Presence Of Antiphospholipid Antibodies Research Articles

Aortic and Renal Artery Thrombosis as the First Clinical Manifestation of COVID-19 in a Heart Transplant Recipient

IntroductionThe relation between coronavirus 2019 disease (COVID-19) and thrombotic events is well established, and both arterial and venous thrombotic events are described. Although arterial events occur in about 3.6 to 10.5% of critically ill patients, they are usually stroke or acute myocardial infarction. Arterial thrombosis of other sites is rare.Case ReportWe report a case of a 28-year-old male heart transplant recipient admitted into emergency department presenting right flank pain associated with fever, chills, nausea and vomiting for three days. Apart from diabetes mellitus and dyslipidemia, he had no other comorbidity and he was on regular immunosuppression. Physical exam revealed right costovertebral angle tenderness. Blood tests showed C-reactive protein of 317mg/dL, lactate dehydrogenase of 1827U/L, D-dimer of 4126ng/mL, ferritin of 651ng/mL and leukocytosis of 16100/mm³. An abdominal and thoracic computed tomography scan (CT scan) revealed sparse luminal peripheral thrombi in the descending thoracic aorta. One of the thrombi extended to right renal artery ostium and caused subocclusion of the proximal segment of this artery. Right kidney presented multiple renal infarcts. Also ground-glass opacities were found in 25% of pulmonary parenchyma. COVID-19 was suspected and nasopharynx real-time fluorescence polymerase chain reaction result for SARS-CoV-2 was positive. Coagulopathy tests were performed because of atypical presentation and lupus anticoagulant (LAC) was positive. Hydration, antibiotics and anticoagulation with enoxaparin were prescribed. The patient recovered and became asymptomatic. Warfarin was prescribed and patient was discharged after 15 days of hospitalization.SummaryThis case report illustrates the heterogeneity of clinical presentation of COVID-19 and reinforces the existence of a prothrombotic state, even in the outpatient setting. Moreover, it adds information to the recent reports regarding the presence of antiphospholipid antibodies in COVID-19, although their importance in the pathophysiology of thromboembolic events in this setting is still not clear. The implication of these findings in transplant recipients is even less established, and this case report highlights the need for further research.

Lipid presentation by the protein C receptor links coagulation with autoimmunity.

Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7-dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid-protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways.

A lipid-protein autoimmunity target

Immunology Several autoimmune diseases, including systemic lupus erythematosus and primary antiphospholipid syndrome, are characterized by the presence of antiphospholipid antibodies (aPLs). These molecules can activate the complement and coagulation cascades, which contributes to pathologies such as thrombosis, stroke, and pregnancy complications. Muller-Calleja et al. found that endothelial protein C receptor (EPCR) in complex with lysobisphosphatidic acid (LBPA) is the cell-surface target for aPL and mediates its internalization (see the Perspective by Kaplan). aPL binding to EPCR-LBPA resulted in the activation of tissue factor–mediated coagulation and interferon-α production by dendritic cells. Interferon-α, in turn, fueled the expansion of B1a cells, which secrete aPLs. The specific blockade of this target in mice inhibited the development of aPL autoimmunity, offering hope for future therapies for these conditions. Science , this issue p. [eaay1833][1]; see also p. [1100][2] [1]: /lookup/doi/10.1126/science.aay1833 [2]: /lookup/doi/10.1126/science.abg6449

Abstract P89: Covid-19 and Ischemic Stroke: A Systematic Review and Meta-Summary of the Literature

