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Hughes Syndrome: Antiphospholipid Syndrome

M. A. Khamashta (eds.)

Second Edition.

Resumen/Descripción – provisto por la editorial

No disponible.

Palabras clave – provistas por la editorial

Internal Medicine; Rheumatology; Cardiology; Neurology; Obstetrics/Perinatology; Immunology

Disponibilidad
Institución detectada Año de publicación Navegá Descargá Solicitá
No detectada 2006 SpringerLink

Información

Tipo de recurso:

libros

ISBN impreso

978-1-85233-873-2

ISBN electrónico

978-1-84628-009-2

Editor responsable

Springer Nature

País de edición

Reino Unido

Fecha de publicación

Información sobre derechos de publicación

© Springer-Verlag London Limited 2006

Tabla de contenidos

Antiphospholipid Antibody-Induced Pregnancy Loss and Thrombosis

Guillermina Girardi; Jane E. Salmon

Increased TF expression may contribute to thrombosis in patients with APS. This effect might ultimately depend on antibody engagement of PL binding proteins on the monocyte and the EC surface, leading to signal transduction and altered cell activity. Understanding the intracellular mechanism(s) of aPL mediated TF activation may help to establish new therapeutic approaches to revert the prothrombotic state observed in APS patients.

Section 3 - Basic Aspects | Pp. 395-402

Mechanism of Thrombosis in Antiphospholipid Syndrome: Binding to Platelets

Joan-Carles Reverter; Dolors Tàssies

Platelets are a potential target for circulating aPL that may cause antibody mediated thrombosis. In vitro studies performed in the aggregometer or in flowing conditions and the evaluation of platelet activation markers in vitro and in vivo in patients with the APS demonstrated the ability of aPL to interact with platelets and promote their function. The most reliable explanation for the prothrombotic action of aPL in platelets includes, first, previous platelet activation and the binding of them to platelet membrane phospholipid bound proteins, mainly β-glycoprotein I. Then, in a second step, aPL may act activating platelets, via FcγRIIA or complement C5-9 formation. However, several points of this suggested mechanism of action of aPL on thrombus formation are not clearly established and further studies on the interaction between platelet and aPL are needed.

Section 3 - Basic Aspects | Pp. 403-414

Interaction of Antiphospholipid Antibodies with Endothelial Cells

Pier Luigi Meroni; Elena Raschi; Cinzia Testoni; Arianna Parisio; Maria Gerosa; Maria Orietta Borghi

It has been demonstrated that the interaction between aPL and anionic phospholipids is mediated by plasma proteins, one of them identified as prothrombin. Antiprothrombin antibodies are frequently found in patients with aPL but the immunological characteristics and mechanisms of action are not completely understood. As thrombotic mechanisms are multifactorial and complex, further investigations are required to define the role of aPT in the pathogenesis of thrombosis. Knowledge of the behavior of specific aPL would aid in defining specific thrombogenic pathways and improved management of patients with APS. However, in order to accomplish this, standardization of the methods for the detection of these antibodies is mandatory.

Section 3 - Basic Aspects | Pp. 415-426

The Influence of Antiphospholipid Antibodies on the Protein C Pathway

Philip G. de Groot; Ronald H. W. M. Derksen

aPL are a heterogeneous population of antibodies directed against different phospholipid binding proteins. It is not clear which mechanism is responsible for the thrombogenic activity of all aPL. There is, however, an attractive hypothesis that suggests that aPL selectively inhibit one of the dominant natural anticoagulant pathways, the protein C pathway. Most attention has been focused on the induction of an acquired APC resistance, probably due to interference of the antibodies with binding of protein C or S to negatively charged phospholipids It is questionable whether in aPL-related thrombosis, an acquired APC resistance is responsible for both arterial and venous events. Although exogenous APC could prevent arterial thrombosis in a number of animal models, deficiencies in the protein C axis are correlated with venous thrombosis and not with arterial thrombosis. A safe conclusion is that interference of the protein C pathway can explain a large part of the venous complications in patients with APS. The observations that suggest a correlation between antibodies against EPCR and pregnancy morbidity warrant further studies.

Section 3 - Basic Aspects | Pp. 427-438

Contribution of Tissue Factor to the Pathogenesis of Thrombosis in Patients with Antiphospholipid Syndrome

Chary López-Pedrera; Francisco Velasco; Maria J. Cuadrado

Increased TF expression may contribute to thrombosis in patients with APS. This effect might ultimately depend on antibody engagement of PL binding proteins on the monocyte and the EC surface, leading to signal transduction and altered cell activity. Understanding the intracellular mechanism(s) of aPL mediated TF activation may help to establish new therapeutic approaches to revert the prothrombotic state observed in APS patients.

Section 3 - Basic Aspects | Pp. 439-445

Annexins in Antiphospholipid Syndrome

Jacob H. Rand; Xiao-Xuan Wu

In conclusion, annexin A5 is a potent anticoagulant protein that forms an antithrombotic shield over anionic phospholipids containing bilayers. Autoantibodies may interfere with this shielding function via high affinity antibodies that recognize phospholipid binding proteins that are capable of interfering with the assembly of the annexin A5 shield on phospholipid surfaces or via direct recognition of annexin A5 functional epitopes by autoantibodies. Antibody mediated interference with the integrity of the two-dimensional annexin A5 crystal shield may be a mechanism for thrombosis and for pregnancy complications, including recurrent spontaneous pregnancy losses, in APS.

