Prevalence and clinical significance of antiphospholipid antibodies among hospitalized COVID-19 patients

Objective:To describe the prevalence of antiphospholipid antibodies in coronavirus disease-19(COVID-19)and to find potential associations between antiphospholipid antibody positivity and clinical outcomes.Methods:From September to November 2020,clinical and laboratory data were collected from 50 COVID-19 patients hospitalized at Saiful Anwar General Hospital in Malang,Indonesia.Antiphospholipid antibodies were measured by finding Ig M anti-β2 glycoprotein,lupus anticoagulant,and Ig M/Ig G anticardiolipin.Clinical characteristics,thrombotic events,ICU admission,and mortality during hospitalization were recorded.Disease severity was defined by the Guidelines for the Prevention and Control of COVID-19,Indonesia.Results:Among 50 patients,5 patients(10.0%)were positive for antiphospholipid antibodies:4 patients(80.0%)had Ig M anti-β2 glycoprotein and 1 patient had Ig G anti-cardiolipin(20.0%)and Ig M anti-cardiolipin(20.0%),none of lupus anticoagulant was detected.Antiphospholipid antibodies were associated with anosmia(OR 8.1;95%CI 1.1-57.9;P=0.018),nausea and vomiting(OR 12.4;95%CI 1.2-122.6;P=0.010),diarrhea(OR 9.8;95%CI 1.3-70.9;P=0.010),cardiovascular disease(OR 1.4;95%CI 1.0-1.9;P=0.001),chronic kidney disease(OR 12.0;95%CI 1.6-90.1;P=0.05),acute coronary syndrome(OR 29.3;95%CI 2.0-423.7;P=0.001),moderate(OR 0.11;95%CI 0.01-1.10;P=0.031)and severe(OR 18.5;95%CI 1.8-188.4;P=0.002)disease severity,and in-hospital mortality(OR 8.1;95%CI 1.1-57.9;P=0.018).However,there is no correlation between the presence of antiphospholipid antibody and ICU admission.Conclusions:In summary,the prevalence of antiphospholipid antibodies in COVID-19 patients is low,mainly against Ig M anticardiolipin,and is associated with an acute coronary syndrome,gastrointestinal manifestations,moderate and severe disease severity,and increased risk of mortality.

THE STUDY OF PRODUCTION AND MECHANISM OF ANTIPHOSPHOLIPID ANTIBODIES IN PATIENTS WITH CORONARY HEART DISEASE

Objective To assess whether there was strong association between antiphospholipid antibodies and coronary heart disease, to study the environmental factors of APA production and APA pathogenic mechanism in patients with CHD.Methods Blood samples from 76 patients with CHD and 30 controls were tested for anticardiolipin antibodies IgG,human cytomegalovirus IgG,IgM by enzyme link immunosorbant assay and 6 keto PGF 1a ,endothelin by radioimmunoassay.Results A total of 27 patients were ACA positive in 76, as compared to 2 of 30 healthy individuals, P <0.05. There was no difference in ACA among acute myocardial infarction, old myocardial infarction, unstable angina pectoris, P >0.05. The number of ACA positive subjects was higher in HCMV infection patients with CHD than no HCMV infectious patients with CHD. There was no PGI 2 and ET level difference between ACA IgG positive and negative CHD.Conclusion There are strong association between APA and CHD. The HCMV infection may be an environmental factor of APA production in CHD patients with raised ACA. The alteration of PGI 2 and ET are not the pathogenic mechanism of ACA in patients with CHD.

Antiphospholipid syndrome and its role in pediatric cerebrovascular diseases: A literature review

Antiphospholipid syndrome(APS)or Hughes syndrome is an acquired thromboinflammatory disorder.Clinical criteria of APS diagnosis are large-and small-vessel thrombosis as well as obstetric problems;laboratory criteria are the presence of antiphospholipid antibodies(lupus anticoagulant,anticardiolipin antibodies and anti-β2-glycoprotein-1).The presence of at least 1 clinical and 1 laboratory criterion allows definitive diagnosis of APS.Primary APS is diagnosed in patients without features of connective tissue disease;secondary APS is diagnosed in patients with clinical signs of autoimmune disease.A high frequency of catastrophic APS as well as a high tendency to evolve from primary APS to secondary syndrome during the course of lupus and lupus-like disease is a feature of pediatric APS.The most characteristic clinical presentation of APS in the pediatric population is venous thrombosis,mainly in the lower limbs,and arterial thrombosis causing ischemic brain stroke.Currently,no diagnostic criteria for pediatric APS exist,which probably results in an underestimation of the problem.Similarly,no therapeutic procedures for APS specific for children have yet been established.In the present literature review,we discussed data concerning APS in children and its role in cerebrovascular diseases,including pediatric arterial ischemic stroke,migraine and cerebral venous thrombosis.

