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Women with criteria and non-criteria obstetric antiphospholipid syndrome (APS) carry an increased risk of pregnancy complications, including fetal growth restriction (FGR). The management of obstetric APS traditionally involves clinicians, obstetricians and gynaecologists; however, the most appropriate prophylactic treatment strategy for FGR prevention in APS is still debated. We performed a systematic review and network meta-analysis (NetMA) to summarize current evidence on pharmacological treatments for the prevention of FGR in APS. We searched PubMed and Embase from inception until July 2020, for randomized controlled trials and prospective studies on pregnant women with criteria or non-criteria obstetric APS. NetMA using a frequentist framework were conducted for the primary outcome (FGR) and for secondary outcomes (fetal or neonatal death and preterm birth). Adverse events were narratively summarised. Out of 1124 citations, we included eight studies on 395 pregnant patients with obstetric APS treated with low-dose aspirin (LDA) + unfractionated heparin (UFH) (n = 132 patients), LDA (n = 115), LDA + low molecular weight heparin (n = 100), LDA + corticosteroids (n = 29), LDA + UFH + intravenous immunoglobulin (n = 7), or untreated (n = 12). No difference among treatments emerged in terms of FGR prevention, but estimates were largely imprecise, and most studies were at high/unclear risk of bias. An increased risk of fetal or neonatal death was found for LDA monotherapy as compared to LDA + heparin, and for no treatment as compared to LDA + corticosteroids. The risk of preterm birth was higher for LDA + UFH + IVIg as compared to LDA or LDA + heparin, and for LDA + corticosteroids as compared to LDA or LDA + LMWH. No treatment was associated with an increased risk of bleeding, thrombocytopenia or osteopenia., (© 2021. The Author(s).)

Antiphospholipid syndrome (APS), which is characterized by the presence of antiphospholipid antibodies (aPL), is associated with increased risk of thrombosis and obstetric complications, including preterm delivery and recurrent pregnancy losses. APS shows diverse clinical manifestations and the risk of complications varies among clinical subtypes. Although these patients are usually treated with aspirin and anticoagulants, the optimal treatment in various clinical settings is unclear, as the risk of complications vary among clinical subtypes and the management strategy depends on whether the patient is pregnant or not. Also, there are unmet needs for the evidence-based, pregnancy-related treatment of asymptomatic women positive for aPL. This review focuses on the management of positive aPL or APS in pregnant and postpartum women, and in women attempting to become pregnant. For asymptomatic aPL positive women, no treatment, low dose aspirin (LDA) or LDA plus anticoagulants can be considered during antepartum and postpartum. In obstetric APS patients, preconceptional LDA is recommended. LDA plus low molecular weight heparin is administered after confirmation of pregnancy. Vascular APS patients should take frequent pregnancy test and receive heparin instead of warfarin after confirmation of pregnancy. During pregnancy, heparin plus LDA is recommended. Warfarin can be restarted 4 to 6 hours after vaginal delivery and 6 to 12 hours after cesarean delivery. Most importantly, a tailored approach and patient-oriented treatment are mandatory., Competing Interests: Lee EB has acted as a consultant to Pfizer, received research grants from GC Pharma and Handok Inc. The other authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

The specific value of IgA Anti-β2glycoprotein I antibodies (aB2GP1) in the diagnosis and management of antiphospholipid syndrome (APS) is still controversial and a matter of active debate. The relevance of the IgA aB2GP1 isotype in the pathophysiology of APS has been increasingly studied in the last years. There is well know that subjects with multiple positive APS tests are at increased risk of thrombosis and/or miscarriage. However, these antibodies are not included in the 2006 APS classification criteria. Since 2010 the task force of the Galveston International Congress on APS recommends testing IgA aB2GP1 isotype in patients with APS clinical criteria in the absence of criteria antibodies. In this review, we summarize the molecular and clinical "state of the art" of the IgA aB2GP in the context of APS. We also discuss some of the characteristics that may help to evaluate the real value of the IgA aB2GP1 determination in basic research and clinical practice. The scientific community should be aware of the importance of clarifying the role of IgA aB2GP1 in the APS diagnosis.

Antiphospholipid antibodies (aPLs) comprise a diverse family of autoantibodies targeted against proteins with the affinity toward negatively charged phospholipids or protein-phospholipid complexes. Their clinical significance, including prothrombotic potential of anti-cardiolipin antibodies (aCLs), anti-β2-glycoprotein I antibodies (aβ2-GPIs), and lupus anti-coagulant (LA), is well-established. However, the ontogeny of these pathogenic aPLs remains less clear. While transient appearance of aPLs could be induced by various environmental factors, in genetically predisposed individuals these factors may eventually lead to the development of the antiphospholipid syndrome (APS). Since the first description of APS, it has been found that a wide variety of microbial and viral agents influence aPLs production and contribute to clinical manifestations of APS. Many theories attempted to explain the pathogenic potential of different environmental factors as well as a phenomenon termed molecular mimicry between β2-GPI molecule and infection-relevant structures. In this review, we summarize and critically assess the pathogenic and non-pathogenic formation of aPLs and its contribution to the development of APS.

