Human reproductive failure is not a clinical feature associated with beta(2) glycoprotein-I antibodies in anticardiolipin and lupus anticoagulant seronegative patients (the antiphospholipid/cofactor syndrome)

It has been suggested that patients with clinical features suggestive of antiphospholipid syndrome but being lupus anticoagulant (LA) and anticardiolipin (aCL) negative, should be tested for antibodies to beta(2) glycoprotein-I (abeta(2)GP-I), a protein involved in the binding of antiphospholipid antibodies (aPL) to phospholipid surfaces. This was investigated in the present study where a total of 385 women aged 相似文献   

Anticardiolipin antibody levels in women undergoing first in vitro fertilization/embryo transfer

BACKGROUND: The clinical relevance of antiphospholipid antibodies (aPL) in women undergoing in vitro fertilization/embryo transfer (IVF/ET) and the role of IVF treatment in affecting antiphospholipid levels are controversial. The aim of this study was to evaluate anticardiolipin antibody (aCL) levels and the effect of IVF treatment on aCL in women undergoing their first IVF/ET cycle. METHODS: Immunoglobulin G (IgG)- and IgM-aCL were determined by enzyme-linked immunosorbent assay in 50 women undergoing IVF/ET, 18 due to endometriosis, 16 to tubal factor (TF) and 16 to male factor, before starting treatment (T0), on the day of oocyte retrieval (T1) and 14 days after ET (T2). A group of 31 age-matched fertile women served as controls. RESULTS: aCL levels detected at T0 in patients were not significantly different compared with the control group. IgG- but not IgM-aCL significantly increased at T2 in comparison with T0 (P < 0.001) and T1 (P < 0.05). The difference between T2 and T0 reached statistical significance in patients with endometriosis (P = 0.003) or TF (P = 0.018). No relationship was found between aCL and pregnancy. CONCLUSIONS: Our results indicate that IVF treatment increases IgG-aCL levels in patients with endometriosis and TF, but their presence seems to have no clinical relevance.     

Prevalence of autoantibodies in patients with recurrent miscarriages

PROBLEM: It is well known that the prevalence of several autoantibodies is higher in patients with recurrent miscarriages than in normal women. However, links between individual autoantibodies are unclear. The present study focuses on the possible association between beta 2-glycoprotein I (beta 2-GPI)-dependent anticardiolipin antibody (aCL), lupus anticoagulant (LA), and antinuclear antibody (ANA) in patients with recurrent miscarriages. METHOD OF STUDY: Three hundred and one patients, with a history of two or more unexplained miscarriages, were studied. The titers of beta 2-GPI-dependent aCL and LA were then compared between single-antibody-positive and three-antibody-positive groups. RESULTS: The prevalences of beta 2-GPI-dependent aCL, LA, and ANA were 3.3, 10.0, and 25.2%, respectively. Four of the 301 patients had all three antibodies. The LA titers in patients with positive values for three antibodies was significantly higher than in cases with only LA. CONCLUSION: beta 2-GPI-dependent aCL, LA, and ANA define three distinct, but partly related populations in patients with recurrent miscarriage. We should test at least two kinds of autoantibodies in recurrent aborters, because it has been found that, e.g., beta 2-GPI-dependent aCL and LA are predictors for miscarriages.     

Does the anti-prothrombin antibodies measurement provide additional information in patients with thrombosis?

