Antiphospholipid antibodies in COVID-19: a meta-analysis and systematic review.

BACKGROUND: Many studies reported high prevalence of antiphospholipid antibodies (aPL) in patients with COVID-19 raising questions about its true prevalence and its clinical impact on the disease course. METHODS: We conducted a meta-analysis and a systematic review to examine the prevalence of aPL and its clinical impact in patients with COVID-19. RESULTS: 21 studies with a total of 1159 patients were included in our meta-analysis. Among patients hospitalised with COVID-19, the pooled prevalence rate of one or more aPL (IgM or IgG or IgA of anticardiolipin (aCL) or anti-ß2 glycoprotein (anti-ß2 GPI) or antiphosphatidylserine/prothrombin, or lupus anticoagulant (LA)) was 46.8% (95% CI 36.1% to 57.8%). The most frequent type of aPL found was LA, with pooled prevalence rate of 50.7% (95% CI 34.8% to 66.5%). Critically ill patients with COVID-19 had significantly higher prevalence of aCL (IgM or IgG) (28.8% vs 7.10%, p<0.0001) and anti-ß2 GPI (IgM or IgG) (12.0% vs 5.8%, p<0.0001) as compared with non-critically ill patients. However, there was no association between aPL positivity and mean levels of C reactive protein (mean difference was 32 (95% CI -15 to 79), p=0.18), D-dimer (mean difference was 34 (95% CI -194 to 273), p=0.77), mortality (1.46 (95% CI 0.29 to 7.29), p=0.65), invasive ventilation (1.22 (95% CI 0.51 to 2.91), p=0.65) and venous thromboembolism (1.38 (95% CI 0.57 to 3.37), p=0.48). CONCLUSIONS: aPLs were detected in nearly half of patients with COVID-19, and higher prevalence of aPL was found in severe disease. However, there was no association between aPL positivity and disease outcomes including thrombosis, invasive ventilation and mortality. However, further studies are required to identify the clinical and pathological role of aPL in COVID-19.

Different subclasses and isotypes of antibodies against phosphorylcholine in haemodialysis patients: association with mortality.

The risk of premature death is high among patients on haemodialysis (HD patients). We previously determined that immunoglobulin (Ig)M antibodies against phosphorylcholine (anti-PC) are negatively associated with increased risk of cardiovascular disease (CVD), atherosclerosis, some autoimmune diseases and mortality among HD patients in this cohort. Here, we also study other subclasses and isotypes of anti-PC in HD patients in relation to mortality, inflammation and gender. The study group is a cohort of 209 prevalent HD patients [median age = 66 years, interquartile range (IQR) = 51-74], vintage time = 29 months (IQR = 15-58; 56% men) with a mean follow-up period of 41 months (IQR = 20-60). Fifty-six per cent were men. We also divided patients into inflamed C-reactive protein (CRP) > 5·6 mg/ml and non-inflamed CRP. Antibody levels were determined by in-house enzyme-linked immunosorbent assay. IgG1 anti-PC below median was significantly associated with increased all-cause mortality (after adjustment for confounders: P = 0·02), while IgG, IgA and IgG2 anti-PC were not associated with this outcome. Among non-inflamed patients, IgM and IgG1 anti-PC were significantly associated with mortality (P = 0·047 and 0·02). IgG1 anti-PC was significantly associated with mortality among men (P = 0·03) and trending among women (P = 0·26). IgM (as previously reported) and IgG1 anti-PC are negatively associated with survival among HD patients and non-inflamed HD patients, but among inflamed patients there were no associations. IgG, IgA or IgG2 anti-PC were not associated with survival in these groups and subgroups. Further studies are needed to determine if raising anti-PC levels, especially IgM and IgG1 anti-PC, through immunization is beneficial.

Novel enzyme immunoassay system for simultaneous detection of six subclasses of antiphospholipid antibodies for differential diagnosis of antiphospholipid syndrome.