Direct oral anticoagulants (DOACs) are indicated in the treatment and prevention of venous thromboembolism (VTE). However, the use of DOACs in unusual VTE, including cerebral venous thrombosis (CVT) and splanchnic venous thrombosis (SVT), and in patients with biological thrombophilia including minor thrombophilia (Factor V Leiden and prothrombin G20210A), major innate thrombophilia (protein C and S deficiency, and antithrombin) and major acquired thrombophilia (antiphospholipid syndrome [APS]), remains controversial due to the paucity of available data. There are some reports of DOACs use in the initial treatment or long-term maintenance of patients with either CVT or SVT, but their efficacy remains unclear. The efficacy of DOACs may be suitable in patients with biological minor or major thrombophilia. The use of DOACs for the long-term maintenance of patients with APS is more contentious. Randomized clinical trials, which are currently underway, should offer definitive insight into the efficacy and safety profiles of DOACs in these patient populations., (Copyright © 2018. Published by Elsevier Ltd.)

DNA vaccines have recently emerged as a therapeutic agent for treating autoimmune diseases, such as multiple sclerosis. Antiphospholipid antibody syndrome (APS) is an autoimmune disease characterized by β2-glycoprotein I (β2-GPI)-targeting antiphospholipid antibodies (APAs) and vascular thrombosis or obstetrical complications. To examine the therapeutic potential of a β2-GPI DNA vaccine, we administered a vaccine mixed with FK506 as an adjuvant to a mouse model of obstetric APS. First, the pCMV3-β2-GPI DNA vaccine, which encodes the full-length human β2-GPI gene, was constructed. Then, we administered the β2-GPI DNA vaccine in 0.1 ml of saline, mixed with or without 100 μg of FK506, intramuscularly to the mice on days 28, 35 and 42. Blood titers of the anti-β2-GPI antibody, platelet counts, activated partial thromboplastin times (aPTTs), and the percentage of fetal loss were measured. We also stimulated murine splenic T cells ex vivo with β2-GPI and determined the T helper cell proportion and cytokine secretion. The administration of the β2-GPI DNA vaccine mixed with FK506 reduced the blood IgG anti-β2-GPI antibody titers and suppressed APS manifestations in mice. The combination also suppressed interferon-γ and interleukin (IL)-17A secretion but increased the Treg cell proportion and IL-10 secretion in murine splenic T cells following ex vivo stimulation with β2-GPI. Our results demonstrated the therapeutic efficacy of a β2-GPI DNA vaccine and FK506 as an adjuvant in a murine model of obstetric APS. Possible mechanisms include the inhibition of Th1 and Th17 responses and the up-regulation of Treg cells., Competing Interests: The authors have declared that no competing interests exist.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Antiphospholipid syndrome (APS) is a clinical disorder characterized by thrombosis and/or pregnancy morbidity in the persistence of the pathogenic autoantibodies, the antiphospholipid antibodies (aPL). Recurernt thrombosis is often observed in patients with APS which requires persistent prophylaxis. However, an uniform prophylactic treatment for APS patients is inadequate and stratification of the thrombotic risks is important as aPL are prevalently observed in other various diseases or elderly population. It is previously known that the multiple positivity or high titre of aPL correlate to the thrombotic events. To progress the stratification of the thrombotic risks and to quantitatively analyze them, antiphospholipid score (aPL-S) and the Global Anti-Phospholipid Syndrome Score (GAPSS) were defined as the scoring-systems. Both of these scoring-systems were raised from the large patient cohort data and either aPL profile classified in detail (aPL-S) or simplified aPL profile with classical thrombotic risk factors (GAPSS) were put into scoring system. They have shown a degree of accuracy in identifying high-risk APS patients, especially those at a high risk of thrombosis. However, there are several areas requiring improvement, or at least that clinicians should be aware of, before these instruments are applied in clinical practice. One such issue is standardisation of the aPL tests, including general testing of phosphatidylserine dependent antiprothrombin antibodies (aPS/PT).

In the antiphospholipid syndrome (APS), patients produce antiphospholipid antibodies (aPL) that promote thrombosis and adverse pregnancy outcomes. Current therapy with anticoagulation is only partially effective and associated with multiple complications. We previously discovered that aPL recognition of cell surface β2-glycoprotein I (β2-GPI) initiates apolipoprotein E receptor 2 (apoER2)-dependent signaling in endothelial cells and in placental trophoblasts that ultimately promotes thrombosis and fetal loss, respectively. Here we sought to identify a monoclonal antibody (mAb) to β2-GPI that negates aPL-induced processes in cell culture and APS disease endpoints in mice. In a screen measuring endothelial NO synthase (eNOS) activity in cultured endothelial cells, we found that whereas aPL inhibit eNOS, the mAb 1N11 does not, and instead 1N11 prevents aPL action. Coimmunoprecipitation studies revealed that 1N11 decreases pathogenic antibody binding to β2-GPI, and it blocks aPL-induced complex formation between β2-GPI and apoER2. 1N11 also prevents aPL antagonism of endothelial cell migration, and in mice it reverses the impairment in reendothelialization caused by aPL, which underlies the non-thrombotic vascular occlusion provoked by disease-causing antibodies. In addition, aPL inhibition of trophoblast proliferation and migration is negated by 1N11, and the more than 6-fold increase in fetal resorption caused by aPL in pregnant mice is prevented by 1N11. Furthermore, the promotion of thrombosis by aPL is negated by 1N11. Thus, 1N11 has been identified as an mAb that attenuates APS-related pregnancy complications and thrombosis in mice. 1N11 may provide an efficacious, mechanism-based therapy to combat the often devastating conditions suffered by APS patients.

