RESUMEN
BACKGROUND: Chorea is recognized as one of the neurologic manifestations of systemic lupus erythematosus (SLE). Most reports show an association between chorea and antiphospholipid (aPL) antibodies in SLE patients. OBJECTIVES: The objective of this study was to describe the association of aPL antibodies with lupus chorea and its possible role in the pathogenesis of chorea. METHODS: We made a retrospective review of all cases of lupus chorea between 1989 and 2007 in a tertiary care center in Mexico City. RESULTS: We found 7 episodes of chorea in 5 patients with SLE. In 2 patients (3 episodes), chorea was associated with cerebral ischemia; one of these cases had positive anticardiolipin (aCL) immunoglobulin G (IgG) antibodies, whereas the other was diagnosed as having vascular lipohyalinosis as the probable cause of cerebral ischemia. In 3 patients (4 episodes), an immune-mediated mechanism was suspected; these cases had negative aPL at the onset of chorea, but IgM aCL antibodies became positive later. CONCLUSIONS: In most episodes, chorea seems to be immunologically mediated and was associated with a later appearance of IgM aCL antibodies. Chorea in patients with lupus may also be caused by cerebral ischemia, and in some cases, it may be associated with IgG aCL antibodies.
Asunto(s)
Corea/etiología , Corea/fisiopatología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/fisiopatología , Adulto , Anticuerpos Anticardiolipina/fisiología , Anticuerpos Antifosfolípidos/fisiología , Barrera Hematoencefálica/fisiopatología , Isquemia Encefálica/complicaciones , Isquemia Encefálica/fisiopatología , Corea/inmunología , Femenino , Humanos , Inmunoglobulina G/fisiología , Inmunoglobulina M/fisiología , Lupus Eritematoso Sistémico/inmunología , Estudios RetrospectivosRESUMEN
The antiphospholipid syndrome is characterized by the presence of arterial or venous thrombosis or recurrent miscarriages in a patient with positive laboratory tests for antiphospholipid antibodies (anticardiolipin antibodies and/or lupus anticoagulant and/or anti-beta2-glycoprotein I). Despite the strong association between antiphospholipid antibodies and thrombosis and obstetric morbidity, their pathogenic role in the development of these clinical features has not been fully elucidated. However, the knowledge of new pathogenic mechanisms might identify novel therapeutic targets and therefore may improve the management of these patients.
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Anticuerpos Monoclonales de Origen Murino/farmacología , Anticoagulantes/uso terapéutico , Síndrome Antifosfolípido/tratamiento farmacológico , Factores Inmunológicos/farmacología , Aborto Habitual/inmunología , Aborto Habitual/patología , Anticuerpos Anticardiolipina/fisiología , Anticuerpos Antifosfolípidos/inmunología , Síndrome Antifosfolípido/inmunología , Femenino , Humanos , Inhibidor de Coagulación del Lupus/inmunología , Inhibidor de Coagulación del Lupus/fisiología , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/inmunología , Rituximab , Trombosis/inmunología , Trombosis/patología , Trombosis de la Vena/inmunología , beta 2 Glicoproteína I/inmunología , beta 2 Glicoproteína I/fisiologíaRESUMEN
OBJECTIVES: This study examined the anticardiolipin antibodies in post-SARS (severe acute respiratory syndrome) osteonecrosis patients to investigate the etiology of post-SARS osteonecrosis, and to eventually provide valuable information for the early diagnosis of nontraumatic osteonecrosis and for the susceptible population screening. METHODS: This study recruited 62 post-SARS osteonecrosis patients and 52 age- and gender-matched healthy controls. Fasting blood samples were collected from all the subjects through cubital veins. Immunoglobulins A, G and M (IgA, G and M) types of anticardiolipin antibodies were examined by enzyme-linked immunosorbent assay. The routine examinations of prothrombin time, thrombin time, prothrombin activity, and international normalized ratio were also performed. RESULTS: There were 21 of 62 post-SARS osteonecrosis patients (33.9%) who showed at least one type of anticardiolipin antibodies. The titers of specific IgA, IgG, and IgM were 11.33 +/- 11.209 APL, 5.127 +/- 5.927 GPL, and 17.821 +/- 10.606 MPL, respectively. There were only 4 of 52 subjects in the control group (7.7%) who showed positive anticardiolipin antibody with titers of IgA at 10.702 +/- 3.126 APL, IgG at 5.184 +/- 4.780 GPL, and IgM at 14.684 +/- 5.516 MPL. There were significant differences between the 2 groups confirmed by t-Test and chi(2) test (P < 0.05), while no significant differences were observed in prothrombin time, thrombin time, prothrombin activity, and international normalized ratio results between the 2 groups. CONCLUSIONS: The incidences of anticardiolipin antibodies were increased in the post-SARS osteonecrosis patients and anticardiolipin antibodies may play a role in the pathogenesis of post-SARS osteonecrosis.