: Antiphospholipid syndrome, which often complicates systemic lupus erythematosus (SLE), features high occurrence of arterial and/or venous thrombosis and recurrent fetal loss. However, which antibody subclass contributes to which clinical event remains uncertain. We newly developed an up-to-date enzyme immunoassay system using the AcuStar automated analyzer (Instrumentation Laboratory, Bedford, Massachusetts, USA) for parallel detection of six subclasses of antiphospholipid antibodies (aPLs): anticardiolipin antibodies (aCL) of IgG, IgM, and IgA and anti-ß2-glycoprotein I antibodies (aß2GPI) of IgG, IgM, and IgA. They were measured in 276 healthy volunteers and 138 patients with SLE: 45 with thromboembolic complications (29 arterial; 16 venous) and 93 without. Lupus anticoagulant activity in their plasma was measured according to the guidelines recommended by the Subcommittee on Lupus Anticoagulant/Phospholipid-Dependent Antibodies. aCL/ß2GPI was measured with a standard ELISA kit commonly used in Japan. The positive results of IgG aCL, IgA aCL, and IgG aß2GPI were closely associated with thromboembolic complications, whereas IgM aCL and IgM aß2GPI were not. receiver operating characteristic analysis revealed that the accuracy of predicting thromboembolic complications based on the composite test results of the former three antibodies were obviously higher than by each alone. Regarding agreement with the test results of lupus anticoagulant activity, IgG aß2GPI showed the closest match. Patients with SLE frequently possess various combinations of the six aPL subclasses, and this antibody spectrum is closely associated with thromboembolic events in these patients. This new automated enzyme immunoassay system allows simultaneous analysis of the profile of aPL subclasses for the differential diagnosis of antiphospholipid antibody syndrome in its early stage.

A novel ELISA system for simultaneous detection of six subclasses of anti-phospholipid antibodies for prediction of thrombotic complications among SLE patients.

BACKGROUND: Anti-phospholipid antibodies (aPLs) are frequently associated with arterial and/or venous thromboembolic complications and recurrent fetal loss in patients with systemic lupus erythematosus (SLE). We recently reported that the clinical picture of SLE apparently depends on subclasses of aPLs in the patient's sera, but the contribution of each subclass remains uncertain. METHODS: We newly developed an ELISA system for simultaneous detection of six specific categories of aPLs: anti-cardiolipin (aCL), anti-ß2-glycoprotein I (aß2GPI), anti-cardiolipin/ß2-glycoprotein I (aCL/ß2GPI), anti-phosphatidylserine (aPS), anti-prothrombin (aPT), and anti-phosphatidylserine/prothrombin (aPS/PT). They were measured in 331 patients with SLE including 63 patients with arterial thromboembolic complications, 64 with venous thromboembolic complications, and 43 with recurrent fetal loss. Lupus anticoagulant (LA) activity in their plasma was measured according to the guidelines recommended by the Subcommittee on Lupus Anticoagulant/Phospholipid-Dependent Antibodies. RESULTS: Multivariate logistic analysis revealed that the concentration of aPS/PT was most closely associated with arterial thrombosis. In contrast, the concentration of aß2GPI was most closely related to venous thrombosis. Furthermore, both aCL/ß2GPI and aPS/PT were independently associated with episodes of recurrent fetal loss. Regarding the relation between APLs and LA activity, aPS/PT, followed by aß2GPI and aPT, showed the closest association with the presence of LA activity. CONCLUSIONS: Anti-phospholipid syndrome in patients with SLE can be classified by antigenic specificities of their aPLs as to their susceptibility to arterial and/or venous thromboembolic complications or obstetric complications.

[Advanced clinical laboratory studies in the graduate school of medicine--studies on pathogenic mechanisms of anti-phospholipid syndrome].

Anti-phospholipid syndrome (APS) is defined based on both clinical findings (recurrent arterial and/or venous thrombosis and recurrent fetal loss) and laboratory evidence of persistent anti-phospholipid antibodies (anti-cardiolipin antibodies, anti-beta2 glycoprotein I antibodies, or LA activity). However, the precise mechanism responsible for arterial and/or venous thromboembolic complications in APS patients remains unclear. To clarify the association between the various types of anti phospholipid antibodies (aPLs) and thrombotic complications, we examined the prevalence of seven types of aPLs [anti-cardiolipin/beta2-glycoprotein I antibodies(anti-CL/beta2-GPI), anti-phosphatidylserine/prothrombin antibodies(anti-PS/PT), anti-beta2-glycoprotein I antibodies (anti-beta2-GPI), anti prothrombin antibodies (anti-PT), anti-protein C antibodies (anti-PC), anti-protein S antibodies(anti-PS), and annexin V antibodies(anti-AN)] in 168 patients with systemic lupus erythematosus (SLE). We confirmed that the presence of anti-CL/beta2-GPI, anti-PS/PT, and anti-beta2-GPI is closely related to arterial thrombosis, and that the presence of anti-protein S is closely related to venous thromboembolism. Furthermore, our in-vitro experiment suggests that anti-CL/beta2-GPI and anti-PS/PT may cooperate to promote platelet activation, and may be involved in the pathogenesis of arterial thrombosis. On the other hand, anti-protein S led to APC resistance, which may represent an important mechanism responsible for the development of venous thrombosis. Furthermore, our study showed that anti-CL/beta2-GPI causes a persistently high-level expression of tissue factor on monocytes, and this may increase the risk of atherosclerosis.

