Abs) is a requisite laboratory feature for the diagnosis to be made. The dominant antigenic targets in APS are beta 2-glycoprotein I (β2-GPI) and prothrombin. There is an accumulating body of experimental evidence that suggests that specific subgroups of aPL Abs may directly contribute to disease pathogenesis. This review critically examines the experimental evidence underlying the various propositions made to explain how these antibodies may predispose to disease in humans. Furthermore, it also examines the evidence relating to the immunologic mechanisms that may contribute to the breakage of peripheral tolerance in this disorder. Delineating the strengths and limitations of the experimental evidence accumulated thus far will hopefully stimulate further experimentation toward achieving the ultimate goal of precisely defining the dominant pathogenic mechanisms operational in APS. This may pave the way for the development of improved therapies.

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