Asunto(s)
Anticuerpos Anticardiolipina/sangre , Osteonecrosis/inmunología , Síndrome Respiratorio Agudo Grave/inmunología , Adulto , Anticuerpos Anticardiolipina/fisiología , Pruebas de Coagulación Sanguínea , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteonecrosis/virología , Adulto JovenRESUMEN
OBJECTIVE: To investigate the expression of protease-activated receptors (PARs), their potential regulation by anticardiolipin antibodies (aCL), and their association with the expression of other molecules relevant to thrombosis in monocytes obtained from 62 patients with primary antiphospholipid syndrome (APS). METHODS: Monocytes were isolated from peripheral blood mononuclear cells by magnetic depletion of nonmonocytes. Expression of tissue factor (TF) and PARs 1-4 genes was measured by quantitative real-time reverse transcription-polymerase chain reaction. Cell surface TF and PARs 1-4 expression was analyzed by flow cytometry. For in vitro studies, purified normal monocytes were incubated with purified APS patient IgG, normal human serum IgG, or lipopolysaccharide, in the presence or absence of specific monoclonal antibodies anti-PAR-1 (ATAP2) or anti-PAR-2 (SAM11) to test the effect of blocking the active site of PAR-1 or PAR-2. RESULTS: Analysis of both mRNA and protein for the 4 PARs revealed significantly increased expression of PAR-2 as compared with the control groups. PAR-1 was significantly overexpressed in APS patients with thrombosis and in the control patients with thrombosis but without APS. PAR-3 expression was not significantly altered. PAR-4 expression was absent in all groups analyzed. In addition, we demonstrated a correlation between the levels of PAR-2 and the titers of IgG aCL, as well as parallel behavior of TF and PAR-2 expression. In vitro, IgG from APS patients significantly increased monocyte expression of PAR-1 and PAR-2. Inhibition studies suggested that there was direct cross-talk between TF and PAR-2, such that inhibition of PAR-2 prevented the aCL-induced expression of TF. CONCLUSION: These results provide the first demonstration of increased expression of PARs in monocytes from patients with APS. Thus, PAR antagonists might have therapeutic potential as antithrombotic agents in APS.
Asunto(s)
Síndrome Antifosfolípido/sangre , Monocitos/química , Receptores Proteinasa-Activados/sangre , Adulto , Anticuerpos Anticardiolipina/fisiología , Anticuerpos Monoclonales/inmunología , Síndrome Antifosfolípido/complicaciones , Femenino , Citometría de Flujo , Humanos , Inmunoglobulina G/aislamiento & purificación , Masculino , Persona de Mediana Edad , ARN/análisis , Receptor Cross-Talk/fisiología , Receptores Proteinasa-Activados/genética , Receptores Proteinasa-Activados/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tromboplastina/análisis , Trombosis/etiologíaRESUMEN
Introdução: Nefrite é uma manifestação freqüente no lúpus eritematoso sistêmico (LES), tendo uma prevalência de 40 a 75%. Embora esteja associada com a ocorrência de anticorpo anti-DNA, outros autoanticorpos podem estar ligados ao seu aparecimento taiscomo o fator reumatóide (FR) e os anticorpos antifospholípides (aPl).Objetivos: verificar a prevalência de nefrite lúpica local e sua associação com o a presença do FR e aPls. Métodos: Revisaram-se 187 prontuários depacientes com LES para presença de nefrite, FR e aPl . Resultados: Encontrou-se uma prevalência de 35,3% de glomerulonefrite. Houve correlação negativa entre nefrite e FR (p=0.001). Não se encontrou associação entre aparecimento de aPl e nefrite, já queo número de pacientes com glomerulonefrite que apresentaram esses testes positivos foram de 8 (32%)em 59; 5 (27,7%) em 58 e 6 (46,1%) em 29, respectivamente. Conclusão: Existe uma prevalência de 35% denefrite na população local de LES a qual tem uma associação negativa com aparecimento do FR. Presença de aPls não influíram no aparecimento da nefrite lúpica.
