Anti-phosphatidyl-serine/prothrombin antibodies (aPS/PT) in isolated lupus anticoagulant (LA): is their presence linked to dual test positivity?

OBJECTIVES: Anti phosphatidylserine/prothrombin antibodies (aPS/PT) are often present in patients with antiphospholipid syndrome (APS) and might be relevant in the pathogenesis of this condition. They are major determinant of lupus anticoagulant (LA) in triple-positive antiphospholipid (aPL) profile. Whether they are present and pathogenic in patients with isolated LA [negative anticardiolipin (aCL) and anti ß2-glycoprotein I (aß2GPI) antibodies] is a matter of debate. METHODS: We measured aPS/PT in a large number of isolated LA with the aim to ascertain whether there is a link between the way isolated LA is assessed and the presence of these antibodies. APS/PT were measured in 86 patients with isolated LA (aCL- and abeta2GPI-). LA was assessed by two test systems, the dilute Russell Viper Venom Time (dRVVT) and the Silica Clotting Time (SCT). RESULTS: Sixty-six (77%) individuals with isolated LA were positive for aPS/PT (IgM 44, IgG and IgM 15, IgG in 7). Diagnosis of LA was made based on positive results in both dRVVT and SCT in 40 patients (Group 1) and based on only one positive test in the remaining 46 patients (Group 2). The rate of positive aPS/PT antibodies was significantly higher in Group 1 (OR=7.2, 95% CI 1.9-27.0, p<0.002). Moreover, the titre of IgM aPS/PT was significantly increased in Group 1 as compared to Group 2 (137 U, IQR 64-179 vs. 43 U, IQR 11-120, p=0.008). CONCLUSIONS: These data indicate an association between LA based on two positive coagulation tests and the presence of aPS/PT antibodies, especially of IgM isotype.

Tromboembolisme pulmonar com a presentació d'una síndrome antifosfolípid / Trombolismo pulmonar como presentación de un síndrome antifosfolípido / Pulmonary thomboembolism as a presenting sign of antiphospholipid syndrome

INTRODUCCIÓ: Els fenòmens tromboembòlics són poc freqüents en l'edat pediàtrica. La majoria de casos són secundaris a un factor de risc identificable. Quan són espontanis, recurrents, de localització inusual o de gravetat desproporcionada, requereixen estudi de trombofília. CAS CLÍNIC: Pacient de 14 anys, home, amb antecedent de trombosi venosa profunda I anticoagulant lúpic positiu, que consulta a urgències per episodi de pèrdua de consciència autolimitada. Presenta afectació de l'estat general, pal·lidesa I taquipnea. Saturació d'oxigen 87%, hipotensió (85/45 mmHg), taquicàrdia (155 ppm) I reompliment capil·lar allargat. En l'analítica sanguínia destaca dímer-D 7.224 ng/mL I troponina T 243 ng/L. Electrocardiograma amb descens difús del segment ST I ones T precordials negatives I radiografia de tòrax normal. Davant d'un quadre compatible amb tromboembolisme pulmonar (TEP) en pacient amb factors de risc de trombosi es completa l'estudi amb angio-TC, que mostra TEP massiu. Ingressa a unitat de cures intensives pediàtriques per tractament fibrinolític I posteriorment anticoagulació. En l'estudi de trombofilia es comprova persistència de l'anticoagulant lúpic positiu, que al costat de trombosi de repetició comporta el diagnòstic de síndrome antifosfolípid (SAF). COMENTARIS: La SAF és un estat d'hipercoagulabilitat d'origen autoimmunitari caracteritzat per la presència de trombosis, complicacions obstètriques I títols elevats d'anticossos antifosfolípids. La importància del seu diagnòstic precoç és la instauració de tractament anticoagulant indefinit per prevenir nous episodis trombòtics i, per tant, millorar el pronòstic

