COVID-19 and Antiphospholipid Antibodies: Time for a Reality Check?

Antiphospholipid antibodies (aPL) comprise a panel of autoantibodies that reflect a potential prothrombotic risk in several autoimmune conditions, most notably antiphospholipid (antibody) syndrome (APS). aPL can be divided into those that form part of the laboratory criteria for APS, namely, lupus anticoagulant (LA), as well as anticardiolipin antibodies (aCL) and anti-β2-glycoprotein I antibodies (aβ2GPI) of the immunoglobulin G and M classes, and those that form a group considered as “noncriteria antibodies.” The noncriteria antibodies include, for example, antiphosphatidylserine antibodies (aPS), antiprothrombin antibodies (aPT), and antiphosphatidylserine/prothrombin complex antibodies (aPS/PT). COVID-19 (coronavirus disease 2019) represents a prothrombotic disorder, and there have been several reports of various aPL being present in COVID-19 patients. There have also been similarities drawn between some of the pathophysiological features of COVID-19 and APS, in particular, the most severe form, catastrophic APS (CAPS). In this review, we critically appraise the literature on aPL and COVID-19. This is a companion piece to a separate review focused on LA. In the current review, we primarily concentrate on the so-called solid phase identifiable aPL, such as aCL and aβ2GPI, but also reflect on noncriteria aPL. We conclude that aPL positivity may be a feature of COVID-19, at least in some patients, but in general, identified “solid-phase” aPL are of low titer and not able to be well-linked to the thrombotic aspects of COVID-19. Also, most publications did not assess for aPL persistence, and where persistence was checked, the findings appeared to represent transient aPL. Importantly, high-titer aPL or multiple aPL positivity (including double, triple) were in the minority of COVID-19 presentations, and thus discount any widespread presence of APS, including the most severe form CAPS, in COVID-19 patients.

Right ventricular thrombus in a case of neonatal lupus: case report

Neonatal thrombosis is considered a rare manifestation with unclear aetiology. We reported a neonatal lupus of a Sjogren’s syndrome mother with recurrent miscarriage secondary to antiphospholipid syndrome; seronegative to anticardiolipin antibodies, lupus anticoagulant and B2GP1. She was serologically positive to antiphosphatidylethanolamine and antiprothrombin antibodies, anti-SSA/Ro and anti-SSB/La. The neonate developed neonatal lupus complicated with right ventricular thrombus assumed to be induced by maternal transmission of antiphosphatidylethanolamine and antiprothrombin antibodies, treated successfully with tissue plasminogen activator and warfarin.

Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study

Objective A task force of scientists at the International Congress on Antiphospholipid Antibodies recognized that phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) might contribute to a better identification of antiphospholipid syndrome (APS). Accordingly, initial and replication retrospective, cross-sectional multicentre studies were conducted to ascertain the value of aPS/PT for APS diagnosis. Methods In the initial study (eight centres, seven countries), clinical/laboratory data were retrospectively collected. Serum/plasma samples were tested for IgG aPS/PT at Inova Diagnostics (Inova) using two ELISA kits. A replication study (five centres, five countries) was carried out afterwards. Results In the initial study ( n = 247), a moderate agreement between the IgG aPS/PT Inova and MBL ELISA kits was observed ( k = 0.598). IgG aPS/PT were more prevalent in APS patients (51%) than in those without (9%), OR 10.8, 95% CI (4.0–29.3), p < 0.0001. Sensitivity, specificity, positive (LR+) and negative (LR–) likelihood ratio of IgG aPS/PT for APS diagnosis were 51%, 91%, 5.9 and 0.5, respectively. In the replication study ( n = 214), a moderate/substantial agreement between the IgG aPS/PT results obtained with both ELISA kits was observed ( k = 0.630). IgG aPS/PT were more prevalent in APS patients (47%) than in those without (12%), OR 6.4, 95% CI (2.6–16), p < 0.0001. Sensitivity, specificity, LR + and LR– for APS diagnosis were 47%, 88%, 3.9 and 0.6, respectively. Conclusions IgG aPS/PT detection is an easily performed laboratory parameter that might contribute to a better and more complete identification of patients with APS.

