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.

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.

scholarly journals Current Promising Biomarkers and Methods in the Diagnostics of Antiphospholipid Syndrome: A Review

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 166
Author(s):  
Pavla Bradacova ◽  
Ludek Slavik ◽  
Jana Ulehlova ◽  
Adela Skoumalova ◽  
Jana Ullrychova ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Lupus Anticoagulant ◽  
Wide Spectrum ◽  
Clinical Manifestations ◽  
Annexin V ◽  
Protein S ◽  
Point Of View ◽  
Laboratory Diagnostics ◽  
Glycoprotein I ◽  
Domain I

Antiphospholipid syndrome (APS) is a hypercoagulation condition associated with the incidence of heterogenic antiphospholipid antibodies (aPLs), which non-specifically affect hemostasis processes. APS is clinically manifested by recurrent arterial and venous thromboses and reproduction losses. The aPL antibodies, which may induce clinical manifestations of APS, include criteria antibodies anti-cardiolipin, anti-β2-glycoprotein-I, and lupus anticoagulant, but also non-criteria antibodies, for example anti-β2-glycoprotein-I domain I, anti-phosphatidylserine/prothrombin, anti-annexin V, and many others. APS occurs mostly in patients of younger and middle age, most frequently in females. Laboratory diagnostics of APS are quite difficult, as they include a wide spectrum of examining methods, which are based on various principles of detection and are performed using various laboratory techniques. The objective of the review is to describe the current state of potentially examined biomarkers and methods in APS diagnostics. The aforementioned biomarkers are lupus anticoagulant, anti-β2-glycoprotein-I, anti-cardiolipin, anti-β2-glycoprotein-I domain I, anti-phosphatidylserine/prothrombin, anti-β2-glycoprotein-I IgA, anti-cardiolipin IgA, anti-annexin V and II, anti-prothrombin, anti-cardiolipin/vimentin, anti-protein S/protein C, and antibodies against phospholipid antigens for whose diagnostics we may use some of the methods established for a long time and some of the modern methods—the coagulation method for the determination of lupus anticoagulant (LA), enzyme-linked imunosorbent assay (ELISA), chemiluminescence analysis (CLIA), multiplex fluorescence flow immunoassay (MFFIA), fluorescence enzyme immunoassay (EliA), line immunoassay (LIA), multiline dot assay (MLDA), and thin-layer chromatography (TLC). Conclusion: Antibodies against phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phosphatidylinositol, cardiolipin/vimentin complex, and annexin V are currently the most studied new markers. However, these assays have not been standardized until now, both from the laboratory and clinical point of view. In this review we summarize the evidence of the most studied aPL markers and their potential clinical significance in seronegative APS (SN-APS).

Atherosclerosis and the antiphospholipid syndrome: A link unravelled?

Lupus ◽  
1998 ◽  
Vol 7 (2_suppl) ◽  
pp. 140-143 ◽  
Author(s):  
Y Shoenfeld ◽  
D Harats ◽  
J George
Keyword(s):  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Dominant Role ◽  
Clinical Manifestations ◽  
Humoral Response ◽  
Arterial System ◽  
Glycoprotein I ◽  
Shock Proteins ◽  
Modified Forms ◽  
Progression Of Atherosclerosis

Atherosclerosis is a multifactorial disease that involves the arterial system. Recent data suggest that immune and autoimmune factors play a dominant role in mediating the progression of atherosclerosis. Among these factors, humoral response to modified forms of LDL and heat-shock proteins has been shown to be influential. The antiphospholipid syndrome (APS) entails clinical manifestations that result from a hypercoagulable state. Antibodies to phospholipids and to β2-glycoprotein I have been suggested to confer the tendency to thrombosis. In a set of recent studies, we have been able to show that generation of antiphospholipid antibodies in mice is associated with enhanced atherosclerosis. These findings imply that APS and atherosclerosis may share a common etiologic background, which may have direct implications for the management of both conditions.

