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1.  Catastrophic antiphospholipid syndrome: a clinical review 
Journal of Nephropathology  2014;3(1):9-17.
Context: Catastrophic antiphospholipid syndrome (CAPS) is a rare life-threatening autoimmune disease characterized by disseminated intravascular thrombosis resulting in multiorgan failure.
Evidence Acquisitions: Directory of Open Access Journals (DOAJ), Google Scholar, PubMed (NLM), LISTA (EBSCO) and Web of Science have been searched.
Results: CAPS is due to antiphospholipid antibodies directed against a heterogeneous group of proteins that are associated with phospholipids. These autoantibodies activate endothelial cells, platelets, and immune cells, thereby promoting a proinflammatory and prothrombotic phenotype. Furthermore, antiphospholipid antibodies inhibit anticoagulants, impair fibrinolysis, and activate complements. Although CAPS can affect a variety of organs and tissues, the kidneys, lungs, central nervous system, heart, skin, liver, and gastrointestinal tract are most commonly affected. The systemic inflammatory response syndrome, likely to extensive tissue damage, accompanies CAPS. The most frequent renal manifestations are hypertension, proteinuria, hematuria, and acute renal failure.In the majority of patients with CAPS, a precipitating factor such as infection, surgery, or medication can be identified. Antiphospholipid antibodies such as lupus anticoagulant and antibodies against cardiolipin, β2-glycoprotein I, and prothrombin are serological hallmark of CAPS. Laboratory tests often reveal antinuclear antibodies, thrombocytopenia, and anemia. Despite widespread intravascular coagulation, blood films reveal only a small number of schistocytes. In addition, severe thrombocytopenia is uncommon.
Conclusions: Histologically, CAPS is characterized by acute thrombotic microangiopathy. CAPS must be distinguished from other forms of thrombotic microangiopathies such as hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, and heparin-induced thrombocyt openia. CAPS is associated with high morbidity and mortality. Therefore, an aggressive multidisciplinary treatment strategy is indicated. Anticoagulation, immunosuppression, plasma exchange, intravenous immunoglobulins, and anti-platelet agents, used in various combinations, have resulted in improved patient outcome.
PMCID: PMC3956908  PMID: 24644537
Catastrophic antiphospholipid; syndrome; Antiphospholipid antibodies; Thrombotic microangiopathy
2.  Mutations in Complement Regulatory Proteins Predispose to Preeclampsia: A Genetic Analysis of the PROMISSE Cohort 
PLoS Medicine  2011;8(3):e1001013.
Jane Salmon and colleagues studied 250 pregnant patients with SLE and/or antiphospholipid antibodies and found an association of risk variants in complement regulatory proteins in patients who developed preeclampsia, as well as in preeclampsia patients lacking autoimmune disease.
Pregnancy in women with systemic lupus erythematosus (SLE) or antiphospholipid antibodies (APL Ab)—autoimmune conditions characterized by complement-mediated injury—is associated with increased risk of preeclampsia and miscarriage. Our previous studies in mice indicate that complement activation targeted to the placenta drives angiogenic imbalance and placental insufficiency.
Methods and Findings
We use PROMISSE, a prospective study of 250 pregnant patients with SLE and/or APL Ab, to test the hypothesis in humans that impaired capacity to limit complement activation predisposes to preeclampsia. We sequenced genes encoding three complement regulatory proteins—membrane cofactor protein (MCP), complement factor I (CFI), and complement factor H (CFH)—in 40 patients who had preeclampsia and found heterozygous mutations in seven (18%). Five of these patients had risk variants in MCP or CFI that were previously identified in atypical hemolytic uremic syndrome, a disease characterized by endothelial damage. One had a novel mutation in MCP that impairs regulation of C4b. These findings constitute, to our knowledge, the first genetic defects associated with preeclampsia in SLE and/or APL Ab. We confirmed the association of hypomorphic variants of MCP and CFI in a cohort of non-autoimmune preeclampsia patients in which five of 59 were heterozygous for mutations.
The presence of risk variants in complement regulatory proteins in patients with SLE and/or APL Ab who develop preeclampsia, as well as in preeclampsia patients lacking autoimmune disease, links complement activation to disease pathogenesis and suggests new targets for treatment of this important public health problem.
Study Registration NCT00198068
Please see later in the article for the Editors' Summary
Editors' Summary
Most pregnancies culminate in the birth of a healthy baby but, sadly, about a quarter of women lose their babies during pregnancy. A common pregnancy-related medical problem that threatens the life of both baby and mother is preeclampsia. Mild and severe preeclampsia affects up to 10% and 1%–2% of pregnancies, respectively. Preeclampsia occurs because of a problem with the function of the placenta, the organ that transfers nutrients and oxygen from mother to baby and removes waste products from the baby. Although preeclampsia begins early in pregnancy, it is diagnosed by the onset of high blood pressure (hypertension) and the appearance of protein in the urine (proteinuria) after 20 weeks of pregnancy. Other warning signs include headaches and swelling of the hands and face. The only cure for preeclampsia is delivery, and labor is usually induced early to prevent eclampsia (seizures), stroke, liver and kidney failure, and breathing and blood vessel problems developing in the mother. Although delivery before 37 weeks of pregnancy is not generally recommended, in cases of preeclampsia it may be too dangerous for both the baby and the mother to allow the pregnancy to continue. Unfortunately when severe preeclampsia occurs in the second trimester, babies weighing only 500 grams may be delivered and they may not survive.
Why Was This Study Done?
Because the exact cause of preeclampsia is unknown, it is difficult to develop treatments for the condition or to find ways to prevent it. Many experts think that immune system problems—in particular, perturbations in complement activation—may be involved in preeclampsia. The complement system is a set of blood proteins that attacks invading bacteria and viruses. The activation of complement proteins is usually tightly regulated (overactivation of the complement system causes tissue damage) and, because preeclampsia may run in families, one hypothesis is that mutations (genetic changes) in complement regulatory proteins might predispose women to preeclampsia. In this study, the researchers test this hypothesis by sequencing genes encoding complement regulatory proteins in pregnant women with the autoimmune diseases systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (APL Ab) who developed preeclampsia. In autoimmune diseases, the immune system attacks healthy human cells instead of harmful invaders. Both SLE and APL Ab are characterized by complement-mediated tissue injury and are associated with an increased risk of preeclampsia and miscarriage.