INTRODUCCIÓN: Los fenómenos tromboembólicos son poco frecuentes en la edad pediátrica. En la mayoría de casos son secundarios a un factor de riesgo identificable. Cuando son espontáneos, recurrentes, de localización inusual o de gravedad desproporcionada, requieren estudio de trombofilia. CASO CLÍNICO: Paciente de 14 años, varón, con antecedente de trombosis venosa profunda y anticoagulante lúpico positivo, que acude a urgencias tras episodio de pérdida de conciencia autolimitada. Presenta afectación del estado general, palidez y taquipnea. Saturación de oxígeno 87%, hipotensión (85/45 mmHg), taquicardia (155 lpm) y relleno capilar prolongado. En la analítica sanguínea destaca dímero-D 7.224 ng/mL y troponina T 243 ng/L. Electrocardiograma con descenso difuso del segmento ST y ondas T precordiales negativas y radiografía de tórax normal. Ante el cuadro compatible con tromboembolismo pulmonar (TEP) en paciente con factores de riesgo de trombosis, se completa el estudio con angio-TC, que muestra TEP masivo. Ingresa en unidad de cuidados intensivos pediátricos para tratamiento fibrinolítico y posteriormente anticoagulación. En el estudio de trombofilia se comprueba la persistencia del anticoagulante lúpico positivo, que junto a trombosis de repetición supone el diagnóstico de síndrome antifos-folípido (SAF). COMENTARIOS: El SAF es un estado de hipercoagulabilidad de origen autoinmune caracterizado por la presencia de trombosis, complicaciones obstétricas y títulos elevados de anticuerpos antifosfolípido. La importancia de su diagnóstico precoz es la instauración de tratamiento anticoagulante indefinido y así prevenir nuevos episodios trombóticos y, por tanto, mejorar el pronóstico

INTRODUCTION: Thromboembolic phenomena are rare in the pediatric age. In most cases they are secondary to an identifiable risk factor. When they are spontaneous, recurrent, in unusual location or of disproportionate severity, they require a work-up for thrombophilia. CASE REPORT: A 14-year-old boy with history of deep vein thrombosis and positive lupus anticoagulant was admitted in the emergency department after an episode of self-limited loss of consciousness. He presented altered general appearance, pallor and tachypnea. Oxygen saturation was 87%, and had hypotension (85/45 mmHg), tachycardia (155 ppm) and prolonged capillary refill. Laboratory evaluation was remarkable for D-Dimer 7224 ng/mL and Troponin T 243 ng/L. Electrocardiogram showed diffuse decline of the ST segment and negative precordial T waves, and chest radiography was normal. Due to the clinical findings compatible with pulmonary thromboembolism (PE) in a patient with risk factors for thrombosis, a CT-angiography was performed and showed massive PE. The patient was admitted to the pediatric intensive care unit for fibrinolytic treatment and subsequently anticoagulation. In the thrombophilia study, persistence of the positive lupus anticoagulant was confirmed, which, together with repeated thrombosis, suggested the diagnosis of antiphospholipid syndrome (APS). COMMENTS: APS is a state of hypercoagulability of autoimmune origin characterized by the presence of thrombosis, obstetric complications and high titers of antiphospholipid antibodies. The importance of early diagnosis is the establishment of indefinite anticoagulant treatment to prevent new thrombotic episodes and therefore improve prognosis

Trombocitopenia como factor de riesgo trombótico en pacientes con anticuerpos antifosfolipídicos sin criterios de enfermedad / Thrombocytopenia as a thrombotic risk factor in patients with antiphospholipid antibodies without disease criteria