Background: B factor (BF) from the alternative complement pathway seems to participate in the pathophysiology of systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS)., Objective: To study the allotypic variability of BF in SLE and their associations with clinical and autoantibodies profile., Methods: BF allotypes were determined by high-voltage agarose gel electrophoresis, under constant cooling, followed by immunofixation with anti-human BF antibody, in 188 SLE patients and 103 controls. Clinical and serological data were obtained from medical examination and records., Results: No significant differences of BF variants between patients and controls were found, neither in relation to epidemiologic or clinical manifestations. Associations of phenotype BF SS07 and allotype BF*S07 were found with anticardiolipin IgM (aCl-IgM) antibodies (p = 0.014 and p = 0.009 respectively), but not with aCl-IgG, lupus anticoagulant (LA), anti β2GPI or clinical APS. A significant decrease in BF*F allotype (p = 0.043) and BF SF phenotype (p = 0.018) was detected in patients with anti-phospholipid antibodies as a whole (aCl-IgG, aCl-IgM, LA and anti β2GPI)., Conclusions: There is a link between phenotype BF SS07 and allotype BF*S07 with aCl-IgM in SLE patients; BF*F allotype could be considered a marker of protection against the development of antiphospholipid antibodies in these patients., (© The Author(s) 2015.)

Background: Cryoglobulinemia is an immune-complex-mediated small vessel vasculitis that classically involves the skin, kidneys and peripheral nerves. Antiphospholipid syndrome (APS) is an autoimmune hypercoagulable disorder which causes blood vessel thrombosis. It can present as a multi-organ microthrombotic disorder which is called catastrophic APS., Objective: In this case series we aim to describe the diagnostic and management challenges that arise when these two severe disorders simultaneously present in the same patient., Methods: We describe four patients who were admitted to our hospital due to multi-organ life threatening damage mediated by cryoglobulinemic vasculitis with concurrent APS., Results: Clinical manifestations included leg ulcers, livedo reticularis, renal failure, and peripheral neuropathy. Suggested etiologies for the combined syndromes were hepatitis C, systemic lupus erythematosus and myeloproliferative disease rectal maltoma. All of our patients were treated with anticoagulation, high-dose corticosteroids, rituximab, intravenous gammaglobulins and plasma exchange., Conclusion: The rare association of severe or catastrophic APS with cryoglobulinemia in patients should be considered by physicians who treat patients with multi-organ ischemia or necrosis., (Copyright © 2014 Elsevier Editora Ltda. All rights reserved.)

Antiphospholipid syndrome (APS) is a clinical condition that has not been well defined yet. Although the clinical component is well established, the laboratory part is a mood issue. According to current guidelines, 3 tests (lupus anticoagulant, anticardiolipin, and anti β2-glycoprotein I antibodies) are officially recommended to assess the presence of antiphospholipid antibodies. According to test positivity, patients are classified into categories in clinical studies. However, it is now clear that classification categories have a different impact on the clinical course of APS. Indeed, patients and healthy carriers with a full positive antibody profile (triple positivity) are those at the highest risk of events. Patients with a single test positivity are those at a lower risk. In this review, on the basis of a laboratory profile, we grade the diagnosis of APS into definite, probable/possible, and uncertain. We also discuss secondary prevention of thrombotic APS, prevention of pregnancy morbidity, and treatment of catastrophic APS. Finally, new tools in laboratory diagnosis and treatment are highlighted.

A 35-year-old woman complained of headache, reduced visual acuity, restricted visual field in the right eye and blindness in the left eye. The examination of the retina showed papilledema and peripapillary hemorrhages in both eyes. Magnetic resonance imaging (MRI) revealed a sinus thrombosis. Despite modern imaging technologies sinus thrombosis is an often overlooked, life-threatening disease and needs immediate treatment in order to avoid long-term consequences. An ophthalmological examination can be pioneering as it leads to further imaging.