Background: Acute ischemic stroke (AIS) is a life-threatening complication of coronavirus disease 2019 (COVID-19) infection. Increasing reports suggest an association between COVID-19 and AIS, although the underlying mechanism remains uncertain. Objectives: We performed a systematic review to characterize the clinical characteristics, neuroimaging findings, and outcomes of AIS in COVID-19 patients. Methods: A literature search was performed in PubMed and Embase using a suitable keyword search strategy from 1st December 2019 to 29th May 2020. All studies reporting AIS occurrence in COVID-19 patients were included. Results: A total of 39 studies comprising 135 patients were studied. The pooled incidence of AIS in COVID-19 patients from observational studies was 1.2% (54/4466) with a mean age of 63.4 ± 13.1 years. The mean duration of AIS from COVID-19 symptoms onset was 10 ± 8 days, and the mean NIHSS score was 19 ± 8. Laboratory investigations revealed an elevated mean D-dimer (9.2 ± 14.8 mg/L) and fibrinogen (5.8 ± 2.0 g/L). Antiphospholipid antibodies were detected in a significant number of cases. The majority of AIS neuroimaging patterns observed was large vessel thrombosis, embolism or stenosis (62.1%, 64/103), followed by multiple vascular territory (26.2%, 27/103). A high mortality rate was reported (38.0%, 49/129). Conclusion: We report the pooled incidence of AIS in COVID-19 patients to be 1.2%, with a high mortality rate. Elevated D-dimer, fibrinogen and the presence of antiphospholipid antibodies appear to be prominent in COVID-19 patients with concomitant AIS, but further mechanistic studies are required to elucidate their role in pathogenesis.

Antiphospholipid Syndrome and Cardiac Bypass: The Careful Balance between Clotting and Bleeding

Antiphospholipid syndrome (APS) is an acquired autoimmune condition characterized by the presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibody, and anti-β2 glycoprotein-I antibody) which leads to clinical thrombosis via a multifactorial mechanism of action. Despite the propensity to form clot in vivo, these antibodies interfere with the assembly of the prothrombinase complex on phospholipids in in vitro assays, leading to prolongation of activated clotting time and activated partial thromboplastin time. This disconnect between what occurs in vivo and in vitro makes monitoring anticoagulation during cardiac surgery particularly complex. We present a patient with APS undergoing coronary artery bypass grafting with cardiopulmonary bypass. We delineate our strategy for managing anticoagulation in the presence of this syndrome using the Hepcon Hemostasis Management System Plus (Medtronic, Inc. Minneapolis, MN) device by targeting whole blood heparin concentration to monitor anticoagulation.

Autoantibodies to Annexin A2 and cerebral thrombosis: Insights from a mouse model.

IntroductionAntiphospholipid syndrome (APS) is an autoimmune disorder manifested by thromboembolic events, recurrent spontaneous abortions and elevated titers of circulating antiphospholipid antibodies. In addition, the presence of antiphospholipid antibodies seems to confer a fivefold higher risk for stroke or transient ischemic attack. Although the major antigen of APS is β2 glycoprotein I, it is now well established that antiphospholipid antibodies are heterogeneous and bind to various targets. Recently, antibodies to Annexin A2 (ANXA2) have been reported in APS. This is of special interest since data indicated ANXA2 as a key player in fibrinolysis. Therefore, in the present study we assessed whether anti-ANXA2 antibodies play a pathological role in thrombosis associated disease.Materials and MethodsMice were induced to produce anti-ANXA2 antibodies by immunization with ANXA2 (iANXA2) and control mice were immunized with adjuvant only. A middle cerebral artery occlusion stroke model was applied to the mice. The outcome of stroke severity was assessed and compared between the two groups.ResultsOur results indicate that antibodies to ANXA2 lead to a more severe stroke as demonstrated by a significant larger stroke infarct volume (iANXA2 133.9 ± 3.3 mm3 and control 113.7 ± 7.4 mm3; p = 0.017) and a more severe neurological outcome (iANXA2 2.2 ± 0.2, and control 1.5 ± 0.18; p = 0.03).ConclusionsThis study supports the hypothesis that auto-antibodies to ANXA2 are an independent risk factor for cerebral thrombosis. Consequently, we propose screening for anti-ANXA2 antibodies should be more widely used and patients that exhibit the manifestations of APS should be closely monitored by physicians.

Role of Tissue Factor in the Pathogenesis of COVID-19 and the Possible Ways to Inhibit It.