Study of the Effect of Intralipid Infusion during Pregnancy as an Additive Treatment for Reducing Pregnancy Complications Caused by Antiphospholipid Antibody Syndrome

Aim: To evaluate the safety and efficacy of intralipid infusion in addition to other lines of treatment in reduction of complications caused by antiphospholipid antibody syndrome. Methods: This study was held in the period from June 1, 2016, to December 1, 2019. This study was conducted in the Department of Obstetrics and Gynecology, Tanta University on patients attending the antenatal care clinic and also on patients attending the researcher’s private clinics for antenatal care, 105 patients were enrolled after application of strict inclusion and exclusion criteria. They were randomized into 2 groups. In group A (study group 1) the patients received in addition to the conventional basic treatment of APS, intralipid 20% (Frezenius, Clayton, NC, USA) in a dose of 4 ml diluted in 250 ml 0.9% regular saline IV and to be repeated every 2 weeks. In group B (control group 2) the patients received the conventional basic treatment of APS. The outcome measures were the incidence of pregnancy complications of APS namely fetal loss, premature delivery, IUGR and preeclampsia. Results: 49 patients were enrolled in the study group, and 48 patients were enrolled in the control group, after exclusion of the skipped cases. The demographic data and the gestational age at the beginning of the study show insignificant differences. There were insignificant differences as regard the gestational age at which the pregnancy was terminated and fetal birth weight in patients with positive ACL test, positive LA test and positive B2 however the mean gestational age at which pregnancy was terminated was higher in study group. Also, there was insignificant difference as regards no of patients who complicated with abortion or who completed to full term. But had significant decrease number of case who complicated with preeclampsia (8, 21 patients in study and control group respectively). Conclusion: Intralipid infusion is a promising treatment option for control and prevention of problems caused by antiphospholipid antibody syndrome.

Myocardial infarction in antiphospholipid antibody syndrome

A 52-year-old man was admitted to hospital with chest pain after physical activity. Emergency coronary angiography showed multiple throm-boembolic occlusions in the anterior descen-ding coronary artery and in the right coronary artery. Further testing revealed anticardiolipin and ?2-glicoprotein antibodies (the patient had been diagnosed for ulcerative colitis and poly-myalgia rheumatica). Heparin and nitrate were administered intravenously in addition to oral aspirin and metoprolol. Soon after, the patient referred a withdrawal of chest oppression, and his general clinical condition rapidly stabilised. A follow-up examination was performed 9 months later the discharge: he had resumed most of his activities and sieric concentration of lupus anticoagulant antibodies and anticardiolipin an- tibodies, IgM isotype, were decreased.

Systemic lupus erythematosus combined with primary hyperfibrinolysis and protein C and protein S deficiency:A case report

BACKGROUND Systemic lupus erythematosus(SLE)is an autoimmune disease characterized by systemic involvement and multiple autoantibodies in the serum.Patients with protein C(PC)and protein S(PS)deficiency are prone to thrombosis.In contrast,patients with primary hyperfibrino-lysis tend to bleed.CASE SUMMARY A 52-year-old female patient with bilateral pleural effusion was diagnosed with"tuberculous pleurisy"and treated with anti-tuberculosis drugs and prednisone.The coagulation-related laboratory results showed decreased fibrinogen,PC activity,PS activity,and antithrombinШactivity.The immune-related laboratory results showed positive antinuclear antibody,anti-Smith antibody,anticardiolipin antibody(ACL),anti-β2-glycoprotein I antibody(aβ2GPI)and direct Coomb’s test and decreased complement 3 and complement 4.Thoracoscopy was performed and bloody pleural fluid was drained.Pathology of the pleural biopsy showed lymphocytes,plasma cells,and a few eosinophils in adipose and fibrous connective tissue.Results of whole exome sequencing of blood showed no genetic mutations suggesting the presence of hereditary hematological diseases.The patient was finally diagnosed with SLE and primary hyperfibrinolysis,and was treated with prednisolone,hydroxychloroquine,and compound cyclophosphamide.CONCLUSION PC and PS deficiency in SLE might be related to ACL and aβ2GPI.SLE and primary hyperfibrinolysis can coexist in one patient,with both a risk of thrombosis and a risk of bleeding.

Antiphospholipid syndrome:a clinical perspective

Antiphospholipid syndrome (APS) is a thromboinflammatory disease with a variety of clinical phenotypes. Primary thrombosis prophylaxis should take an individualized risk stratification approach. Moderate-intensity vitamin K antagonist such as warfarin remains the primary strategy for secondary thrombosis prophylaxis among APS patients, especially for patients with predominantly venous disease. For now, direct oral anti-coagulants should be avoided in most APS patients, especially those with history of arterial manifestations. Obstetric APS management should be tailored based on an individual patient’s antiphospholipid antibody profile, and obstetric and thrombotic history. Pharmacological agents beyond anticoagulants may be considered for the management of microthrombotic and nonthrombotic manifestations of APS, although more data are needed. A relatively recent discovery in the area of APS pathogenesis is the implication of neutrophil extracellular traps in thrombin generation and initiation of inflammatory cascades. APS is a complex thromboinflammatory disease with a broad clinical spectrum. Personalized therapy according to an individual’s unique thrombosis and obstetric risk should be advocated.