Introducción: El síndrome antifosfolípido (SAF) es un trastorno inmunitario adquirido, definido por la presencia de trombosis (arterial y/o venosa) y/o morbilidad del embarazo junto con la presencia de anticuerpos antifosfolipídicos (aFL) positivos. Existe una relación clara entre los aFL y algunas manifestaciones no incluidas en los criterios clínicos, entre ellas, las hematológicas. Objetivos: a) estudiar la probabilidad de desarrollar SAF clínico en pacientes con aFL positivos y trombocitopenia; b) identificar posibles factores de riesgo para trombosis, y c) estudiar la asociación entre trombocitopenia y aFL. Métodos: Estudio retrospectivo de 138 pacientes con aFL positivos sin cumplir criterios clínicos de SAF. Se definió trombocitopenia como una cifra de plaquetas≤100.000/μl. Se excluyeron los pacientes con otras causas de trombocitopenia. Resultados: Diecisiete de los 138 (12%) pacientes incluidos en el estudio presentaban trombocitopenia. La cifra media de plaquetas fue de 60.000/μl. El riesgo para desarrollar trombocitopenia fue mayor en los pacientes fumadores (OR 2,8; p=0,044), en aquellos con anticoagulante lúpico (OR 13,5; p<0,001) y en los que tenían una mayor carga de aFL (OR 50,8; p<0,001). Tras un seguimiento medio de 146±60,3 meses, 5 pacientes con trombocitopenia (29,4%) desarrollaron trombosis. Conclusiones: En nuestra serie, la incidencia de trombocitopenia es del 12%. Los pacientes con aFL positivos que desarrollan trombocitopenia tienen un riesgo potencial de desarrollar trombosis. El tabaco podría ser un factor de riesgo para trombocitopenia. La carga de autoanticuerpos es un factor de riesgo para el desarrollo de trombocitopenia (AU)

Introduction: The antiphospholipid syndrome (APS) is an acquired immune disorder defined by the presence of thrombosis (arterial and/or venous) and/or pregnancy morbidity along with the presence of positive antiphospholipid antibodies (aPL). There is a clear relationship between aPL and some events not included in the clinical criteria, including haematologic. Objectives: a) to study the probability of developing clinical APS in patients with positive aPL and thrombopenia; b) to identify potential risk factors for thrombosis, and c) to study the association between thrombocytopenia and aPL. Methods: A retrospective study of 138 patients with positive aPL without fulfilling clinical criteria for APS. Thrombocytopenia was defined as a platelet count≤100,000/μl. Patients with other causes of thrombocytopenia were excluded. Results: Seventeen of the 138 (12%) patients in the study had thrombocytopenia. The mean platelet count was 60,000/μl. The risk of developing thrombocytopenia was higher in smokers (OR 2.8; P=.044), in those with lupus anticoagulant (OR 13.5; P<.001) and those with higher burden of aPL (OR 50.8; P<.001). After a mean follow-up of 146±60.3 months, 5 patients with thrombocytopenia (29.4%) developed thrombosis. Conclusions: In our series, the incidence of thrombocytopenia is 12%. aPL-positive patients who develop thrombocytopenia have a potential risk of developing thrombosis. Tobacco could be a risk factor for thrombocytopenia. Autoantibodies load is a risk factor for the development of thrombocytopenia (AU)

Una causa inusual de hematomas / An unusual cause of bruising

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Anticoagulante lúpico en Pediatría. Experiencia en nuestro centro / Lupus anticoagulant in Pediatrics. Experience in our center

