Lupus anticoagulant and antibodies to beta 2-glycoprotein I, annexin V, and cardiolipin as a cause of recurrent spontaneous abortion

The prevalence of lupus anticoagulant (LAC), anticardiolipin (ACA), anti-beta(2) glycoprotein I (beta(2)GPI), and antiannexin V antibodies were determined in 200 recurrent spontaneous abortion (RSA) patients and 200 age-matched control women. ACA IgG was associated with early, while antiannexin V IgG and LAC were associated with late, and ACA IgG, antiannexin V IgG, and LAC were associated with combined early + late RSA, thereby recommending inclusion of their screening in RSA workout.     

Lupus anticoagulant as a marker of autoimmunity in recurrent pregnancy loss; a case report

We present a patient with primary antiphospholipid syndrome, as defined by nine pregnancy losses, the presence of lupus anticoagulant (LAC), and the absence of clinical signs and symptoms of autoimmunity. A successful pregnancy was achieved by treatment with low-dose prednisone (15 mg daily) and aspirin (100 mg daily). The patient was followed-up throughout her two last pregnancies and a 6 months postpartum period. Our data indicate that LAC serves as a marker of disease in women with previous pregnancy wastages, and that aspirin-prednisone therapy is beneficial in carefully selected patients.     

Correlation between trimester of fetal wastage and anti-cardiolipin antibody titer.

The existence of circulating lupus anticoagulant and anti-cardiolipin antibodies (ACA) has been reported to be associated with recurrent fetal loss. We used an enzyme-linked immunosorbent assay (ELISA) for detection of ACA in plasma samples from 104 women with a history of recurrent fetal loss. The normal range of the ACA level was defined as less than 6 GPL (IgG anti-cardiolipin) units (n = 100 normal plasma samples). Nine women (9.7%) were positive for ACA. The population was divided into two groups on the basis of medical history, and analysis revealed that 42.8% (3/7) of the group of patients with at least one fetal loss in the second or third trimester were positive for ACA; their mean ACA titer was 34 GPL units.     

Antiphospholipid antibodies in early repeated abortions: a case-controlled study

The relation among lupus anticoagulant (LAC), anticardiolipin antibodies (ACA), and repeated abortions was evaluated in a case-controlled study of 49 women with two or more unexplained spontaneous abortions (cases) compared with 141 control subjects, who had had one or more normal pregnancies and no previous spontaneous abortion. The women were admitted to the same hospital where the cases had been identified for acute conditions other than immunologic neoplastic, gynecologic or cardiovascular. LAC was detected in 7 out of 49 cases (14%, 95% confidence limits 8% to 26%) but in none of the 141 controls. Similarly, ACA were detected in four cases (8%, 95% confidence limits 0.3% to 30%) but no controls. These differences in frequency were statistically significant. These findings confirm that LAC and ACA are associated with a history of repeated abortions in clinically asymptomatic patients for immunologic conditions.     

Lupus anticoagulant in pregnancy

In a group of 10 women with circulating lupus anticoagulant 25 intrauterine deaths were previously documented in the nine multigravidae. The presence of lupus anticoagulant activity was confirmed by showing prolongation of the activated partial thromboplastin time and kaolin clotting time with failure of correction of the prolongation on incubation with normal plasma. A clinical diagnosis of systemic lupus erythematosus (SLE) was made in four women. Three had deep vein thrombosis in pregnancy, one chorea gravidarum while two had only recurrent fetal losses. All the women had positive antinuclear antibody tests and blood platelet counts less than 175 X 10(9)/l. Anti-smooth muscle antibody and VDRL tests were each positive in half the patients; anti-DNA antibody was present in two patients with clinically active SLE. In six pregnancies correction of the activated partial thromboplastin and kaolin clotting time was attempted using prednisone (40-60 mg/day); aspirin, 75 mg/day, was added. Five live infants were obtained, four by spontaneous delivery, when the restoration of the clotting abnormalities to normal was achieved. In one woman presenting with extensive deep vein thrombosis a live infant was delivered following therapeutic doses of heparin and low dose aspirin. Maternal lupus anticoagulant activity has major implications for pregnancy and should be excluded in women with a clinical suspicion of SLE, a positive antinuclear antibody test, thrombotic episodes, biologically false-positive VDRL and unexplained late or repetitive early fetal losses.     