Treatment options for patients who have antiphospholipid syndromes.

The antiphospholipid thrombosis syndrome, associated with anticardiolipin (aCL) or subgroup antibodies, can be divided into one of six subgroups (I-VI). There is little overlap (about 10% or less) between these subtypes, and patients usually conveniently fit into only one of these clinical types. Although there appears to be no correlation with the type, or titer, of aCL antibody and type of syndrome, the subclassification of thrombosis and aCL antibody patients into these groups is important from the therapy standpoint. This article also reviews the clinical presentations associated with each of these six subgroups.

Sole existence of antithrombin antibody in patients with systemic lupus erythematosus showing tendency of its antigenic determinants directing against exosite II (antithrombin/heparin binding site) of thrombin.

We conducted an investigation to determine the antigenic determinants of antithrombin antibody (aThr), which has recently been recognized as a new antiphospholipid antibody mostly co-existing with antiprothrombin antibody, employing patients with systemic lupus erythematosus and antiphospholipid syndrome. Using an enzyme-linked immunosorbent assay we found aThr in 34 of 83 patients (40.9%), and 27 of these 34 patients (79.4%) with aThr were all negative for other antiphospholipid antibodies. An optical density value of six of 30 patients (20.0%) with aThr showed more than a 40% reduction of reactivity to thrombin with the addition of antithrombin in a dose-dependent manner. The inhibition percentage of aThr to thrombin was prominently increased to 11 of 30 (37%) along with its inhibition rate (100% at the highest) by the co-existence of heparin. Seven out of 30 patients with aThr (23.3%) showed a reduction of the optical density value with the addition of hirudin. Our findings suggest that aThr exists solely in patients with systemic lupus erythematosus without other antiphospholipid antibodies, and the antigenic determinants of aThr are directed to exosite I (hirudin binding site) and exosite II (antithrombin/heparin binding site) on the thrombin surface, with exosite II predominance. Accordingly, aThr could be an isolated and additional new marker of thrombosis/hemostasis. Since our patients who were positive only for aThr do not have a past history of antiphospholipid-associated complications at this stage, however, further long-term follow-up and additional studies in these clinical settings are needed to verify our hypothesis in the future.

Hyperhomocysteinemia relates to the subtype of antiphospholipid antibodies in non-SLE patients.

Abnormal increases of antiphospholipid antibody and plasma homocysteine levels are recently emerging as nonlipidic risk factors for cerebral atherogenesis and thrombosis. Both antiphospholipid antibody and homocysteine share many similar bioeffects in hemostasis, but their interaction is still inconsistent. In this study, we examined the relation between the plasma homocysteine level and lupus anticoagulant, anticardiolipin antibody, and anti-beta2-glycoprotein I antibody in patients with noncardiac cerebral ischemia. Systemic lupus erythrematosus patients were excluded. The results showed a higher frequency of moderate hyperhomocysteinemia in patients with an abnormal increase of lupus anticoagulant only. Neither the serum folate and cobalamin levels nor methylenetetrahydrofolate reductase allele mutation contributes to this result. Accordingly, homocysteine interacts with lupus anticoagulant to promote cerebral atherosclerosis and ischemia. The role of vasculopathic or prothrombotic autoantibody generation in response to specific pathological change such as hyperhomocysteinemia warrants further investigation.

Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the antiphospholipid syndrome) study.