What Did the Researchers Do and Find?
Two hundred fifty women with SLE and/or APL Ab were enrolled into the PROMISSE study (a multi-center observational study to identify predictors of pregnancy outcome in women with SLE and/or APL Ab) when they were 12 weeks pregnant and followed through pregnancy. Thirty patients developed preeclampsia during the study and ten more had had preeclampsia during a previous pregnancy. The researchers sequenced the genes for complement regulatory proteins: membrane cofactor protein (MCP), factor I, and factor H in these 40 patients. Seven women (18%) had mutations in one copy of one of these genes (there are two copies of most genes in human cells). Five mutations were alterations in MCP or factor I that are gene variants that increase the risk of hemolytic uremic syndrome, a disease characterized by blood vessel damage. The sixth mutation was a new MCP mutation that impaired MCP's ability to regulate complement component C4b. The final mutation was a factor H mutation that did not have any obvious functional effect. No mutations in complement regulatory proteins were found in 34 matched participants in PROMISSE without preeclampsia but, among a group of non-autoimmune women who developed preeclampsia during pregnancy, 10% had mutations in MCP or factor I.
What Do These Findings Mean?
These findings identify MCP and factor I mutations as genetic defects associated with preeclampsia in pregnant women with SLE and/or APL Ab. Importantly, they also reveal an association between similar mutations and preeclampsia in women without any underlying autoimmune disease. Taken together with evidence from previous animal experiments, these findings suggest that dysregulation of complement activation is involved in the development of preeclampsia. Although further studies are needed to confirm and extend these findings, these results suggest that proteins involved in the regulation of complement activation could be new targets for the treatment of preeclampsia and raise the possibility that tests could be developed to identify women at risk of developing preeclampsia.
Additional Information
Please access these Web sites via the online version of this summary at
Tommy's, a UK charity that funds scientific research into the causes and prevention of miscarriage, premature birth, and stillbirth, has information on preeclampsia
The March of Dimes Foundation, a nonprofit organization for pregnancy and baby health, has information on preeclampsia
The UK National Health Services Choices website also has information about preeclampsia
Wikipedia has pages on the complement system, on autoimmune disease, and on preeclampsia (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
More information on the PROMISSE study is available
PMCID: PMC3062534  PMID: 21445332
3.  Value of Isolated IgA anti-β2GPI Positivity in the Diagnosis of the Antiphospholipid Syndrome 
Arthritis and rheumatism  2013;65(12):3186-3193.
To examine the prevalence of isolated IgA anti-β2Glycoprotein I (anti-β2GPI) positivity and the association of these antibodies, and a subgroup that bind specifically to domain IV/V of β2GPI, with clinical manifestations of the Antiphospholipid Syndrome (APS) in three patients groups. The pathogenicity of IgA anti-β2GPI was also evaluated in a mouse model of thrombosis.
Patients with systemic lupus erythematosus (SLE) from a multiethnic, multicenter cohort (LUpus in MInorities, NAture versus nurture [LUMINA]) (n=558), patients with SLE from the Hopkins Lupus Cohort (n=215), and serum samples referred to the Antiphospholipid Standardization Laboratory (APLS) (n=5,098) were evaluated. IgA anti-β2GPI titers and binding to domain IV/V of β2GPI were examined by enzyme-linked immunosorbent assay (ELISA). CD1 mice were inoculated with purified IgA anti- β2GPI antibodies, and surgical procedures and ELISAs were performed to evaluate thrombus development and tissue factor (TF) activity.
A total of 198 patients were found to be positive for IgA anti-β2GPI isotype, and 57 patients were positive exclusively for IgA anti-β2GPI antibodies. Of these, 13 of 23 patients (56.5%) in the LUMINA cohort, 17 of 17 patients (100%) in the Hopkins cohort, and 10 of 17 patients (58.9%) referred to APLS had at least one APS-related clinical manifestation. Fifty-four percent of all the IgA anti-β2GPI positive serum samples reacted with domain IV/V of anti-β2GPI, and 77% of those had clinical features of APS. Isolated IgA anti-β2GPI positivity was associated with an increased risk for arterial thrombosis (p<0.001), venous thrombosis (p=0.015) and all thrombosis (p<0.001). The association between isolated IgA anti-β2GPI and arterial thrombosis (p=0.0003) and all thrombosis (p=0.0003) remained significant after adjusting for other risk factors for thrombosis. In vivo mouse studies demonstrated that IgA anti-β2GPI antibodies induced significantly larger thrombi and higher TF levels compared to controls.
Isolated IgA anti-β2GPI positive titers may identify additional patients with clinical features of APS. Testing for these antibodies when other antiphospholipid (aPL) tests are negative and APS is suspected is recommended. IgA anti-β2GPI antibodies directed to domain IV/V of β2GPI represent an important subgroup of clinically relevant antiphospholipids.
PMCID: PMC4048705  PMID: 23983008
4.  Isolated IgA Anti-β2 Glycoprotein I Antibodies in Patients with Clinical Criteria for Antiphospholipid Syndrome 
Journal of Immunology Research  2014;2014:704395.
Seronegative antiphospholipid syndrome (SNAPS) is an autoimmune disease present in patients with clinical manifestations highly suggestive of Antiphospholipid Syndrome (APS) but with persistently negative consensus antiphospholipid antibodies (a-PL). IgA anti-β2 Glycoprotein I (aB2-GPI) antibodies are associated with APS. However, they are not currently considered to be laboratory criteria due to the heterogeneity of published works and the use of poor standardized diagnostic systems. We have aimed to assess aPL antibodies in a group of patients with clinical manifestations of APS (C-APS) to evaluate the importance of the presence of IgA aB2GPI antibodies in APS and its relation with other aPL antibodies. Only 14% of patients with C-APS were positive for any consensus antibody, whereas the presence of isolated IgA aB2GPI antibodies was found in 22% of C-APS patients. In patients with arterial thrombosis IgA aB2GPI, antibodies were the only aPL antibodies present. Serologic profile in primary APS (PAPS) is different from systemic autoimmune disorders associated APS (SAD-APS). IgA aB2GPI antibodies are more prevalent in PAPS and IgG aB2GPI antibodies are predominant in SAD-APS. The analysis of IgA aB2GPI antibodies in patients with clinical manifestations of PAPS might avoid underdiagnosed patients and provide a better diagnosis in patients with SAD-APS. Laboratory consensus criteria might consider including analysis of IgA aB2GPI for APS diagnosis.