肝素对反复妊娠丢失伴抗磷脂抗体阳性孕妇的疗效探讨

目的　探讨肝素治疗因抗磷脂抗体所致反复性妊娠丢失及对孕妇血液中抗体的影响。　方法　前瞻性地将 4 8例反复性妊娠丢失患者 (排除遗传、感染、内分泌及子宫附件等导致流产的其它因素 ) ,狼疮抗凝抗体 (lupusanticoagulation ,LA)和 /或抗心磷脂抗体 (anticardiolipinantibody ,ACA)阳性患者 ,就诊后一经诊断为妊娠即随机分为两组 ,各 2 4例 ,分别给予肝素 (研究组 )和小剂量阿司匹林加强的松 (对照组 )治疗 ,观察两组治疗前后LA和ACA的量和妊娠结局。　结果　 ( 1)研究组 2 4例中 ,2 1例足月产 ( 87.5 0 % )、2例早产 ( 8 33% )、新生儿Apgar评分 5min≥ 8分 ;1例流产( 4 .17% ) ,活婴 2 3例 ,活产率 95 .83% ( 2 3/2 4 ) ,与对照组的 19例足月产 ( 79.17% )相比 ,差异无显著性 (P >0 .0 5 )。 ( 2 )研究组 2 4例妊娠者中 17例抗体被清除 ,清除率为 70 .83% ,与对照组 2 9.17% ( 7/2 4 )比较 ,差异有显著性 (P <0 .0 1)。　结论　肝素对抗磷脂抗体所致的反复妊娠丢失治疗效果肯定 ,对清除抗体效果肯定     

Intravenous immunoglobulin therapy for aspirin-heparinoid-resistant antiphospholipid syndrome

We encountered a woman who had a history of repeated fetal losses and positive tests for lupus anticoagulant, phosphatidylserine-dependent antiprothrombin (aPS/PT) IgG, IgM and kininogen-dependent antiphosphatidylethanolamine (aPE) IgG, IgM. Her previous pregnancy had ended in intrauterine fetal death at 24 weeks of gestation despite a therapy of low-dose aspirin, prednisolone and danaparoid. During the present pregnancy, she was treated with repeated intravenous infusions of immunoglobulin (IVIg) together with low-dose aspirin, prednisolone and heparin. When thrombocytopenia developed, she delivered a female baby weighing 2,152 g at 34 weeks of gestation by cesarean section. Titers of aPS/PT IgM and aPE IgM were reduced or maintained at low levels by repeated IVIg therapies. The IVIg therapy might be effective for aspirin-heparinoid-resistant antiphospholipid syndrome.     

Treatment outcome in women suffering from recurrent miscarriages and antiphospholipid syndrome

OBJECTIVE: To evaluate the outcomes of treatment in patients suffering from recurrent spontaneous abortion and antiphospholipid syndrome. MATERIALS AND METHODS: 148 observed women suffering from recurrent abortion with presence of lupus anticoagulant antibodies (LA) and/or high moderate concentration of anticardiolipin antibodies (ACA) have been divided randomly into followed three treated groups: I--56 patients treated by low-dose of acetylsalicylic acid (LDA, 75 mg daily); II--39 patients treated by low molecular weight heparin (applied in dose of 20 g daily); III--53 patients treated by LDA and low molecular weight heparin simultaneously. RESULTS: It has been affirmed that coincidental application of low-dose of acetylsalicylic acid and low molecular weight heparin statistically more often increase the percentage of successful pregnancy in comparison with application of low molecular weight heparin or acetylsalicylic acid alone. In the group where only low-dose of acetylsalicylic acid was applied the success of pregnancy equaled 89.3%, in the group where only low molecular weight heparin was applied the successful pregnancy equaled 81.1% and in the group with acetylsalicylic acid and low molecular weight heparin being applied together the successful pregnancy equaled 92.5%. In has simultaneously been affirmed that the percentage of pregnancy loss is statistically higher in the women suffering from isolated occurrence of lupus anticoagulant antibodies (21.2%) in comparison with the women suffering from occurrence of anticardiolipin antibodies (6.7%) and anticardiolipin antibodies with lupus anticoagulant antibodies simultaneously. CONCLUSION: 1. Simultaneous application of low-doses of acetylsalicylic acid and low molecular weight heparin seems to be the best solution in patients suffering from recurrent spontaneous abortion and antiphospholipid syndrome. 2. The occurrence of anticardiolipin antibodies in the serum of blood in patients suffering from antiphospholipid syndrome is a better foretelling factor for the future pregnancy outcome than the occurrence of lupus anticoagulant antibodies.     

