Risk factors for thrombotic events in Korean patients with systemic lupus erythematosus.

Thrombotic events (TE), including deep vein thrombosis, stroke, and myocardial infarction, occur in 30-40% of patients with systemic lupus erythematosus (SLE) resulting in substantial morbidity and mortality. We explored the risk factors for TE in SLE patients. We analyzed data obtained during a prospective cohort based on the KORean lupus NETwork (KORNET) registry, and enrolled 259 SLE patients with clinical data available at the onset of SLE. TE was defined as the presence of arterial or venous thrombosis. Multivariate Cox-proportional hazards analysis was performed to investigate risk factors for TE. During a mean follow-up of 103.3 months (SD 53.4), 27 patients (10.4%) had a TE. In multivariate analysis, hypertension (hazard ratio [HR] 7.805, 95% confidence interval [CI]: 1.929-31.581; P = 0.004), anti-phospholipid syndrome (APS) (HR 12.600, 95% CI: 4.305-36.292; P < 0.001), mean daily prednisolone > 5 mg/day (HR 3.666, 95% CI: 1.318-10.197; P = 0.013), and SLICC/ACR Damage Index (SDI) score (HR 1.992, 95% CI: 1.465-2.709; P < 0.001) were significantly associated with the development of TE in SLE patients. Instead, use of an ACEi or ARB (HR 0.159, 95% CI: 0.043-0.594; P = 0.006) was a protective factor against TE development in these patients. In conclusion, hypertension, higher mean daily dose of prednisolone, diagnosis of APS, and higher SDI were risk factors for TE in patients with SLE. On the other hand, the use of an ACEi or ARB was associated with a reduced risk of TE.

Antiphospholipid antibodies and cerebrovascular thrombosis in the pediatric population: Few answers to many questions.

Most of the knowledge in pediatric antiphospholipid syndrome (APS) is derived from studies performed on the adult population. As in adults, antiphospholipid antibodies (aPL) can contribute to thrombosis, especially cerebrovascular thrombosis, in neonates and children. Since aPL have the potential to cross the placental barrier, and since the pediatric population is prone to infections, re-testing for their positivity is essential to specify their role in cerebrovascular thrombosis.In this review, we aimed at assessing the prevalence of aPL, criteria or non-criteria, in neonatal and childhood ischemic stroke and sinovenous thrombosis trying to find an association between aPL and cerebrovascular thrombosis in the neonatal and pediatric population. Also, we looked into the effect of aPL and anticoagulants/antiplatelets on the long term neurological outcomes of affected neonates or children. The questions regarding the prevalence of aPL among pediatric patients with cerebrovascular thrombosis, the relationship between the titers of aPL and incidence and recurrence of cerebrovascular events, the predictability of the long term neurological outcomes, and the most optimal anticoagulation plan are still to be answered. However, it is crucial for clinicians to screen neonates and children with cerebrovascular thrombosis for aPL and confirm their presence if positive.

CD40LG mutations in Vietnamese patients with X-linked hyper-IgM syndrome; catastrophic anti-phospholipid syndrome as a new complication.

BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a rare primary immunodeficiency caused by CD40 ligand defects. METHODS: We identified three patients with XHIGM in Ho Chi Minh City, Vietnam. Whole-exome sequencing, immunological analyses and western blot were performed to investigate phenotypic and genotypic features. RESULTS: Despite showing symptoms typical of XHIGM, including recurrent sinopulmonary infections, oral ulcers and otitis media, the diagnosis was significantly delayed. One patient developed anti-phospholipid syndrome, which has been documented for the first time in XHIGM syndrome. Two patients had elevated IgM levels and all of them had low IgG levels. Exome sequencing revealed mutations in the CD40LG gene: one novel splicing mutation c.156+2T>A and two previously characterised mutations (non-frameshift deletion c.436_438delTAC, stop-gain c.654C>A). Due to these mutations, the CD40 ligand was not expressed in any of the three patients, as demonstrated by western blot analysis. CONCLUSION: This is the first report of XHIGM syndrome in Vietnam indicates that an effective diagnostic strategy, such as sequencing analysis, contributes to reliable diagnosis and subsequent therapy.