The aim of this study is to get new insight into the relevance of IgG anti-prothrombin antibodies in patients with thrombosis and to determine whether human prothrombin alone (aPT) or complexed to phosphatidylserine (aPS/PT) should be preferentially used for measuring these antibodies by enzyme-linked immunosorbent assay (ELISA). To this end, prevalence of anti-prothrombin antibodies, their characteristics in terms of avidity and heterogeneity, and their relationship with anti-beta2 glycoprotein I antibodies (abeta2GPI) were studied in 152 patients with thrombosis. Patients were divided into two groups according to the presence or absence of antiphospholipid antibodies (aPL), called aPL+ or aPL-, respectively. In the aPL- group (n=90), the prevalence of anti-prothrombin antibodies was substantial (10%) but not significantly different from that of control (5%). In the aPL+ group (n=62), lupus anticoagulant (LA) or anticardiolipin antibodies (aCL) positive, 61% were positive for anti-prothrombin antibodies with no statistical difference between aPT and aPS/PT prevalence (42% vs. 55%, respectively). In the whole thrombotic population, 19% were only aPT and 34% only aPS/PT suggesting the presence of different antibodies. Absorption experiments confirmed the heterogeneity of aPT and aPS/PT. No difference in their avidity was demonstrated. From the aPL+ group, 60 were LA positive. Among them, 18% were negative for abeta2GPI and anti-prothrombin antibodies showing that the detection of these antibodies could not substitute for LA determination. In conclusion, our data show that the screening of the different anti-prothrombin antibodies is not warranted in the aPL+ group since these antibodies do not provide additional information compared to aCL, LA and/or abeta2GPI measurement. Nevertheless, the substantial prevalence of anti-prothrombin antibodies in the aPL- group should be further explored in a large prospective study.     

Autoantibody panel screening in recurrent miscarriages

PROBLEM: Antiphospholipid autoantibodies (aPL), antithyroid antibodies and anti-extractable nuclear antigens (anti-ENA) have all been reported to be associated with recurrent miscarriages (RM) and infertility. However, this association remained controversial. MATERIALS AND METHODS: Fifty-eight women with impaired fertility (38 women with RM and 20 women with infertility, but no miscarriages) and 28 control parous women were screened for seven autoantibodies [antithyroglobulin (aTG), antithyroid peroxidase (aTPO), anticardiolipin (aCL), antiphosphatidyl-serine (aPS), antiprothrombin antibodies (aPT), anti-beta 2 glycoprotein 1 (abeta2GP1), and anti-ENA]. There was no evidence for autoimmune diseases in the patients or the control. The analysis was also performed with several panels of autoantibodies, each of which contained two or more autoantibodies. RESULTS: Anti-TPO was the only antibody to be associated with RM (P = 0.01). A significant association was found between RM, and autoantibodies in the 'aTG + aTPO + anti-ENA' or 'aTG + aTPO' panels. The 'aTG + aTPO + anti-ENA' panel was also associated with RM when the analysis was performed only on 17 women who had secondary infertility: 10 from the 38 women with RM, and seven from the 20 women with infertility and no miscarriages. A significant association (P < 0.001) was also apparent between anti-CL and anti-PS and infertility compared with the 28 control women. CONCLUSIONS: RM was associated with autoantibodies to aTPO and the combined panel of aTPO, aTG and anti-ENA, but not with aPL. aPL were associated with infertility.     

The prevalence of antiphospholipid antibodies in cases of recurrent pregnancy loss

Antiphospholipid antibodies (aPL) are a diverse family of autoantibodies reactive against negatively charged phospholipid-protein complexes. The clinically significant members include lupus anticoagulant (LA), anticardiolipin antibody (aCL) and reaginic antibodies causing biological false positive (BFP) venereal disease laboratory test (VDRL). Although detected in various clinical scenarios, unexplained fetal loss in women of reproductive age group is the commonest association. Fifty pregnant women of first and second trimester with a history of two or more unexplained pregnancy losses were studied for the presence of LA, aCL and reaginic antibodies. Thirty pregnant women of the same trimester without any history of fetal loss were taken as control. LA was detected in nine (18%) cases and aCL in 12 (24%) cases of the study group. The control group was negative for any autoantibody. The prevalence of aPL in the study group found to be statistically significant. Detection of aPL must be considered in women with previous pregnancies complicated by unexplained fetal wastage.     