PMCID: PMC3987939  PMID: 24741618
5.  Antiphospholipid antibodies and HLA associations in primary Sjögren's syndrome. 
Annals of the Rheumatic Diseases  1992;51(4):495-498.
Blood samples from 65 patients with primary Sjögren's syndrome were evaluated for the presence of antiphospholipid antibodies. Increased levels of antiphospholipid antibodies were found in 13 of 65 (20%) of patients. These antiphospholipid antibodies were predominantly of the IgA isotype, in contrast with the IgG isotype antiphospholipid antibodies found in patients with systemic lupus erythematosus (SLE). The presence of IgA antiphospholipid antibodies in the patients with primary Sjögren's syndrome was not significantly associated with arterial or vascular thrombosis, nor peripheral or central nervous system vasculitis. There was no association with laboratory determined features such as lupus anticoagulant or false positive results of the Venereal Disease Research Laboratory (VDRL) test. Oligonucleotide specific DNA amplification and hybridisation with allele specific probes was used to examine the HLA-D antigens occurring in this group of patients with primary Sjögren's syndrome. Of 13 patients with antiphospholipid antibodies, seven had the genotype HLA-DR2/DR3. However, compared with the whole group of 65 patients with Sjögren's syndrome, no increased occurrence of haplotype DR2 or DR3 was noted. These results suggest that gene interaction between DR2 and DR3 may play a part in the production of antiphospholipid antibodies in patients with Sjögren's syndrome. In contrast with patients with SLE, the IgA antiphospholipid antibodies in patients with Sjögren's syndrome are not risk factors for thrombosis or vasculitis. The presence of IgA antiphospholipid antibodies in patients with Sjögren's syndrome probably reflects its production at mucosal sites of inflammation and the absence of vasculopathy may be due to the inability of IgA antibodies to activate complement.
PMCID: PMC1004699  PMID: 1586247
6.  Reappraisal of the Etiology of Extracorpuscular Non-Autoimmune Acquired Hemolytic Anemia in 2657 Hospitalized Patients with Non-Neoplastic Disease 
Unlike autoimmune hemolytic anemia (AIHA), literature on the etiological study of non-autoimmune hemolytic anemia (non-AIHA) is scarce. The incidence and prevalence of non-AIHA in different geographic regions are largely unknown perhaps owing to the lack of perspective investigation and different profiles of etiologies from different geographic regions. We aimed to examine the real-world etiology or mechanisms of the non-hereditary non-AIHA from a nationwide population-based administrative claim database in Taiwan.
The National Health Insurance Research Database of Taiwan was adopted for this research. The studied population was total inpatient claim records including both pediatric and adult patients, contributed by a population of 23 million insured individuals in Taiwan. From 2002 to 2008, we retrieved 3,903 patients having no pre-existing malignancy discharged after inpatient management for acquired hemolytic anemia, which was defined as coding in discharge diagnoses containing ICD-9-CM code 283. By contrast, ICD-9-CM code 282 and all of the sub-codes are for hereditary hemolytic anemias.
AIHA accounted for 32% of the total cases. Among 2,657 patients with non-AIHA, mechanical or microangiopathic mechanism accounted for 19% of cases; hemolytic-uremic syndrome (HUS) 4%, hemoglobinuria because of hemolysis from external causes such as paroxysmal nocturnal hemoglobinuria (PNH) and march hemoglobinuria 7%, and chronic idiopathic hemolytic anemia or other unspecified non-AIHA 69%. We looked further for specific etiology or mechanism for this group of patients with non-hereditary extrinsic non-AIHA (n = 2,657). The explanatory disease states or conditions were splenomegaly; alcohol use disorder (spur cell hemolysis); heart-valve prosthesis; malignant hypertension; disseminated intravascular coagulation; transfusion reaction; dengue fever-induced hemolytic anemia; direct parasitization; snake, lizard, or spider bite; and Wilson’s disease with internal toxin mechanism. All these cases can explain up to 34.6% of all the non-hereditary extrinsic non-AIHA cases. Fragmentation hemolysis (HUS, heart-valve prosthesis, malignant hypertension, and disseminated intravascular coagulation) accounted for 7.4% of non-AIHA hospitalized patients with non-neoplastic disease.
This article is the first one to clearly demonstrate that the non-neoplastic-induced HUS requiring hospitalization cases in Taiwan, which has a population of over 23 million were 110 over a span of seven years, 16 cases per year. Although the etiologies of non-AIHA are well known and described in the literature, this work added the statistical percentages of the various etiologies of non-AIHA in Taiwan.
PMCID: PMC3999811  PMID: 24808725
non-immune hemolytic anemia; anemia; hemolytic; etiology; causality; extracorpuscular; hospitalized; NHIRD
7.  601 Autoimmune Thrombocytopenic Purpura Associated with Common Variable Immunodeficiency 
Common variable immunodeficiency (CVID) is a condition characterized by antibody deficiency, and therefore susceptible to recurrent pyogenic infections, cancer and autoimmune diseases. It is a heterogeneous syndrome in primary immunodeficiencies and clinically the most important is often diagnosed in adulthood. Autoimmunity occurs in 5% of the general population, in patients with CVID the percentage increased to 20 to 48%, cytopenias being the most common cause of autoimmunity in these patients. Autoimmune thrombocytopenic purpura and autoimmune hemolytic anemia are the most common autoimmune consequences, occurring in 5% to 8% of all patients with CVID. Some patients develop these disorders before the diagnosis of CVID.
We present the case of a woman of 45 year old, with a history of lower respiratory tract and urinary tract infections in recurrent Pulmonary Tuberculosis. Enter the program short-course treatment strictly supervised for pulmonary tuberculosis with appropriate response. Autoinmune thrombocytopenic purpura refractory to steroids (WWTP) for performing splenectomy.
Anti DNA antibodies, anti nuclear, anti-protease, C. ANCA/PR3 antimieloperoxidasa, serology for hepatitis B, C, HIV negative. Serum immunoglobulins were as follow: IgG, 158 mg/dL (normal 700 to 1600), IgM, 55 mg/dL (normal 40–230), IgA, 36 mg/dL (normal 70–400), and, IgE, 38.7 IU/mL (normal 0–100) in more than 2 occasions with values below 2 standard deviations. CD4 T lymphocytes (19%) CD4/CD8 ratio (0.54).
