Comparison of Acquired Activated Protein C Resistance, Using the CAT and ST-Genesia® Analysers and Three Thrombin Generation Methods, in APS and SLE Patients

Background: Acquired activated protein C resistance (APCr) has been identified in antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). Objective: To assess agreement between the ST-Genesia® and CAT analysers in identifying APCr prevalence in APS/SLE patients, using three thrombin generation (TG) methods. Methods: APCr was assessed with the ST-Genesia using STG-ThromboScreen and with the CAT using recombinant human activated protein C and Protac® in 105 APS, 53 SLE patients and 36 thrombotic controls. Agreement was expressed in % and by Cohen's kappa coefficient. Results: APCr values were consistently lower with the ST-Genesia® compared to the CAT, using either method, in both APS and SLE patients. Agreement between the two analysers in identifying APS and SLE patients with APCr was poor (≤65.9%, ≤0.20) or fair (≤68.5%, ≥0.29), regardless of TG method, respectively; no agreement was observed in thrombotic controls. APCr with both the ST Genesia and the CAT using Protac®, but not the CAT using rhAPC, was significantly greater in triple antiphospholipid antibody (aPL) APS patients compared to double/single aPL patients (p < 0.04) and in thrombotic SLE patients compared to non-thrombotic SLE patients (p < 0.05). Notably, the ST-Genesia®, unlike the CAT, with either method, identified significantly greater APCr in pregnancy morbidity (median, confidence intervals; 36.9%, 21.9–49.0%) compared to thrombotic (45.7%, 39.6–55.5%) APS patients (p = 0.03). Conclusion: Despite the broadly similar methodology used by CAT and ST-Genesia®, agreement in APCr was poor/fair, with results not being interchangeable. This may reflect differences in the TG method, use of different reagents, and analyser data handling.

Does Adjusted Global Antiphospholipid Syndrome Score (aGAPSS) Predict the Obstetric Outcome in Antiphospholipid Antibody Carriers? A Single-Center Study

The adjusted Global Antiphospholipid Syndrome (APS) Score (aGAPSS) is a tool proposed to quantify the risk for antiphospholipid antibody (aPL)-related clinical manifestations. However, aGAPSS has been validated mainly for thrombotic events and studies on APS-related obstetric manifestations are scarce. Furthermore, the majority of them included patients with positive aPL and different autoimmune diseases. Here, we assess the utility of aGAPSS to predict the response to treatment in aPL carriers without other autoimmune disorders. One-hundred and thirty-seven women with aPL ever pregnant were included. Sixty-five meet the APS classification criteria, 61 had APS-related obstetric manifestations, and 11 were asymptomatic carriers. The patients’ aGAPSS risk was grouped as low (< 6, N = 73), medium (6–11, N = 40), and high risk (≥ 12, N = 24). Since vascular risk factors included in the aGAPSS were infrequent in this population (< 10%), the aGAPSS score was mainly determined by the aPL profile. Overall, the live birth rate was 75%, and 37.2% of the patients had at least one adverse pregnancy outcome (APO). When considering patients according to the aGAPSS (high, medium, and low risk), no significant differences were found for pregnancy loss (29.2%, 25%, and 21.9%) or APO (33.3%, 47.5%, and 32.9%). In the present study, including aPL carriers without other autoimmune diseases, aGAPSS is not a valuable tool to identify patients at risk for obstetric complications despite treatment. In these patients with gestational desire, in addition to the aPL profile, other pregnancy-specific factors, such as age or previous obstetric history, should be considered.