Antiphospholipid Antibodies with LAC Activity That Bind beta2-Glycoprotein I Cause Increased Resistance Against Activated Protein C.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3622-3622
Author(s):  
Bas de Laat ◽  
Sander B. Meijer ◽  
Carel M. Eckmann ◽  
M. van Schagen ◽  
Koen Mertens ◽  
...  
Keyword(s):  
Antiphospholipid Antibodies ◽  
Protein C ◽  
Activated Protein C ◽  
Plasma Samples ◽  
Surface Plasmon Resonance Analysis ◽  
Resonance Analysis ◽  
Igm Antibodies ◽  
Apc Resistance ◽  
Glycoprotein I ◽  
Direct Binding

Abstract Background: The antiphospholipid syndrome is characterized by the occurrence of vascular thrombosis combined with the presence of antiphospholipid antibodies (aPL) in plasma of patients. Recently it was published that aPL with lupus anticoagulant activity (LAC), caused by anti-beta2-glycoprotein I (beta2GPI) antibodies, highly correlate with a history of thrombosis. aPL-related resistance against activated protein C (APC) is one of the proposed mechanism responsible for thrombosis. We investigated a possible correlation between a beta2GPI-dependent LAC and increased APC-resistance in a population of 22 plasma samples with LAC activity. Methods: Twenty-two LAC-positive plasma samples were tested for beta2GPI-dependence (titration of cardiolipin into an APTT-based assay), increased APC-resistance, anti-beta2GPI IgG/IgM antibodies, anti-prothrombin IgG/IgM antibodies and anti-protein C IgG/IgM antibodies. In addition, a monoclonal anti-beta2GPI antibody and patient-purified IgG (both with LAC activity) were diluted in plasma with/without protein C and tested for occurrence of a beta2GPI-dependent LAC (normalization of clotting time by the addition of cardiolipin). To study aPL-induced APC-resistance in more detail, surface plasmon resonance analysis was used to investigate binding between APC and beta2GPI in the presence/absence of a mouse-derived monoclonal anti-beta2GPI antibody. Results: Eleven plasma samples that displayed a beta2GPI-dependent LAC also showed increased APC resistance. In contrast, only 1 of the 11 plasma samples with a beta2GPI-independent LAC displayed increased APC-resistance. None of the other serological parameters (antibodies against beta2-glycoprotein I, prothrombin or protein C) displayed the same association with increased APC resistance as a beta2-glycoprotein I dependent LAC. Furthermore, we found a linear correlation between the potency of a beta2GPI-dependent LAC and the level of APC-resistance. When a monoclonal anti-beta2GPI antibody and a patient-purified IgG were tested for a beta2GPI-dependent LAC, both antibodies did not display a beta2GPI-dependent LAC when diluted in protein C deficient plasma. In literature it has been proposed that direct binding of beta2GPI to APC results in a decreased activity of APC. By using surface plasmon resonance analysis, we found that beta2GPI displayed a higher affinity for coated APC in the presence of the monoclonal anti-beta2GPI antibody (4 nM) compared to beta2GPI alone (400 nM). Conclusion: The results of this study indicate that by adding cardiolipin into an APTT-based clotting assay, one can detect beta2GPI-dependent LAC based on increased resistance against APC. Increased resistance against activated protein C might result from direct binding of beta2GPI to activated protein C. In conclusion, our observations indicate a direct correlation between a major clinical symptom of APS (thrombosis), a diagnostic assay (beta2GPI-dependent LAC) and a potential mechanism responsible for thrombosis in the antiphospholipid syndrome (increased APC-resistance).

scholarly journals Isolated IgA Anti-β2 Glycoprotein I Antibodies in Patients with Clinical Criteria for Antiphospholipid Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Raquel Ruiz-García ◽  
Manuel Serrano ◽  
José Ángel Martínez-Flores ◽  
Sergio Mora ◽  
Luis Morillas ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Arterial Thrombosis ◽  
Clinical Manifestations ◽  
Diagnostic Systems ◽  
Clinical Criteria ◽  
Glycoprotein I ◽  
Standardized Diagnostic ◽  
Disease Present