Antiphospholipid antibodies and risk of post-COVID-19 vaccination thrombophilia: The straw that breaks the camel's back?

Antiphospholipid antibodies (aPLs), present in 1-5 % of healthy individuals, are associated with the risk of antiphospholipid syndrome (APS), which is the most common form of acquired thrombophilia. APLs may appear following infections or vaccinations and have been reported in patients with COronaVIrus Disease-2019 (COVID-19). However, their association with COVID-19 vaccination is unclear. Notably, a few cases of thrombocytopenia and thrombotic events resembling APS have been reported to develop in recipients of either adenoviral vector- or mRNA-based COVID-19 vaccines. The aim of this review is therefore to speculate on the plausible role of aPLs in the pathogenesis of these rare adverse events. Adenoviral vector-based vaccines can bind platelets and induce their destruction in the reticuloendothelial organs. Liposomal mRNA-based vaccines may instead favour activation of coagulation factors and confer a pro-thrombotic phenotype to endothelial cells and platelets. Furthermore, both formulations may trigger a type I interferon response associated with the generation of aPLs. In turn, aPLs may lead to aberrant activation of the immune response with participation of innate immune cells, cytokines and the complement cascade. NETosis, monocyte recruitment and cytokine release may further support endothelial dysfunction and promote platelet aggregation. These considerations suggest that aPLs may represent a risk factor for thrombotic events following COVID-19 vaccination, and deserve further investigations.

Exosome-Contained APOH Associated With Antiphospholipid Syndrome.

Background: Antiphospholipid syndrome (APS) is a systemic autoimmune disease that can lead to thrombosis and/or pregnancy complications. Exosomes, membrane-encapsulated vesicles that are released into the extracellular environment by many types of cells, can carry signals to recipient cells to affect angiogenesis, apoptosis, and inflammation. There is increasing evidence suggesting that exosomes play critical roles in pregnancy. However, the contribution of exosomes to APS is still unknown. Methods: Peripheral plasma was collected from healthy early pregnancy patients (NC-exos) and early pregnancy patients with APS (APS-exos) for exosome extraction and characterization. The effect of exosomes from different sources on pregnancy outcomes was determined by establishing a mouse pregnancy model. Following the coincubation of exosomes and human umbilical vein endothelial cells (HUVECs), functional tests examined the features of APS-exos. The APS-exos and NC-exos were analyzed by quantitative proteomics of whole protein tandem mass tag (TMT) markers to explore the different compositions and identify key proteins. After incubation with HUVECs, functional tests investigated the characteristics of key exosomal proteins. Western blot analysis was used to identify the key pathways. Results: In the mouse model, APS-exos caused an APS-like birth outcome. In vitro experiments showed that APS-exos inhibited the migration and tube formation of HUVECs. Quantitative proteomics analysis identified 27 upregulated proteins and 9 downregulated proteins in APS-exos versus NC-exos. We hypothesized that apolipoprotein H (APOH) may be a core protein, and the analysis of clinical samples was consistent with finding from the proteomic TMT analysis. APOH-exos led to APS-like birth outcomes. APOH-exos directly enter HUVECs and may play a role through the phospho-extracellular signal-regulated kinase pathway. Conclusions: Our study suggests that both APS-exos and APOH-exos impair vascular development and lead to pregnancy complications. APOH-exos may be key actors in the pathogenesis of APS. This study provides new insights into the pathogenesis of APS and potential new targets for therapeutic intervention.

Micronized / ultramicronized palmitoylethanolamide (PEA) as natural neuroprotector against COVID-19 inflammation.