Objetivo. Estudio descriptivo de las formas de presentación, características biológicas y evolución de los pacientes pediátricos diagnosticados de anticoagulante lúpico en nuestro Hospital. Pacientes y métodos. Revisión retrospectiva de todos los pacientes que cumplieron los criterios establecidos por la Sociedad Internacional de Trombosis y Hemostasia para diagnóstico de anticoagulante lúpico. Resultados. Cumplieron los criterios establecidos 16 niños, 9 varones (53,6%) y 7 mujeres, con una mediana de edad decimal al diagnóstico de 6,25 años (rango: 1,1-13). Los motivos del estudio de coagulación fueron: preoperatorio (n: 6, 37,5%), estudio por trombosis (n: 4, 25%), infección (n:3, 18,8%), hemorragia (n: 2, 12,5%) e ingesta de raticida (n:1, 6,3%). Diez casos (62,5%) permanecieron asintomáticos y correspondieron a los casos de preoperatorio, infecciones e ingesta de raticida. Cuatro de los pacientes presentaron trombosis (25%), en dos de ellos se encontraron además trombofilia primaria y patología inmunitaria o tumoral y en otro caso se cumplieron criterios de síndrome antifosfolípido primario, único de los casos en que el anticoagulante lúpico fue persistente. Dos casos (12,5%) presentaron hemorragias asociadas a disminución de algún factor de coagulación (déficits transitorios de FII y FVIII).Conclusiones. El anticoagulante lúpico es un hallazgo poco frecuente en Pediatría. Se encuentra con más frecuencia en preoperatorio de procesos ORL y/o infecciones. La gran mayoría son transitorios y sin relevancia clínica. Cuando se asocia trombosis frecuentemente se asocia a trombofilia primaria y patología inmunitaria o tumoral y cuando lo hace a hemorragias, a déficit de factores procoagulantes (AU)

Objective. A descriptive study of the presentation forms, biological and evolution characteristics of the pediatric patients diagnosed of lupus anticoagulant in our hospital. Patients and methods. Retrospective review of all the patient who met the criteria established by the International Society of Thrombosis and Hemostasis for diagnosis of lupus anticoagulant. Results. The established criteria were met by 16 children, 9 males (53.6%) and 7 women, with a mean decimal age on diagnosis of 6.25 years (range: 1.1-13). The reasons for the coagulation study were: preoperative (n: 6, 37.5%), thrombosis study (n: 4, 25%), infection (n: 3, 8.8%), hemorrhaging (n: 2, 12.5%) and taking of rodenticide (n: 1, 6.3%). Ten cases (62.5%) remained asymptomatic and corresponded to pre-operative cases, infections and intake of rodenticide. Four of the patients had thrombosis (25%). In two of the latter, primary thrombophilia and immune or tumor pathology were also found and another case fulfilled the criteria of primary antiphospholipid syndrome, this being the only case in which the lupus anticoagulant was persistent. Two cases (12.5%) presented hemorrhages associated to decrease of a coagulation factor (transient deficits of FII and FVIII).Conclusions. Lupus anticoagulant is an uncommon finding in Pediatrics. It is more frequently found in the preoperative of ENT and/or infectious processes. The vast majority are transient and do not show clinical significance. When thrombosis is associated, it is frequently associated to primary thrombophilia and immune or tumor disorder and when it is associated to hemorrhages, it is associated to a deficit of procoagulant factors (AU)

Estrategias terapéuticas en el síndrome antifosfolipídico / Therapeutic strategies in antiphospholipid syndrome

El síndrome antifosfolipídico (SAF) se caracteriza por la asociación de los anticuerpos antifosfolipídicos (AAF) con trombosis de repetición, abortos o pérdidas fetales recurrentes y trombocitopenia. Los AAF más estudiados son los anticuerpos anticardiolipina, el anticoagulante lúpico y los anticuerpos anti-ß2-glucoproteína I. El SAF puede presentarse de forma aislada, denominándose SAF primario, o bien asociado a otras enfermedades autoinmunes sistémicas, fundamentalmente a lupus eritematoso sistémico. Más recientemente, se ha descrito un subgrupo de SAF en el que los pacientes desarrollan múltiples trombosis durante un corto espacio de tiempo, que se ha denominado SAF catastrófico. Aunque parece clara la asociación entre la presencia de AAF y trombosis, la actitud terapéutica no debe ir dirigida primariamente a la eliminación o a la reducción de los niveles de estos anticuerpos mediante recambios plasmáticos, gammaglobulinas intravenosas o inmunodepresores (excepto en el SAF catastrófico), ya que no existe una clara correlación entre los niveles de los AAF y los episodios trombóticos. El tratamiento de estos pacientes debe basarse en el uso de antiagregantes plaquetarios o anticoagulantes(AU)

