Risk factors for ischemic antiphospholipid syndrome: A case-control study.

OBJECTIVE: The objective of this study was to identify clinical and laboratory risk factors for ischemic stroke (IS) in primary antiphospholipid syndrome (APS) patients. MATERIALS AND METHODS: We performed a case-control study with consecutive primary APS patients divided into two groups, those who presented with IS, vs. those with no history of stroke. Demographics, vascular risk factors, therapeutic approaches, laboratory, imaging and functional outcomes were recorded. RESULTS: Fifty-three confirmed primary APS patients with IS and sixty-six non-stroke primary APS controls were recruited. Most patients were female (65.5 %), with a median age of 33 years. The main vascular risk factors for primary APS-associated stroke were hypertension (11.3 %), diabetes (11.3 %) and hypercholesterolemia (9.4 %). Among patients with stroke, median NIHSS score was 6; 15.1 % of these patients presented a recurrent stroke, and 88.8 % had a good functional outcome at the final follow-up. Positive lupus anticoagulant (OR = 6.1, 95 %CI 2.7-13.5), anti-ß2 glycoprotein IgG (OR = 3.6, 95 %CI 1.7-7.9), and anticardiolipin IgG (OR = 2.8, 95 %CI 1.3-5.9) were more prevalent in non-stroke primary APS, with a triple-positive antibody presence in 46.4 % of controls vs. 22.2 % of patients with stroke (OR = 3.0, 95 %CI 1.3-6.7). At the time of the index event (arterial or venous), 14 known primary APS patients were using vitamin K antagonists, but only 35.7 % of them had achieved therapeutic INR. CONCLUSION: Patients with primary APS and IS have similar vascular risk factors and lower antibody positivity than those with extracranial thrombosis.

Anti-RNP/Sm antibodies in patients with systemic lupus erythematosus and its role in thrombosis: a case-control study.

OBJECTIVE: To validate the association of thrombotic events with positive lupus anticoagulant (LA) and co-presence of anti-RNP/Sm, as well as the diagnostic accuracy of this combination of antibodies for thrombosis. METHODS: Case-control study of patients with systemic lupus erythematosus (SLE) who presented thrombosis after SLE diagnosis and controls with SLE without thrombosis. Comorbidities, traditional risk factors, clinical variables, and treatment were evaluated. Antiphospholipid (aPL) and anti-RNP/Sm antibodies were determined. RESULTS: Sixty-three cases and 63 controls were studied, 88% women, median age of 40 years, and disease duration of 135 months at study inclusion. No differences were found between groups regarding age, comorbidities, or clinical characteristics at SLE diagnosis. Patients with thrombosis were more frequently positive for anti-RNP/Sm (p = 0.001), IgG aCL (p = 0.02), IgG anti-B2GPI (p = 0.02), IgM anti-B2GPI (p = 0.02), LA (p < 0.001), the combination of anti-RNP/Sm + LA (p < 0.001), and aPL triple marker (p = 0.002), compared to controls. The combination of anti-RNP/Sm + LA, SLEDAI-2 K, and prednisone dose was associated with thrombosis (p < 0.05). The combination of anti-RNP/Sm + LA showed 56% sensitivity, 79% specificity, 73% positive predictive value, 64% negative predictive value, positive likelihood ratio (LR) 2.69, and negative LR 0.56 for predicting thrombosis. No difference was found in the comparison of area under the curve between LA alone and the combination of anti-RNP/Sm + LA (p = 0.73). CONCLUSION: Thrombosis was associated with disease activity, dose of prednisone, and the combination of anti-RNP/Sm antibodies and LA. This combination of antibodies could be useful in the identification of SLE patients at risk of thrombosis.

Non-Criteria or Seronegative Obstetric Antiphospholipid Syndrome?