Summary: Nephritis is a frequent manifestation of systemic lupus erythematosus (SLE), with an averageof 40 to 75%. Its associated with the presence of anti-DNA antibodies;other antibodies may also be involved,such as rheumatoid factor (RF), and antiphospholipid antibodies (aPl).Objectives: to verify the prevalence of lupus nephritis and its association with RF and aPl antibodies. Methods: The charts of 187 patients with SLE werereviewed for the presence of nephritis, RF and aPl. Results: A prevalence of 35.3% of nephritis was found. There was a negative correlation betweennephritis and presence of rheumatoid factor (p=0,001). No association between the presence of aPl and nephritis was found, since the number of patients with glomerulonephritis that were positive for these tests wasof 8 (32%) in 59, 5 (27,77%) in 58 and 6 (46,1%) in 29, respectively.Conclusion: There is a prevalence ofglomerulonephritis of 35% in the local SLE population, which has a negative association with rheumatoid factorpresence. Antiphospholipid antibodies arent associated to the occurrence of lupus nephritis.
Asunto(s)
Humanos , Masculino , Femenino , Preescolar , Niño , Adolescente , Adulto , Persona de Mediana Edad , Anticuerpos Anticardiolipina , Lupus Eritematoso Sistémico , Nefritis Lúpica , Factor Reumatoide , Anticuerpos Anticardiolipina/fisiología , Anticuerpos Anticardiolipina/metabolismo , Anticuerpos Anticardiolipina , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/patología , Nefritis Lúpica/complicaciones , Nefritis Lúpica/epidemiología , Nefritis Lúpica/metabolismo , Nefritis Lúpica/patologíaRESUMEN
In the course of Systemic Lupus Erythematosus (SLE), a variety of neuropsychiatric disturbances is reported with a prevalence ranging from 17% to 75%. The diagnosis of these syndromes is difficult and requires a careful psychiatric evaluation. Distinct autoantibodies detectable in serum or cerebrospinal fluid of patients with SLE are associated with the presence of neuropsychiatric disorders. These autoantibodies may have a pathogenic relevance in neuropsychiatric SLE or they may be merely an epiphenomenon. This review describes the various autoantibodies reported to be associated with neuropsychiatric manifestations in SLE and discusses their possible role.
Asunto(s)
Autoanticuerpos/fisiología , Lupus Eritematoso Sistémico/complicaciones , Trastornos Mentales/etiología , Anticuerpos Anticardiolipina/fisiología , Anticuerpos Antinucleares/fisiología , Células Endoteliales/inmunología , Gangliósidos/inmunología , Proteína Ácida Fibrilar de la Glía/inmunología , Humanos , Lupus Eritematoso Sistémico/psicología , Proteínas Asociadas a Microtúbulos/inmunología , Neuronas/inmunología , Monoéster Fosfórico Hidrolasas/inmunología , Receptores de N-Metil-D-Aspartato/inmunología , Ribosomas/inmunologíaRESUMEN
AIM: To assess the role of hyperhomocysteinemia (HHC) in development of vascular complications in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). MATERIAL AND METHODS: A total of 125 participants (24 males and 101 females aged 38 +/- 13 years) were divided into three groups: group 1--SLE patients (n=51); group 2--SLE+APS patients (n=49); group 3--primary APS patients (n=25). The patients had the disease for 14 +/- 11 years. Lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) marked APS serologically. Homocystein (HC) was assayed by high performance liquid chromatography. HHC (HC > 15 mcg/l) was diagnosed in 82 of 125 (66%) patients: in 59% patients of group 1, 67%--of group 2 and 76%--of group 3. There was a relationship between HHC and digital necrosis (DN): 80% of DN patients had HHC while HHC was diagnosed in 57% patients free of DN (chi-square = 4.76, p = 0.03). Development of occlusions in APS was associated with HHC. Elevated levels of HC in blood was registered in 43 of 55 (78%) APS patients with thromboses vs. 9 of 19 (47%) patients with APS free of thromboses (p = 0.03). HHC occurred significantly more frequently in patients with arterial thromboses (in all 14 patients) than in patients with venous thromboses (in 16 of 23--69.6%, p = 0.03) and in the absence of thromboses (in 9 of 19, 47.4%, p = 0.04). HHC was associated with thromboses of cerebral, peripheral arteries (90 vs. 47% in patients without thrombosis, p = 0.005; 84 vs. 47%, p = 0.04, respectively), coronary vessels (79 vs. 47%, p = 0.04). In APS patients having arterial thromboses with duration of postthrombocytic period (PTP), estimated as time from thrombosis to entering the trial, less than 2 months, HC concentration was significantly higher (22.9 +/- 7.0 mcg/l) compared to patients with PTP more than 2 years (16.6 +/- 3.7 mcg/l (p = 0.04). CONCLUSION: More than 50% patients with SLE and APS, irrespective of APS variants, had an elevated HC level in the blood. Correlation between HHC and development of thromboses, primarily arterial, in APS gives grounds for the role of HHC in development of vascular complications in SLE and APS.