Coronavirus Disease 2019 (COVID-19) is upsetting the world and innovative therapeutic solutions are needed in an attempt to counter this new pandemic. Great hope lies in vaccines, but drugs to cure the infected patient are just as necessary. In the most severe forms of the disease, a cytokine storm with neuroinflammation occurs, putting the patient's life at serious risk, with sometimes long-lasting sequelae. Palmitoylethanolamide (PEA) is known to possess anti-inflammatory and neuroprotective properties, which make it an ideal candidate to be assumed in the earliest stage of the disease. Here, we provide a mini-review on the topic, pointing out phospholipids consumption in COVID-19, the possible development of an antiphospholipid syndrome secondary to SARS-CoV-2 infection, and reporting our preliminary single-case experience concerning to a 45-year-old COVID-19 female patient recently treated with success by micronized / ultramicronized PEA.

Hematologic autoimmune disorders in the course of COVID-19: a systematic review of reported cases.

OBJECTIVE: As COVID-19 is a new emerging disease, the hematological/immunological changes that develop in the infected patients remain unknown. This study aims to systematically review the hematologic autoimmune complications in these patients. METHOD: Data from three online databases including Medline (via PubMed), Scopus and Web of Science were searched on 19 December 2020, and after excluding duplicate, irrelevant and inappropriate records, eligible documents were identified. Afterwards, information such as patients' history, presentations, paraclinical data, treatment course and outcome were extracted from the records. RESULTS: A total of 58 documents were considered to be eligible for data extraction which described 94 patients with COVID-19 who developed hematologic autoimmune disorder in their course of infection. Of these patients with COVID-19, the most common hematologic autoimmune disorder was immune thrombocytopenic purpura (55 cases) followed by autoimmune hemolytic anemia (22 cases). Other hematologic autoimmune disorders include antiphospholipid syndrome, thrombotic thrombocytopenic purpura, Evans syndrome and autoimmune neutropenia. CONCLUSION: The current study would help us to always consider an autoimmune etiology for cases with abnormal hematologic finding which further lead to an appropriate treatment of the patients, especially when the symptoms present in about 1-2 weeks after the first manifestation of the infection symptoms. Maybe, at least in this pandemic, it should be recommended to evaluate patients with unexpected and unexplained decrease in their hemoglobulin or platelet count for COVID-19. Another challenging issue is the treatment options. Given the multiorgan involvement and multifaceted nature of the infection, an individualized approach should be taken for each patient.

Characteristics of Acquired Inhibitors to Factor VIII and Von Willebrand Factor Secondary to Systemic Lupus Erythematosus: Experiences From a Chinese Tertiary Medical Center.

OBJECTIVE: Because acquired hemophilia (AH) is a rare entity in systemic lupus erythematosus (SLE), we aimed to investigate the clinical features of SLE-related AH in Chinese patients. METHODS: This is a medical records review study carried out at a large tertiary care hospital in China from years 1986 to 2018. We searched the case database in Peking Union Medical College Hospital using the International Classification of Diseases. The clinical data on SLE-related AH patients were collected. RESULTS: A total of 9282 SLE patients had been hospitalized. Six female SLE-related AH patients were identified. Four patients had acquired hemophilia A (AHA), and 2 patients had acquired von Willebrand syndrome. Their mean age was 33.67 ± 13.77 years. Five patients had active disease. The mean SLE disease activity index measured at the time of diagnosis of AH was 10.50 ± 5.28. The average level of activated partial thromboplastin time was 86.5 seconds. Coexistence of secondary antiphospholipid syndrome and AHA was found in one case, and pulmonary embolism was observed 3 years later. After immunosuppressive therapy and symptomatic treatment, an overall remission rate of 83.3% was achieved. CONCLUSIONS: The frequency of SLE-related AH was low. The development of AH in SLE patients frequently occurs with active disease. The AH could be the first clinical presentation of SLE. Secondary antiphospholipid syndrome and AHA could appear in the same SLE patient. Early and aggressive treatment contributes to a favorable prognosis.

Anti-DNA antibodies cross-reactive with ß2-glycoprotein I induce monocyte tissue factor through the TLR9 pathway.