Meets diagnostic criteria for Common Variable Immunodeficiency (CVID) and starting treatment with intravenous immunoglobulin at a dose of 400 mg/kg (every 21 days) with significant clinical improvement and has even managed to integrate into your daily activities. Today, he continues with danazol for WWTP. Therefore, CVID is necessary to consider in the differential diagnosis of autoimmune thrombocytopenic purpura and autoimmune hemolytic anemia in adults (1).
PMCID: PMC3513167
8.  Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice 
Journal of Clinical Investigation  2006;116(2):512-520.
Complement C5a, a potent anaphylatoxin, is a candidate target molecule for the treatment of inflammatory diseases, such as myocardial ischemia/reperfusion injury, RA, and the antiphospholipid syndrome. In contrast, up until now, no specific contribution of C5a and its receptor, C5aR, was recognized in diseases of antibody-dependent type II autoimmunity. Here we identify C5a as a novel key mediator of autoimmune hemolytic anemia (AIHA) and show that mice lacking C5aR are partially resistant to this IgG autoantibody–induced disease model. Upon administration of anti-erythrocyte antibodies, upregulation of activating Fcγ receptors (FcγRs) on Kupffer cells, as observed in WT mice, was absent in C5aR-deficient mice, and FcγR-mediated in vivo erythrophagocytosis was impaired. Surprisingly, in mice deficient in FcγRI and FcγRIII, anti-erythrocyte antibody–induced C5 and C5a production was abolished, demonstrating the existence of a previously unidentified FcγR-mediated C5a-generating pathway. These results show that the development of a full-blown antibody-dependent autoimmune disease requires C5a — produced by and acting on FcγR — and may suggest therapeutic benefits of C5 and/or C5a/C5aR blockade in AIHA and other diseases closely related to type II autoimmune injury.
PMCID: PMC1359043  PMID: 16453025
9.  Ocular disorders as the prevailing manifestations of antiphospholipid syndrome: a case series 
Cases Journal  2009;2:159.
Antiphospholipid syndrome is an autoimmune disorder characterized by either a history of vascular thrombosis (one or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ) or pregnancy morbidity in association with the presence of antiphospholipid antibodies. The systemic features of the syndrome are characterized by large variability depending on the affected organ(s). Among them, neurological and behavioural disturbances, dermatological features as livedo reticularis and renal, ocular, liver or valvular heart manifestations have been reported in antiphospholipid syndrome patients. However, studies on the frequency and clinical presentation of the ocular manifestations as the prevailing (first) sign of antiphospholipid syndrome in patients suffering from "unexplained" ocular disease are missing. Herein, we present three cases suffering from unexplained ocular disease as first manifestation of antiphospholipid syndrome.
Case presentation
All the three patients were referred to our department because of unexplained ocular features from the anterior or posterior segment and unexplained neuro-ophthalmologic symptoms. The first patient had bilateral retinal occlusive disease, the second and the third patient had unilateral nonarteritic anterior ischemic optic neuropathy with macular oedema. Moderate to high levels of antiphospholipid antibodies were detected in all of them at baseline as well as 6 to 12 weeks after initial testing confirming the presence of antiphospholipid antibodies. Anticoagulant treatment with acenocoumarol was instituted resulting in stabilization and/or improvement of ocular signs in all of them.
Due to the important diagnostic and therapeutic implications of antiphospholipid syndrome, the possibility of ocular features as the first clinical manifestation of antiphospholipid syndrome should be kept in mind of the physicians particularly in patients with no evident risk factors for ocular disease. In this case, prompt anticoagulant treatment and close follow-up seem to be essential for vision salvation and stabilization.
PMCID: PMC2783115  PMID: 19946530
10.  Catastrophic Antiphospholipid Syndrome with Severe Acute Thrombotic Microangiopathy and Hemorrhagic Complications  
Case Reports in Medicine  2013;2013:915309.
The catastrophic antiphospholipid syndrome (CAPS) is a rare life-threatening form of the antiphospholipid syndrome characterized by disseminated vascular thrombosis resulting in multiorgan failure. On an exceedingly rare occasion, CAPS can be associated with severe hemorrhagic manifestations. We report a young woman with a history of several spontaneous miscarriages who presented with menorrhagia and hemoptysis. The patient developed respiratory failure due to diffuse alveolar hemorrhage. Laboratory tests demonstrated severe hemolytic anemia, profound thrombocytopenia, markedly elevated fibrin degradation products, and renal failure. Blood films revealed numerous schistocytes. Serologic tests disclosed hypocomplementemia and autoantibodies directed against several nuclear antigens. Coagulation studies revealed lupus anticoagulant. Echocardiography demonstrated reduced ejection fraction and moderate to severe mitral and tricuspid regurgitation. The patient was diagnosed with CAPS with hemorrhagic manifestations in the setting of new-onset SLE. The patient was treated with hemodialysis, high-dose glucocorticoids, plasma exchange, intravenous cyclophosphamide, and rituximab. Over the ensuing four weeks, the combination therapy led to hematological, cardiopulmonary, and renal recovery. This exceedingly rare case emphasizes that hemorrhagic manifestations, severe microangiopathic hemolytic anemia, and profound thrombocytopenia can dominate the clinical picture in CAPS.
PMCID: PMC3872153  PMID: 24382968
11.  Utility of Antiphosphatidylserine/Prothrombin and IgA Antiphospholipid Assays in Systemic Lupus Erythematosus 
The Journal of rheumatology  2013;40(3):282-286.
Currently, 3 antiphospholipid assays are widely used clinically [lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-β2-glycoprotein I (anti-β2-GPI)]. LAC is the most specific assay, conferring the highest risk of thrombosis and pregnancy loss, but it cannot be validly performed in an anticoagulated patient. We investigated the usefulness of antiphosphatidyl-serine/prothrombin (anti-PS/PT) and its association with thrombosis. Anti-PS/PT is strongly associated with the presence of LAC. We also studied the association of IgA antiphospholipid isotypes and specific domains of β2-GPI with thrombosis in systemic lupus erythematosus (SLE).