Incidence of anticardiolipin antibodies and lupus anticoagulant factor among women experiencing unexplained recurrent abortion and intrauterine fetal death

The aim of this research study was to estimate anticardiolipin (IgG & IgM) antibodies (aCL) and lupus anticoagulant (LA) factor in patients of recurrent unexplained pregnancy loss and intrauterine fetal deaths (IUFD). 82 women were selected for this study by virtue of having more than two consecutive unexplained pregnancy losses in their first trimester and were referred by the department of Obstetrics and Gynecology, King Saud Medical City Hospital, Riyadh, KSA. All patients had gone through a standardized investigation sequence. Lupus anticoagulants and Anticardiolipin antibodies (IgM and IgG) were detected in the serum by the enzyme linked immunosorbent assay method. To check the significance of aCL and LA, two-tailed t-test was done. Non parametric data was calculated either by Chi-Square test or Fischer exact test when relevant. Total 82 females grouped as 52 cases of recurrent (≥ 2) mainly first and second trimester miscarriage and 30 cases of recurrent (≥ 2) late intrauterine fetal death. Lupus anticoagulants was observed in twenty one (21) cases (25.6%) while anticardiolipin antibodies IgM and or IgG positive cases were estimated in forty four (44) cases (53.65%). The prevalence of APS in both studied group was thirty five (35) cases (42.68%). Antiphospholipid antibodies are calculated as the most important reason for recurrent abortion. The patients with unexplained recurrent pregnancy loss must be advised to go for a screening test for all this aPL antibodies.     

Anticardiolipin, other antiphospholipid antibody tests and diagnosis of the antiphospholipid syndrome

The frequent occurrence of false positive results in the anticardiolipin (aCL) enzyme linked immunosorbent assay (ELISA) hampers its application in identifying the antiphospholipid syndrome (APS), a condition characterized by a myriad of clinical presentations. This study highlights some of the pitfalls in the use of assays for antiphospholipid (aPL) antibody in clinical practice. The aCL ELISA, commercially prepared anti-beta2-gylcoprotein 1 (beta2-GP1) and antiphospholipid (APhL) assays were evaluated in the diagnosis of antiphospholipid syndrome (APS) in 94 pregnant women who had spontaneous abortion and a group of 177 healthy blood donors. Serological tests were used to rule out syphilis as the cause of false positive results in the aCL ELISA. The prevalences of positive aCL ELISA results (29/94, 31% v 26/177, 14%; p = 0.001) and aCL antibodies of the IgM isotype (19/94, 20% v 6/177, 3%; $p = 0.001$) were significantly higher in aborters compared to healthy subjects. The majority of the sera which were positive in the aCL ELISA were shown to be false positives as 93% (27/29) of aCL positive aborters and 67% (8/24) of aCL positive healthy subjects were negative in the anti-beta2-GP1 assay. Similarly, the sensitivity of the APhL ELISA was low and only 1% (1/94) of the sera of aborters and 6% (11/177) of healthy subjects were positive in this assay. The frequent occurrence of anticardiolipin antibodies of the authentic non-autoimmune variety and the low sensitivity of the other more specific aPL assays make the positive aCL ELISA difficult to interpret. We recommend that the diagnosis APS be made with strict adherence to the preliminary criteria for classification of APS.     

Clinical relevance of multiple antibody specificity testing in anti-phospholipid syndrome and recurrent pregnancy loss

We wanted to evaluate whether testing for anti-phosholipid antibodies other than anti-cardiolipin (aCL) and anti-beta-2 glycoprotein I (abeta2GPI) immunoglobulin (Ig)G and IgM identifies patients with recurrent pregnancy loss (RPL) who may be positive for anti-phospholipid syndrome (APS). In a cross-sectional study comprising 62 patients with APS, 66 women with RPL, 50 healthy blood donors and 24 women with a history of successful pregnancies, we tested IgM and IgG antibodies to phosphatidic acid, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl glycerol, phosphatidyl inositol and phosphatidyl serine with and without beta-2 glycoprotein I (beta2GPI) from a single manufacturer as well as aCL and abeta2GPI antibodies. Diagnostic accuracies of individual and combined anti-phospholipid (aPL) assays were assessed by computing sensitivities, specificities, positive predictive values and negative predictive values together with their 95% confidence intervals. There was a general trend for increased sensitivities in the presence of beta2GPI co-factor with significant effect for certain specificities. The overall combined sensitivity of the non-recommended aPL assays was not significantly higher than that of the aCL and aB2GPI tests. Multiple aPL specificities in RPL group is not significantly different from controls and therefore of no clinical significance.     