Section 3 - Basic Aspects | Pp. 446-456

Plasminogen Activation, Fibrinolysis, and Cell Proteolytic Activity in Antiphospholipid Syndrome

Eduardo Anglés-Cano

Our observations, and those from others, give further support to our hypothesis that “autoimmune aPL” may be generated by immunization with products from bacteria or viruses after incidental exposure or infection. We also were able to generate APS-like syndrome in a strain of mice susceptible to autoimmunity, indicating that other factors are likely to be involved, such as genetic predisposition. Furthermore, not all aPL generated were pathogenic. Based on the clinical experience and on the numerous reports indicating presence of aPL in large number of infectious diseases, it may be expected that not all aPL produced during infection will be pathogenic. A limited number aPL induced by certain viral/bacterial products would be pathogenic in certain genetically predisposed individuals. Further studies to identify the agents responsible for induction the pathogenic aPL are needed. Identification of those bacterial and/or viral agents may help finding strategies for the prevention of production of aPL “pathogenic” antibodies. Alternatively, free peptides may be used to induce tolerance against aPL production or to abrogate their pathogenic effects.

Drugs such as procainamide and phenothiazines can also induce aPL. The prevalence and pathogenicity of drug-induced aPL is generally low and has been discussed in this chapter.

Section 3 - Basic Aspects | Pp. 457-469

Lessons from Sequence Analysis of Monoclonal Antiphospholipid Antibodies

Ian P. Giles; David A. Isenberg; Anisur Rahman

From the published sequences of monoclonal aPL there is no evidence that particular human Ig V region genes are used preferentially to encode aPL. Somatic mutations which are antigen driven confer high specificity binding in IgG aPL but do not play a role in the formation of similar binding characteristics in the more specific IgM aPL. We have identified a common factor between these 2 groups of aPL, which is the presence of Arg, Asn, and Lys residues in CDRs and contact sites. These are germline encoded in the more specific IgM aPL but often arise due to somatic mutations in the IgG aPL. Our hypothesis is that the Arg, Asn, and Lys residues increase the affinity of binding via electrostatic interactions and hydrogen bonds with negatively charged epitopes upon PL and domain I of β-GPI. We have demonstrated the relative importance of certain surface exposed Arg residues at critical positions within the light chain CDR1 and heavy chain CDR3 of different human monoclonal aPL in conferring the ability to bind CL. It is now important to test the effects of sequence changes involving these amino acids on pathogenic functions of these aPL. Such tests may help to define the nature of interactions between aPL, PL, and β-GPI. This may eventually help in the development of drugs to interfere with those interactions, and thereby improve the treatment of APS.

Section 3 - Basic Aspects | Pp. 470-491

Apoptosis and Antiphospholipid Antibodies

Keith B. Elkon; Neelufar Mozaffarian; Natalia Tishkevich

The first aCL test was developed in 1983 and subsequently standardized. Although in the last 6 to 7 years new and more specific tests have become available, the aCL ELISA and the LA tests are still the first choice to be used in diagnosis of APS. While there is now doubt that the aCL test is useful in the diagnosis of APS, limitations of the assay have caused uncertainty and misinterpretation of the value of the test. Utilization of validated ELISA kits with well-tested calibrators and an in-house standard may enable more reproducible measurements. Reporting results semi-quantitatively preserves the clinical use of the test without the misinterpretation of a quantitative result that may lack precision, The development of newer tests, such as the β-GPI ELISA and the APhL® ELISA Kit utilizing the phospholipid mixture, gives promise to a more specific and reliable diagnosis of APS while retaining good sensitivity. Other tests such as ELISA for prothrombin antibodies and annexin V antibodies are still under development and will require standardization and extensive evaluation.

Section 3 - Basic Aspects | Pp. 492-500

Accelerated Atherogenesis and Antiphospholipid Antibodies

Eiji Matsuura; Kazuko Kobayashi; Luis R. Lopez

Diverse conditions associated with thrombotic lesions either in large vessels or in the microvasculature may be part of the APS clinical spectrum. Besides the classic clinical manifestations, including arterial and venous thrombosis or recurrent fetal loss, a number of other clinical conditions characterized as microangiopathic syndromes have been associated with APS. These syndromes can affect several organs including skin, brain, heart, and kidneys. Osteonecrosis may be another distinct clinical feature of APS associated with arterial or venous microthrombosis. Clinicians should be aware of the possible association between APS and osteonecrosis because early diagnosis may lead to early and proper management of this disabling disease. Patients with persistent symptoms originating from sites most susceptible to osteonecrosis should undergo MRI evaluation. A systematic screening for aPL in all cases with diagnosed osteonecrosis in the absence of precipitating factors should also be considered.

Section 3 - Basic Aspects | Pp. 501-520