432 ACS-STEMI in a young man with triple positive antiphospholipid syndrome: clinical implications about antithrombotic therapy management

Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disorder characterized by venous and arterial thromboembolic (TE) disease, and/or pregnancy morbidity, associated with persistent elevated antiphospholipid antibodies (lupus anticoagulant, LA, anticardiolipin, aCL, and anti-beta2-glycoprotein I, anti-β2GPI). A 51 year-old man, smoker, presented to our ER with chest pain. EKG showed Q waves and STE in the anterior leads, with increased troponin levels. A diagnosis of anterior STEMI was made and he was taken into our catheterization laboratory, where a high burden thrombotic plaque determining LM and ostial LAD subocclusion was treated with PPCI and a DES implantation; in addition, multiple failed PCI attempts were performed on a distal LAD occlusion, and an integrilin bolus was administered. The patient was admitted to our CICU and a DAPT with ASA and Ticagrelor was started. TTE showed LVEF 40%, apical akinesis, septal and anterior hypokinesis, and no significant valve disease. An aPTT abnormal value (100.5 s; reference range 25–38.5 s) was detected, not corrected by aPTT mixing study. Given suspected autoimmune prothrombotic state, normal Hb and PLT values and low bleeding risk, LMWH 100 IU/kg every 12 h was started, in addition to DAPT with switch from Ticagrelor to Clopidogrel. LA and aCL and anti-β2GPI IgG were positive, with negativity of others rheumatologic tests, confirming primary APS diagnosis. Repeat TTE showed EF 50%. The patient was discharged in ‘triple therapy’ (DAPT plus LMWH), and referred to the rheumatology clinic. LA, aCL, and anti-β2GPI tests 12 weeks later were positive, confirming a triple positive APS and satisfying revised Sapporo criteria. The rheumatologist switched therapy to Clopidogrel plus Warfarin. At 3 months follow-up, the patient, former smoker, was asymptomatic and TTE confirmed EF 50%, so he was recommended to continue with his medical therapy. APS is rarely associated with AMI (∼5.5%) and in only 2.8% cases AMI represents the onset of the disease. AMI pathogenesis in APS is considered to be acute thrombosis of coronary arteries, in contrast with atherosclerotic plaque rupture in typical AMI. Key discriminators to identify APS as potential underlying cause of AMI include young age, previous unprovoked thromboses, low platelets count (they are consumed in the thrombotic process), high aPTT value (LA may interfere with assembly of the prothrombinase complex on phospholipids), coronary artery thromboses in the setting of otherwise normal otherwise appearing coronary arteries. APS antibodies have also pro-inflammatory activity on vascular endothelial cells, leading to accelerated atherosclerosis. aGAPSS score (high risk ≥10) is useful for risk stratification of recurrent thrombosis and AMI in young patients with APS. The treatment of AMI in APS is therefore a clinical challenge. Strict management of additional CV risk factors is crucial. VKA (INR &gt;3 with Warfarin, INR2–3 with Warfarin and ASA) should be provided for life, because of the very high risk of recurrent TE. DOACs are less effective and less safe than VKAs for TE prevention in APS. The role of coronary stents, considering higher rates of stent thrombosis after PCI in APS patients triple therapy concomitant risks, requires further studies. Due to lack of large, randomized, prospective studies, there is no clear experts consensus about optimal antithrombotic therapy in secondary prevention after arterial TE. APS patients with STEMI should undergo PCI, usually associated with thrombus aspiration, and in selected cases DES implantation in culprit lesion followed by triple antithrombotic therapy with short-term DAPT and long-term VKA.

Pathophysiology of the Antiphospholipid Antibody Syndrome

The antiphospholipid syndrome is characterized by antibodies directed against phospholipid-binding proteins and phospholipids attached to cell membrane receptors, mitochondria, oxidized lipoproteins, and activated complement components. When antibodies bind to these complex antigens, cells are activated and the coagulation and complement cascades are triggered, culminating in thrombotic events and pregnancy morbidity that further define the syndrome. The phospholipid-binding proteins most often involved are annexins II and V, β2-glycoprotein I, prothrombin, and cardiolipin. A distinguishing feature of the antiphospholipid syndrome is the “lupus anticoagulant”. This is not a single entity but rather a family of antibodies directed against complex antigens consisting of β2-glycoprotein I and/or prothrombin bound to an anionic phospholipid. Although these antibodies prolong in vitro clotting times by competing with clotting factors for phospholipid binding sites, they are not associated with clinical bleeding. Rather, they are thrombogenic because they augment thrombin production in vivo by concentrating prothrombin on phospholipid surfaces. Other antiphospholipid antibodies decrease the clot-inhibitory properties of the endothelium and enhance platelet adherence and aggregation. Some are atherogenic because they increase lipid peroxidation by reducing paraoxonase activity, and others impair fetal nutrition by diminishing placental antithrombotic and fibrinolytic activity. This plethora of destructive autoantibodies is currently managed with immunomodulatory agents, but new approaches to treatment might include vaccines against specific autoantigens, blocking the antibodies generated by exposure to cytoplasmic DNA, and selective targeting of aberrant B-cells to reduce or eliminate autoantibody production.