COVID-19 (Coronavirus Disease 2019) is a highly contagious infection and associated with high mortality rates, primarily in elderly; patients with heart failure; high blood pressure; diabetes mellitus; and those who are smokers. These conditions are associated to increase in the level of the pulmonary epithelium expression of angiotensin-converting enzyme 2 (ACE-2), which is a recognized receptor of the S protein of the causative agent SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). Severe cases are manifested by parenchymal lung involvement with a significant inflammatory response and the development of microvascular thrombosis. Several factors have been involved in developing this prothrombotic state, including the inflammatory reaction itself with the participation of proinflammatory cytokines, endothelial dysfunction/endotheliitis, the presence of antiphospholipid antibodies, and possibly the tissue factor (TF) overexpression. ARS-Cov-19 ACE-2 down-regulation has been associated with an increase in angiotensin 2 (AT2). The action of proinflammatory cytokines, the increase in AT2 and the presence of antiphospholipid antibodies are known factors for TF activation and overexpression. It is very likely that the overexpression of TF in COVID-19 may be related to the pathogenesis of the disease, hence the importance of knowing the aspects related to this protein and the therapeutic strategies that can be derived. Different therapeutic strategies are being built to curb the expression of TF as a therapeutic target for various prothrombotic events; therefore, analyzing this treatment strategy for COVID-19-associated coagulopathy is rational. Medications such as celecoxib, cyclosporine or colchicine can impact on COVID-19, in addition to its anti-inflammatory effect, through inhibition of TF.

Dissecting the Thrombotic Events in the Presence of Antiphospholipid Antibodies in COVID-19 Spanish Patients

Several thrombotic complications in patients affected with SARS-CoV-2 have been reported. Single-centre pilot study aimed to analyse the coexistence of antiphospholipid antibodies and thrombotic events on SARS-CoV-2 infected patients. Antiphospholipid antibodies were measured by solid phase enzyme immunoassay. Clinical data were collected from electronic history and clinical records. Over 25 patients studied we report four cases of COVID-19 patients who presented circulating antiphospholipid antibodies and arterial or venous thrombotic events. No patient had a previous history of thrombosis. Two cases presented with pulmonary embolism, one with pulmonary embolism and pulmonary infarction and one with a stroke. All of them showed positive anti-cardiolipin antibodies. One patient died and three were discharged. The presence of antiphospholipid antibodies in these patients might represent an epiphenomenon secondary to the immune stimulation by the virus. It could be reasonable to consider measuring antiphospholipid antibodies as part of the study of a thrombotic event in COVID-19 patients to better understand the impact of these antibodies in the development of thrombotic events and we highlight the value of a periodic determination to define the need of long-term anticoagulant therapy. Keywords: Antiphospholipid antibodies, COVID-19, thrombosis

Management of Women with Antiphospholipid Antibodies or Antiphospholipid Syndrome during Pregnancy.

Antiphospholipid syndrome (APS), which is characterized by the presence of antiphospholipid antibodies (aPL), is associated with increased risk of thrombosis and obstetric complications, including preterm delivery and recurrent pregnancy losses. APS shows diverse clinical manifestations and the risk of complications varies among clinical subtypes. Although these patients are usually treated with aspirin and anticoagulants, the optimal treatment in various clinical settings is unclear, as the risk of complications vary among clinical subtypes and the management strategy depends on whether the patient is pregnant or not. Also, there are unmet needs for the evidence-based, pregnancy-related treatment of asymptomatic women positive for aPL. This review focuses on the management of positive aPL or APS in pregnant and postpartum women, and in women attempting to become pregnant. For asymptomatic aPL positive women, no treatment, low dose aspirin (LDA) or LDA plus anticoagulants can be considered during antepartum and postpartum. In obstetric APS patients, preconceptional LDA is recommended. LDA plus low molecular weight heparin is administered after confirmation of pregnancy. Vascular APS patients should take frequent pregnancy test and receive heparin instead of warfarin after confirmation of pregnancy. During pregnancy, heparin plus LDA is recommended. Warfarin can be restarted 4 to 6 hours after vaginal delivery and 6 to 12 hours after cesarean delivery. Most importantly, a tailored approach and patient-oriented treatment are mandatory.

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 IgM anti-β2 glycoprotein, lupus anticoagulant, and IgM/IgG 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 IgM anti-β2 glycoprotein and 1 patient had IgG anti-cardiolipin (20.0%) and IgM 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 IgM anticardiolipin, and is associated with an acute coronary syndrome, gastrointestinal manifestations, moderate and severe disease severity, and increased risk of mortality.