BACKGROUND: Obstetric antiphospholipid syndrome (Obs-APS) is one of the most commonly identified causes of recurrent pregnancy loss and its accurate diagnosis is a requirement for optimal treatment. Some patients do not fulfill the revised Sapporo classification criteria, the original APS classification criteria, and are considered to be non-criteria Obs-APS. In these patients with non-criteria, there is controversy about their inclusion within the spectrum of APS and eventually their treatment as having Obs-APS. A subset of patients may also have clinical characteristics of Obs-APS even though lupus anticoagulant (LA), anticardiolipin antibodies, and anti-ß2-glycoprotein I (aß2GPI) antibodies are consistently negative. These patients are recognized as seronegative Obs-APS. We reviewed evidence of non-criteria Obs-APS and discuss a case of a woman with a diagnosis of active systemic lupus erythematosus (SLE) and non-criteria Obs-APS with four consecutive pregnancy losses. After an accurate diagnosis the patient received prenatal counseling and benefited from the optimal treatment of Obs-APS that led to a successful pregnancy. The applicability of this successful experience about outcomes in women with non-criteria, or seronegative, Obs-APS is also evaluated.

The role of lupus anticoagulant and triple marker positivity as risk factors for rethrombosis in patients with primary antiphospholipid syndrome.

OBJECTIVES: To ascertain rethrombotic risk factors in patients with primary antiphospholipid syndrome (PAPS). METHODS: We retrospectively evaluated 95 patients according to their rethrombotic status. We registered anticoagulation (OA) status, comorbidities, traditional thrombotic factors, prevalence of aCL (IgG-IgM), anti-ß2GP-I (IgG-IgM), LA and triple marker positivity (LA, aCL and anti-ß2GP-I). RESULTS: Forty-two patients had rethrombosis and 53 were rethrombosis-free. The median follow-up was 4.5 (0.3-26) years. There were no differences in comorbidities and traditional thrombotic factors. Patients with rethrombosis had more frequently LA (62% vs. 40%, p=0.04), were younger (41 vs. 47 years, p=0.01) and received less frequently OA (23% vs. 54%, p=0.002). A logistic regression analysis showed that the OA status (OR 0.17, 95% CI 0.05-0.57, p=0.004) and age (OR 0.94, 95% CI 0.90-0.98, p=0.01) remained significant. Patients who discontinued OA and developed rethrombosis (Group 1, n=32) vs. patients who discontinued OA, but remained rethrombosis-free (Group 2, n=24) were also analysed. We found a higher prevalence of LA and triple marker positivity in Group 1 (67% vs. 31%; OR= 4.5, 95% CI 1.3-14.9, p= 0.01 and 57% vs. 27%; OR 3.6, 95% CI 1.7-12; p=0.03), respectively. Both variables remained associated with rethrombosis when compared with the overall rethrombosis group vs. Group 2 (LA 62% vs. 31%, OR= 3.6 95% CI 1.1-11.2, p=0.03; triple marker 54% vs. 27%; OR 32 95% CI 1.01-10.2, p=0.05). CONCLUSIONS: LA positivity and triple aPL positivity confer a more severe risk of rethrombosis in PAPS patients, irrespective of their anticoagulation status and known conventional risk factors.

Lupus anticoagulant: a marker for stroke and venous thrombosis in primary Sjögren's syndrome.

Antiphospholipid antibodies (aPL) and antiphospholipid syndrome (APS) have been described in primary Sjögren's syndrome (pSS) with controversial findings regarding aPL prevalence and their association with thrombotic events. We evaluated 100 consecutive pSS patients (American-European criteria) and 89 age-gender-ethnicity-matched healthy controls for IgG/IgM anticardiolipin (aCL), IgG/IgM anti-beta2-glycoprotein-I (aß2GPI), and lupus anticoagulant (LA) (positivity according to APS Sydney's criteria). Clinical analysis followed standardized interview and physical examination assessing thrombotic and nonthrombotic APS manifestations and thrombosis risk factors. aPLs were detected in 16 % patients and 5.6 % controls (p = 0.035). LA was the most common aPL in patients (9 %), followed by aß2GPI (5 %) and aCL (4 %). Thrombotic events occurred in five patients [stroke in two, myocardial infarction in one and deep-vein thrombosis (DVT) in four], but in none of controls (p = 0.061). Mean age at time of stroke was 35 years. Three patients with thrombotic events (including the two with stroke) had APS (Sydney's criteria) and were positive exclusively for LA. Comparison of patients with (n = 16) and without (n = 84) aPL revealed similar mean age, female predominance, and ethnicity (p > =0.387). Frequencies of livedo reticularis (25 vs. 4.8 %, p = 0.021), stroke (12.5 vs. 0 %, p = 0.024), and DVT (18.8 vs. 1.2 %, p = 0.013) were significantly higher in APL + patients. Conversely, frequencies of hypertension, dyslipidemia, diabetes, obesity, smoking, sedentarism, and hormonal contraception were similar in patients with or without aPL (p ≥ 0.253). Our study identified LA as an important marker for APS in pSS, particularly for stroke in young patients, warranting routine evaluation of these antibodies and rigorous intervention in modifiable risk factors.