Immunomodulation in antiphospholipid-antibody associated endocarditis: A case report and review of the literature

BACKGROUND Non-infectious endocarditis is a rare complication in patients with systemic lupus erythematosus or antiphospholipid syndrome. The mitral valve is mainly affected, usually showing vegetations on the ventricular and atrial side of the valve. CASE SUMMARY A 27—year - old female patient with a known antiphospholipid syndrome was referred to our hospital with night sweats, weight loss, reduction in performance and dizziness. A floating structure associated to the mitral valve was identified in a transesophageal echocardiogram with typical changes, in accordance with a non-infectious endocarditis (Libman—Sacks). Only a trace of mitral regurgitation was present and a mass on the PML. Laboratory findings showed antibody and inflammatory marker measurements either negative or within normal range. The patient received therapeutic oral anticoagulation using a vitamin K antagonist and a combined immunosuppression consisting of hydroxychloroquine and prednisolone. The symptoms of the patient resolved within 3 months after starting the initial treatment. The Follow-up echocardiogram showed an almost normal mitral valve function with only a slight regional thickening of the posterior mitral leaflet and no stenosis. Following a 7 - year period of observation being on a medical regimen of hydroxychloroquine and a vitamin K antagonist, no evidence of clinical and/or echocardiographic recurrence was detected. DISCUSSION This case report represents a successful medical management of non—infectious endocarditis using immunosuppressive and anticoagulation therapies without significant residual lesions. Although optimal management of nonbacterial endocarditis remains in the area of uncertainty, this combination therapy deems promising.

302. Using Antiphospholipid Antibody Presence as an Additional Biomarker to Identify COVID-19 Positive Patients with High Risk for Thrombosis

Background Patients who are hospitalized with Coronavirus 2019 (COVID-19) are known to have increased risk for thrombosis. Several mechanisms have been proposed for increased thrombogenesis, including antiphospholipid antibodies (APLs). We sought to better understand the relationship between a commonly used marker of thrombosis, D-dimer, and antiphospholipid antibodies in relation to thrombosis in COVID-19. Methods This was a single-center prospective cohort study. Participants were adults admitted to the hospital with COVID-19 between March and December of 2020. Included patients required a positive COVID-19 nasopharyngeal nucleic acid amplification testing (NAAT), coagulation studies, and regular assessment of D-dimer levels. Patients who were excluded were pregnant adults, use of oral anticoagulants prior to admission, and absence of a positive COVID-19 nasopharyngeal NAAT. We tested 52 patients for antiphospholipid antibodies (APLs), including lupus anticoagulant (LA), anti-beta-2 glycoprotein antibodies (B2GP), and anti-cardiolipin antibodies (aCL). The endpoint for analysis was hospital discharge or development of a confirmed thrombosis. Results Twenty-nine of fifty-two patients (55.7%) with COVID-19 had non-negative APLs. Of these patients, twenty-seven (93.1%) had non-negative aCLs, the majority of which were IgM antibodies. There was a total of 7 thrombotic events in our cohort. The sensitivity of D-dimer alone was 85% and the sensitivity of APLs alone was 71%. In patients with an intermediate D-dimer level (i.e., greater than 2 milligrams per liter (mg/L) but less than 5 mg/L), the addition of non-negative APLs increased the sensitivity of D-dimer to 100%. In patients with a high D-dimer (i.e., greater than 5), the combined sensitivity of D-dimer and APLs was 60%. Out of the 7 thrombotic events in our cohort, two patients had negative APLs, however both patients had a D-dimer of greater than 5 mg/L. Conclusion The use of APLs can assist in risk-stratifying patients in an intermediate-risk D-dimer group to consider prophylactic anticoagulation if APLs are negative and to consider therapeutic anticoagulation if APLs are non-negative. In the high-risk group (i.e., a D-dimer greater than 5 mg/dL), a therapeutic anticoagulation approach may be more appropriate. Disclosures All Authors: No reported disclosures