A prospective, controlled multicenter study on the obstetric risks of pregnant women with antiphospholipid antibodies.

OBJECTIVES: A prospective, controlled multicenter study was performed to estimate the obstetric risks of antiphospholipid antibodies (the lupus anticoagulant and anticardiolipin antibodies). In addition, the risks of prior thrombosis, obstetric history, systemic lupus erythematosus, and high-dose prednisone treatment were evaluated. STUDY DESIGN: After screening for antiphospholipid antibodies in patients with lupus erythematosus or women with prior fetal loss(es), 59 subsequent pregnancies with and 54 without these antibodies were followed. RESULTS: The presence of the lupus anticoagulant and a history of at least three spontaneous abortions could predict fetal loss (p = 0.032 and 0.001, respectively). In live born infants, a low birth weight could be predicted by the presence of anticardiolipin antibodies (p = 0.034), prior intrauterine fetal death (p = 0.025), and treatment with high-dose prednisone (p = 0.002). No relationships were seen between antiphospholipid antibodies and small-for-gestational-age newborns and pregnancy-induced hypertension or preeclampsia. The disappearance of antiphospholipid antibodies during pregnancy was not correlated with live birth. CONCLUSION: It is concluded that the presence of antiphospholipid antibodies is a risk factor for adverse pregnancy outcome.     

Plasmapheresis and pregnancy outcome in patients with antiphospholipid syndrome.

OBJECTIVE: To assess plasmapheresis with low dose prednisone on obstetric and neonatal outcomes among unsuccessfully treated pregnant women with documented antiphospholipid syndrome (APS). METHODS: Eighteen pregnant women received prednisone (10 mg/day) and plasmapheresis at 7.08+/-0.6 weeks of gestation, for 3 sessions per week, until lupus anticoagulant activity suppressed and IgG anticardiolipin lowered. Serial pulsatility indexes (PI) of umbilical and uterine arteries were performed. RESULTS: The live birth rate was 100%; mild pre-eclampsia 5.5%; preterm deliveries 22.22%; intrauterine growth restriction 11.11%; thrombocytopenia 5.5%; oligohydramnios and fetal distress 16.6%. There were no perinatal deaths, thrombotic events or lupus flare. Uterine artery PI was reduced and umbilical artery PI was >95th percentile. CONCLUSION: Plasmapheresis and low dose prednisone were associated with a low rate of obstetric and neonatal complications. Plasmapheresis may be used to treat pregnant women with documented APS when first lines (aspirin and/or heparin) fail to prevent pregnancy loss.     

Autoimmune antibodies and pregnancy outcome in women with false-positive syphilis test results. A retrospective controlled investigation of women from 5170 deliveries

Nine pregnant women with false-positive syphilis test results, and 13 matched controls, were screened for autoimmune antibodies to ascertain whether any relationship might exist between their presence and the occurrence of obstetric problems. Investigations included assays for anti-cardiolipin antibodies (ACA), lupus anticoagulant (LAC), anti-nuclear antibodies (ANA) (including antibodies against extractable nuclear antigen), anti-smooth muscle antibodies, anti-mitochondrial antibodies, anti-DNA antibodies, IgM-RF and complement factors. We found no significant difference in the incidence of obstetric problems between the two groups. Except that significantly more women were positive for ACA in the group with false-positive syphilis tests than in the control group, there were no differences between the groups with regard to the antibodies tested for. There was only one case of SLE, a patient positive for LAC, and who had had several miscarriages and no pregnancy resulting in a live birth. Our findings suggest that it would be unwarranted to devote resources to routine screening for these antibodies in healthy women with a false-positive syphilis test result, though the presence of LAC could possibly be used as an indicator of the risk of spontaneous abortion due to SLE.     