Additional risk factors associated with thrombosis and pregnancy morbidity in a unique cohort of antiphospholipid antibody-positive patients

Background:Antiphospholipid syndrome(APS)is an autoimmune prothrombotic condition with significant morbidity.The objective of this study was to identify additional clinical and epidemiological risks of arterial thrombosis,venous thrombosis,and pregnancy morbidities in a large cohort of persistent antiphospholipid antibodies(aPLs)-positive carriers.Methods:This was a cross-sectional cohort study of 453 consecutive patients with a documented positive aPL who attended Peking University People's Hospital.Among 453 patients screened,297 patients had persistent positive aPL.We compared asymptomatic aPL carriers with thrombotic and obstetric APS patients.And the univariate analysis and multivariable logistic regression were used to evaluate the association between different risk factors and APS clinical manifestations.The levels of circulating markers of neutrophil extracellular traps(NETs)(cell-free DNA and citrullinated histone H3[Cit-H3])were assessed and compared among aPL-positive carriers with or without autoimmune disease and APS patients.Results:Additional risk factors associated with arterial thrombosis among aPL-positive carriers included:smoking(odds ratio[OR]=6.137,95%confidence interval[CI]=2.408-15.637,P=0.0001),hypertension(OR=2.368,95%CI=1.249-4.491,P=0.008),and the presence of underlying autoimmune disease(OR=4.401,95%CI=2.387-8.113,P<0.001).Additional risks associated with venous thrombosis among aPL carriers included:smoking(OR=4.594,95%CI=1.681-12.553,P=0.029)and the presence of underlying autoimmune disease(OR=6.330,95%CI=3.355-11.940,P<0.001).The presence of underlying autoimmune disease(OR=3.301,95%CI=1.407-7.744,P=0.006)is the additional risk,which demonstrated a significant association with APS pregnancy morbidity.Higher circulating levels of cell-free DNA and Cit-H3 were observed among APS patients and aPL patients with autoimmune diseases compared with those aPL carriers without underlying autoimmune diseases.Furthermore,control neutrophils that are conditioned with APS patients'sera have more pronounced NET release compared with those treated with aPL carriers'sera without underlying autoimmune diseases.Conclusions:We identified several potential additional risk factors for APS clinical manifestations among a large cohort of Chinese aPL carriers.Our data may help physicians to risk stratify aPL-positive Asian patients.

Antiphospholipid Antibody Titers and Clinical Outcomes in Patients with Recurrent Miscarriage and Antiphospholipid Antibody Syndrome： A Prospective Study

Background： The management of patients with recurrent miscarriage （RM） and antiphospholipid antibody syndrome （APS） includes prolonged treatment with heparin and aspirin, starting from the confirmation of pregnancy and continuing until 6 weeks after birth. This study was conducted to determine the relationship between changes in antiphospholipid antibody titers and clinical outcomes. The effect of a shortened treatment regimen was also evaluated. Methods： A prospective study of 123 patients with RM and APS between March 2012 and May 2014 was conducted. Patients were pretreated with a low dose of prednisone plus aspirin before pregnancy, and heparin was added after conception. The levels of antiphospholipid antibodies and pregnancy outcomes were evaluated. Results： All patients were positive for anti-β2-glycoprotein 1 （anti-β2-GP 1） IgM. Atier prepregnancy treatment with low-dose prednisone plus aspirin, 99 of 123 patients became pregnant, and 87 of those pregnancies resulted in successful live births, while 12 resulted in miscarriage, showing a success rate of 87.9%. In the live birth group, levels of anti-β2-GP1 were 56.8±49.0 RU/ml before the pretreatment regimen, 32. 1± 26.0 RU/ml after 2 months of pretreatment, and 24.1 ± 23. IRU/ml during early pregnancy （P 〈 0.05）. In the miscarriage group, antiphospholipid antibody titers were 52.8 ±30.7 RU/ml before pretreatment, 38.5 ±34.2 RU/ml after pretreatment, and 33.9 ±24.7 RU/ml during early pregnancy; the decrease in antiphospholipid antibodies was lower in the miscarriage group than in the live birth group （P 〈 0.05）. Of the 24 inferthe patients, the average antibody titer did not decline after pretreatment （P = 0.802）. Conclusions： Anti-[32-GP1 IgM was the predominant form of antibody in patients with RM and APS. The decreases in antiphospholipid antibody titers correlated with better pregnancy outcomes. The shorter treatment regimen was effective and economical.