Renal transplantation in patients with antiphospholipid antibodies has historically proven challenging due to increased risk for thrombosis and allograft failure. This is especially true for patients with antiphospholipid antibody syndrome (APS) and its rare subtype, the catastrophic antiphospholipid antibody syndrome (CAPS). Since a critical mechanism of thrombosis in APS/CAPS is one mediated by complement activation, we hypothesized that preemptive treatment with the terminal complement inhibitor, eculizumab, would reduce the extent of vascular injury and thrombosis, enabling renal transplantation for patients in whom it would otherwise be contraindicated. Three patients with APS, two with a history of CAPS, were treated with continuous systemic anticoagulation together with eculizumab prior to and following live donor renal transplantation. Two patients were also sensitized to human leukocyte antigens (HLA) and required plasmapheresis for reduction of donor-specific antibodies. After follow-up ranging from 4 months to 4 years, all patients have functioning renal allografts. No systemic thrombotic events or early graft losses were observed. While the appropriate duration of treatment remains to be determined, this case series suggests that complement inhibitors such as eculizumab may prove to be effective in preventing the recurrence of APS after renal transplantation., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Treatment of pregnant women with antiphospholipid syndrome (APS) should be set apart from that from thrombotic APS patients. Patients with a history of pregnancy morbidity but no vascular thrombosis are usually treated with a prophylactic dose of heparin plus low-dose aspirin; whereas, those with previous vascular thrombosis alone or associated with previous pregnancy morbidity, are commonly treated with a therapeutic dose of heparin generally combined with low-dose aspirin. However, in about 20% of pregnant APS women these regimens fail. In this context, we conducted a case-control study on a large multicentre cohort of conventionally treated pregnancies to verify whether specific laboratory profiles and/or clinical characteristics are predictive of unsuccessful pregnancy outcome during conventional treatments. Multivariate analysis showed that pregnancy failure during conventional therapies was independently associated with a history of both thrombosis and pregnancy morbidity, the presence of systemic lupus erythematosus (SLE) or other systemic autoimmune diseases and triple antiphospholipid antibody positivity. With the aim to discover the most effective and safe treatments in high-risk pregnant APS women a large-scale multicentre study focusing on the effect of treatments on pregnancy outcome in women with APS and further risk factors for pregnancy failure has been designed.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity in the presence of circulating antiphospholipid antibodies (aPL). Different pathogenic mechanisms for aPL-mediated pregnancy failure have been proposed. In particular a direct effect of aPL on both maternal and fetal side of the placental tissue has been reported, since their reactivity with β2-glycoprotein I (β2GPI) makes them adhere to trophoblast and human endometrial endothelial cell (HEEC) membranes. β2GPI can be recognized by aPL that, once bound, interfere with both trophoblast functions and with the HEEC differentiation.APS patients can be successfully treated with Low Molecular Weight Heparin (LMWH). Recent reports suggest that LMWH acts through mechanisms alternative to its well known anticoagulant effect, because of its ability to bind β2GPI. In our previous studies, we showed that LMWH is able to reduce the aPL binding to trophoblasts and restore cell invasiveness and differentiation. So far, however, no study has described its effects on endometrial angiogenesis.The aim of our research was to evaluate whether two LMWHs, tinzaparin and enoxaparin, have an effect on the aPL-inhibited endometrial angiogenesis. This prompted us to investigate: (i) in vitro HEEC angiogenesis through a Matrigel assay; (ii) VEGF secretion by ELISA; (iii) matrix metalloproteinase-2 (MMP-2) activity by gelatin zymography; (iv) Nuclear Factor-κB (NF-κB) DNA binding activity by colorimetric assay; (v) STAT-3 activation by a sandwich-ELISA kit. Furthermore, using an in vivo murine model we investigated the LMWHs effects on angiogenesis.We demonstrated that the addition of LMWHs prevents aPL-inhibited HEEC angiogenesis, both in vitro and in vivo, and is able to restore the aPL inhibited NF-κB and/or STAT-3 activity, the VEGF secretion and the MMPs activity.The demonstration of a beneficial role for LMWHs on the aPL-inhibited HEEC angiogenesis might provide additional mechanisms whereby this treatment protects early pregnancy in APS.

Antiphospholipid (aPL)/anti-β(2) glycoprotein I (anti-β(2)GPI) antibodies stimulates tissue factor (TF) expression within vasculature and in blood cells, thereby leading to increased thrombosis. Several cellular receptors have been proposed to mediate these effects, but no convincing evidence for the involvement of a specific one has been provided. We investigated the role of Apolipoprotein E receptor 2 (ApoER2') on the pathogenic effects of a patient-derived polyclonal aPL IgG preparation (IgG-APS), a murine anti-β(2)GPI monoclonal antibody (E7) and of a constructed dimeric β(2)GPI I (dimer), which in vitro mimics β(2)GPI-antibody immune complexes, using an animal model of thrombosis, and ApoER2-deficient (-/-) mice. In wild type mice, IgG-APS, E7 and the dimer increased thrombus formation, carotid artery TF activity as well as peritoneal macrophage TF activity/expression. Those pathogenic effects were significantly reduced in ApoER2 (-/-) mice. In addition, those effects induced by the IgG-APS, by E7 and by the dimer were inhibited by treatment of wild-type mice with soluble binding domain 1 of ApoER2 (sBD1). Altogether these data show that ApoER2 is involved in pathogenesis of antiphospholipids antibodies.