Fetal demise associated with lupus anticoagulant: clinical features and results of treatment

There are many reports in the literature associating lupus anticoagulant with fetal death. Successful pregnancies have been reported following suppression of the antibody by prednisone and the addition of antiaggregants and possibly anticoagulants. This report describes our experience treating such patients and the outcome of subsequent pregnancies. The results are less successful than the figures in the literature, 13 live births out of 27 pregnancies in 19 patients. This may be due to lupus anticoagulant being diagnosed as the cause for a wide variety of clinical presentations including habitual first trimester abortion, mid trimester fetal death, intrauterine growth retardation and placental dysfunction in the third trimester. Our experience shows that steroids and antiaggregants have a definite place in cases of second and third trimester fetal death and in cases of clinical systemic lupus erythematosus. However, lupus anticoagulant is one of a spectrum of autoantibodies whose pathophysiology has not been fully elucidated. It is questionable whether this regimen of treatment has a place in patients with no previous fetal loss or in cases of primary habitual abortion.     

Antiphospholipid autoantibodies in women treated for infertility

OBJECTIVE: To evaluate an occurrence of selected antiphospholipid antibodies (APL) in infertility women. STUDY DESIGN: An enzyme-linked immunoabsorbent assay (ELISA) has been used to determine a titre of anticardiolipin antibodies (ACA). APTT (activated partial thromboplastin time) and PT (prothrombin time) measurements and direct commercial assay have been also used to study occurrence of LAC (lupus anticoagulant antibodies). The group of 268 observed women has been divided into five subgroups according to the cause of infertility: I-endometriosis, II-tubal occlusion caused by others diseases than endometriosis, III-occurrence of antisperm antibodies (ASA), IV-polycystic ovariorum syndrome (PCOS) and V-unexplained etiology. Results have been compared to 44 healthy controls. RESULTS: Occurrence of ACA has been found statistically more often in patients suffering from infertility than in controls (17.9% vs 4.5%, p < 0.05). Moreover ACA have been statistically more often observed in patients with endometriosis (21 from 44, 47.7%). ACA were more common in patients with other cause of infertility (except PCOS) compared to controls, though statistically this was not significant. Frequency of ACA was also more common than LAC (17.9% vs 13.6%). Compared to controls LAC tests were more often positive in infertile women with endometriosis (I), tubal occlusion (II) and with the occurrence of antisperm antibodies (III) but results were not statistically significant. CONCLUSIONS: Antiphospholipid antibodies are observed more often in patients suffering from infertility compared to women with a regular fertility. This suggests a role of APL in etiology of infertility. The occurrence of anticardiolipin antibodies in almost every second woman suffering from endometriosis suggests existing of autoimmunologic disturbances in this disease.     

Control of the pulmonary circulation in the fetus and during the transitional period to air breathing.

During fetal life and the transition to extra-uterine air breathing, pulmonary vascular tone is regulated by a complex, interactive group of mechanisms. Arachidonic acid metabolites play an important role in this regulation. Although prostaglandins may not be central to regulation of the resting fetal pulmonary circulation, PGI2 acts to modulate tone and thereby maintain pulmonary vascular resistance relatively constant. PGI2 also may play an important role as one of the components involved in the major changes that occur with the onset of air breathing. Leukotrienes, also metabolites of arachidonic acid and potent smooth muscle constrictors, may play an active role in maintaining the normally high fetal pulmonary vascular resistance, because leukotriene receptor blockade or synthesis inhibition increases pulmonary blood flow about eight-fold; the presence of leukotrienes in fetal tracheal fluid further supports this. In addition to PGI2, vascular endothelial cells produce other vasoactive factors. These include potent vasodilators, such as endothelium-derived relaxing factor (EDRF). EDRF, known to be nitric oxide (NO) and often called endothelium-derived nitric oxide (EDNO), is produced by endothelial cells in response to varied stimuli, generally involving specific receptors and the activation of endothelial NO synthetase (eNOS); subsequent smooth muscle relaxation is produced by a NO/guanylyl cyclase/cGMP-mediated mechanism. NO clearly is involved in regulation of vascular tone in the fetal pulmonary circulation, although it plays a far more important role in the postnatal transition to air breathing. Superfused fetal sheep pulmonary arteries release NO when stimulated with bradykinin. In fetal lambs the vasodilating effects of bradykinin are attenuated by methylene blue and resting tone falls with N(omega)-nitro-L-arginine, an inhibitor of NO synthesis, suggesting that a NO/cGMP-dependent mechanism continuously modulates or offsets the increased tone of the resting fetal pulmonary circulation. Inhibition of NO synthesis blocks the pulmonary vasodilation with oxygenation of fetal lungs in utero. Shear stress-induced NO production as well as the relationship of oxygenation to NO production further support the important function of NO in the transition. Although endothelin-1 (ET-1) has potent vasoactivity as well as ontogenetic differences in effect on pulmonary vascular resistance, its exact physiological role has not been defined. Adrenomedullin and calcitonin gene-related peptide (CGRP), two additional vasoactive substances, have profound, and prolonged, vasodilating effects in the fetal pulmonary circulation. Their physiological roles have not yet been established.     