To assess the clinical significance of lupus anticoagulants (LAs) and antiphospholipid antibodies (aPLs) toward thrombosis and abortions, we measured them in 112 patients whose samples were available at enrollment in the warfarin in the antiphospholipid syndrome (WAPS) study. Enzyme-linked immunosorbent assay (ELISA) and coagulation test values in the highest and lowest tertiles were compared. When considered separately, IgG antibodies to beta2-glycoprotein I (abeta2GPI) and prothrombin (aPT) were associated with anamnestic arterial and venous thrombosis, respectively, and those to annexin AV (aAnAV) with abortions. IgM antibodies to protein S and the lupus ratio of the dilute prothrombin time were associated with prospective thrombosis. No other association for IgM antibodies was seen. LA-positive patients who carried abeta2GPI antibodies were at risk of anamnestic arterial and total thrombosis and aPT antibodies to that of anamnestic venous and total thrombosis. LA-positive patients who carried IgG abeta2GPI and aAnAV antibodies were at risk for both anamnestic abortion and prospective thrombosis. Overall, these data support the inclusion of abeta2GPI antibodies in and suggest the removal of anticardiolipin antibodies from the laboratory criteria of the antiphospholipid syndrome. They also suggest that the measurement of aPT and aAnAV antibodies is useful in some selected situations and that there is little role for IgM antibody detection.

[Laboratory diagnosis of antiphospholipid syndrome]. / Diagnostic biologique du syndrome des antiphospholipides.

PURPOSE: The antiphospholipid syndrome is a bioclinical entity defined by the occurrence of thromboses, and/or obstetrical complications in the persistent presence of antiphospholipid antibodies, i.e. lupus anticoagulant and/or anticardiolipin antibodies. This review focuses on the methods for antiphospholipid antibodies detection and their clinical usefulness. CURRENT KNOWLEDGE AND KEY POINTS: Lupus anticoagulant is the strongest risk factor for thrombosis in antiphospholipid syndrome. Twenty years after its description, anticardiolipin ELISA, despite a still improvable standardization and its lack of specificity, is still required for sensitive diagnosis of antiphospholipid syndrome. FUTURE PROSPECTS AND PROJECTS: A better knowledge of the beta-2-glycoprotein-I role in the pathophysiology of antiphospholipid syndrome might lead to the development of new markers of thrombotic risk.

Predictive value of persistent versus transient antiphospholipid antibody subtypes for the risk of thrombotic events in pediatric patients with systemic lupus erythematosus.

Study objectives were to determine, in children with systemic lupus erythematosus (SLE), (1) the association of antiphosholipid antibody (APLA) subtypes with thrombotic events (TEs) and (2) the predictive value of persistent versus transient antibodies for TEs. This is a cohort study of 58 SLE children in whom lupus anticoagulants (LAs), anticardiolipin antibodies (ACLAs), anti-beta2-glycoprotein-I (anti-beta2-GPI), and antiprothrombin (anti-PT) were assessed on at least 2 occasions (more than 3 months apart). Antibodies were classified as persistent (positive on at least 2 occasions) or transient (positive once). Outcomes were symptomatic TEs confirmed by objective radiographic tests identified retrospectively and prospectively. Seven of the 58 patients (12%) had 10 TEs; 5 patients had TEs during prospective follow-up. Persistent LAs showed the strongest association with TEs (P < .001). Persistent ACLAs (P = .003) and anti-beta2-GPI (P = .002) were significantly associated with TEs; anti-PT (P = .063) showed a trend. Persistent or transient LAs and anti-beta2-GPI showed similar strength of association, while ACLAs and anti-PT were no longer associated with TEs. Positivity for multiple APLA subtypes showed stronger associations with TEs than for individual APLA subtypes because of improved specificity. Lupus anticoagulant is the strongest predictor of the risk of TEs; other APLA subtypes provide no additional diagnostic value. Anticardiolipin antibodies and anti-PT require serial testing because only persistent antibodies are associated with TEs.

Antiphospholipid antibodies.

Antiphospholipid antibodies (APAs) have been associated with thromboembolic events. Since they were fi rst described in 1906, APAs have been the subject of multidisciplinary studies seeking to link them to potential pathophysiologic mechanisms. This review summarizes the different types of APAs, antigenic targets, clinical complications associated with APAs, and APA syndrome. In addition, the currently available methods for laboratory identification of lupus anticoagulants are discussed, as is the laboratory diagnosis of anticardiolipin antibodies.

Antiphospholipid thrombosis syndromes.