Stored samples from patients with SLE, with and without past thrombosis, were assayed for antibodies to the whole β2-GPI protein (IgG/IgM/IgA), to β2-GPI domain 1 (IgG), to β2-GPI domain 4/5 (IgA), aCL (IgG/IgM/IgA), and anti-PS/PT (IgG, IgM, and IgG/M). LAC was detected using the dilute Russell’s viper venom time (dRVVT) with confirmatory testing.
Anti-PS/PT IgG and IgG/M and anti-β2-GPI IgG, IgM, and IgA were highly associated with a history of LAC by dRVVT (p < 0.0001). For all thrombosis, of the traditional ELISA assays, anti-β2-GPI IgA, IgG, and aCL IgA were most associated. Anti-PS/PT IgG and IgG/M had a similar magnitude of association to the traditional ELISA. For venous thrombosis, of the traditional ELISA, anti-β2-GPI (IgG and IgA), anti-PS/PT (IgG and IgG/M), and aCL IgA were associated. Again, anti-PS/PT (IgG and IgG/M) had the same magnitude of association as the traditional ELISA. For stroke, significant association was seen with anti-β2-GPI IgA D4/5.
In anticoagulated patients, where LAC testing is not valid, anti-PS/PT, either IgG or IgG/IgM, might serve as useful alternative tests to predict a higher risk of thrombosis. Anti-PS/PT antibodies were associated with all thrombosis and with venous thrombosis. IgA isotypes in secondary antiphospholipid syndrome are associated with thrombosis. Anti-β2-glycoprotein domain 1 was not shown to be associated with thrombosis in SLE.
PMCID: PMC3605900  PMID: 23378459
12.  Severe refractory autoimmune hemolytic anemia with both warm and cold autoantibodies that responded completely to a single cycle of rituximab: a case report 
Mixed warm and cold autoimmune hemolytic anemia runs a chronic course with severe intermittent exacerbations. Therapeutic options for the treatment of hemolysis associated with autoimmune hemolytic anemia are limited. There have been only two reported cases of the effective use of rituximab in the treatment of patients with mixed autoimmune hemolytic anemia. We report a case of severe mixed autoimmune hemolytic anemia that did not respond to steroids and responded to four weekly doses of rituximab (one cycle).
Case presentation
A 62-year-old Caucasian man presented with dyspnea, jaundice and splenomegaly. His blood work revealed severe anemia (hemoglobin, 4.9 g/dL) with biochemical evidence of hemolysis. Exposure to cold led to worsening of the patient's hemolysis and hemoglobinuria. A direct antiglobulin test was positive for immunoglobulin G and complement C3d, and cold agglutinins of immunoglobulin M type were detected. A bone marrow biopsy revealed erythroid hyperplasia. A positron emission tomographic scan showed no sites of pathologic uptake. There was no other evidence of a lymphoid or myeloid disorder. Initial therapy consisted of avoidance of cold, intravenous methylprednisolone and a trial of plasmapheresis. However, there was no clinically significant response, and the patient continued to be transfusion-dependent. He was then started on 375 mg/m2/week intravenous rituximab therapy. After two treatments, his hemoglobin stabilized and the transfusion requirement diminished. Rituximab was continued for a total of four weeks and led to the complete resolution of his hemolytic anemia and associated symptoms. At the patient's last visit, about two years after the initial rituximab treatment, he continued to be in complete remission.
To the best of our knowledge, this is the first reported case of mixed-type autoimmune hemolytic anemia that did not respond to steroid therapy but responded completely to only one cycle of rituximab. The previous two reports of rituximab use in mixed autoimmune hemolytic anemia described an initial brief response to steroids and the use of rituximab at the time of relapse. In both of these case reports, the response to one cycle of rituximab was short-lived and a second cycle of rituximab was required. Our case report demonstrates that severe hemolysis associated with mixed autoimmune hemolytic anemia can be unresponsive to steroid therapy and that a single cycle of rituximab may lead to prompt and durable complete remission.
PMCID: PMC3096571  PMID: 21504611
13.  A Case of Autoimmune Hemolytic Anemia Associated with an Ovarian Teratoma 
Journal of Korean Medical Science  2006;21(2):365-367.
Autoimmune hemolytic anemia associated with an ovarian teratoma is a very rare disease. However, treating teratoma is the only method to cure the hemolytic anemia, so it is necessary to include ovarian teratoma in the differential diagnosis of autoimmune hemolytic anemia. We report herein on a case of a young adult patient who had severe autoimmune hemolytic anemia that was induced by an ovarian teratoma. A 25-yr-old woman complained of general weakness and dizziness for 1 week. The hemoglobin level was 4.2 g/dL, and the direct and indirect antiglobulin tests were all positive. The abdominal computed tomography scan revealed a huge left ovarian mass, and this indicated a teratoma. She was refractory to corticosteroid therapy; however, after surgical resection of the ovarian mass, the hemoglobin level and the reticulocyte count were gradually normalized. The mass was well encapsulated and contained hair and teeth. She was diagnosed as having autoimmune hemolytic anemia associated with an ovarian teratoma. To the best of our knowledge, this is the first such a case to be reported in Korea.
PMCID: PMC2734022  PMID: 16614532
Teratoma; Ovary; Anemia, Hemolytic, Autoimmune
14.  Primary antiphospholipid syndrome: features of patients with raised anticardiolipin antibodies and no other disorder. 
Annals of the Rheumatic Diseases  1989;48(5):362-367.
Raised levels of serum antiphospholipid antibodies have most commonly been reported in patients with systemic lupus erythematosus (SLE). There remains, however, a group of patients with raised antiphospholipid antibody levels who do not have any other well defined disease, but do have clinical features associated with these raised antibodies. The clinical, haematological, and serological features of 20 such patients are reported. Antiphospholipid antibody levels were measured by a solid phase assay for anticardiolipin activity. Fourteen patients had raised IgG antiphospholipid antibodies, 12 had raised IgM, and six had both. Nine out of 19 had raised antinuclear antibody levels; however, non fulfilled criteria for the diagnosis of SLE. Seven patients had a history of venous thrombosis and five of definite or presumed arterial thrombosis-for example, stroke. Of the 15 female patients who underwent pregnancy, 12 experienced fetal loss with up to eight abortions each (mean 3.6). Six individuals had thrombocytopenia and four others had migraines. Other clinical features included livedo reticularis, cardiac and neuropsychiatric disorders, arthralgias, and Raynaud's phenomenon. These findings confirm that the clinical features of individuals with what may be called the 'primary antiphospholipid syndrome' are similar to those in patients with other diagnoses who have raised antiphospholipid antibodies. They indicate that the antiphospholipid syndrome may be related to SLE and other autoimmune diseases, but that, although it frequently overlaps with these disorders, it also exists as a distinct entity.