Fetal distress associated with the anticardiolipin antibody and a history of intrauterine fetal demise. A case report

A woman with a history of fetal demise, an elevated anticardiolipin antibody titer, lupus anticoagulant but no evidence of systemic lupus erythematosus received anticoagulation with heparin in adjusted subcutaneous doses. Daily fetal monitoring demonstrated reactive nonstress tests and normal biophysical profiles initially. At 30 weeks' gestation, however, repeated spontaneous decelerations developed, and fetal bradycardia necessitated delivery. The combination of a poor obstetric history and the presence of high cardiolipin antibody titers requires close fetal surveillance. The benefits of anticoagulation in this setting deserve further study.     

Antibodies to β2-glycoprotein I and annexin V in women with early and late idiopathic recurrent spontaneous abortions

Anti-phospholipid antibodies (APA) are heterogeneous group of autoantibodies that target phospholipid or phospholipid-binding proteins. APAs were previously shown to induce several thrombotic states, including idiopathic recurrent spontaneous abortion (RSA). Unlike the contribution of the classical lupus anticoagulant (LAC) and anticardiolipin antibodies (ACA), the contribution of anti-β2 glycoprotein 1 (β2GPI) and anti-annexin V antibodies to RSA risk remain poorly understood. We assessed anti-β2GPI and anti-annexin V IgM and IgG antibodies as RSA risk factors for RSA in 172 Tunisian women with >3 consecutive idiopathic pregnancy losses, together with 173 matched control women. The prevalence of anti-β2GPI IgG (P=0.41, OR=1.64) and IgM (P=0.50, OR=1.70) were comparable between cases and controls. Higher anti-annexin V IgG (P=0.02, OR=5.28), but not IgM (P=0.25, OR=1.78), levels were seen in cases. Regression analysis showed that anti-β2GPI IgM (OR=8.90; 95% CI=1.23–64.63) was associated with early RSA, while anti-annexin V IgG (OR=9.35, 95% CI=1.44–60.86) was associated with late RSA. For combined early + late RSA, the only variable selected was BMI (OR=0.93; 95% CI=0.87–0.99), and neither anti-annexin V nor anti-β2GPI IgM and IgG were associated with early + late RSA. Anti-annexin V and anti-β2GPI appear to be independent risk markers of RSA.     

Lupus and pregnancy

Systemic lupus erythematosus (SLE) disproportionately affects women in their reproductive age years. Pregnancy in this systemic autoimmune disease has long been associated with poor obstetric outcomes. However, the frequency of pregnancy loss in lupus has dropped to a level commensurate with that of the general US population. The outcomes of lupus pregnancies are better if conception is delayed until the disease has been inactive for at least 6 months, and the medication regimen has been adjusted in advance. Pregnancy in lupus is prone to complications, including flares of disease activity during pregnancy or in the postpartum period, preeclampsia, miscarriage, stillbirth, intrauterine growth retardation, and preterm birth. Active lupus nephritis poses the greatest risk. The recognition of a lupus flare during pregnancy may be difficult because the signs and symptoms may mimic those of normal pregnancy. Monitoring should include baseline and monthly laboratory tests, serial ultrasonography, fetal surveillance tests, and fetal m-mode echocardiography for mothers with SS-A (Ro) or SS-B (La) antibodies. In the absence of any signs or symptoms of active SLE, affected patients require no specific treatment during pregnancy. If hydroxychloroquine was in use before conception, it should be maintained throughout pregnancy. If a woman with SLE has antiphospholipid antibodies, prophylactic treatment with aspirin and/or low-molecular weight heparin is indicated to prevent fetal loss. Lupus flares during pregnancy are generally treated with hydroxychloroquine, low-dose prednisone, pulse intravenous methylprednisolone, and azathioprine. High-dose prednisone and cyclophosphamide are reserved for severe lupus complications but are associated with significant pregnancy-related complications and poor obstetrical outcomes.     