Antibodies specific for cardiolipin (CL)-ß2-glycoprotein I (ß2GPI) are known to induce tissue factor (TF) expression by monocytes and endothelial cells which leads to a prothrombotic state in antiphospholipid syndrome (APS), but the mechanism is not fully elucidated. Previously, we reported that the mouse monoclonal anti-CL-ß2GPI antibody WB-6 cross-reacts with DNA, enters monocytes via binding to cell surface DNA, and induces TF expression. The current study aimed to identify the intracellular signaling pathways involved in this process. The binding of WB-6 to CL-ß2GPI or DNA, and endocytosis was not prevented by chloroquine, but pre-treatment of the cells with chloroquine significantly suppressed TF expression. TLR9 inhibitory oligodeoxynucleotide also suppressed the WB-6-induced TF expression, suggesting a pivotal role of the TLR9 pathway in TF production. Serum antibodies obtained from a patient with APS accompanying systemic lupus erythematosus (SLE) bound to both CL-ß2GPI and DNA, and induced TF in normal monocytes. This effect was suppressed by chloroquine, and abolished by removal of the DNA-binding activity. These results suggest that induction of TF expression results from TLR9 activation by DNA which was internalized together with cross-reactive antibodies produced in secondary APS accompanying SLE.

Prevalence, outcome and management of patients with SLE and secondary antiphospholipid antibody syndrome after aPL seroconversion.

OBJECTIVE: The withdrawal of oral anticoagulation (OAC) in patients with SLE and secondary aPL syndrome (SAPS) who become seronegative has not been clearly investigated to date. Our aim was to evaluate the prevalence of aPL seroconversion and the prognosis of SLE patients with SAPS who withdrew OAC after aPL negativization. METHODS: We retrospectively analysed data of all SLE patients (ACR criteria) with SAPS (Sydney criteria) prospectively followed-up in our clinic. aPL seroconversion was defined as negativization of lupus anticoagulant, aCL, and anti-ß2glycoprotein-1 antibodies on two or more consecutive measurements, at least 12 weeks apart. OAC discontinuation was defined as the definitive withdrawal of all anticoagulants. RESULTS: Fifty-five out of 513 (10.7%) SLE patients had vascular SAPS. Sixteen patients (29.1%) became aPL seronegative during follow-up. Immunosuppressive therapy predicted aPL negativization (odds ratio 5.211, 95%CI 1.341, 20.243), whereas APS diagnosis prior to that of SLE (odds ratio 0.078, 95%CI 0.008, 0.799) and triple-positive profile (odds ratio 0.264, 95%CI 0.115, 0.609) were negative predictors of aPL negativization. OAC was discontinued in 13/55 patients (23.6%), after a median follow-up of 45 months (range 1-276) from aPL seroconversion. SLE-related modifiable risk factors for thrombosis were observed in 10/13 patients (77%) at the time of the thrombotic event. No thrombotic recurrences were observed during a mean follow-up time of 44 (19) months from OAC discontinuation. CONCLUSIONS: Our results suggest that OAC can be safely discontinued in SLE patients who became persistently seronegative for aPL, at least when aPL-related thrombotic events occurred in presence of other thrombotic risk factors.

Arterial thrombosis in antiphospholipid syndrome (APS): Clinical approach and treatment. A systematic review.

Thrombotic Antiphospholipid Syndrome (APS) is a condition affecting young individuals in whom a thromboembolic event occurs in the presence of circulating antiphospholipid antibodies (aPL). An extensive body of literature has covered the most common clinical presentation of the syndrome, venous thromboembolism. Arterial thrombosis in APS, a lesser clinical expression, is less studied. This review will concentrate on the body of literature concerning pathogenesis, clinical presentation and management of arterial thrombosis in APS.

Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19.