Antiphospholipid and other autoantibodies in a cohort of habitual aborters and healthy multiparous women in Jamaica.

Blood samples from 50~women who had had recurrent spontaneous abortions and 135 healthy multiparous women were investigated for anticardiolipin (aCL) antibodies and anti-ß2 Glycoprotein 1 (anti-ß2 GP1) dependent aCL antibodies by enzyme-linked immunosorbent assays (ELISA), lupus anticoagulant activity was measured by activated partial thromboplastin time, antinuclear antibodies, rheumatoid factors and thyroid antibodies using standard techniques. Serological tests for syphilis were performed on all sera and thyroid function was evaluated. There was no significant difference in the prevalence of autoantibodies in habitual aborters and control subjects (60% and 44%, respectively). Habitual aborters differed from controls only in the prevalence of positive aCL antibody tests (15/50, 30% vs. 15/135, 11%; χ² = 8.5, P= 0.01); medium/high concentrations of aCL antibodies (9/50, 18% vs. 9/135, 7%; χ² 4.3, P= 0.05); aCL antibodies of the IgM isotype (8/50, 16% vs. 7/135, 5%; χ² = 4.5, P= 0.05) and anti-ß2- GPI antibodies (7/50, 14% vs. 3/135, 2%; χ² 6.1, P= 0.05). We recommend aCL antibody screening in habitual aborters and the performance of the anti-ß2 GP1 antibody tests to identify those most at risk.

Primary antiphospholipid syndrome with thrombotic thrombocytopenic purpura: a very unusual association.

This report considers the rare situation in which primary antiphospholipid syndrome (PAPS) is linked with thrombotic thrombocytopenic purpura (TTP). It describes the case of a young lady with PAPS, characterized by recurring cerebro-vascular abnormalities and marked livedo reticularis, combined with circulating anticardiolipin and lupus anticoagulant antibodies. On follow-up, while on oral anticoagulation, she developed severe thrombocytopenia associated with hematuria, microangiophatic anaemia and neurological manifestations consistent with a diagnosis of TTP. The patient was treated with pulses of methylprednisolone and plasmapheresis with plasma exchange. The result was a favourable outcome. To our knowledge, this is the seventh report on this rare association in the English-language literature of this field.

Lung adenocarcinoma and antiphospholipid antibodies.

Thrombosis is a frequent finding in cancer patients, being referred to as a poor prognostic factor. The mechanisms underlying the thrombophilic state in malignancy are not well elucidated but involve a complex interaction between tumor and host cells as well as the hemostatic system. A number of studies have demonstrated the presence of antiphospholipid antibodies (aPL) in cancer patients, suggesting a potential role in tumor-associated thrombosis. A prospective analysis has been performed in a group of lung adenocarcinoma patients in respect to the presence of aPL and thrombotic manifestations. Lupus anticoagulant (LAC) was identified in 61 out of 105 patients and it correlated highly with thrombosis (22/61, LAC positive vs 2/44, LAC negative RR=7.93; p<0.001). On the other hand, patients that displayed IgM anti-beta2-glycoprotein I (abeta2GPI) (22/80) showed an unexpected decrease in thrombosis risk (2/22, with IgM abeta2GPI vs 18/58, without IgM abeta2GPI RR=0.29; p=0.04). Considerations on the mechanisms that link cancer, thrombosis and aPL are discussed in this article.