Antiphospholipid syndrome (APS) had been previously diagnosed in three pregnant women aged 32, 27 and 36 years, respectively. All three of them were using low-molecular weight heparin for the prevention of thromboembolic complications. The first two women were admitted because of foetal growth retardation. In the first patient, either HELLP syndrome or exacerbation of APS was suspected. A caesarean section was performed due to foetal distress. The patient's condition deteriorated further postoperatively. Multiple infarctions in liver and placenta were identified. Catastrophic antiphospholipid syndrome (CAPS) was diagnosed. Despite intensive medical treatment including anticoagulation the patient died of massive pulmonary embolism. The second patient suffered from thrombocytopaenia, disturbances in hepatic function and epigastric pain. CAPS was diagnosed. The condition improved after treatment with glucocorticoids, but because of a poor foetal prognosis, delivery was induced and a lifeless son was born. The third woman was admitted due to pyelonephritis. Shortly thereafter, symptoms of HELLP syndrome developed and she was administered glucocorticoids. Hepatic infarcts and petechiae developed, indicating CAPS. Delivery was induced and a girl was born. Glucocorticoid treatment was resumed and combined with immunoglobulins and plasmapheresis. The patient recovered and was discharged together with her daughter. CAPS is a life-threatening variation of APS. It is characterised by multiple thromboses and rapidly progressive multi-organ failure. Mortality is high, but seems to diminish with treatment by immunosuppressive therapy. In pregnancy, clinical signs of CAPS are similar to those of HELLP syndrome. Since the treatment for HELLP syndrome is different from CAPS, a correct diagnosis is essential. Because of the rarity of this condition in combination with high rates of perinatal and maternal mortality, care for pregnant patients with APS should be centralised in academic centres and close cooperation between obstetricians and internal medicine is necessary.

The role of antiphospholipid syndrome (APS) in the pathogenesis of retinal vein occlusion has been discussed for several years. Conflicting results of the published studies are caused by small numbers of investigated patients and lack of control groups. We performed a meta-analysis of all case-control studies published up to July 2007 that investigated the prevalence of APS according to current diagnostic criteria for this syndrome.The results of meta-analysis show a significantly higher prevalence of APS in patients with retinal vein occlusion compared with controls. Patients with APS are treated with anticoagulants to reduce the risk of recurrence of thrombosis. Therefore, screening for APS seems to be indicated in all patients with retinal vein occlusion, and, in the case of a positive result, initiation of anticoagulation. For patients with retinal vein occlusion with APS, no data are currently available regarding the recurrence of thrombosis. To give a clear recommendation, a prospective randomized study is required to investigate the benefit of anticoagulation.

Background: Heparan sulphates play key roles in conception and early pregnancy events. The role of heparin, a structural analogue, and its application to assisted conception, is largely unknown., Methods: Relevant studies were identified by searching PubMed 1966-November 2007 and Google Scholar without limitations. Sensitive search strategies were combined with relevant medical subject headings and text words., Results: The similarities of heparin and heparan, the haemostatic changes induced by ovarian stimulation and the risk of thrombosis, the contribution of thrombophilia to pregnancy and infertility outcomes, early embryo-maternal dialogue and how these various aspects of assisted conception may be modified by heparin are reviewed., Conclusions: Heparin can alter the haemostatic response to controlled ovarian stimulation and modify the risk of thrombosis. It can also modulate many of the fundamental physiological processes required for blastocyst apposition, adherence and implantation and as well as trophoblast differentiation and invasion due to its similarities with heparan sulphates and has the potential to improve pregnancy rates and outcomes.

Antiphospholipid syndrome is one of the few treatable causes of pregnancy loss, and successful pregnancy rates of 70% or more can be achieved with appropriate treatment. Pregnancy in these women is associated with increased rates of preeclampsia, placental insufficiency, and preterm delivery. Several studies indicate that heparin, usually combined with low-dose aspirin, is beneficial in this indication. Recent works underlines the role of complement activation in a murine model of antiphospholipid pregnancy loss, which should be confirmed in Human.

Objective: This study was undertaken to determine whether BAFF blockade can be used to prevent or treat antiphospholipid syndrome in a mouse model., Methods: Eight- and 12-week-old (NZW x BXSB)F(1) mice were treated with BAFF-R-Ig or TACI-Ig alone or in addition to a short course of CTLA-4Ig. Mice were monitored for thrombocytopenia and proteinuria. Sera were tested for anticardiolipin antibodies (aCL), BAFF levels, and levels of soluble vascular cell adhesion molecule and E-selectin. Mice were killed at 17, 22, or 32 weeks of age, and kidneys and hearts were subjected to histologic examination. Spleen cells were phenotyped and enzyme-linked immunospot assays for autoantibody-producing B cells were performed., Results: Both BAFF-R-Ig and TACI-Ig prevented disease onset and significantly prolonged survival. Treated mice had significantly smaller spleens than controls, with fewer B cells and fewer activated and memory T cells. BAFF blockade did not prevent the development of aCL, and there was only a modest delay in the development of thrombocytopenia. However, treated mice had significantly less nephritis and myocardial infarcts than did controls., Conclusion: Our findings suggest that aCL are generated in the germinal center, which is relatively independent of BAFF. Effector function of antiplatelet antibodies was only modestly affected by BAFF blockade. In contrast, myocardial infarctions were prevented, suggesting that triggering of thromboses requires both autoantibodies and mediators of inflammation. Similarly, renal damage requires both immune complexes and effector cells. The dissociation between autoantibody production and inflammation that may occur with B cell-depleting therapies underscores the role of B cells as effector cells in the autoimmune response.