Retinal ischemia as the first manifestation of antiphospholipid antibody syndrome

Antiphospholipid antibody syndrome (APS) is characterized by the development of venous and/or arterial thrombosis and by gestational morbidity (recurrent fetal losses) in the presence of antiphospholipid antibodies. We report the case of a 38-year-old woman who was diagnosed with primary APS from thromboembolic abnormalities in the retinal periphery that led to retinal ischemia. The aim of this study is to share with physicians and medical undergraduates an atypical manifestation of the syndrome that is the most common acquired thrombophilia, [...]

Spinal Anesthesia for Cesarean Section in a Coagulated Patient with Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by vascular thrombosis or pregnancy complications with the presence of antiphospholipid antibodies. It is a rare disease affecting 40–50/100,000 population yet responsible for 10%–15% of recurrent pregnancy loss. Diagnosis requires at least one clinical and one laboratory criteria to be met. Perioperative management in obstetric APS underwent cesarean section stressed on the management of anticoagulation and proper choice of anesthesia technique. We report the case of a 21-years-old woman, 39 weeks pregnant, diagnosed with APS since the 8th week of gestation. She had two previous miscarriages and an elevated level of anticardiolipin antibody (aCL IgG: 21 GPL U/ml) with normal aCL IgM and lupus anticoagulant. She was treated with a prophylactic dose of low-molecular-weight heparin (0.4 IU subcutaneous enoxaparin) and oral aspirin 80 mg daily. She presented to the obstetric department and scheduled for an urgent cesarean section. Enoxaparin was held, and the surgery was done with spinal anesthesia. Anticoagulation resumed 12 h after surgery. No complications on the mother and baby were found after 3 days of observation.

Thromboembolism, Hypercoagulopathy, and Antiphospholipid Antibodies in Critically Ill Coronavirus Disease 2019 Patients: A Before and After Study of Enhanced Anticoagulation

Retrospective. Tertiary intensive care unit. Two cross-sectional cohorts of ICU-treated coronavirus disease 2019 patients were included before (cohort 1, n = 12) and after (cohort 2, n = 14) enhanced prophylactic anticoagulation strategy. Before and after study of enhanced anticoagulation. Thromboelastometry point-of-care coagulation tests were performed by thromboelastography (Tem International GmbH, Munich, Germany), standard blood tests were extracted from patient charts, and presence of antiphospholipid antibodies in plasma was measured. All patients were males on mechanical ventilation. In cohort 1 (low-molecular-weight heparin dose: 129 ± 53 U/kg/24 hr), 50% had pulmonary embolism, and thromboelastography analysis revealed hypercoagulation in a majority of patients and greater than 80% had detectable antiphospholipid antibodies. In the second cohort (enhanced low-molecular-weight heparin dose: 200 ± 82 U/kg/24 hr; p = 0.04 vs cohort 1), we found a nonsignificantly lower prevalence of pulmonary embolism (21%; p = 0.22), lower fibrinogen (6.3 ± 2.5 vs 8.7 ± 2.0; p = 0.02), reduced fibrinogen-dependent thromboelastography (p < 0.001), and lower inflammatory markers. In these two cross-sectional cohorts of ICU-treated coronavirus disease 2019 patients, thromboembolic complications, hypercoagulation, and antiphospholipid antibodies were common. A more aggressive anticoagulation regime was associated with a reduction in inflammatory biomarkers including plasma fibrinogen and a reduction in fibrinogen-dependent hypercoagulation, as indicated by thromboelastography analyses.