Patients with COVID-19 are at high risk for thrombotic arterial and venous occlusions. Lung histopathology often reveals fibrin-based blockages in the small blood vessels of patients who succumb to the disease. Antiphospholipid syndrome is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies targeting phospholipids and phospholipid-binding proteins (aPL antibodies). Case series have recently detected aPL antibodies in patients with COVID-19. Here, we measured eight types of aPL antibodies in serum samples from 172 patients hospitalized with COVID-19. These aPL antibodies included anticardiolipin IgG, IgM, and IgA; anti-ß2 glycoprotein I IgG, IgM, and IgA; and anti-phosphatidylserine/prothrombin (aPS/PT) IgG and IgM. We detected aPS/PT IgG in 24% of serum samples, anticardiolipin IgM in 23% of samples, and aPS/PT IgM in 18% of samples. Antiphospholipid autoantibodies were present in 52% of serum samples using the manufacturer's threshold and in 30% using a more stringent cutoff (≥40 ELISA-specific units). Higher titers of aPL antibodies were associated with neutrophil hyperactivity, including the release of neutrophil extracellular traps (NETs), higher platelet counts, more severe respiratory disease, and lower clinical estimated glomerular filtration rate. Similar to IgG from patients with antiphospholipid syndrome, IgG fractions isolated from patients with COVID-19 promoted NET release from neutrophils isolated from healthy individuals. Furthermore, injection of IgG purified from COVID-19 patient serum into mice accelerated venous thrombosis in two mouse models. These findings suggest that half of patients hospitalized with COVID-19 become at least transiently positive for aPL antibodies and that these autoantibodies are potentially pathogenic.

Probable catastrophic antiphospholipid syndrome secondary to chronic myelomonocytic leukaemia in an adult patient and a mini review.

Catastrophic antiphospholipid syndrome (CAPS) is a rare and life-threatening form of antiphospholipid syndrome (APS), which could be triggered by malignancy. Chronic myelomonocytic leukaemia (CMML) is an uncommon hematologic malignancy. We report a case of a 49-year-old male patient who presented multiple thromboses with a high titre of anti-ß2-glycoprotein-I antibody. Unexpectedly, there was persistent monocytosis combined with <20% blasts in his bone marrow. Thus, a diagnosis of probable CAPS and CMML was made. After treatment with prednisone, hydroxychloroquine and warfarin, the thromboses dissolved, and an improved presentation of peripheral blood and bone marrow was observed. Here, we also provide a mini review of cases of APS complicated with CMML identified from searches of MEDLINE, EMBASE and Web of Science databases. The review describes the clinical characteristics, laboratory data, treatments and outcomes.

Nine-test panel has superior sensitivity to detect antiphospholipid antibody syndrome in patients with or without SLE.

Anti-phospholipid antibodies (aPL) and lupus anticoagulant (LAC) represent diagnostic criteria for systemic lupus erythematosus (SLE) and underlie anti-phospholipid syndrome (APS) in patients with and without SLE. 526 healthy controls and 1633 SLE and 1835 primary APS (PAPS) patients were evaluated. LAC was assessed by hexagonal phase phospholipid neutralization assay (HPPNA), diluted Russell viper venom test (dRVVT), and platelet neutralization procedure (PNP). ß2-glycoprotein-I and cardiolipin IgG, IgM, and IgA antibodies (aCL-IgG, aCL-IgM, aCL-IgA) were measured. 222/1633 SLE patients had APS based on the nine-test panel, which afforded the highest sensitivity (74%) and negative predictive value (90%) but lowest specificity (52%). HPPNA was the most sensitive individual test at 52%. The nine-test panel yielded the greatest sensitivity for aPL detection (70%) relative to HPPNA, the most sensitive individual test (36%) in PAPS. Superior sensitivity of a nine-test aPL panel has major implications for preventing potentially fatal thrombotic events in SLE and PAPS.

A Case of Antiphospholipid Syndrome Following Gastric Signet Ring Cell Adenocarcinoma.