The classical clinical picture of the antiphospholipid syndrome (APS) is characterized by venous or arterial thromboses, fetal losses and thrombocytopenia, in the presence of antiphospholipid antibodies (aPL), namely lupus anticoagulant, anticardiolipin antibodies or antibodies directed to various proteins, mainly â2 glycoprotein I, or all three. Apart from being “primary” (without any discernable underlying systemic autoimmune disease), or associated to another disease (usually to systemic lupus erythematosus), it may also occur rapidly over days or weeks when it has been termed “catastrophic” APS. Therapy should not primarily be directed at effectively reducing the aPL levels and the use of immunotherapy (including high dose steroid administration, immunosuppression or plasma exchange) is generally not indicated, unless in the catastrophic APS. Treatment of APS patients should be based on the use of antiaggregant and anticoagulant therapy(AU)

Nefropatía IgA y anticoagulante lúpico: ¿una asociación casual? / No disponible

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Inhibidores adquiridos de la coagulación en una paciente con lupus eritematoso sistémico y anticuerpos antifosfolipídicos: respuesta a rituximab / Aquired inhibitors of coagulation in a patient with systemic lupus erythematosus and antiphospholipid antibodies: response to rituximab

Las manifestaciones hematológicas de los pacientes con lupus eritematoso sistémico (LES) son diversas. Aunque el desarrollo de anticuerpos antifosfolipídicos se asocia con una prolongación in vitro de los tiempos de coagulación, las manifestaciones clínicas suelen ser trombóticas. Los anticoagulantes circulantes que aparecen en pacientes sin anomalías previas de la coagulación son consecuencia del desarrollo de autoanticuerpos contra los factores II, V, VII, VIII y IX, XI, XIII, factor de Von Willebrand u otras glucoproteínas de membrana. Todos ellos condicionan coagulopatías poco comunes, 1 caso por millón de personas por año, y que pueden comprometer seriamente la vida de los pacientes. Presentamos el caso de una mujer con LES y anticuerpos antifosfolipídicos, que presentó síndrome de Evans, como primera manifestación, y posteriormente desarrolló un síndrome hemorrágico, presumiblemente por anticuerpos contra múltiples factores de la cascada de coagulación, sin respuesta a dosis altas de esteroides e inmunosupresores, que finalmente respondió a rituximab (AU)

Hematologic signs of systemic lupus erythematosus are diverse (SLE). Although a delayed coagulation time is anti-phospholipid antibody related, thrombotic events are the usual clinical manifestation. Spontaneous appearance of circulating anticoagulant in the absence of a previous coagulation disorder is secondary to the development of antibodies to factors II, V, VIII, IX, XI, XII, vonWillebrand, and other membrane glucoproteins, all of them uncommon causes (1 case per million persons per year) of life threatening coagulopathies. We report a case of SLE and antiphospholipid antibodies in a woman with a hemorrhagic syndrome, probably caused by multiple antibodies to coagulation factors, unresponsive to steroids and high-dose immunosupressive therapy and a favorable response to rituximab (AU)

Presence of lupus anticoagulant in an asymptomatic Nigerian.

BACKGROUND: The lupus anticoagulant (LA) is one of the antiphospholipid antibodies (aPL), which prolong phospholipid- dependent coagulation tests by interfering with coagulation reactions that depend on protein - phospholipid complexes in vitro. METHOD: A 25 year old 'healthy' male Nigerian was screened for the presence of any coagulation abnormality using the KCT, PT and platelet count; after volunteering for his plasma to be used in the preparation of normal pooled plasma in a study. RESULTS: He was discovered to have a prolonged KCT, PT and normal platelet count. Based on the prolonged KCT his plasma was subjected to mixing studies with various concentration of normal pooled plasma; the KCT index was calculated and a curve was plotted. His KCT index was 1.6 and the curve convex in the left axis suggesting the presence of LA. His past medical history and physical examination were not remarkable. Three months after the initial study, a repeat KCT index was 1.4 and the subject asymptomatic. CONCLUSION: From literature review this is the first report of LA in an asymptomatic adult Nigerian; the importance of this finding is discussed.