PMCID: PMC1003764  PMID: 2730164
15.  Double seronegative myasthenia gravis with antiphospholipid syndrome: a case report 
Myasthenia gravis is an autoimmune disease characterized by fluctuating muscle weakness. It is often associated with other autoimmune disorders, such as thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, and antiphospholipid syndrome. Many aspects of autoimmune diseases are not completely understood, particularly when they occur in association, which suggests a common pathogenetic mechanism.
Case presentation
We report a case of a 42-year-old Caucasian woman with antiphospholipid syndrome, in whom myasthenia gravis developed years later. She tested negative for both antibodies against the acetylcholine receptor and against muscle-specific receptor tyrosine-kinase, but had typical decremental responses at the repetitive nerve stimulation testing, so that a generalized myasthenia gravis was diagnosed. Her thromboplastin time and activated partial thromboplastin time were high, anticardiolipin and anti-β2 glycoprotein-I antibodies were slightly elevated, as a manifestation of the antiphospholipid syndrome. She had a good clinical response when treated with a combination of pyridostigmine, prednisone and azathioprine.
Many patients with myasthenia gravis test positive for a large variety of auto-antibodies, testifying of an immune dysregulation, and some display mild T-cell lymphopenia associated with hypergammaglobulinemia and B-cell hyper-reactivity. Both of these mechanisms could explain the occurrence of another autoimmune condition, such as antiphospholipid syndrome, but further studies are necessary to shed light on this matter.
Clinicians should be aware that patients with an autoimmune diagnosis such as antiphospholipid syndrome who develop signs and neurological symptoms suggestive of myasthenia gravis are at risk and should prompt an emergent evaluation by a specialist.
PMCID: PMC3917420  PMID: 24380508
Antibodies against acetylcholine receptor; Antibodies against muscle-specific receptor tyrosine-kinase; Antibodies against ryanodine receptor; Antibodies against titin; Antiphospholipid syndrome; Autoimmune disorders; Seronegative myasthenia gravis
16.  Autoimmunity in Wiskott–Aldrich Syndrome: An Unsolved Enigma 
Wiskott–Aldrich Syndrome (WAS) is a severe X-linked Primary Immunodeficiency that affects 1–10 out of 1 million male individuals. WAS is caused by mutations in the WAS Protein (WASP) expressing gene that leads to the absent or reduced expression of the protein. WASP is a cytoplasmic protein that regulates the formation of actin filaments in hematopoietic cells. WASP deficiency causes many immune cell defects both in humans and in the WAS murine model, the Was−/− mouse. Both cellular and humoral immune defects in WAS patients contribute to the onset of severe clinical manifestations, in particular microthrombocytopenia, eczema, recurrent infections, and a high susceptibility to develop autoimmunity and malignancies. Autoimmune diseases affect from 22 to 72% of WAS patients and the most common manifestation is autoimmune hemolytic anemia, followed by vasculitis, arthritis, neutropenia, inflammatory bowel disease, and IgA nephropathy. Many groups have widely explored immune cell functionality in WAS partially explaining how cellular defects may lead to pathology. However, the mechanisms underlying the occurrence of autoimmune manifestations have not been clearly described yet. In the present review, we report the most recent progresses in the study of immune cell function in WAS that have started to unveil the mechanisms contributing to autoimmune complications in WAS patients.
PMCID: PMC3399097  PMID: 22826711
Wiskott–Aldrich syndrome; autoimmunity; primary immunodeficiency; T lymphocytes; B lymphocytes
17.  Dendritic cells: An important link between antiphospholipid antibodies, endothelial dysfunction, and atherosclerosis in autoimmune and non-autoimmune diseases 
Clinical immunology (Orlando, Fla.)  2012;146(3):197-206.
The presence of dendritic cells, antigen-presenting cells that link innate and adaptive immunity, is necessary to generate and maintain the production of antiphospholipid antibodies in response to exposed intracellular phospholipids on the outer surface of apoptotic cells. In turn, antiphospholipid antibodies enhance dendritic cell-induced inflammatory and proatherogenic responses in a number of conditions that are associated with accelerated atherosclerosis, including diabetes, chronic kidney disease, periodontal infections, and aging. While altering dendritic cells by modifying the ubiquitin-proteasome system enhances antiphospholipid antibody production and leads to development of accelerated atherosclerosis and autoimmune features, inducing tolerance by dendritic cell manipulation leads to decreased atherosclerosis and thrombosis. Therefore, further translational studies are needed to understand the interplay between dendritic cells and antiphospholipid antibodies, and to develop potential new therapies for antiphospholipid syndrome and atherosclerosis. Here we review current experimental and translational studies that have examined the role of dendritic cells in antiphospholipid antibody formation and in antiphospholipid-associated atherosclerosis and thrombosis.
PMCID: PMC3904226  PMID: 23376063
dendritic cells; antiphospholipid antibodies; atherosclerosis; antiphospholipid syndrome
18.  Review on Effectiveness of Primary Prophylaxis in aPLs with and without Risk Factors for Thrombosis: Efficacy and Safety 
ISRN Rheumatology  2014;2014:348726.
Context. Antiphospholipid antibodies syndrome is an autoimmune disorder that is characterized by the association between presence of antiphospholipid antibodies and risk of thrombosis and/or pregnancy morbidity. Objectives. To systematically review the evidence for primary prophylaxis in patients with antiphospholipids antibodies syndrome or APS with or without other traditional risk factors of thrombosis when they did not have any thrombotic event yet. Methods. PubMed, the Cochrane Library, and Allied Health Literature were searched for studies that examined the efficacy and safety of primary prophylaxis in aPL patients from 1990 to February 2013. We examined literature looking at patients with aPLs with other risk factors for thrombosis and aPLs with no additional risk factors for thrombosis. Conclusion. We concluded that, in patients with aPLs, primary prophylaxes with HCQ and aspirin have been observed to reduce the frequency of thrombotic events in the case of asymptomatic aPL-positive patients with SLE. We also in this study concluded that LDA was effective in patients with autoimmune diseases. Independent cardiovascular risk factors include autoimmune defects such as SLE, rheumatoid arthritis, and atherosclerosis, where overall venous thrombosis will be induced by systemic inflammation. This review concludes that HCQ is an effective primary approach when compared to aspirin.