Asunto(s)
Síndrome Antifosfolípido/epidemiología , Hiperhomocisteinemia/epidemiología , Hiperhomocisteinemia/fisiopatología , Lupus Eritematoso Sistémico/epidemiología , Adulto , Anticuerpos Anticardiolipina/fisiología , Encéfalo/irrigación sanguínea , Encéfalo/fisiopatología , Circulación Cerebrovascular/fisiología , Endotelio Vascular/fisiología , Femenino , Humanos , Hiperhomocisteinemia/diagnóstico , Trombosis Intracraneal/epidemiología , Trombosis Intracraneal/fisiopatología , Masculino , Índice de Severidad de la EnfermedadRESUMEN
This paper reviews anticardiolipin antibodies and ocular disease. Its aim is to present the latest knowledge regarding the relationship between the two. It focuses mainly on ocular features and treatment, but also describes the epidemiology, main systemic features, immunology, and immunopathology of the antiphospholipid syndrome.
Asunto(s)
Anticuerpos Anticardiolipina/fisiología , Oftalmopatías/inmunología , Síndrome Antifosfolípido/inmunología , HumanosRESUMEN
Anticardiolipin antibodies have been associated as a risk factor of atherosclerosis. The aim of this study was to evaluate the association between anticardiolipin antibodies and intermittent claudication. Forty consecutive patients (33 men, 7 women; age range: 45-84 years, mean 65.5) who were seen in the angiology and vascular surgery department with intermittent claudication were evaluated. Exclusion criteria included prior revascularization, angioplasty, or a history of thrombosis of a lower limb. Forty individuals (23 men, 17 women; age range: 58-82 years, mean 67.1) who attended a support group for senior citizens and who were apparently healthy formed the control group. Anticardiolipin antibodies were evaluated by means of enzyme-linked immunosorbent assay (ELISA) for quantitative measurement of immunoglobulin G (IgG) and IgM antibodies against cardiolipins in serum. IgG levels were considered normal when < 7, borderline from 7 to 10, and elevated at > 10 GPL units/mL; IgM levels were normal when < 4, borderline from 4 to 7, and elevated at > 7 MPL, as recommended by the test manufacturers. Statistical analysis used the relative risk test with a confidence interval of 95%. Twenty-three patients from the study group and 6 individuals from the control group were found to have elevated levels of anticardiolipin antibodies giving a relative risk of 3.833 (ranging from 1.749 to 8.4; p value < 0.0001). In conclusion, patients who have elevated levels of anticardiolipin antibodies present a 3.8 times greater risk of developing intermittent claudication.
Asunto(s)
Anticuerpos Anticardiolipina/fisiología , Claudicación Intermitente/inmunología , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Claudicación Intermitente/sangre , Masculino , Persona de Mediana Edad , Factores de RiesgoAsunto(s)
Síndrome Antifosfolípido/complicaciones , Obstrucción de la Arteria Renal/etiología , Anticuerpos Anticardiolipina/fisiología , Síndrome Antifosfolípido/fisiopatología , Arteriosclerosis/fisiopatología , Endotelinas/fisiología , Humanos , Hipertensión Renovascular/etiología , Obstrucción de la Arteria Renal/fisiopatologíaRESUMEN
Cancer-related thromboembolism is a severe but not uncommon paraneoplastic syndrome in mucinous cancer patients. However, cancer-induced venous gangrene is extremely rare and has never been reported in the English literature. Here, we present a case of lung cancer complicated with venous gangrene of the left foot. An elevated serum anticardiolipin level was detected during hospitalization, but the patient's clinical condition stabilized after heparinization. We suggest that in cancer patients, an elevated serum anticardiolipin antibody level might be a warning sign of an impending thrombotic event and that low-molecular-weight heparin is a sensible choice in treating this kind of cancer-related thromboembolism.