Seronegative antiphospholipid syndrome (SNAPS) is an autoimmune disease present in patients with clinical manifestations highly suggestive of Antiphospholipid Syndrome (APS) but with persistently negative consensus antiphospholipid antibodies (a-PL). IgA anti-β2 Glycoprotein I (aB2-GPI) antibodies are associated with APS. However, they are not currently considered to be laboratory criteria due to the heterogeneity of published works and the use of poor standardized diagnostic systems. We have aimed to assess aPL antibodies in a group of patients with clinical manifestations of APS (C-APS) to evaluate the importance of the presence of IgA aB2GPI antibodies in APS and its relation with other aPL antibodies. Only 14% of patients with C-APS were positive for any consensus antibody, whereas the presence of isolated IgA aB2GPI antibodies was found in 22% of C-APS patients. In patients with arterial thrombosis IgA aB2GPI, antibodies were the only aPL antibodies present. Serologic profile in primary APS (PAPS) is different from systemic autoimmune disorders associated APS (SAD-APS). IgA aB2GPI antibodies are more prevalent in PAPS and IgG aB2GPI antibodies are predominant in SAD-APS. The analysis of IgA aB2GPI antibodies in patients with clinical manifestations of PAPS might avoid underdiagnosed patients and provide a better diagnosis in patients with SAD-APS. Laboratory consensus criteria might consider including analysis of IgA aB2GPI for APS diagnosis.

Platelet-Endothelial Interactions: Sepsis, HIT, and Antiphospholipid Syndrome

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 497-519 ◽  
Author(s):  
Theodore E. Warkentin ◽  
William C. Aird ◽  
Jacob H. Rand
Keyword(s):  
Antiphospholipid Syndrome ◽  
Protein C ◽  
Clinical Laboratory ◽  
Activated Protein C ◽  
Platelet Factor ◽  
Glycoprotein I ◽  
Acquired Abnormalities ◽  
Risk For Thrombosis ◽  
Condition Diagnosis

Abstract Acquired abnormalities in platelets, endothelium, and their interaction occur in sepsis, immune heparin-induced thrombocytopenia (HIT), and the antiphospholipid syndrome. Although of distinct pathogeneses, these three disorders have several clinical features in common, including thrombocytopenia and the potential for life- and limb-threatening thrombotic events, ranging from microvascular (sepsis > antiphospholipid > HIT) to macrovascular (HIT > antiphospholipid > sepsis) thrombosis, both venous and arterial. In Section I, Dr. William Aird reviews basic aspects of endothelial-platelet interactions as a springboard to considering the common problem of thrombocytopenia (and its mechanism) in sepsis. The relationship between thrombocytopenia and other aspects of the host response in sepsis, including activation of coagulation/inflammation pathways and the development of organ dysfunction, is discussed. Practical issues of platelet count triggers and targeted use of activated protein C concentrates are reviewed. In Section II, Dr. Theodore Warkentin describes HIT as a clinicopathologic syndrome, i.e., the diagnosis should be based on the concurrence of an appropriate clinical picture together with detection of platelet-activating and/or platelet factor 4-dependent antibodies (usually in high levels). HIT is a profound prothrombotic state (odds ratio for thrombosis, 20–40), and the risk for thrombosis persists for a time even when heparin is stopped. Thus, pharmacologic control of thrombin (or its generation), and postponing oral anticoagulation pending substantial resolution of thrombocytopenia, is appropriate. Indeed, coumarin-associated protein C depletion during uncontrolled thrombin generation of HIT can explain limb loss (coumarin-associated venous limb gangrene) or skin necrosis syndromes in some patients. In Section III, Dr. Jacob Rand presents the most recent concepts on the mechanisms of thrombosis in the antiphospholipid syndrome, and focuses on the role of β2-glycoprotein I as a major antigenic target in this condition. Diagnosis of the syndrome is often complicated because the clinical laboratory tests to identify this condition have been empirically derived. Dr. Rand addresses the practical aspects of current testing for the syndrome and current recommendations for treating patients with thrombosis and with spontaneous pregnancy losses.

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.

