Prevalence and clinical correlation of anti-phospholipid-binding protein antibodies in anticardiolipin-negative patients with systemic lupus erythematosus and women with unexplained recurrent miscarriages
Anti-phospholipid antibodies (aPL) are a heterogeneous group of autoantibodies, the presence of which is associated with thrombotic events and miscarriage.
To establish whether antibodies directed against phospholipid-binding plasma proteins such as beta(2)-glycoprotein I (beta(2)GPI), prothrombin (PT), and annexin V (Anx V) constitute a risk factor for thromboembolism in patients with systemic lupus erythematosus (SLE) and for miscarriage in women with recurrent pregnancy loss (RPL), independently of the presence of the classic anticardiolipin (aCL) antibodies, and whether their determination together with that of aCL would help to increase the diagnostic sensitivity of aPL tests.
The prevalence of various antibodies directed toward phospholipids (CL and other anionic phospholipids [APL]) and phospholipid-binding proteins (beta(2)GPI, PT, and Anx V) was determined by immunoenzymatic methods in 311 serum samples.
Twenty-five patients with aCL-positive primary anti-phospholipid syndrome (pAPS); 89 patients with SLE, 23 of whom had thrombotic complications (SLE/APS) and 66 of whom had no thrombosis; and 77 women with unexplained recurrent pregnancy loss comprised our study group. One hundred twenty healthy subjects matched for age and sex were studied as the control group.
Immunoglobulin (Ig) G and/or IgM aAPL, anti-beta(2)GPI, anti-PT, and IgG anti-Anx V antibodies were detected in 25 (100%), 20 (80%), 15 (60%), and 6 (24%), respectively, of the 25 aCL-positive pAPS patients; IgG and/or IgM aCL, aAPL, anti-beta(2)GPI, anti-PT, and IgG anti-Anx V antibodies were detected in 33 (37%), 42 (47%), 31 (35%), 40 (45%), and 12 (13%) of the 89 SLE patients, respectively. Of the 56 SLE patients who proved to be aCL negative, anti-beta(2)GPI was present in 3 patients (5%), anti-PT in 13 (23%) patients, and anti-Anx V in 5 (9%) patients. In the subset of 23 SLE/APS patients, IgG anti-PT prevalence was higher than that of the other autoantibodies (87% vs 70% aCL, 66% aAPL, 57% anti-beta(2)GPI, and 4% anti-Anx V), and in 26% of cases, IgG anti-PT was the only antibody present. Anti-PT had a slightly lower specificity than aCL (46% vs 49%); however, the occurrence of both antibodies brought the specificity to 92.4%. The highest risk for thrombosis in SLE patients was associated with the presence of IgG anti-PT antibody (odds ratio [OR] 15.3, P < .001, vs 6.5 aCL, 3.5 aAPL, 3.4 anti-beta(2)GPI, 0.2 anti-Anx V). Fifty-one of the 77 women with recurrent pregnancy loss were negative for all antibodies investigated; the prevalence of IgG and/or IgM aCL, aAPL, anti-beta(2)GPI, anti-PT, and IgG anti-Anx V antibodies was 6% (5), 12% (9), 6% (5), 16% (12), and 17% (13), respectively. Of the 67 aCL-negative women, none had anti-beta(2)GPI antibodies, 7 (11%) were anti-PT positive, and 13 (19%) were anti-Anx V positive. In the subgroup of 26 recurrent pregnancy loss patients who had at least one antibody, anti-Anx V was present in 50% of cases (in 42% as the sole antibody) and was the only antibody significantly associated with miscarriage (P = .02).
The results of this study indicate that it is useful to measure anti-PT antibodies in addition to the more widely used aCL and anti-beta(2)GPI antibodies in the prognostic evaluation of SLE patients for the risk of thrombosis, and the results also confirm that anti-Anx V antibodies may play an important role in recurrent pregnancy loss.