Asunto(s)
Adenocarcinoma/complicaciones , Neoplasias Pulmonares/complicaciones , Trombosis de la Vena/etiología , Anticuerpos Anticardiolipina/fisiología , Femenino , Gangrena , Humanos , Persona de Mediana Edad , Dedos del Pie/patología , Trombosis de la Vena/patologíaRESUMEN
Antiphospholipid antibodies are well recognized as associated with serious clinical complications such as arterial and venous thrombosis and recurrent spontaneous abortion. These complications are collectively called antiphospholipid syndrome(APS). The mechanisms responsible for the thrombosis are unclear. We reported three mechanisms. beta 2-glycoprotein I(beta 2GPI) inhibited activated protein C(APC) activity and, furthermore, APC activity decreased by the addition of monoclonal aCL and beta 2GPI. Monoclonal anticardiolipin antibodies(aCL) seemed to enhance the inhibition of APC procoagulant activity caused by beta 2GPI. Monoclonal aCL in the presence of beta 2GPI also increased the activity of plasminogen activator inhibitor(PAI)-1 in the mixture of tissue-plasminogen activator(t-PA) and PAI-1 by inhibiting the function of beta 2GPI, which increased the remaining t-PA activity in the mixture. The formation of thrombin-antithrombin complexes(TAT) in APS was impaired. The level of TAT in APS did not increase, however the level of prothrombin fragment 1 + 2 (F1 + 2) increased. Therefore, free thrombin present in patients' blood may contribute to thrombosis in APS. These reports indicate that thrombosis in APS may be caused by several thrombogenic factors that stimulate aCL.
Asunto(s)
Anticuerpos Anticardiolipina/fisiología , Síndrome Antifosfolípido , Trombosis/etiología , Síndrome Antifosfolípido/clasificación , Antitrombina III/metabolismo , Fibrinólisis , Glicoproteínas/fisiología , Humanos , Péptido Hidrolasas/metabolismo , Inhibidor 1 de Activador Plasminogénico/fisiología , Proteína C/fisiología , Activador de Tejido Plasminógeno/fisiología , beta 2 Glicoproteína IRESUMEN
Apoptosis (programmed cell death) is accompanied by loss of phospholipid asymmetry, i.e., translocation of aminophospholipids such as phosphatidylserine to the outer leaflet of the plasma membranes, which results in recognition of these cells by macrophages. In the present study, I studied on the involvement of beta 2-glycoprotein I (beta 2-GPI) and anti-beta 2-GPI antibodies in apoptotic lymphocytes. By flowcytometric analysis, I demonstrated that beta 2-GPI could bind to a human T cell line, Jurkat cells, treated with an anti-Fas antibody, CH11. beta 2-GPI-bound cells were detected 2 hr later after anti-Fas treatment and the most cells were bound to beta 2-GPI by 6 hr later. The accumulation of beta 2-GPI-bound cells paralleled with morphological changes and DNA fragmentation of the cells. I also demonstrated that anti-beta 2-GPI antibodies and a beta 2-GPI-dependent anti-cardiolipin antibody, established from a patient with antiphospholipid syndrome, could recognize beta 2-GPI-bound Jurkat cells treated with anti-Fas-antibody. These results imply that beta 2-GPI and anticardiolipin antibody may have a role in the clearance of apoptotic cells from the blood stream.
Asunto(s)
Apoptosis/inmunología , Autoanticuerpos/inmunología , Glicoproteínas/inmunología , Células Jurkat/inmunología , Anticuerpos Anticardiolipina/fisiología , Reacciones Antígeno-Anticuerpo , Síndrome Antifosfolípido/inmunología , Células Cultivadas , Humanos , Linfocitos/citología , Linfocitos/inmunología , beta 2 Glicoproteína IRESUMEN
The presence of antiphospholipid antibodies (aPL) in plasma is an important risk factor for the development of thrombosis. A major breakthrough came in 1990 with the finding that aPL do not react with phospholipids per se, but are directed towards beta2-glycoprotein I, a plasma protein with affinity for anionic phospholipids. Afterwards other plasma proteins with affinity for phospholipids have been identified as possible antigens for aPL. Human beta2-glycoprotein I is a heavily glycosylated plasma protein that has been implicated in the binding of aPL to negatively charged phospholipids. We recently solved the crystal structure of beta2-glycoprotein I. In this review we will discuss what the 3-dimensional structure teaches us about the role of beta2-glycoprotein I in the pathogenesis of the thrombotic complications characteristic of the antiphospholipid syndrome.