Effect of anti-beta2glycoprotein I Lupus Anticoagulants on fibrin polymerization and fibrinolysis.

Anti-beta2-Glycoprotein I (beta2GPI) autoantibodies are the prominent laboratory feature of Hughes syndrome. By prolonging some coagulation tests in the presence of exogenous phospholipids (PL), they behave as classical Lupus Anticoagulants (LA). We investigated the effect of 3 affinity-purified anti-beta2GPI IgG preparations from patients with Hughes syndrome on fibrin polymerization and fibrinolysis of normal plasma, measured by comparing the optical densities of assay mixtures in the presence of the autoantibodies or normal IgG. The presence of anti-beta2GPI IgG in diluted Russell Viper Venom Time (dRVVT) assays, carried out using a PL dilution of 1:8 or 1:64, resulted in a delay in the onset of polymerization by 30-40 and 60-70s, respectively. Fibrin polymerization was complete after 250s for both anti-beta2GPI IgG and normal IgG. The inhibitory effect of the anti-beta2GPI antibodies was not observed in the presence of excess PL, as expected for LA. Anti-beta2GPI IgG increased the plateau level of polymerization when dRVVT was performed in the presence of 1.5 nM recombinant tissue plasminogen activator, but did not impair the fibrinolytic process, which was almost complete after 250 min. The autoantibodies did not delay the onset of fibrin polymerization in tests carried out using recombinant tissue factor. On the contrary, the autoantibodies enhanced polymerization in prothrombin time assays, and accelerated it in tissue thromboplastin inhibition tests, with no effect on fibrinolysis. These data provide evidence that anti-beta2GPI LA may act as either anticoagulants or procoagulants in different in vitro coagulation tests.

Purification and characterization of lupus anticoagulant like protein from Agkistrodon halys brevicaudus venom.

By means of CM-Sephadex C-25, DEAE-Sephadex A-50, Sephadex G-200, and Sephadex G-75 chromatographies, a lupus anticoagulant like protein (LALP) from Agkistrodon halys brevicaudus was purified. On SDS-PAGE, the purified LALP had a molecular weight of 25,500 daltons under non-reducing condition and 15,000 daltons under reducing condition. The isoelectric point was pH 5.6. Its N terminal amino acid sequencing revealed a mixture of 2 sequences: DCP(P/S)(D/G)WSSYEGH(C/R)(Q/K). It was devoid of phospholipase A, fibrino(geno)lytic, 5'-nucleotidase, L-amino acid oxidase, phosphomonoesterase, phosphodiesterase and thrombin-like activities, which were found in crude venom. In the presence of LALP, PT, aPTT, and dRVVT of human plasma were markedly prolonged and its effects were concentration-dependent but time-independent. The inhibitory effect of LALP on the plasma clotting time was enhanced by decreasing phospholipid concentration in TTI test. The individual clotting factor activity was not affected by LALP when higher dilutions of LALP-plasma mixture were used for assay. Russell's viper venom time was shortened when high phospholipid confirmatory reagent was used. Therefore, the protein has lupus anticoagulant property.

Transient hemorrhagic diathesis associated with an inhibitor of prothrombin with lupus anticoagulant in a 1 1/2-year-old girl: report of a case and review of the literature.

Acquired inhibitors of coagulation causing bleeding manifestations are rare in children, particularly without an associated underlying disorder such as autoimmune disease. We describe an otherwise healthy 1 1/2-year-old girl who had extensive spontaneous bruising and prolonged bleeding from venipuncture sites. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were prolonged, with evidence of an immediate-acting inhibitor. Thrombin clotting time, fibrinogen, and platelets were normal. Biologic assay of factors II, V, VII, and X were all low, with increasing values at higher dilutions. However, by immunoassay and/or chromogenic assays, only factor II was reduced. An antibody which failed to neutralize prothrombin activity in vitro was detected against radiolabeled prothrombin. Coagulation studies normalized in parallel with clinical recovery and disappearance of the antibody. This case demonstrates acute hypoprothrombinemia-lupus anticoagulant syndrome as a rare presentation of bleeding diathesis in a healthy young child.