Primary, secondary, and catastrophic antiphospholipid syndrome: what's in a name?

The association of the lupus anticoagulant with thrombosis and recurrent pregnancy loss was first recognized over a 20-year period between the early 1960s and early 1980s. The introduction of the anticardiolipin test in 1983 and the recognition of its association with clinical features similar to the lupus anticoagulant led to an exponential growth of interest in this disorder. The belief that anticardiolipin antibodies and lupus anticoagulant belonged to the family of antiphospholipid antibodies led to the disorder being named the antiphospholipid syndrome (APS). Efforts by individual investigators to introduce criteria for classification of APS and to standardize anticardiolipin antibody and lupus anticoagulant tests were started in the mid-1980s to ensure more reliable recognition and treatment of affected patients. Another layer of complexity was introduced with recognition that many anticardiolipin antibody-positive sera also bound the antigen beta (2) glycoprotein I. With increasingly sophisticated epidemiologic and prospective studies in the 1990s, more structured and better-documented criteria for APS were introduced in 1999 and modified in 2006. These criteria have been widely adopted. Whereas data supporting subclassification of APS into primary and secondary subgroups remain tenuous, a small percentage of patients do appear subject to clinical features termed the catastrophic antiphospholipid syndrome. Introduction of classification criteria for APS has enabled more reliable prospective studies, the promise of better management, and more valid tests for recognition of the disorder.

Prevalence of antiphospholipid antibodies in Chilean patients with rheumatoid arthritis.

Antiphospholipid (aPL) antibodies found in patients with autoimmune diseases are also detected in those with inflammatory diseases. The purpose of this study was to examine the prevalence of these antibodies in patients with rheumatoid arthritis (RA), and to evaluate the association of these antibodies with thrombosis and/or other clinical characteristics of this inflammatory disorder. Eighty-four patients with RA and 82 normal controls were studied. Anticardiolipin (aCL), anti-beta(2) glycoprotein I (anti-beta(2)GPI), and antiprothrombin (aPT) antibodies and the lupus anticoagulant (LA) activity were determined. Seven out of 84 (8.3%) patients were positive for aCL, six out of 84 (7.2%) for anti-beta(2)GPI, and six out of 84 (7.2%) for aPT, while in controls the overall prevalence of aPL antibodies was 3.6% (3 out of 82). All patients and controls were LA negative. There was no correlation between the presence of aPL with thrombosis and/or other clinical features of the antiphospholipid syndrome. We found aPL antibodies in 19.1% (16 out of 84) of the patients with rheumatoid arthritis and this prevalence was statistically higher than in normal controls (P<0.003). In this study, the presence of aPL antibodies was not associated with the development of thrombosis and/or thrombocytopenia. Whether the presence of aPL antibodies implies an increased risk for thrombosis and atherosclerosis in these patients should be studied further.

Anticoagulante lúpico en enfermedades autoinmunes / Lupus anticoagulant in autoimmune diseases

El tromboembolismo venoso es una complicación reconocida en diferentes enfermedades autoinmunes. Se ha establecido que la detección del anticoagulante lúpico (AL) y posiblemente los anticuerpos anticardiolipina (AAC) tipo Ig G en título alto y medio, ayuden a identificar pacientes con riesgo de trombosis. Estudiamos el AL en 81 pacientes con enfermedades autoinmunes: 25 pacientes con lupus eritematoso sistémico (LES), 28 pacientes con púrpura trombocitopénica idiopática (PTI), 15 con anemia hemolítica autoinmune (AHAI) y 13 que se incluyeron en el grupo de otras enfermedades, que comprendían vasculitis cutánea de pequeños vasos, enfermedad mixta del tejido conectivo, artritis reumatoidea y esclerodermia. El AL se encontró en el 19,7 por ciento del total de los estudiados: 16 por ciento en pacientes con LES, 21,4 por ciento en pacientes con PTI y 40 por ciento en la AHAI. En el grupo de otras enfermedades no se halló ningún paciente con el AL positivo. El 56,3 por ciento de los pacientes con AL positivo presentaron alguna manifestación atribuible al síndrome antifosfolípido (SAF)(AU)