Asunto(s)
Anticuerpos Anticardiolipina/fisiología , Enfermedades Cardiovasculares/fisiopatología , Glicoproteínas/fisiología , Inhibidor de Coagulación del Lupus/fisiología , Glicoproteínas de Membrana/fisiología , Animales , Anticuerpos Anticardiolipina/inmunología , Epítopos , Humanos , Inhibidor de Coagulación del Lupus/inmunología , Trombosis/fisiopatología , beta 2 Glicoproteína IRESUMEN
Autoantibodies in systemic lupus erythematosus react with multiple epitopes on highly conserved molecules such as nucleic acids, cytoskeletal proteins, phospholipids, and phospholipid-binding proteins. Analysis of the heavy- and light-chain variable sequences (VH and VL) has shown that a restricted set of V genes gives rise to these autoantibodies. Several monoclonal antibodies were developed from a strain of mouse prone to lupus (F1 male NZW x BXSB). Two of these antibodies, A1.72 and A1.84, reacted directly with cardiolipin and their VH and VL sequences were analyzed. Surprisingly, these two antibodies had identical light-chain variable sequences despite having substantially different heavy-chain variable sequences. This VL sequence, VL 72/84 was 97% identical with the germ-line sequences with only four single nucleotide substitutions. When this VL sequence was shuffled with the VH sequence of other monoclonal antibodies and expressed as single chain variable fragment (scFv) in Escherichia coli, it imparted cardiolipin-binding activity to the hybrids. Furthermore, the VL 72/84 sequence, when expressed alone without any VH sequence, also bound to cardiolipin. The antibodies and their recombinant fragments were immunoaffinity-purified on cardiolipin liposomes. The dissociation constant of the light chain for cardiolipin was similar to the intact molecule (21 +/- 0.01 vs 20 +/- 0.03 nM). These studies demonstrate that the VL sequence alone, in the absence of any other immunoglobulin domains, can mediate cardiolipin binding, raising the possibility that antigen specificity of certain antibodies may exclusively reside in their light-chain sequences.
Asunto(s)
Cardiolipinas/inmunología , Cardiolipinas/metabolismo , Cadenas Ligeras de Inmunoglobulina/metabolismo , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Secuencia de Aminoácidos , Animales , Anticuerpos Anticardiolipina/metabolismo , Anticuerpos Anticardiolipina/fisiología , Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales/fisiología , Afinidad de Anticuerpos , Especificidad de Anticuerpos , Secuencia de Bases , Sitios de Unión de Anticuerpos , Bovinos , Cruzamientos Genéticos , Susceptibilidad a Enfermedades , Cadenas Ligeras de Inmunoglobulina/fisiología , Lupus Eritematoso Sistémico/genética , Masculino , Ratones , Ratones Endogámicos NZB , Datos de Secuencia Molecular , Unión Proteica/inmunologíaRESUMEN
The relationship between thrombotic or thrombocytopenic complications and the existence of anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA) was studied in 146 patients with systemic lupus erythematosus (SLE). The prevalence of arterial thrombosis was obviously higher in patients who had both aCL and LA than in patients with either aCL or LA alone or in those with neither. Since a substantial fraction of the former group of patients with arterial thrombosis also had thrombocytopenia, there is a possibility that aCL and LA might enhance platelet activation and aggregation. To test this hypothesis, we studied the in vitro effects of aCL and LA on the enhancement of platelet activation by flow cytometric analysis using anti-CD62P and anti-CD41 monoclonal antibodies directed against platelet activation-dependent granule-external membrane (PADGEM) protein and platelet glycoprotein IIb (GPIIb). The IgG fraction purified from aCL+.LA+ plasma apparently enhanced platelet activation induced by adenosine diphosphate (ADP) at a low concentration, but IgG fractions from aCL+.LA- or aCL-.LA+ plasma did not cause enhancement of platelet activation. These results suggest that aCL and LA may cooperate to promote platelet activation, and may be involved, at least partially, in the pathogenesis of arterial thrombosis in patients with SLE.