Juvenile systemic lupus erythematosus (JSLE) represents 15-20% of all SLE cases. The leading presenting symptoms of JSLE are constitutional and not specific such as fatigue, headache, weight loss or mood swings. They are also encountered in healthy adolescents, which explains frequent diagnosis delay. The frequency of irreversible damage is high in JSLE and involves especially the renal, musculoskeletal and neuropsychiatric systems. Although the overall prognosis has markedly improved, thanks to earlier diagnosis and new therapeutic approaches, cardiovascular, hematological events and chronic renal failure remain severe, and constitute the main disease-related causes of death. Treatment is based on hydroxycloroquine and corticosteroids. Immunosuppressive agents must be discussed to decrease the duration of corticosteroids use. New drugs and monoclonal antibodies targeting B-cells and B-cell related cytokines are being evaluated with encouraging results. Management of JSLE has to challenge three objectives: controlling disease progression, obtaining patient's adherence to treatment, and preventing consequences of medication side effects on growth, puberty, development and fertility. Patients' quality of life and psychosocial development have also to be taken into account, as well as the organization of a successful transition from paediatric to adult care.

Background: Patients with heparin-induced thrombocytopenia II (HIT II) need an alternative nonheparin-based method of anticoagulation for cardiopulmonary bypass (CPB) to prevent thrombosis and thrombosis related complications., Methods: Bivalirudin was used during CPB and deep hypothermic circulatory arrest (DHCA) for resection of multiple right atrial masses in a patient with HIT II and antiphospholipid antibodies syndrome (APS). Anticoagulation was monitored with the activated clotting time (ACT) and a target ACT of 450 seconds or greater was maintained., Results: Surgical removal of multiple right atrial masses was successful and there was no evidence of thromboembolic events. Clot was noticed in the cardiotomy and venous reservoir after CPB was discontinued and the system flushed. The postoperative course was uneventful., Conclusions: Anticoagulation was successfully managed with bivalirudin, a new short-acting, and direct thrombin inhibitor. Further studies are necessary to evaluate the safety of bivalirudin during DHCA.

Thromboembolic disease remains a leading cause of maternal mortality during pregnancy and the puerperium. Rational and risk-adapted administration of heparin prophylaxis depends on 1. the identification of those women who have an increased risk of thrombosis and 2. the accurate quantification of this risk. In women without prior thrombosis, the presence of a heterozygous factor V Leiden or heterozygous G20210A mutation in the prothrombin gene is associated with a pregnancy-associated thrombotic risk of approximately 1 in 400. Thus, in pregnant carriers of either one of these mutations the risk of venous thromboembolism is low. Therefore, no heparin prophylaxis is recommended. A combination of the two genetic risk factors can increase the risk to a modest level of 1 in 25. In women with a single episode of prior thrombosis associated with a transient risk factor, e.g. surgery or trauma, and no additional genetic risk factor, the probability of a pregnancy-associated thrombosis appears also to be low. However, data are sparse and conflicting. In contrast, in women with a prior idiopathic venous thrombosis who carry an additional hereditary risk factor or who have a positive family history of thrombosis, a high risk (>10%) can be expected supporting the indication for active antepartum and postpartum heparin prophylaxis. Despite the remarkable progress in risk stratification, the absolute magnitude of risk and the optimal management in many cases is an issue of ongoing debate.

Sexual hormones, particularly estrogens, appear to play a role in the development of SLE. Pregnancy as well as the use of exogenous sexual hormones prescribed as contraceptives, as substitutive therapy, or to induce ovulation can be associated with disease flares. However, pregnancy can be envisaged in SLE patients with well controlled disease, on the condition that medical follow-up is observed. To prevent fetal loss due to antiphospholipid syndrome prophylactic anticoagulation is required. The presence of maternal anti-SSA antibodies is an indication for a tight pregnancy follow-up for early detection of fetal cardiac conduction block. Finally, in the absence of antiphospholipid antibodies, oral contraception with low-dose estrogens and progestatives may be contemplated.

Numerous questions exist regarding the proper management of patients with the antiphospholipid antibody syndrome (APS). Several recent, randomized-controlled trials have been conducted that attempt to answer the fundamental questions of whom to treat, how to treat, and for how long treatment should last. These studies suggest that APS should be categorized by disease manifestations, and these presentations may have different treatment algorithms. A better understanding of the immune mechanisms that govern thrombosis in this syndrome has led to a wide array of innovative treatment approaches that will require meticulous study.