Anticoagulante lúpico en enfermedades autoinmunes / Lupus anticoagulant in autoimmune diseases

El tromboembolismo venoso es una complicación reconocida en diferentes enfermedades autoinmunes. Se ha establecido que la detección del anticoagulante lúpico (AL) y posiblemente los anticuerpos anticardiolipina (AAC) tipo Ig G en título alto y medio, ayuden a identificar pacientes con riesgo de trombosis. Estudiamos el AL en 81 pacientes con enfermedades autoinmunes: 25 pacientes con lupus eritematoso sistémico (LES), 28 pacientes con púrpura trombocitopénica idiopática (PTI), 15 con anemia hemolítica autoinmune (AHAI) y 13 que se incluyeron en el grupo de otras enfermedades, que comprendían vasculitis cutánea de pequeños vasos, enfermedad mixta del tejido conectivo, artritis reumatoidea y esclerodermia. El AL se encontró en el 19,7 por ciento del total de los estudiados: 16 por ciento en pacientes con LES, 21,4 por ciento en pacientes con PTI y 40 por ciento en la AHAI. En el grupo de otras enfermedades no se halló ningún paciente con el AL positivo. El 56,3 por ciento de los pacientes con AL positivo presentaron alguna manifestación atribuible al síndrome antifosfolípido (SAF)

An ELISA system to detect anti-factor VIII antibodies without interference by lupus anticoagulants. Preliminary data in hemophilia A patients.

BACKGROUND AND OBJECTIVES: Difficulties in identifying the coexistence of neutralizing anti-factor VIII antibodies (anti-fVIII) and lupus anticoagulant (LA) are mainly due to the interference of LA on anti-fVIII assays. Our aim was to reveal the presence of anti-fVIII using a system that is not affected by LA. DESIGN AND METHODS: We developed an enzyme-linked immunosorbent assay (ELISA) method that uses phospholipid-free recombinant factor VIII as the antigen. A monoclonal anti-fVIII was tested as a positive control, excluding non-specific binding by using two unrelated monoclonal antibodies. The ELISA was performed on hemophilic plasmas with anti-fVIII and negative LA (n=12) or without inhibitors (n=12). Two hemophilic plasmas with LA and presumably anti-fVIII were also assayed. Positive LA (n=12) and normal (n=10) plasmas were tested as negative controls. RESULTS: All (12/12) plasmas with anti-fVIII and 5/12 hemophilic plasmas without inhibitors were positive; LA and normal plasma controls were negative. INTERPRETATION AND CONCLUSIONS: Results presented here show that LA does not interfere with the anti-fVIII ELISA: However, the assay detects both neutralizing and non-neutralizing anti-fVIII antibodies, therefore a neutralizing effect must be confirmed through functional tests.

Síndrome dos anticorpos antifosfolipídeos e perda gestacional recorrente / Antiphospholipid antibody syndrome and recurrent fetal loss

Os anticorpos antifosfolipídeos estäo associados a fenômenos trombóticos (venosos e arteriais). Em mulheres a presença desses anticorpos tem sido associada a abortamentos espontâneos do primeiro trimestre assim como mortes fetais no segundo ou início do terceiro trimestre da gestaçäo. Seu diagnóstico é realizado através de sinais clínicos (tais como trombose recorrente ou perda gestacional) e pela presença de anticorpos antifosfolipídeos (anticorpos anticardiolipina ou anticoagulante lúpico). Diversos tratamentos têm sido propostos para as mulheres portadoras dessa síndrome durante a gestaçäo incluindo baixas doses de aspirina, predinisona, heparina e gama globulina com uma diminuiçäo na taxa de perdas gestacionais nessas pacientes.