Role of Autoantibodies in Infertility, Miscarriage, and Assisted Reproductive Technology Outcomes

Although considerable advances have been made in the field of assisted reproductive technology(ART),millions of couples still suffer from infertility and miscarriage.In a large number of cases,the etiology of these common reproductive failures remains unknown.However,the significance of autoantibodies in infertility and miscarriage has sparked extensive interest because of their pleiotropic roles in disrupting normal pregnancy.This review discusses the pleiotropic roles of a series of autoantibodies in infertility and miscarriage.A brief recapitulation of how the autoantibodies interfere with ART outcomes and treatments for this type of idiopathic infertility or miscarriage is also provided.While several disputes remain to be resolved,further studies employing better designs and larger sample sizes are required in view of the therapeutic potential of autoantibody inhibitors and the future of contraceptive vaccines.

Catastrophic Antiphospholipid Antibody Syndrome:Clinical Presentation,Management,and Guidance for Future Pregnancy

To editor:Antiphospholipid antibody syndrome(APS)is an autoimmune condition characterized by the production of antiphospholipid antibodies(aPL)with clinical features such as vascular thrombosis or obstetric morbidity.1 APS is associated with spontaneous abortions and pregnancy loss.Pregnancies resulting in live births may be complicated by fetal growth restriction,uteroplacental insufficiency,preeclampsia,hemolysis elevated liver enzymes,and low platelets(HELLP)syndrome,and preterm birth.

Antiphospholipid Antibody Syndrome:Pathogenesis,Diagnosis,and Management in Pregnancy

Antiphospholipid antibody syndrome is an autoimmune disorder that primarily affects reproductive age women and poses significant obstetric complications.Here we review the pathogenesis,diagnosis,obstetric complications,and management in women with antiphospholipid antibody syndrome.

The Application of Aspirin in Pregnancy-Related Complications

Aspirin,one of the most widely applied medicines,not only possesses the effects on reducing fever,anti-vascular hyperplasia,and anti-inflammation,but also has the capacity of preventing platelet aggregation.So far,it is acceptable to adopt aspirin,especially low-dose aspirin(LDA),to prevent pregnancy-related complications,such as pregnancy complicated by antiphospholipid syndrome,systemic lupus erythematosus,or preeclampsia;unexplained recurrent spontaneous abortion;fetal growth restriction;and preterm birth.In this article,we reviewed the possible mechanism of action and applications of aspirin in these pregnancy-related complications.

Inactivated SARS-CoV-2 vaccine does not influence the profile of prothrombotic antibody nor increase the risk of thrombosis in a prospective Chinese cohort

The presence of antiphospholipid antibodies was shown to be associated with thrombosis in coronavirus disease 2019(COVID-19)patients.Recently,according to reports from several studies,the vaccineinduced immune thrombotic thrombocytopenia is mediated by anti-platelet factor 4(PF4)-polyanion complex in adenovirus-vectored COVID-19 vaccine recipients.It is impendent to explore whether inactivated COVID-19 vaccine widely used in China influences prothrombotic autoantibody production and induces thrombosis.In this prospective study,we recruited 406 healthcare workers who received two doses,21 days apart,of inactivated severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)vaccine(BBIBP-CorV,Sinopharm).Paired blood samples taken before vaccination and four weeks after the second vaccination were used in detecting prothrombotic autoantibodies,including anticardiolipin(aCL),anti-b2 glycoprotein I(ab2GP1),anti-phosphatidylserine/prothrombin(aPS/PT),and anti-PF4-heparin.The seroconversion rate of SARS-CoV-2 specific antibodies was 95.81%(389/406)four weeks after vaccination.None of the subjects had spontaneous thrombosis or thrombocytopenia over a minimum follow-up period of eight weeks.There was no significant difference in the presence of all ten autoantibodies between samples collected before and after vaccination:for aCL,IgG(7 vs.8,P=0.76),IgM(41 vs.44,P=0.73),IgA(4 vs.4,P=1.00);anti-b2GP1,IgG(7 vs.6,P=0.78),IgM(6 vs.5,P=0.76),IgA(3 vs.5,P=0.72);aPS/PT IgG(0 vs.0,P=1.00),IgM(6 vs.5,P=0.76);aPF4-heparin(2 vs.7,P=0.18),and antinuclear antibody(ANA)(18 vs.21,P=0.62).Notably,seven cases presented with anti-PF4-heparin antibodies(range:1.18–1.79 U/mL)after vaccination,and none of them exhibited any sign of thrombotic disorder.In conclusion,inactivated SARS-CoV-2 vaccine does not influence the profile of antiphospholipid antibody and anti-PF4-heparin antibody nor increase the risk of thrombosis.