Management of Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS), is an acquired autoimmune disorder characterised by thrombosis, pregnancy morbidity, and the presence of antiphospholipid antibodies (aPL). Although venous thromboembolism is the most common manifestation, thrombotic events in APS may also occur in virtually any vascular bed, with cerebral circulation being the arterial territory most commonly affected. As APS is a heterogeneous condition, its management should be tailored with a patient-centred approach based on individual risk assessment, which includes the aPL profile, concomitant auto-immune diseases, and traditional cardiovascular risk factors. Although literature data are conflicting regarding primary prophylaxis, there is some evidence indicating that antiplatelet agents may reduce the risk of a first thrombotic event in individuals with a high-risk profile. In patients with thrombotic APS, current evidence-based guidelines recommend lifelong vitamin K antagonists (VKAs), preferably warfarin. The optimal intensity of anticoagulation following arterial thrombosis remains controversial. Arterial thrombosis should be treated either with high-intensity warfarin at a target INR > 3.0, or low-dose aspirin (LDA) combined with moderate-intensity warfarin (INR 2.0–3.0). It is recommended to avoid direct oral anticoagulants (DOACs) in patients with high-risk APS, mainly those with triple-positive PL and previous arterial events. They would only be used exceptionally in selected patients with low-risk venous thromboembolism (VTE). In low-risk VTE patients currently treated with a DOAC due to warfarin intolerance or a previous unstable International Normalized Ratio on warfarin, the decision of continuing DOACs would be taken in carefully selected patients. In women with obstetric APS, the combination therapy with LDA plus heparin remains the conventional strategy.

Hypothesis: Alpha-1-antitrypsin is a promising treatment option for COVID-19

No definitive treatment for COVID-19 exists although promising results have been reported with remdesivir and glucocorticoids. Short of a truly effective preventive or curative vaccine against SARS-CoV-2, it is becoming increasingly clear that multiple pathophysiologic processes seen with COVID-19 as well as SARS-CoV-2 itself should be targeted. Because alpha-1-antitrypsin (AAT) embraces a panoply of biologic activities that may antagonize several pathophysiologic mechanisms induced by SARS-CoV-2, we hypothesize that this naturally occurring molecule is a promising agent to ameliorate COVID-19. We posit at least seven different mechanisms by which AAT may alleviate COVID-19. First, AAT is a serine protease inhibitor (SERPIN) shown to inhibit TMPRSS-2, the host serine protease that cleaves the spike protein of SARS-CoV-2, a necessary preparatory step for the virus to bind its cell surface receptor ACE2 to gain intracellular entry. Second, AAT has anti-viral activity against other RNA viruses HIV and influenza as well as induces autophagy, a known host effector mechanism against MERS-CoV, a related coronavirus that causes the Middle East Respiratory Syndrome. Third, AAT has potent anti-inflammatory properties, in part through inhibiting both nuclear factor-kappa B (NFκB) activation and ADAM17 (also known as tumor necrosis factor-alpha converting enzyme), and thus may dampen the hyper-inflammatory response of COVID-19. Fourth, AAT inhibits neutrophil elastase, a serine protease that helps recruit potentially injurious neutrophils and implicated in acute lung injury. AAT inhibition of ADAM17 also prevents shedding of ACE2 and hence may preserve ACE2 inhibition of bradykinin, reducing the ability of bradykinin to cause a capillary leak in COVID-19. Fifth, AAT inhibits thrombin, and venous thromboembolism and in situ microthrombi and macrothrombi are increasingly implicated in COVID-19. Sixth, AAT inhibition of elastase can antagonize the formation of neutrophil extracellular traps (NETs), a complex extracellular structure comprised of neutrophil-derived DNA, histones, and proteases, and implicated in the immunothrombosis of COVID-19; indeed, AAT has been shown to change the shape and adherence of non-COVID-19-related NETs. Seventh, AAT inhibition of endothelial cell apoptosis may limit the endothelial injury linked to severe COVID-19-associated acute lung injury, multi-organ dysfunction, and pre-eclampsia-like syndrome seen in gravid women. Furthermore, because both NETs formation and the presence of anti-phospholipid antibodies are increased in both COVID-19 and non-COVID pre-eclampsia, it suggests a similar vascular pathogenesis in both disorders. As a final point, AAT has an excellent safety profile when administered to patients with AAT deficiency and is dosed intravenously once weekly but also comes in an inhaled preparation. Thus, AAT is an appealing drug candidate to treat COVID-19 and should be studied.