NZW "x" BXSB F1 mice develop SLE that is associated with an anti-phospholipid syndrome characterized by anti-cardiolipin antibodies, thrombocytopenia and small coronary artery thrombosis. This syndrome is immune mediated and, dependent, on CD4+T cells. To determine whether disease in these mice can be treated with blockade of T cell costimulation we treated them with the CD28 antagonist CTLA4Ig at 9 or 12 weeks of age. CTLA4Ig completely prevented both SLE nephritis and myocardial infarcts if it was given at 9 weeks of age, before anti-cardiolipin antibodies could be detected in the serum and prevented both B cell expansion and activation and the development of peripheral monocytosis. If treatment was delayed until 12 weeks of age after cardiolipin antibodies had arisen but before the onset of clinical disease, CTLA4Ig had very little effect on disease progression. These findings indicate that CD4+T cell activation through CD28 is critical for disease initiation in this model but plays little role in disease progression or tissue damage. These findings have relevance to the treatment of anti-phospholipid syndrome in humans.

The diagnosis of the antiphospholipid syndrome is based on well defined clinical and serological criteria. We report the results of a two-years observational study in our hospital focusing on the number of correct diagnosis, required to identify subjects in which prophylaxis or treatment is needed.

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.

Hypothetical circumstances that may require prophylaxis for a potential antiphospholipid syndrome (primary prophylaxis), or in some instances when there already had been some manifestations ofthe syndrome (secondary prophylaxis), were presented to a panel of experts for their consideration on potential prophylactic intervention. These were subsequently presented to the participants in the First International Consensus on Treatment of the Antiphospholipid Syndrome. In most instances there was consensus in adding low dose aspirin, an exception being aspirin allergy when other antiaggregants could be used in nonpregnant subjects. General measures to prevent thrombosis and other vasoprotective actions should also be provided. Higher risk of fetal loss or thrombosis called for anticoagulation with coumadin in nonpregnant subjects or subcutaneous low molecular weight heparin in pregnant ones. When indicated, prophylaxis of the antiphospholipid syndrome should be provided in systemic lupus erythematosus patients who are being treated for their disease. In no instance should corticosteroids or immunosuppresants be given as prophylactic of an antiphospholipid syndrome.

Objective: Antiphospholipid antibodies (aPL) are major risk factors for thrombosis. Other clinical factors exist in antiphospholipid syndrome (APS) patients which may have an additive or preventive effect on thrombosis. We therefore performed a cross-sectional study to analyse additive clinical thrombotic risk factors and possible preventive treatments in APS patients, and to compare the results with those obtained in asymptomatic aPL-positive (no history of vascular thrombosis or pregnancy morbidity) patients., Methods: We identified 77 APS patients with non-gravid thrombotic events (group A) and 56 asymptomatic aPL-positive patients (group B). The study periods were defined as 6 months prior to the time of first vascular event in group A and 6 months prior to the patient's last visit in group B. Medical records were reviewed to evaluate the incidence of hypertension, diabetes mellitus, hypercholesterolaemia, regular cigarette smoking, oral contraceptive use or hormone replacement therapy, surgical procedures, pregnancy with or without an APS-related event, malignancy and infections. In addition, any history of thrombocytopenia or the use of aspirin, hydroxychloroquine, corticosteroids or immunosuppressives during the study periods was recorded. Bivariate statistical analysis and logistic regression tests were performed to compare groups., Results: In group A, 75% (n=58) of patients and in group B 48% (n=27) of patients had at least one of the additional risk factors during the study periods. In the bivariate analysis, pregnancy (P=0.005) and surgical procedures (P=0.04) were significantly more frequent in group A, while aspirin (P<0.001), hydroxychloroquine (P<0.001) and corticosteroids (P=0.002) were used significantly more frequently in group B. In logistic regression, the probability of an event was decreased by taking aspirin and/or hydroxychloroquine. In women only, the probability of an event was increased with thrombocytopenia and pregnancy or surgical procedures. The incidences of hypertension and smoking and the presence of more than one risk factor were significantly associated with arterial thrombosis but not venous thrombosis., Conclusion: While traditional risk factors were similar between groups, pregnancy and surgical procedures increased the risk of thrombosis. Hypertension and smoking were associated with arterial events. Possessing a combination of risk factors may increase the occurrence of arterial thrombosis but not venous thrombosis. Use of aspirin and/or hydroxychloroquine may be protective against thrombosis in asymptomatic aPL-positive individuals.

The paper surveys literature referring to criteria of the antiphospholipid syndrome in obstetrics as well as to the pathomechanism and prophylactic treatment. Criteria of that syndrome were modified in 1999. Generally accepted are two clinical criteria--thromboembolic complications and recurrent pregnancy loss, as well as two laboratory criteria--presence of lupus anticoagulant and/or anticardiolipin antibodies in the medium or high titer. Thrombocytopenia is no longer treated as a criterion. Diagnosis is formulated on the basis of at least one clinical and one laboratory criterion. It is assumed that obstetric complications are the result of immunological reaction of antiphospholipid antibodies with antigen located in trophoblast or vascular endothelium of the spiral arteries. The elimination of the activity of placental anticoagulant--annexin V--is the main mechanism of local thrombosis and infractions in placenta. Improvement in the results of obstetrics care can be achieved through prophylactic treatment: from the beginning of pregnancy until delivery, acetylosalicylic acid (aspirin) is applied in low doses, i.e. 80 mg/24 h and low molecular weight heparin or standard heparin in low-doses. It is recommended that for 6 weeks after delivery oral anticoagulants should be used in prophylactic doses in cases of primary syndrome, and in the secondary syndrome even constant antithrombotic prophylaxis is advised.