β2-Glycoprotein I Modulates the Anticoagulant Activity of Activated Protein C on the Phospholipid Surface

1996 ◽  
Vol 75 (01) ◽  
pp. 049-055 ◽  
Author(s):  
Tatsuyuki Mori ◽  
Hiroyuki Takeya ◽  
Junji Nishioka ◽  
Esteban C Gabazza ◽  
Koji Suzuki
Keyword(s):  
Protein C ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Protein S ◽  
Inhibitory Effect ◽  
Factor V ◽  
Clotting Time ◽  
Factor Va ◽  
Glycoprotein I ◽  
Prothrombinase Activity

SummaryThe objective of this study was to determine whether (β2-glycoprotein I (β2GPI) has procoagulant activity by inhibiting the anticoagulant activity of activated protein C (APC). β2GPI inhibited significantly the APC-catalyzed inactivation of factor Va in an assay using factor V-deficient plasma and physiological levels of protein S and factor Va. This inhibitory effect was diminished by the addition of increasing concentrations of phospholipids, suggesting that β2GPI competitively inhibits the binding of APC to the phospholipid surface. β2GPI inhibited weakly factor Va- and phospholipid-dependent prothrombinase activity at concentrations similar to those to inhibit APC activity. The depletion of β2GPI from plasma led to only a slight shortening of the diluted Russell’s viper venom-dependent clotting time, but to a strong and significant potentiation of the anticoagulant activity of APC. These results suggest that under certain physiological conditions β2GPI has procoagulant property by inhibiting the phospholipid-dependent APC anticoagulant activity.

β2-glycoprotein I Binding to Platelet Microparticle Membrane Specifically Reduces Immunoreactivity of Glycoproteins IIb/IIIa

2001 ◽  
Vol 85 (02) ◽  
pp. 314-319 ◽  
Author(s):  
Laurent Vallar ◽  
Véronique Regnault ◽  
Véronique Latger-Cannard ◽  
Thomas Lecompte
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Annexin V ◽  
Human Platelets ◽  
Resonance Spectroscopy ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Anionic Phospholipids ◽  
Glycoprotein I ◽  
Specific Influence

SummaryWe have investigated β2-glycoprotein I (β2GPI) binding to platelet-derived microparticles (PMP) and its effect on GPIIb/IIIa. PMP were isolated from washed human platelets after stimulation with A23187, and analyzed by surface plasmon resonance spectroscopy. β2GPI as well as activated protein C (APC) or annexin V bound to PMP-coated sensorchips, demonstrating exposure of anionic phospholipids on immobilized PMP. β2GPI binding was impaired by calcium and occurred in a concentration-dependent manner with apparent kon = 2.6104 M-1.s-1 and koff = 4.410-3 s-1, corresponding to a KD value of 1.710-7 M. When analyzed by flow cytometry, the binding of certain mAbs specific for GPIIb and/or GPIIIa was reduced in the presence of β2GPI but not of APC or annexin V, whereas the binding of anti-GPIb or anti-P-selectin mAbs, or of soluble fibrinogen remained unchanged. These results suggest a broad but specific influence of β2GPI on GPIIb/IIIa immunoreactivity, and indicate that β2GPI may act as a modulator of GPIIb/IIIa-dependent functions of PMP.

Protein C and other Cofactors Involved in the Binding of Antiphospholipid Antibodies: Relation to the Pathogenesis of Thrombosis

Lupus ◽  
1996 ◽  
Vol 5 (5) ◽  
pp. 488-493 ◽  
Author(s):  
PG de Groot ◽  
DA Horbach ◽  
RHWM Derksen
Keyword(s):  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Protein C ◽  
Protein S ◽  
Complex Iii ◽  
Complex Iv ◽  
C Complex

In this review we will discuss the possible interference of antiphospholipid antibodies with the protein C system. Antiphospholipid antibodies can interfere with the protein C system in different ways: (i) via inhibiting the formation of thrombin; (ii) via interference with the activation of protein C by the thrombomodulin-thrombin complex; (iii) via inhibition of the assembly of the protein C complex; (iv) via inhibition of the activity of protein C, directly or via its cofactor protein S, and (v) via antibodies directed against the substrates of APC, factors Va and VIIIa, thereby protecting them for inactivation. The experimental and theoretical indications that one of these mechanisms will explain the pathogenesis of the antiphospholipid syndrome is critically examined.

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