PMCID: PMC4040209  PMID: 24944829
19.  36-Year-Old Female with Catastrophic Antiphospholipid Syndrome Treated with Eculizumab: A Case Report and Review of Literature 
Case Reports in Hematology  2014;2014:704371.
Catastrophic antiphospholipid syndrome (CAPS) is a rare but potentially life-threatening condition characterized by diffuse vascular thrombosis, leading to multiple organ failure developing over a short period of time in the presence of positive antiphospholipid antibodies (aPL). CAPS is a severe form of antiphospholipid syndrome, developing in about 1% of cases of classic antiphospholipid syndrome, manifesting as microangiopathy, affecting small vessels of multiple organs. It is acute in onset, with majority of cases developing thrombocytopenia and less frequently hemolytic anemia and disseminated intravascular coagulation. Lupus anticoagulant and anticardiolipin antibodies have been reported as predominant antibodies associated with CAPS. Treatment options often utilized in CAPS include anticoagulation, steroids, plasma exchange, cyclophosphamide therapy, and intravenous immunoglobulin therapy. Even though the reported incidence of this condition is considered to be low, the mortality rate is approaching 50%. The high rate of mortality should warrant greater awareness among clinicians for timely diagnosis and treatment of this life-threatening condition. Studies have shown that complement activation plays a key role in the pathogenesis of aPL mediated thrombosis in CAPS. We report a case of a 36-year-old female admitted with clinical and laboratory findings consistent with CAPS successfully treated with eculizumab, a terminal complement inhibitor.
PMCID: PMC4214168  PMID: 25389502
20.  Prolonged extracorporeal membrane oxygenation therapy for severe acute respiratory distress syndrome in a child affected by rituximab-resistant autoimmune hemolytic anemia: a case report 
Autoimmune hemolytic anemia in children younger than 2 years of age is usually characterized by a severe course, with a mortality rate of approximately 10%. The prolonged immunosuppression following specific treatment may be associated with a high risk of developing severe infections. Recently, the use of monoclonal antibodies (rituximab) has allowed sustained remissions to be obtained in the majority of pediatric patients with refractory autoimmune hemolytic anemia.
Case presentation
We describe the case of an 8-month-old Caucasian girl affected by a severe form of autoimmune hemolytic anemia, which required continuous steroid treatment for 16 months. Thereafter, she received 4 weekly doses of rituximab (375 mg/m2/dose) associated with steroid therapy, which was then tapered over the subsequent 2 weeks. One month after the last dose of rrituximab, she presented with recurrence of severe hemolysis and received two more doses of rrituximab. The patient remained in clinical remission for 7 months, before presenting with a further relapse. An alternative heavy immunosuppressive therapy was administered combining cyclophosphamide 10 mg/kg/day for 10 days with methylprednisolone 40 mg/kg/day for 5 days, which was then tapered down over 3 weeks. While still on steroid therapy, the patient developed an interstitial pneumonia with Acute Respiratory Distress Syndrome, which required immediate admission to the intensive care unit where extracorporeal membrane oxygenation therapy was administered continuously for 37 days. At 16-month follow-up, the patient is alive and in good clinical condition, with no organ dysfunction, free from any immunosuppressive treatment and with a normal Hb level.
This case shows that aggressive combined immunosuppressive therapy may lead to a sustained complete remission in children with refractory autoimmune hemolytic anemia. However, the severe life-threatening complication presented by our patient indicates that strict clinical monitoring must be vigilantly performed, that antimicrobial prophylaxis should always be considered and that experienced medical and nursing staff must be available, to deliver highly specialized supportive salvage therapies, if necessary, during intensive care monitoring.
PMCID: PMC2726476  PMID: 19830103
21.  Immune-Related and Inflammatory Conditions and Risk of Lymphoplasmacytic Lymphoma or Waldenström Macroglobulinemia 
Chronic immune stimulation appears to be associated with lymphoplasmacytic lymphoma (LPL)-Waldenström macroglobulinemia (WM); however, available information is sparse. We conducted, to our knowledge, the most comprehensive study to date to evaluate associations between a personal or family history of many immune-related and/or inflammatory disorders and the subsequent risk of LPL-WM.
We used Swedish population-based registries to identify 2470 case patients with LPL-WM, 9698 matched control subjects, and almost 30 000 first-degree relatives of either case patients or control subjects. We evaluated a wide range of autoimmune, infectious, allergic, and inflammatory conditions. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for each condition by use of logistic regression.
An increased risk of LPL-WM was associated with a personal history of the following autoimmune diseases: systemic sclerosis (OR = 4.7, 95% CI = 1.4 to 15.3), Sjögren syndrome (OR = 12.1, 95% CI = 3.3 to 45.0), autoimmune hemolytic anemia (OR = 24.2, 95% CI = 5.4 to 108.2), polymyalgia rheumatica (OR = 2.9, 95% CI = 1.6 to 5.2), and giant cell arteritis (OR = 8.3, 95% CI = 2.1 to 33.1). An increased risk of LPL-WM was associated with a personal history of the following infectious diseases: pneumonia (OR = 1.4, 95% CI = 1.1 to 1.7), septicemia (OR = 2.4, 95% CI = 1.2 to 4.3), pyelonephritis (OR = 1.7, 95% CI = 1.1 to 2.5), sinusitis (OR = 2.7, 95% CI = 1.4 to 4.9), herpes zoster (OR = 3.4, 95% CI = 2.0 to 5.6), and influenza (OR = 2.9, 95% CI = 1.7 to 5.0). An increased risk of LPL-WM was associated with a family history of the following autoimmune or infectious diseases: Sjögren syndrome (OR = 5.0, 95% CI = 2.1 to 12.0), autoimmune hemolytic anemia (OR = 3.8, 95% CI = 1.1 to 13.2), Guillain–Barré syndrome (OR = 4.1, 95% CI = 1.8 to 9.4), cytomegalovirus (OR = 2.7, 95% CI = 1.4 to 5.3), gingivitis and periodontitis (OR = 1.9, 95% CI = 1.3 to 2.7), and chronic prostatitis (OR = 4.3, 95% CI = 1.7 to 11.1).