Antiphospholipid antibodies are strongly associated with thrombosis and are the most common of the acquired blood protein defects causing thrombosis. Although the precise mechanism(s) whereby antiphospholipid antibodies alter hemostasis to induce a hypercoagutable state remain unclear, numerous theories, as previously discussed, have been advanced. The most common thrombotic events associated with anticardiolipin antibodies are deep vein thrombosis and pulmonary embolus (type I syndrome), coronary or peripheral artery thrombosis (type II syndrome), or cerebrovascular/retinal vessel thrombosis (type II syndrome); occasionally, patients present with mixtures of these types (type IV syndrome). Type V patients are those with antiphospholipid antibodies and RMS. It is as yet unclear how many seemingly normal individuals who may never develop manifestations of antiphospholipid syndrome (type VI) harbor asymptomatic antiphospholipid antibodies. The relative frequency of anticardiolipin antibodies in association with arterial and venous thrombosis strongly suggests that these should be looked for in any individual with unexplained thrombosis; all three idiotypes (IgG, IgA, and IgM) should be assessed. Also, the type of syndrome (I through VI) should be defined if possible, as this may dictate both type and duration of both immediate and long-term anticoagulant therapy. Unlike those with anticardiolipin antibodies, patients with primary lupus anticoagulant thrombosis syndrome usually experience venous thrombosis. Because the aPTT is unreliable inpatients with lupus anticoagulant (prolonged in only about 40 to 50% of patients) and is not usually prolonged in patients with anticardiolipin antibodies, definitive tests, including ELISA for anticardiolipin antibodies, the dRVVT for lupus anticoagulant, hexagonal phospholipid neutralization procedure, and beta-2-GP-I (IgG, IgA, and IgM) should be immediately ordered when suspecting antiphospholipid syndrome or in individuals with otherwise unexplained thrombotic or thromboembolic events. If results of these tests are negative, in the appropriate clinical setting, subgroups should also be assessed. Finally, most patients with antiphospholipid thrombosis syndrome will fail warfarin therapy and, except for retinal vascular thrombosis, may fail some types of antiplatelet therapy; thus it is of major importance to make this diagnosis so that patients can be treated with the most effective therapy for secondary prevention--LMWH or UH in most instances, and clopidogrel in some instances.

Anticuerpos antifosfolipidos y embarazo / Antiphospholipid antibodies and pregnancy

La frecuencia de los anticuerpos antifosfoslípidos durante el embarazo es variable y depende de los antecedentes maternos. La historia de perdidas fetales previas, es el mejor predictor de riesgo para nuevas pérdidas, principalmente en mujeres con lupus eritematoso sistémico. Estos anticuerpos ocasionan complicaciones fetales y maternas. El tratamiento médico de éste síndrome durante el embarazo es controvertido y debe ser individual. Por carencia de estudios controlados y aleatorizados, la combinación heparina y aspirina, continúa siendo la terapia de elección. Los corticoesteroides, los antimaláricos y la gamaglobulina endovenosa, se reservan para situaciones especiales. El cuidado y manejo de estos pacientes requiere de un equipo de expertos de diferentes disciplinas médicas

Anticorpos antifosfolipídios: novos critérios / Antiphospholipid antibody: new criteria

Suggested modifications of the clinical diagnostic criteria of antiphospholipid antibody syndrome and therapeutic approaches are related in this letter

The characteristics of bronchoalveolar lavage from a patient with antiphospholipid syndrome who developed acute respiratory distress syndrome.

The purpose of this study was to investigate the biochemical characteristics as well as the occurrence and specificity of antiphospholipid antibodies in the bronchoalveolar lavage (BAL) fluid from a patient with both antiphospholipid antibodies syndrome (APS) and acute respiratory distress syndrome (ARDS). Proteins, lipids, cells and autoantibodies were determined. Immunoglobulins were purified with affinity chromatography. Autoantibody identification was assessed with enzyme-linked immunosorbent assay (ELISA) and with electrophoresis, followed by immunoblotting and revelation with antihuman IgG-peroxidase conjugate. Antiphospholipid antibodies were found to be present in the BAL fluid as well as in the serum from a patient with APS. Specifically, antiphosphatidylserine and antiphosphatidic acid IgG antibodies in the BAL fluid and antiphosphatidylcholine and anticardiolipin IgG antibodies in the serum were detected at high levels. BAL fluid protein and the percentage of neutrophils were found to be increased. A quantitative as well as qualitative deficiency of surfactant phospholipids was also observed. Antibodies directed against surfactant phospholipids could cause surfactant abnormalities and an inflammatory reaction. These disorders may be one of the causes of the ARDS or a factor in the perpetuation of the inflammation.