P041 Systemic Lupus Erythematosus in Algerian Children: clinical, immunological profile and prognosis

Background Pediatric Systemic Lupus Erythematosus (pSLE) is a chronic mutisystemic autoimmune disease with complex clinical manifestations whose diagnosis is not always easy and the course is generally severe and the treatment is not very well codified and often extrapolated from that of adults. This study aims to describe the clinical, immunological, therapeutic characteristics and short outcome of systemic lupus erythematosus in Algerian children. Methods This was a prospective, multicentre and descriptive study 36 months (January 2015 - December 2018) at the department of Pediatrics of University Hospital Nefissa Hamoud ex Parnet Algiers. Children less than16 years of age fulfilling the American College of Rheumatology SLE criteria were included. Disease activity estimated by Systemic Lupus Erythematosus Disease Activity index (SLEDAI) whose use has been validated in children and damage index based on Systemic Lupus International Collaborating Clinics (SLICC) score were determined. Results Eighty-three (83) patients were studied. Female: male ratio was1:49. Mean ages at lupus onset and diagnosis were respectively: 10, 12 ± 3, 88 and 11, 3 ± 3, 62 years. All patients had skin involvement while constitutional signs including fever and asthenia were observed in (98.8%). Rheumatological, renal, neuropsychiatric, cardiac, hepato-digestive, pleuropulmonary and ocular disorders were observed respectively: 65, 1%, 44, 6%, 41%, 27, 7%, 41%, 19, 3% and 7, 2%. All patients were positive for antinuclear antibodies. Anti-double-stranded DNA (75%) was the most frequently observed autoantibody profile. Antiphospholipid antibody positivity was noted in 52% whereas hypocomplementemia in fractions C3, C4 was observed in 55% and 56% respectively. In our study, the severe forms were more frequent (83%) than the mild ones (17%) with a significant difference (P = &lt; 10–6). Overall, the mean SLEDAI at disease onset was 22.11 ± 11.87 with high activity ≥ 20 in 59% of cases. The mean damage score was 1.8 ± 2.045 (interquartile range 0–8). Among induction drugs, oral corticosteroids were the most frequently used (92%), and in a third of cases intravenously at high doses in combination with immunosuppressive therapy. In induction therapy, cyclophosphamide (CYC) was the most used drug (23%) compared with mycophenolate mofetil (MMF) (14%). Unlike the maintenance phase where MMF observed an increase (28%) vs (8%) CYC. The use of MMF was correlated with severe lupus nephritis with a significantly effective difference in the decrease in SLEDAI (P = 0.0001). The use of hydroxychloroquine (HCQ) was observed in 81% in induction and 89% in maintenance treatment. The correlation of HCQ use with survival was significantly positive (P = 0.04). Indeed, adherence to treatments and essentially HCQ was a protective factor, its odds ratio is &lt; 1 with a significant p-value, [OR 0.016 95% CI (0.001–0.353)]. Mortality was estimated at 11%. Multivariable regression analysis showed that the neurological involvement (odds ratio = 6,093 95% confidence interval ((1,1 8 0 ∼ 31 446)) and macrophage activation syndrome were associated with a high risk of mortality. Conclusion we report a series of pSLE characterized by great clinical and biological heterogeneity. It follows a severe course of the disease with high disease activity at the diagnosis and therefore leads to high morbidity and mortality. However, these results must be confirmed by other pediatric studies which could form the basis of a diagnostic and therapeutic approach more adapted for children. Keywords Algeria, Child, Clinical features, Disease activity, lupus