Personal history of certain immune-related and/or infectious conditions was strongly associated with increased risk of LPL-WM. The association of both personal and family history of Sjögren syndrome and autoimmune hemolytic anemia with risk of LPL-WM indicates the potential for shared susceptibility for these conditions.
PMCID: PMC2857799  PMID: 20181958
22.  IgA Anti-β2-Glycoprotein I Autoantibodies Are Associated with an Increased Risk of Thromboembolic Events in Patients with Systemic Lupus Erythematosus 
PLoS ONE  2010;5(8):e12280.
The clinical utility of testing for antiphospholipid antibodies (aPL) of IgA isotype remains controversial.
Methodology/Principal Findings
To address this issue, we reasoned that if IgA aPL contribute to the clinical manifestations of the antiphospholipid syndrome, then an association with thromboembolic events should manifest in patients whose only aPL is of IgA isotype. We performed a retrospective chart review of 56 patients (31 with systemic lupus erythematosus [SLE] and 25 without SLE) whose only positive aPL was IgA anti-β2-glycoprotein I (isolated IgA anti-β2GPI) and compared their clinical features with 56 individually matched control patients without any aPL. Patients with isolated IgA anti-β2GPI had a significantly increased number of thromboembolic events, as compared to controls. When patients were stratified into those with and without SLE, the association between isolated IgA anti-β2GPI and thromboembolic events persisted for patients with SLE, but was lost for those without SLE. Titers of IgA anti-β2GPI were significantly higher in SLE patients who suffered a thromboembolic event. Among patients with isolated IgA anti-β2GPI, there was an increased prevalence of diseases or morbidities involving organs of mucosal immunity (i.e., gastrointestinal system, pulmonary system, and skin).
The presence of isolated IgA anti-β2GPI is associated with an increased risk of thromboembolic events, especially among patients with SLE. IgA anti-β2GPI is associated with an increased prevalence of morbidities involving organs of mucosal immunity.
PMCID: PMC2924386  PMID: 20808864
23.  Prevalence of anti- beta2GPI antibodies and their isotypes in patients with renal diseases and clinical suspicion of antiphospholipid syndrome 
Journal of Nephropathology  2013;2(3):181-189.
Background: Antiphospholipid antibodies (aPL) are autoantibodies that are associated with a clinical state of hypercoagulability and diverse clinical manifestations collectively known as antiphospholipid syndrome (APS).
Objectives: To investigate the prevalence of anti-beta2glycoproteinI-antibodies (anti-β2GPI) and their isotypes in patients with renal diseases and clinical suspicion of antiphospholipid syndrome (APS).
Patients and Methods: This is a retrospective study in which we have analyzed the prevalence of anti-β2GPI and its isotypes in 170 patients on initial testing and in 29 patients repeated after 12 weeks for confirmation of APS.  The clinical information was provided by the treating physicians or retrieved from the clinical records. The tests for anti-β2GPI screening and its isotypes (IgG, IgM and IgA) detection were assessed.
Results: On initial samples, anti-β2GPI was positive in 118patients.  IgA-β2GPI positivity (93; 79%) was significantly higher than IgM and IgG isotypes.  Out of anti-β2GPI positive patients, clinical features in 95 patients were suggestive of APS or had SLE.  Of these, IgA isotypes was found in 66% (P = 0.010), IgM in 31% (P = 0.033), and IgG in 11% (P = 0.033). On repeat testing, anti-β2GPI was persistently found In 22 patients with a continual predominance of IgA-anti-β2GPI over IgM and IgG isotypes (91% vs. 45.5% and 18% respectively).
Conclusions:   Our results show that IgA-anti-β2GPI antibodies are the most prevalent isotypes in patients with renal disease or on renal replacement therapy in our population.  Thus inclusion of IgA-anti-β2GPI in the testing repertoire may increase the diagnostic sensitivity for APS in patients with renal diseases.
PMCID: PMC3891139  PMID: 24475447
IgA-anti-β2GPI; Anti-β2-glycoproteinI antibodies; Antiphospholipid syndrome; Arterio-venous-fistula-formation failures; Renal APS; Renal transplant recipients; systemic lupus erythematosus
24.  Catastrophic antiphospholipid antibody syndrome in a child with thrombotic microangiopathy 
Indian Journal of Nephrology  2012;22(4):310-313.
Thrombotic microangiopathic hemolytic anemia (TMHA) is not uncommon in clinical nephrology practice while antiphospholipid syndrome (APS) is uncommon. Although less than 1% of patients with APS develop catastrophic APS (CAPS), its potential lethal outcome because of thrombosis in multiple organs and subsequent multiorgan failure emphasizes its importance in nephrology practice. Here is a case of catastrophic APS in a 7-year-old girl, who presented to us with TMHA associated with antiphospholipid antibodies and subsequently died because of CAPS.
PMCID: PMC3495358  PMID: 23162280
Catastrophic antiphospholipid syndrome; renal failure; thrombotic microangiopathic hemolytic anemia
25.  Autoimmune hemolytic anemia predominantly associated with IgA anti-E and anti-c. 
Journal of Korean Medical Science  2002;17(5):708-711.
A patient with warm autoimmune hemolytic anemia (AIHA) due to predominance of immunoglobulin A (IgA) with an Rh specificity, considered to be the first case in Korea, is described. A 13-year-old male patient with severe hemolytic anemia showed a weak reactivity (1+) in the direct antiglobulin test (DAT) by using anti-IgG antiglobulin reagent. This finding, however, could not fully explain the patient's severe AIHA. When anti-IgA reagent was used for the DAT, strong reactivity (4+) was observed and free anti-E and anti-c autoantibodies were also detected by anti-IgA and anti-IgG reagents. The patient's hemoglobin began to rise with the administration of steroids. Because RBCs coated with multiple types of immunoglobulins are associated with more severe hemolysis than those only with IgG, the DATs using anti-IgA and other reagents are needed for the correct diagnosis when the result of DAT is not compatible with patient's clinical manifestations.
PMCID: PMC3054947  PMID: 12378029

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