Asunto(s)
Anticuerpos Anticardiolipina/fisiología , Inhibidor de Coagulación del Lupus/fisiología , Lupus Eritematoso Sistémico/complicaciones , Trombocitopenia/etiología , Trombosis/etiología , Adolescente , Adulto , Anciano , Síndrome Antifosfolípido/etiología , Células Cultivadas , Humanos , Lupus Eritematoso Sistémico/inmunología , Persona de Mediana Edad , Activación PlaquetariaRESUMEN
The effect of antiphospholipid antibodies (aPL) on the action of activated protein C (APC) was examined in 32 patients: 19 with lupus anticoagulant (LA), 6 with anticardiolipin antibodies (aCL), and 7 with LA and aCL. Eighteen patients had a ratio of activated partial thromboplastin time (APTT) with APC to APTT without APC (APTT ratio) <2.06 (cut-off level) and no factor V Leiden mutation; these patients showed APC-resistance (APC-R) phenotype. The mean prolongation of APTT after addition of APC in a control group was 45.3 seconds, with a lower limit of 31.4 seconds. Only 3 of the 18 patients with low APTT ratio had a prolongation of <31.4 seconds; they were classified as true APC-R phenotype, whereas the other 15 patients were classified as spurious APC-R. Of the 3 patients with true APC-R, 2 had deep venous thrombosis, 1 with pulmonary embolism, and the third had recurrent abortion. Of the other 15 patients, 2 had had ischemic stroke, 1 had recurrent abortion, and 12 were asymptomatic. Circulating APC level was measured in 14 of the 18 aPL patients with a low APTT ratio; it was lower than the normal lower limit in 4 patients and within the lower limit in 2. Three of the 4 patients with reduced APC levels had a history of thrombosis. We conclude that patients with aPL who show APC-R phenotype due to a low APTT ratio without the factor V Leiden mutation can be classified into two groups: true and spurious APC-R phenotype. Since those with true APC-R phenotype could have greater thrombotic risk, adequate classification of these patients is important. Moreover, aPL can sometimes interfere with the activation of protein C, thus reducing the circulating levels of APC, and this could constitute another thrombotic risk factor.
Asunto(s)
Anticuerpos Antifosfolípidos/fisiología , Proteína C/antagonistas & inhibidores , Aborto Habitual/etiología , Adolescente , Adulto , Anciano , Anticuerpos Anticardiolipina/fisiología , Coagulación Sanguínea , Plaquetas/química , Trastornos Cerebrovasculares/etiología , Niño , Preescolar , Femenino , Humanos , Inhibidor de Coagulación del Lupus/fisiología , Masculino , Persona de Mediana Edad , Tiempo de Tromboplastina Parcial , Fenotipo , Fosfolípidos/sangre , Embarazo , Proteína C/metabolismo , Proteína C/farmacología , Tromboflebitis/etiologíaRESUMEN
The antiphospholipid syndrome (APS) is associated with production of autoantibodies with lupus anticoagulant (LA) activity. These antibodies cause prolongation of in vitro clotting tests by inhibition of the conversion of prothrombin to thrombin in the presence of anionic phospholipid (PL). The extent to which this inhibition reflects antibody binding to, or functional inhibition of, phospholipids alone, prothrombin alone, or a prothrombin-phospholipid complex is pertinent to our understanding of the pathophysiology of this syndrome. Immunoglobulin fractions (IgG) from 18 patients with LA activity were tested for inhibitory activity against prothrombin activation by either factor Xa, in a purified prothrombinase system, or by purified fractions of snake venoms (E. carinatus, E. multisquamatus) which cleave prothrombin at the same initial site as the prothrombinase complex but do not require anionic phospholipid as a cofactor. Parallel testing of the same IgG samples for prothrombin binding by immunoassay was performed. Although all IgG samples inhibited the prothrombinase reaction, only three exhibited any inhibition of venom protease prothrombin activation in either the presence or absence of PL. Only one sample exhibited prothrombin binding by Western blot. These results suggest that lupus anticoagulant antibodies are heterogenous and that many, if not most, of the autoantibody populations responsible for LA activity impair prothrombin activation by interaction either with phospholipid alone or with a restricted range of prothrombin-phospholipid epitopes expressed by prothrombin only as part of the intact prothrombin-prothrombinase complex.