El síndrome antifosfolípido / The antiphospholipid syndrome

Los anticuerpos antifosfolípidos (AAP) son un grupo de autoanticuerpos con afinidades variables por complejos de proteínas y fosfolípidos. Los anticuerpos anticardiolipina (ACAs) son detectados usualmente por técnicas de ELISA, mientras que el anticoagulante lúpico es medido como una actividad que prolonga las reacciones de la coagulación dependientes de fosfolípidos. Se han descrito en enfermedades autoinmunes, infecciosas, asociados a drogas, en neoplasias y en individuos sanos y se han asociado con fenómenos trombóticos venosos y arteriales, abortos a repetición y trombocitopenia, constituyendo lo que se denomina "síndrome antifosfolípido" (SAF) (AU)

El síndrome antifosfolípido / The antiphospholipid syndrome

Los anticuerpos antifosfolípidos (AAP) son un grupo de autoanticuerpos con afinidades variables por complejos de proteínas y fosfolípidos. Los anticuerpos anticardiolipina (ACAs) son detectados usualmente por técnicas de ELISA, mientras que el anticoagulante lúpico es medido como una actividad que prolonga las reacciones de la coagulación dependientes de fosfolípidos. Se han descrito en enfermedades autoinmunes, infecciosas, asociados a drogas, en neoplasias y en individuos sanos y se han asociado con fenómenos trombóticos venosos y arteriales, abortos a repetición y trombocitopenia, constituyendo lo que se denomina "síndrome antifosfolípido" (SAF)

Transient lupus anticoagulants associated with hemorrhage rather than thrombosis: the hemorrhagic lupus anticoagulant syndrome.

Lupus anticoagulants (LAs) represent a diverse group of antibodies directed against phospholipids. Patients with LAs may be free of symptoms but can have thrombotic complications including stroke, placental infarction, and fetal loss. Rarely hemorrhagic symptoms have been reported. We describe six previously healthy children who were first seen with clinical bleeding and prolonged activated partial thromboplastin time. Laboratory evaluation revealed positive results on mixing studies and evidence of phospholipid dependence of the anticoagulant, suggesting LAs. Four of six patients had anticardiolipin antibodies, and all four who were tested had reduced factor II activity levels. In all patients, bleeding symptoms resolved spontaneously within 3 months, and laboratory findings returned to normal within 6 months. The hemorrhagic LA syndrome should be considered in previously healthy children with new-onset bleeding and prolonged activated partial thromboplastin time. This clinical entity probably represents pathogenic mechanism distinct from thrombotic LA syndromes.

Neutralization of lupus anticoagulant activity by human immunoglobulin "in vitro".

We studied the in vitro effect of human intravenous immunoglobulin (IVIg) on the lupus anticoagulant (LA) activity present in sera of 11 patients. LA potency was determined in all the cases and a fixed dilution of each serum was chosen to perform the dose-dependent neutralization experiments. For each patient, the dilute serum was incubated for 3 h at 37 degrees C with phosphate buffer saline (PBS) alone or containing IVIg at final concentrations of 0 to 50 mg/ml. Aliquots of the incubation mixtures were added to equal volumes of normal plasma and APTTs were performed. IVIg partially neutralized the LA activity present in 10 out of 11 patients sera. These neutralizations showed an IVIg dose-dependent behaviour. Statistically significant neutralizations were observed at least at one molar ratio (MR = [IVIg]/patient's [IgG] or [IgM]). In every case, a particular MR was found in which the neutralization was maximal (N%max). The N%max ranged from 33.6% to 79.5%. Eight patients showed maximal LA neutralization at MR ranging from 8.9 to 56.8. In one patient with drug-induced LA and another exhibiting LA cofactor effect, MRs were more elevated. We found poor negative correlation between N%max and LA potency (r = -0.46) or N%max and MR of N%max (r = 0.47), although no statistic significance was reached. However, there was good agreement between LA potency and MR of N%max (r = 0.98, p less than 0.001). We have shown that IVIg may neutralize LA activity in vitro. In view of these results, we believe that IVIg should be considered as an alternative therapy in patients with LA-related clinical complications.