Purification of anticardiolipin and lupus anticoagulant activities by using cardiolipin immobilized on agarose beads.

We describe a novel method for the purification of aPL, in which pure CL is immobilized on octyl-sepharose beads by hydrophobic interaction. No lipid contamination was present in eluates, and the system could be reutilized three times without loosing extracting capacity. Four patients with antiphospholipid syndrome were studied. A marked decrease in aCL and LA activities was found in all patient plasmas after the passage through a CL-octyl-sepharose column. Both activities were recovered in eluates which contained beta 2-GP-I and IgGs. beta 2-GP-I was also present in normal plasma eluates, which showed no aCL and slight LA activity. This method represents an improvement in the purification of aPL, and could be useful in explaining the mechanism of action of antibodies that are obtained using pure phospholipid as extracting matrix.

[Antiphospholipid syndrome: a new clinical entity? Part 1: antiphospholipid antibodies: specificity and methodological problems]. / Le syndrome des antiphospholipides: une nouvelle entité clinique? Partie 1: Anticorps antiphospholipides: spécificité et problèmes méthodologiques.

A new clinical entity, the antiphospholipid syndrome, has recently been described. It is based on the detection of antiphospholipid antibodies either by coagulation tests or by ELISA assay. The precise epitopes towards which these antibodies are directed is a matter of controversy. It is even possible that the name antiphospholipid is inappropriate. The diagnosis of lupus like anticoagulant (LA) detected by coagulation tests requires a three step procedure after appropriate processing of plasma samples. Antiphospholipid antibodies can also be identified by ELISA; this assay is simpler, but there is still a need for standardization. LA and antiphospholipid antibodies identified by ELISA are similar, but not identical; they have similar clinical implications. Due to the heterogeneity of the antibodies and the antigens it is necessary to use a panel of tests to establish or exclude the presence of antiphospholipid antibodies. In the future a better knowledge of antibodies' specificity should help in selecting the most useful test for clinical purposes.

Anticardiolipin antibodies block the inhibition by beta 2-glycoprotein I of the factor Xa generating activity of platelets.

Antiphospholipid antibodies, defined either by lupus anticoagulant (LA) activity or positive anticardiolipin immunoabsorbent assay (ACA) are associated with a predisposition to thromboses, recurrent fetal loss or thrombocytopenia. The mechanisms for these predispositions remain undefined. We have enriched immunoglobulin fractions from two patient plasmas to obtain antibodies with LA activity but no ACA, or conversely, with ACA positivity but no LA, in order to investigate in vitro characteristics which might explain a thrombotic propensity. beta 2-glycoprotein I (beta 2-GPI), the plasma cofactor required for ACA binding to negatively charged phospholipid, has previously been shown to inhibit prothrombinase generation in the presence of activated platelets (8). We now report that beta 2-GPI, at physiological concentrations, inhibits the generation of factor Xa in the presence of activated gel-filtered platelets. Further, ACA interferes with this inhibition, resulting in protracted, unopposed factor Xa generation. This interference with beta 2-GPI, a natural anticoagulant component of plasma, is potentially prothrombotic. LA immunoglobulins behave differently and inhibit factor Xa generation in a manner similar to beta 2-GPI. These findings provide the basis for a previously unsuspected mechanism for thrombosis in patients with aPL.

Beta 2-glycoprotein I is a requirement for anticardiolipin antibodies binding to activated platelets: differences with lupus anticoagulants.