Primary prevention of thrombosis in subjects with positive antiphospholipid antibodies

A major cause of stroke, as well as other arterial and venous thromboembolic disease has been identified-the presence of antiphospholipid antibodies (aPL). Now it is possible to identify individuals positive for aPL and still free of thrombosis. The tests to measure aPL have been standardized (aCL by ELISA and LA by coagulometric assays) and they are routinely performed in patients with SLE and other connective tissue diseases and women with recurrent pregnancy loss. However, very little is known about the risk of thrombosis in individuals positive for aPL but still free of thrombosis. Should these individuals receive any treatment? If so, which one?     

In-vitro fertilization results from thirteen women with anti-sperm antibodies

Thirteen infertile women with high titres of spermagglutinatingantibodies in their serum and/or in cervical mucus underwentin-vitro fertilization (IVF) and embryo transfer (ET). Fertilizationoccurred in 68% of the oocytes in a serumfree medium. Eightpregnancies were obtained in 22 IVF cycles (36.4%). Anti-spermantibodies were found in the follicular fluids of 5 out of the11 women with circulating antibodies. Fertilization resultswere independent of both the localization and the level of anti-spermantibodies. From these data we can conclude that IVF-ET is asuitable treatment for long tasting female infertility linkedto anti-sperm immunity.     

Stress and stress-related hormones during in-vitro fertilization treatment

Whether stress and infertility are linked as cause or consequenceis unclear, and there is no consensus on the most appropriatemethods for measuring stress in infertile women. To addressthis question, we measured changes in biochemical and questionnaire-basedassessments of stress in infertile women. Median baseline, follicularphase and pre-operative serum prolactin (229, 311 and 457 mIU/1)cortisol (278, 369 and 496 nmol/1) and state anxiety score (38,40 and 49) respectively all increased during stimulated in-vitrofertilization (IVF) treatment There was no such increase ina control group having similar laparoscopic surgery unrelatedto infertility, or in women having unstimulated IVF withoutlaparoscopy, suggesting that anxiety levels are greatest instimulated IVF, increase as a result of the treatment, and areadequately reflected by state anxiety scores. Baseline serumprolactin in unstimu-lated IVF (384 mIU/I) was significantlyhigher than control (177 mIU/1), although this was not reflectedin serum cortisol or state anxiety score. Trait anxiety wasconstant within and between groups, suggesting that stress isnot contributing greatly to the infertility. Women who achieveda pregnancy had similar state anxiety scores to those who failed,suggesting that the degree of anxiety observed during IVF treatmentis unlikely to influence the chance of pregnancy. There wasa trend towards lower trait anxiety in women who became pregnant,but the numbers were small.     

Results of immunotherapy for patients with unexplained secondary recurrent abortions

Twenty-six unexplained secondary recurrent aborters underwent vaccinations by using their husband's mononuclear leukocytes according to the protocol adopted for primary recurrent aborters (group I). No mixed lymphocyte culture reaction-blocking antibodies (MLR-BAbs) detected by one-way MLR between spouses were observed in these patients prior to vaccination. In all 26 patients, MLR-BAbs appeared in their sera after vaccination with the husband's mononuclear leukocytes. Of 22 newly pregnant patients after vaccinations, pregnancy successfully continued in 20; thus, the success rate of the therapy was 90.9%. Pregnancy outcome was also analyzed in unexplained secondary recurrent aborters who revealed positive MLR-BAbs without immunotherapy (group II). In this group, in 9 of 12 patients (75.0%), the pregnancy continued successfully. The rate of continuation of pregnancy was not significantly different between groups I and II. Furthermore, the outcome of 11 pregnancies in 9 unexplained secondary recurrent aborters was analyzed in those who were negative for MLR-BAbs and had become pregnant without immunotherapy (group III). Pregnancy was successfully continued in only 2 cases (18.2%) in this group. The rate of successful pregnancy in experimental groups I and II was significantly higher compared with that in group III (P < 0.0005 and P < 0.01, respectively). Thus, immunotherapy using the husband's mononuclear leukocytes on unexplained secondary recurrent aborters with negative MLR-BAbs appears to be effective.     