Asunto(s)
Anticuerpos Anticardiolipina/fisiología , Síndrome Antifosfolípido/metabolismo , Endopeptidasas/fisiología , Factor V/antagonistas & inhibidores , Factor X/antagonistas & inhibidores , Factor Xa , Inmunoglobulina G/fisiología , Protrombina/antagonistas & inhibidores , Trombina/antagonistas & inhibidores , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Humanos , Inhibidor de Coagulación del Lupus/metabolismoRESUMEN
We compared the sensitivity and specificity of a tissue factor-based assay (FVR) with the addition of a phospholipid/silica preparation, to the commercially available aPTT-based method, APCR (CoatestTM), and a modified aPTT-based method (APCM) which utilized factor V-depleted plasma, for the detection of the factor V Leiden mutation. A total of 110 patients were included in this study. This included 32 patients on coumadin therapy, 7 patients on heparin therapy, 5 patients on both anticoagulants therapy, and 24 patients who were positive for anticardiolipin antibody (ACL) and/or lupus inhibitor (LI). Our data demonstrate that the FVR is not affected by anticoagulation treatment or ACL/LI antibodies, whereas in the APCR method, 33 patients cannot be determined either due to the anticoagulant therapy or presence of the ACL and/or LI. With the APCM method, the clotting endpoint could not be determined in 1 patient due to the presence of a strong LI. The additional phospholipid/silica material utilized in the FVR enhanced the APC degradation of factor Va and therefore sharpened the demarcation between the factor V Leiden-positive and -negative patients. The sensitivity for the APCR, APCM and FVR was 42, 97 and 100% respectively. The specificity for the APCR, APCM and FVR was 94, 96 and 100% respectively.
Asunto(s)
Pruebas de Coagulación Sanguínea/métodos , Factor V/análisis , Resistencia a la Proteína C Activada/sangre , Resistencia a la Proteína C Activada/diagnóstico , Anticuerpos Anticardiolipina/fisiología , Síndrome Antifosfolípido/genética , Factor V/genética , Humanos , Indicadores y Reactivos , Caolín , Inhibidor de Coagulación del Lupus/fisiología , Mutación , Tiempo de Tromboplastina Parcial , Fosfolípidos , Reacción en Cadena de la Polimerasa , Valores de Referencia , Sensibilidad y Especificidad , Dióxido de Silicio , Tromboplastina/análisisRESUMEN
BACKGROUND: Recurrent arterial thrombosis and venous thrombosis are frequent complications of the antiphospholipid syndrome (APS). Patients produce anti-cardiolipin antibodies, but the role of these antibodies in thrombus formation is uncertain. This study used a unique CD-1 mouse model of thrombosis to determine whether anti-cardiolipin and anti-beta 2 glycoprotein 1 (beta 2 GP1) antibodies induced immunologically in these animals are thrombogenic. METHODS AND RESULTS: The CD-1 mouse model enables measurement of the kinetics of a thrombus induced in the femoral vein of the animal. Animals are first anesthetized, then one femoral vein is exposed and subjected to a standardized, nonpenetrating "pinch" injury that induces a thrombus. The vein is trans-illuminated, and the growing thrombus is visualized on a television screen. The rate of formation and disappearance of the thrombus as well as its area can be measured by a computer attached to the television. Three groups of CD-1 mice (each group comprising seven animals) were studied. Group 1 mice were actively immunized with beta 2GP1, resulting in production of anti-beta 2GP1 and anti-cardiolipin antibodies. Group 2 mice were actively immunized with human immunoglobulin G (IgG) anti-cardiolipin antibodies and produced anti-human IgG as well as anti-cardiolipin antibodies (the latter by an idiotype-anti-idiotype reaction). These animals did not produce anti-beta 2GP1 antibodies. Group 3 mice were immunized with human serum albumin (HSA) and produced anti-HSA but not anti-cardiolipin antibodies. The kinetics of thrombus formation induced in the femoral veins of the experimental mice were compared. Results showed that the mean thrombus area as well as mean time during which thrombi persisted were significantly greater in group 1 and group 2 mice compared with group 3. There was no statistical difference between group 1 or group 2. CONCLUSIONS: Demonstration of a thrombogenic effect of murine anti-cardiolipin antibodies suggests that these antibodies may be pathogenic in humans with APS.