Antiphospholipid (aPL) antibodies are of major interest not only because the lupus anticoagulant (LA) causes an inhibition of in vitro blood coagulation, but also because the presence of aPL antibodies confers a risk of thrombosis. The inhibition of in vitro phospholipid-dependent coagulation (LA) is thought to be caused by the binding of LA to procoagulant phospholipid surfaces, thus impeding the clotting process. Another class of aPL antibodies are those originally described to be directed against negatively charged phospholipids, in particular cardiolipin (ACA). ACA are usually directed against a complex antigen consisting of negatively charged phospholipid and a plasma protein, beta 2-glycoprotein I (beta 2-GPI). Further, there is antibody heterogeneity even within individual patients so that ACA and LA are separable using physicochemical techniques such as ion exchange chromatography and chromatofocusing. Using such techniques we have enriched Ig fractions for LA and ACA from two patient plasmas. The majority of Ig with LA activity had a pI of 7.2 to 7.3 whereas ACA had a pI of 5.0 to 5.2. Using these enriched fractions labeled with [125I]-iodine we have shown that LA binds to platelets in a specific and saturable manner. Binding is dependent on thrombin activation. [125I]-ACA behaves differently. Like LA, binding is specific and dependent on thrombin activation but in this case requires the presence of beta 2-GPI. ACA, in the presence of beta 2-GPI, competes for binding with LA suggesting the same or contiguous site. There is no cross-reactivity of these antibodies with GPIIb/IIIa and the most likely binding site is phospholipid. In neither case does LA nor ACA have an effect on thrombin-induced release of serotonin or beta-thromboglobulin nor do they affect platelet aggregation induced by a number of agonists. This antibody binding may play an etiological role in thrombocytopenia associated with aPL, but does not explain thrombosis on the basis of hyperaggregability or increased platelet release.

Anticoagulante lúpico: análisis clínico y de laboratorio de 45 pacientes

El anticoagulante lúpico (ACL) es un anticuerpo antifosfolipídico que prolonga las pruebas de coagulación dependientes de fosfolípidos como el tiempo de tromboplastina parcial activado (TTPa). El objetivo del presente estudio es informar la experiencia clínica y de laboratorio con 45 pacientes portadores de esta anomalía que clásicamente se manifiesta por trombosis, abortos a repetición y trombocitopenia. Los 45 pacientes se estudiaron en un período de 67 meses y represetan el 1.76 por ciento de todos los pacientes evaluados hemostáticamente en este tiempo. Cuarenta por ciento de los casos de ACL se presentó en pacientes con lupus eritematoso sistemico (LES); 25 por ciento en pacientes con neoplasia hematológica y 35 por ciento restante en pacientes con enfermedades benignas. Hubo 15 episodios de trombosis en 13 pacientes (28.8 por ciento de la muestra), ocho de estos tenian LES (44.4 por ciento). Dos pacientes con LES dieron historia de abortos a repetición (4.5 por ciento) y cuatro casos presentaron fenómenos hemorragiparos (9 por ciento). El estudio sugiere como grupo de riesgo elevado para trombosis a los pacientes con LES y VDRL falso positivo.

Anticoagulante lúpico: paradoja de la medicina

El anticoagulante lúpico es un inhibidor de la coagulación sanguínea adquirido espontáneamente que interfiere con la activación de la protrombina por el complejo activador. Este inhibidor, una inmunoglobulina, aparece más comúnmente en el plasma de pacientes con desórdenes autoinmunes incluyendo el lupus eritematoso sistémico, pero también ha sido asociado con enfermedades no relacionadas directamente con el sistema inmune y en pacientes sin ninguna enfermedad demostrable. Los pacientes con este "anticoagulante" usulamente están libres de sangrado a pesar de las anormalidades en su coagulación. Paradójicamente, han sido reportados episodios de trombosis venosa profunda, trombosis arterial u oclusión cerebrovascular, embolismo pulmonar y trombosis en la circulación renal. El mecanismo de estas asociaciones es desconocido, pero su comprensión será necesaria para un mejor diagnóstico y tratamiento de esta nueva entidad