Fluorinated quinolones exert their bactericidal activity by inhibiting bacterial type II topoisomerases. At therapeutic concentrations, quinolones superinduce interleukin-2 (IL-2) and interferon-gamma production by mitogen-activated human peripheral blood T lymphocytes. At the molecular level, a stronger activation of the nuclear factor AP-1 ('activator protein-1') is observed in cells incubated with ciprofloxacin, resulting in enhanced cytokine gene transcription. Several cytokine and immediate early (e.g., c-fos and c-jun) mRNAs are upregulated by ciprofloxacin, possibly reflecting a mammalian stress response. In cultures with murine splenocytes, quinolones enhance IL-3 and granulocyte-macrophage colony stimulating factor (GM-CSF) synthesis. The stimulation of these hematopoietic growth factors prolongs survival of mice with depressed bone marrow and prevents experimental antiphospholipid syndrome (APS). In contrast, quinolones inhibit both human and mouse monocytic IL-1 and TNF-alpha synthesis, an effect that is beneficial in rat experimental type II collagen induced arthritis and LPS-induced septic chock in mice. The intriguing immunomodulatory activities of fluoroquinolones warrant future investigations with new tailored derivatives.

Hemostatic aspects of antiphospholipid syndrome (APS) present unique challenges to clinicians and laboratory personnel alike, particularly in the perioperative period. These challenges are especially evident in patients requiring cardiac valve replacement surgery. However, the literature outlining the optimal approach in such patients is limited. We present the case of a 25-year-old woman with severe aortic regurgitation as a result of APS with particular reference to the precautions necessary during perioperative care. Particularly important are the prevention of thrombotic or hemorrhagic complications, management of associated thrombocytopenia, and laboratory methods of perioperative anticoagulation monitoring in the setting of prolonged clotting times.

Antiphospholipid syndrome (APS) is characterized by recurrent fetal loss, repeated thromboembolic phenomena, and thrombocytopenia. The syndrome is believed to be caused by antiphospholipid beta-2-glycoprotein-I (beta2GPI)-dependent Abs or anti-beta2GPI Abs by themselves. Using a hexapeptide phage display library, we identified three hexapeptides that react specifically with the anti-beta2GPI mAbs ILA-1, ILA-3, and H-3, which cause endothelial cell activation and induce experimental APS. To enhance the binding of the peptides to the corresponding mAbs, the peptides were lengthened to correspond with the site of the beta2GPI epitope being recognized by these mAbs. As a result, the following three peptides were prepared: A, NTLKTPRVGGC, which binds to ILA-1 mAb; B, KDKATFGCHDGC, which binds to ILA-3 mAb; and C, CATLRVYKGG, which binds to H-3 mAb. Peptides A, B, and C specifically inhibit both in vitro and in vivo the biological functions of the corresponding anti-beta2GPI mAbs. Exposure of endothelial cells to anti-beta2GPI mAbs and their corresponding peptides led to the inhibition of endothelial cell activation, as shown by decreased expression of adhesion molecules (E-selectin, ICAM-1, VCAM-1) and monocyte adhesion. In vivo infusion of each of the anti-beta2GPI mAbs into BALB/c mice, followed by administration of the corresponding specific peptides, prevented the peptide-treated mice from developing experimental APS. The use of synthetic peptides that focus on neutralization of pathogenic anti-beta2GPI Abs represents a possible new therapeutic approach to APS.

SLE is still the prototype experimental animal and human autoimmune disease. The clinical manifestations are so diverse that some have come to regard it as the incumbent 'luetic heir apparent' of the late 20th century. The aberrations of the immune disturbance have up until now defied clear explanation but have certainly generated a level of academic and research interest far greater than the frequency of the disease would initially suggest. The clear understanding of the immune derangements in SLE will probably lead to the understanding of the core mechanisms of the immune system and thus to better ways of its specific manipulation in the management of many other conditions including cancer. Research currently being undertaken on the mechanisms of control of immunologically mediated inflammation and the possible use of immunogenetic therapy in the treatment of various forms of SLE will hopefully further improve SLE related morbidity and mortality.

Experimental models for antipospholipid syndrome (APS) have been established recently in lupus-prone mice and induced in naive mice. The induction of APS is performed by passive infusion or active immunization of antiphospholipid antibodies (aPL) or the cofactor beta 2GP-1. High levels of diverse aPL develop in the animals in conjunction with clinical manifestations similar to the human disease, entailing low fecundity rate, fetal resorptions, thrombocytopenia, prolonged activated partial thromboplastin time, and neurological and behavioral impairments. The pathogenicity of aPL was confirmed in an in vivo thrombosis model. Immunomodulation of APS manifestations and treatment regimens in the experimental models are discussed.