Assay principles of antiphospholipid antibodies and heterogeneity of the antibodies

The antiphospholipid syndrome(APS) is characterized by predominant clinical features of venous and arterial thrombosis and recurrent pregnancy loss accompanied by antiphospholipid antibodies(aPL) such as anticardiolipin antibodies(aCL) and lupus anticoagulant(LA). In 1990, three individual research groups, including us, first reported that a 50 kD plasma cofactor is required for the binding of aCL to cardiolipin(CL) and now, beta 2-glycoprotein I(beta 2-GPI), which binds to anionic phospholipids(PLs), is widely believed to be the major antigen for aCL. It was also reported that epitopes for such aCL are cryptic and that they appear only when beta 2-GPI interacts with lipid membranes containing anionic PLs, such as CL and phosphatidylserine, or with a polyoxygenated polystyrene surface. In contrast, prothrombin was recently identified as the "true" antigen for LA. In this review paper, we would like to describe on specificity of aPL and also on a possible mechanism on autoantibody-dependent development of atherosclerosis.     

Detection of antiphospholipid antibodies by automated chemiluminescence assay

The laboratory diagnosis of antiphospholipid antibody syndrome (APS) requires the demonstration of antiphospholipid antibodies (aPL) by lupus anticoagulant (LAC) measured through coagulation assays, anticardiolipin IgG or IgM antibodies (aCL) and/or anti-β2-glycoprotein I IgG or IgM antibodies (anti-β2-GPI), usually detected by ELISA. In this study we tested aCL by a new automated system using the chemiluminescence principle. Our results showed that, while almost all the sera from APS patients, positive for IgG aCL and anti-β2-GPI by ELISA, were also positive for IgG aCl by chemiluminescence, only 30.13% of patients without clinical manifestations of APS, but positive for aCL and persistently negative for anti-β2-GPI (by ELISA) and LA, confirmed the positive test by chemiluminescence. This difference was highly significant (p<0.0001). Interestingly, this test also prompted to identify 20% of patients positive for LA, but persistently negative for both aCL and anti-β2-GPI IgG (ELISA). Thus, the new technology of automated chemiluminescence assay for measuring aPL may represent an useful tool to identify "true" APS patients.     

Tubal infertility and silent chlamydial salpingitis

Antibodies to Chlamydia trachomatis (serum IgG antibodies witha titre of at least 32) were detected in 141 (86.0%) of 164infertile women with tubal infertility (TF group) and in 20(28.6%) in 70 infertile women with normal tubes (NTF group).The difference was highly significant (P < 0.001), as wasthe difference in geometric mean titre of antibody-positivecases, 181 and 87, respectively. Pregnant, agematched womenwere used as controls. Significantly fewer of these women (P< 0.001) had antibodies, when compared with the TF group,60 (36.6%) of 164, but not when the comparison was made withthe NTF group, 31 (44.3%) of 70. There was a history of salpingitisin 64 (39.0%) of the 164 infertile women with damaged tubes.Neither the frequency nor the geometric mean titre of chlamydialantibodies differed between tubal factor infertility patientswith and without a history of salpingitis. Previous chlamydialinfection, reflected by serological markers, is strongly associatedwith tubal damage leading to tubal infertility. A large proportionof these cases run a silent course, since a majority of theantibody-positive patients with tubal infertility have neverhad salpingitis     

A Rational Basis for the Use of Combined Heparin/Aspirin and IVIG Immunotherapy in the Treatment of Recurrent IVF Failure Associated with Antiphospholipid Antibodies