FACTORS ASSOCIATED WITH THE DEEP VEIN THROMBOSIS IN PATIENTS WITH ANTIPHOSPHOLIPID SYNDROME

Introduction. Patients with antiphospholipid syndrome (APS) may have a large spectrum of thrombotic clinical events (arterial or venous), but the factors that determine the occurrence of specific clinical manifestation has not been clearly established. Objective. The aim of the study was to determine the factors associated with a history of deep vein thrombosis (DVT) in patients with APS. We were especially interested to fi nd an association between the criteria and non-criteria antiphospholipid antibodies (APLAs) and the DVT. Methods. We realized a cross-sectional study, with consecutive enrollment of all patients presented in our department with the diagnosis of APS in the period 2008-2011. From the total of 106 patients for which the demographic, clinical and biological parameters were collected, the assessment of the criteria and non-criteria APLAs was performed in 73 patients. Results. The mean age at inclusion was 44.7 years, the female-to-male ratio 6.6, and the mean APS disease duration 6.7 years. The majority of the patients included presented with secondary APS (70 patients). Lupus anticoagulant was the most frequent immunological marker used to sustain the diagnosis of APS, found positive in 102 patients (96.2%). The recurrent DVT was more frequently observed in patients with primary APS than in those with secondary APS (p = 0.02). No significant association with DVT was found for the clinical parameters traditionally associated with the risk of thrombosis that we have taken into study: smoking, body mass index (BMI), waist circumference and waist-to-hip ratio. We found a positive association between the DVT history and the positivity for the IgM anti-β2 glycoprotein I antibodies [OR (95%CI) = 6.95 (1.36-35.58), p = 0.01]. The titer of IgG antiprothrombin antibodies and IgG antiphosphatidylethanolamine antibodies was higher in patients with previous DVT [3.0 (0.0-151.0) versus 2.0 (0.0-2.0), p = 0.01, respectively 5.0 (1.0-33.0) versus 3.0 (1.0-7.0), p = 0.01]. In the subgroup of patients with secondary APS, the previous DVT was associated only with the positivity for IgM anti-β2 glycoprotein I antibodies [OR (95%) = 13.63 (1.46-127.15), p = 0.02]. In the same subgroup, the levels of IgG anticardiolipin and the IgG antiphosphatidylethanolamine antibodies were higher in patients with previous DVT [2.0 (0.0-64.0) versus 1.0 (0.0-20.0), p = 0.02, respectively 3.0 (0.0-151.0) versus 2.0 (0.0-7.0), p = 0.03]. In patients with primary APS, the titer of IgG antiprothrombin antibodies was significantly higher when DVT history were present [5.0 (1.0-3.0) versus 3.0 (1.0-7.0), p = 0.01. Only the titer of IgG antiprothrombin antibodies was associated with the history of recurrent thrombosis [5.0 (1.0-3.0) versus 3.0 (1.0-7.0), p = 0.01]. Conclusions. In patients with APS, the DVT history was related with the prevalence of the anti-β2 glycoprotein I antibodies, but also with the levels of some non-criteria antibodies, IgG antiprothrombin antibodies and IgG antiphosphatidylethanolamine antibodies. In patients with primary APS, previous DVT is associated only with the titer of IgG antiprothrombin antibodies, whereas in patients with secondary APS, the DVT history were related with the presence of anti-β2 glycoprotein I antibodies and with the titers of both criteria antibodies (IgG anticardiolipin antibodies) and non-criteria antibodies (IgG antiphosphatidylethanolamine antibodies). The risk of recurrent thrombosis was higher in patients with primary APS when compared with those with secondary APS. Only the titers of IgG antiprothrombin antibodies were correlated with recurrent thrombosis.

PROTITELESA PROTI PROTROMBINU

In patients with the antiphospholipid syndrome (APS), the presence of a group of pathogenic autoantibodies called antiphospholipid antibodies causes thrombosis and pregnancy complications. The most frequent antigenic target of antiphospholipid antibodies are phospholipid bound β2-glycoprotein 1 (β2GPI) and prothrombin. The international classification criteria for APS connect the occurrence of thrombosis and/or obstetric complications together with the persistence of lupus anticoagulant, anti-cardiolipin antibodies (aCL) and antibodies against β2GPI (anti-β2GPI) into APS. Current trends for the diagnostic evaluation of APS patients propose determination of multiple antiphospholipid antibodies, among them also anti-prothrombin antibodies, to gain a common score which estimates the risk for thrombosis in APS patients. Antiprothrombin antibodies are common in APS patients and are sometimes the only antiphospholipid antibodies being elevated. Methods for their determination differ and have not yet been standardized. Many novel studies confirmed method using phosphatidylserine/prothrombin (aPS/PT ELISA) as an antigen on solid phase encompass higher diagnostic accuracy compared to method using prothrombin alone (aPT ELISA). Our research group developed an in-house aPS/PT ELISA with increased analytical sensitivity which enables the determination of all clinically relevant antiprothrombin antibodies. aPS/PT exhibited the highest percentage of lupus anticoagulant activity compared to aCL and anti-β2GPI. aPS/PT antibodies measured with the in-house method associated with venous thrombosis and presented the strongest independent risk factor for the presence of obstetric complications among all tested antiphospholipid antibodies.