"While some studies identify antiprothrombin antibodies as a strong risk factor for early pregnancy loss in APS patients  , others do not detect a significant association in APS or SLE patients    or women with recurrent miscarriages in Italian women . Anti-annexin V antibodies have been found to be significantly associated with recurrent miscarriage in studies from such geographically diverse areas as Italy, Tunisia, and Japan     , but this is not a consistent finding either  . Finally, the results from a large Czech study indicate that antibodies against various negatively charged phospholipids, in particular phosphatidylinositol and phosphatidylserine, were significantly more frequent in women with 3 miscarriages or repeated in vitro fertilization failure  "
[Show abstract][Hide abstract] ABSTRACT: There are multiple epidemiological studies that document the potential adverse affects of autoimmunity on nearly every aspect of reproduction, even in the absence of clinically manifest autoimmune disease. Two decades ago, it was suggested that women with autoimmune diseases avoid pregnancy due to inordinate risks to the mother and the child. In contrast, newer epidemiological data demonstrated that advances in the treatment of autoimmune diseases and the management of pregnant women with these diseases have similarly improved the prognosis for mother and child. In particular, if pregnancy is planned during periods of inactive or stable disease, the result often is giving birth to healthy full-term babies without increased risks of pregnancy complications. Nonetheless, pregnancies in most autoimmune diseases are still classified as high risk because of the potential for major complications. These complications include disease exacerbations during gestation and increased perinatal mortality and morbidity in most autoimmune diseases, whereas fetal mortality is characteristic of the anti-phospholipid syndrome (APS). In this review, we will discuss these topics, including issues of hormones, along with potential long-term effects of the microchimerism phenomenon. With respect to pregnancy and autoimmune diseases, epidemiological studies have attempted to address the following questions: 1) Is it safe for the mother to become pregnant or are there acute or chronic effects of pregnancy on the course of the disease? 2) Does the disease alter the course and/or the outcome of a pregnancy and thereby represent an inordinate risk for the fetus and infant? And do new therapeutic and management approaches improve the pregnancy outcomes in women with autoimmune diseases? 3) Does passage of maternal autoantibodies represent a risk to the child? 4) Do pregnancy, parity, or other factors influencing hormonal status explain the female predominance of many autoimmune diseases, and is the pregnancy effect related to microchimerism? Answering these questions has taken on additional importance in recent decades as women in western countries now frequently choose to delay pregnancies and have some or all of their pregnancies after disease onset. In this paper, we primarily focus on APS, systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), and type 1 diabetes (T1D).
Journal of Autoimmunity 05/2010; 34(3):J287-99. DOI:10.1016/j.jaut.2009.11.015 · 8.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Riassunto La misurazione degli anticorpi anti-cardiolipina, anti-β β β β β 2-glicoproteina I e del lupus anticoagulant ha consentito negli ultimi 15 anni di migliorare sostanzialmente l'approccio diagnostico e tera-peutico dei pazienti con evento tromboembolico su base autoimmune. Tuttavia, nonostante la loro importanza clinica, questi test rimangono ancora poco riproducibili a causa della carente standar-dizzazione dei metodi. A complicare il quadro, intervengono l'elevato numero di richieste in pa-zienti con bassa probabilità pre-test di malattia, la approssimativa definizione dei livelli decisio-nali, la non uniforme modalità di refertazione e la difficile interpretazione clinica dei risultati. Que-sta rassegna prende in esame i numerosi aspetti controversi che sono alla base della variabilità pre e post-analitica dei test per la determinazione degli anticorpi anti-fosfolipidi, la cui conoscenza è necessaria per una corretta interpretazione dei risultati e per la compilazione del referto. Summary Interpretation of antibody results in the anti-pho-spholipid syndrome. In the last 15 years the evaluation of anti-cardiolipin antibodies, anti-β 2-glicoprotein I and lupus anticoagu-lant has substantially improved the diagnostic and the-rapeutic approach in patients with an autoimmune ba-sed thromboembolic event. However, in spite of their clinical value, these tests are poorly reproducible due to the poor level of method standardization. Matters are complicated further by the high number of reque-sts from patients with low pre-test probability of di-sease, the approximate definition of decisional levels, the lack of uniformity in report modalities, and the difficult clinical interpretation of the results. This re-view analyzes the various controversial aspects of tests used to determine the anti-phospholipid antibodies and their fundamental role in the pre-and post-analytical variability, the knowledge of which is necessary in or-der to correctly interpret results and compile the me-dical report.
[Show abstract][Hide abstract] ABSTRACT: Anti-annexin A5 antibodies are directed against annexin A5 — a phospholipid-binding protein that belongs to the ubiquitous
annexin family. These antibodies were first discovered in 1994 by Matsuda et al. in women with recurrent fetal loss or preeclampsia
and in patients with systemic lupus erythematosus and positive lupus anticoagulant and/or anticardiolipin antibodies. Since
then anti-annexin A5 antibodies have been the focus of research. In addition to their well known prothrombotic and procoagulant
activities the authors discuss the involvement of these antibodies in the pathogenesis of antiphospholipid syndrome, recurrent
pregnancy loss, systemic lupus erythematosus and other immune and non-immune disorders. Controversial reports are presented
and a possible interpretation of the results is given. The authors suggest the significance of anti-annexin A5 antibodies
as an additional diagnostic marker and discuss the necessity of more extensive research on their clinical significance.
Central European Journal of Medicine 02/2009; 5(1):6-11. DOI:10.2478/s11536-009-0132-4 · 0.15 Impact Factor
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