PROBLEMS: 1) Does the administration of heparin and aspirin (H/A) in combination with intravenous immunoglobulin G (IVIG) improve in vitro fertilization (IVF) implantation and birth rates in patients with recurrent IVF failures? 2) Is the effect of such treatment related to the antiphospholipid antibody (APA) status of the patients concerned? METHOD OF STUDY: Subjects consisted of 89 women younger than 36 years of age whose infertility was a result of causes other than male infertility and who had experienced four or more failed IVF/embryo transfer procedures. Fifty-two women were APA+ (group A), and 37 were APA- (group B). All patients, regardless of their APA status, received H/A (5000 U sq bid), aspirin (81 mg po qd) from the inception of menotropin therapy along with IVIG (20 g) through a single infusion 3 to 10 days before egg retrieval. RESULTS: Twenty-two (42%) of group A and 7 (19%) of group B patients achieved live births (P = 0.020). CONCLUSIONS: IVF outcome is significantly improved when H/A and IVIG are administered to APA+ women with repeat IVF failures. APA- women do not seem to benefit from such treatment.     

Antiphospholipid antibodies as non-traditional risk factors in atherosclerosis based cardiovascular diseases without overt autoimmunity. A critical updated review

The role of antiphospholipid antibodies (aPL) associated with cardiovascular diseases has been extensively studied in autoimmune patients, however it was largely unknown whether and how aPL associate with coronary artery disease (CAD), ishemic stroke (IS) and peripheral artery disease (PAD) in non-autoimmune patients. The current review attempts to prioritize for the first time clinical studies based on cause-outcome and strengths relationships in reference to aPL and CAD/PAD, in addition to supplementing Brey's comprehensive review on IS with other, additional studies. Our overview indicates that all case-control and cross-sectional studies found an aPL association with CAD, PAD and IS, while cohort and nested case-control studies reported a prevailing negative risk association between aPL and IS (confirming Brey), with an unclear/unresolved risk association between aPL and CAD. The only cohort, follow-up study found in PAD reported on positive risk association between aPL and disease. The most frequently associated aPL in all studies reported, irrespective of disease, was aCL, with a less frequent association reported for LA, aβ2GPI and other aPL.     

Different Antiphospholipid Antibody Specificities are Found in Association with Early Repeated Pregnancy Loss Versus Recurrent IVF-Failure Patients

PROBLEM: Patients having in vitro fertilization and embryo transfer (IVF-ET) failures show an increased incidence of antiphospholipid (aPL) antibodies; but controversy exists whether aPL can induce IVF-failure. This study was designed to compare aPL specificities between recurrent IVF-failure patients versus repeated early pregnancy loss (RPL) patients. METHOD OF STUDY: Anticardiolipin (aCL), lupus anticoagulant (LA), antiphosphatidylserine (aPS), antiphosphatidylethanolamine (aPE), and antinuclear antibodies (ANA) were measured in 74 recurrent IVF-ET failure patients and compared with 273 early RPL patients ( < 10 weeks). RESULTS: An increased incidence of IgG-aPE and ANA was observed for both groups in comparison with controls. Patients with recurrent IVF-ET failure showed a significantly higher prevalence of IgG-aPS (P = 0.02) and IgG-aCL (P = 0.02) when compared with early RPL patients or controls. CONCLUSIONS: IgG-aPS and IgG-aCL may be responsible for some IVF-failures. Additional studies are needed to clarify the pathogenic role of IgG-aPS and IgG-aCL on IVF-ET failure.     

女性不孕与支原体、衣原体感染和抗精子抗体的相关性

目的研究支原体(ureaplasma urealyticum UU)、衣原体(chlamydia trachomatic CT)感染与抗精子抗体(antisperm antibodies ASAb)对女性不孕的影响.方法聚合酶链反应(PCR)法和ELISA法分别对128例原发性和195例继发性不孕患者的宫颈分泌物进行UU、CT和ASAb检测,同时选择健康已孕妇女96人作为对照组.结果不孕组UU、CT感染率、ASAb阳性率与对照组比均有显著性差异(P＜0.05);原发不孕组与继发不孕组UU、CT感染率、ASAb阳性率相比无显著性差异(P＞0.05);不孕组中UU、CT感染阳性患者ASAb阳性率明显高于UU、CT阴性患者(P＜0.01).结论女性生殖道UU、CT感染和ASAb与不孕有着密切的相关性,特别是继发性不孕患者尤为显著,且ASAb的产生与CT,UU感染有关.