Lupus anticoagulant and pregnancy

A subset of women with a high rate of fetal wastage is identifiable among those with serologic but not necessarily clinical evidence of connective tissue disease. The presence of lupus anticoagulant in the plasma of a pregnant woman serves as a marker for a high rate of fetal wastage and risk of thrombosis. Lupus anticoagulant is best identified by the activated partial thromboplastin time or kaolin clotting time and can be specifically confirmed by the platelet neutralization procedure. Review of the obstetric literature indicates a total of 49 women with 160 unsuccessful pregnancies and 13 live births. Prednisone in immunosuppressive doses (40 to 60 mg/day) combined with low-dose aspirin (75 mg/day) has been demonstrated to be effective in suppressing activity of lupus anticoagulant in pregnant women and successful pregnancies have been obtained with this treatment. Lupus anticoagulant should be excluded in women with suspected collagen disease, with repeated early abortions and all unexpected late fetal losses.     

Prostacyclin production by human placental cells in short-term culture

Human placentae of varying gestational ages have been cultured in vitro with little variation in cell type and pattern of growth found. Cell types found are similar morphologically and histochemically to those previously described. The biological specificity of the cells in culture was also confirmed by human placental lactogen production. Placental cells in culture appear to synthesize and release PGI2 which can be identified by gas chromatography-mass spectrometry. Production of PGI2 was routinely measured by radioimmunoassay (RIA) for 6-oxo-PGF1alpha and 13,14-dihydro-6,15-dioxo-PGF1alpha in culture supernatants. Good agreement was found between RIA and gas chromatography-mass spectrometry measurements. PGI2 production in culture was not affected by mode of delivery, and synthetic capability was found to increase with gestational age. Production of PGI2 by cells from preterm and term placentae was similar but significantly greater than that of first-trimester cells. As the proportion of PGI2 produced in culture supernatants as 13,14-dihydro-6,15-dioxo-PGF1alpha changed with time of incubation, it appears pertinent to measure this metabolite when assessing total PGI2 production. Synthesis of PGI2 wa inhibited by the cyclo-oxygenase inhibitors indomethacin and aspirin and PGI2 synthetase inhibitor 15 hydroperoxyarachidonic acid. However, in the culture system tranylcypromine, a putative specific inhibitor of PGI2 synthetase, produced weak inhibition only before becoming cytotoxic. The cell culture system appears to offer a reliable and reproducible means for measuring placental PGI2 production in vitro and in which to study factors controlling its production and metabolism.     

Management of heparin-associated thrombocytopenia in pregnancy with subcutaneous r-hirudin

Heparin-induced thrombocytopenia type II is a serious, immune-mediated complication of heparin therapy. Due to its low cross-reactivity with heparin-associated antibodies (10-20%), danaparoid has successfully been administered in these patients. In recent studies, r-hirudin as a potent and specific thrombin inhibitor, was demonstrated to be a safe and effective anticoagulant. We report a pregnant woman with systemic lupus erythematosus and recurrent venous thromboembolism who suffered from heparin-induced thrombocytopenia type II while treated with dalteparin sodium. Positive cross-reactivities with danaparoid were found. Anticoagulation with 15 mg subcutaneous r-hirudin was performed twice daily from the 25th week of pregnancy until delivery. No thromboembolism or bleeding or fetal toxicity of r-hirudin was detected. Recombinant hirudin is a potent and specific thrombin inhibitor that can be used as a safe and effective anticoagulant in pregnancy.