BACKGROUND Antiphospholipid syndrome (APS) is a rare autoimmune disease characterized by arterial, venous, and small-vessel thrombosis, pregnancy-related morbidity and the presence of antiphospholipid antibodies such as anticardiolipin antibody, and/or anti-beta2-glycoprotein I. In the recent years, APS was observed in patients with solid tumors and the renal cancer, lung carcinoma and breast tumors were the most common tumors linked with APS. CASE REPORT A 53-year-old female presented with pain and pitting edema of left lower extremity that had begun 6 months prior to hospitalization. Deep vein thrombosis (DVT) in the popliteal vein diagnosed by Doppler ultrasonography and the patient was treated with heparin followed by warfarin. Following subdural hematoma, anticoagulant therapy was stopped, and the patient underwent craniotomy. One month later, the patient returned with pain and DVT diagnosed in its right leg. Laboratory tests showed high levels of lupus anticoagulant, IgM and IgG anticardiolipin antibodies. Following a high alkaline phosphatase, diffuse bone marrow involvement was found by whole body bone scan. Looking to find primary tumor, a large infilterable lesion in gastric was seen by endoscopic images, and biopsy histopathology showed a signet ring cell adenocarcinoma. The patient refused chemotherapy and died 6 months after diagnosis. CONCLUSIONS APS is associated with gastric signet ring cell adenocarcinoma.

Catastrophic antiphospholipid syndrome as a complication of systemic sclerosis.

A 62-year-old man with a history of systemic sclerosis was admitted with diffuse alveolar hemorrhage and acute kidney injury without clinical data suggestive of glomerulonephritis. Laboratory tests showed anemia, leukocytosis with neutrophilia, thrombocytopenia, elevated serum creatinine and metabolic acidosis. Antinuclear antibodies were positive at a titer of 1/640 (speckled, 1/160; nucleolar, 1/320) while rheumatoid factor, anti Scl-70, anti-centromere, anti-neutrophil cytoplasmic antibody and anti-glomerular basement membrane antibodies were negative and serum complement levels were within normal range. During the following days, the patient developed multiple organ failure and, eventually, died. Lupus anticoagulant was revealed positive after the patient's death, suggesting a catastrophic antiphospholipid syndrome. Clinical data and autopsy were consistent with this diagnosis.

Causes and factors related to hospitalizations in patients with systemic lupus erythematosus: analysis of a 20-year period (1995-2015) from a single referral centre in Catalonia.

INTRODUCTION: Although extensively characterized in the outpatient setting, systemic lupus erythematosus (SLE) in the hospitalization wards is still scarcely portrayed, particularly in the perspective of its evolution over the years. METHODS: Retrospective analysis of SLE patients hospitalized in the Department of Autoimmune Diseases of a university hospital during a 20-year period (1995-2015), describing hospitalization characteristics, causes and predictors of outcome. RESULTS: A total of 814 hospitalizations concerning 339 patients were analysed. The main causes of admission were flare (40.2%), infection (19.2%), diagnostic procedures (18.8%) and thrombotic events (5.4%). Therapy with cyclophosphamide (odds ratio (OR) 1.908, p = 0.047) was associated with admission due to infection, while antimalarials displayed a protective effect (OR 0.649, p = 0.024). Nearly 3.9% of patients required admission to an intensive care unit, with associated antiphospholipid syndrome (OR 7.385, p = 0.04) standing as a predicting factor for this outcome. Readmission at 30 days occurred in 5.8% of patients, with thrombocytopenia (OR 6.007, p = 0.002) and renal involvement (OR 3.362, p = 0.032) featuring as predicting factors. Eight patients died, with antiphospholipid syndrome (OR 26.814, p = 0.02) and thrombocytopenia (OR 31.523, p = 0.01) being associated with mortality. There was no significant variation in patients' demographics or admission causes across the 20-year period, except for a decrease in admissions due to thrombotic and musculoskeletal causes. Recently, an increase in the use of mycophenolate mofetil and lower doses of glucocorticoids were noted. CONCLUSION: While demographics of SLE hospitalizations have not markedly changed over the past 20 years, changes in therapy patterns were observed. Thrombocytopenia, antiphospholipid syndrome and renal involvement featured as predictors of poor outcome.

Environmental Triggers of Autoreactive Responses: Induction of Antiphospholipid Antibody Formation.

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-ß2-glycoprotein I antibodies (aß2-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 ß2-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.