Anti-β2-glycoprotein I autoantibodies influence thrombin generation parameters via various mechanisms

IntroductionAntiphospholipid syndrome (APS) is a systemic autoimmune disease characterised by recurrent thrombotic events, pregnancy loss and thrombocytopenia and the presence of antiphospholipid antibodies (APL). The exact pathomechanism of APS is still unknown, thus we investigated the effect of anti-β2-glycoprotein I (anti-β2GPI) on thrombin generation in different plasma samples. MethodsFor the separation of anti-β2GPI IgG, overall 12 APS patients were selected. The criteria were the existence of lupus anticoagulant, and the presence of anti-CL and anti-β2GPI, the latter exceeding at least 25 times the upper reference limit. We purified anti-β2GPI IgG antibodies from APS patients by affinity chromatography and added the antibodies to normal pooled, and heterozygous forms of inherited thrombophilia plasma samples (prothrombin G20210A, factor V Leiden). To further specify the mechanism of the effect, we also used factor deficient plasmas in the thrombin generation assay. ResultsIn normal pooled plasma, the anti-β2GPI significantly prolonged Lag Time according to the lupus anticoagulant effect, in contrast, it also elevated Peak Thrombin significantly, which suggests a procoagulant effect. The antibody was also able to exert this multi-faceted effect both in FVLeiden heterozygous plasma and prothrombin G20210A heterozygous polymorphism, however, the prolonging effect was more remarkable in the latter. By using factor deficient plasmas, it was found that FVII is required for the prolongation, while intrinsic factors are needed for the elevation of the Peak Thrombin. ConclusionThe anti-β2GPI autoantibodies exert their effect in both normal and thrombophilic plasmas via various mechanisms.

Eculizumab for Refractory Thrombosis in Antiphospholipid Syndrome

Introduction:Antiphospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis in the presence of antiphospholipid antibodies. Recently, derangement in the complement pathway has been implicated in APS pathophysiology. Refractory cases of APS with recurrent and potentially fatal thrombosis have prompted use of the monoclonal antibody eculizumab, which inhibits generation of the terminal complement complex. We present the successful use of eculizumab in controlling and preventing recurrent thrombosis in a refractory case of APS. Case Description:An 18-year-old female received a diagnosis of antiphospholipid syndrome after developing extensive unprovoked deep vein thrombosis of axillary, inferior vena caval and brachiocephalic veins. Thrombophilia evaluation revealed triple positivity for lupus anti-coagulant (LA), beta-2 glycoprotein I (GP) IgG 84.9 SGU Units, IgM 76.5 SMU Units, IgA 66.7 SAU Units and strongly positive anti-cardiolipin (aCL) antibodies (each &amp;gt;&amp;gt;40U/mL) with persistent positive titers after 12 weeks of initial evaluation. She was refractory with trials of multiple anticoagulants alone and with antiplatelet and adjunctive therapies. Anticoagulants used were enoxaparin, fondaparinux, apixaban, rivaroxaban, and warfarin; antiplatelet agents used were aspirin and clopidogrel; and adjunctive therapies included hydroxychloroquine, immunosuppression with steroids and rituximab, and plasmapheresis. Despite these interventions, she continued to develop recurrent thrombosis of subclavian, femoral, common femoral, iliac, popliteal and saphenous veins. She additionally developed a potentially life-threatening hepatic infarction and pulmonary embolism, and 6 weeks of plasma exchange failed to decrease antiphospholipid antibody titers. Following this event, eculizumab (600mg weekly x 4 weeks, followed by 900mg once on week 5, followed by 900mg every 2 weeks) was initiated in combination with fondaparinux, aspirin, clopidogrel, and hydroxychloroquine. She has remained on this regimen with additional anticoagulation and antiplatelet therapy without recurrence of thrombosis over the subsequent year. Discussion:Recent evidence has shown complement activation playing a role in pathophysiology of antiphospholipid syndrome. This is thought to occur through C3 and C5a causing platelet and endothelial activation, leading to microvascular thrombosis. Histological evidence of such processes is supported by the demonstration of anti-beta-2 GP1 IgG-C5b-9 immune complexes in microvascular organ thrombi in individuals with APS leading to thrombotic microangiopathy and multiorgan failure. Such evidence of complement induced thrombosis in antiphospholipid syndrome led us to use eculizumab following failure of available therapies including anticoagulation, antiplatelet therapy, immune modulation and plasmapheresis in a potentially life-threatening event. Absence of recurrent thrombotic events over approximately one year with eculizumab combined with anticoagulation and antiplatelet therapy highlights the potential role of complement inhibition in preventing thrombosis in APS. While the role of complement in thrombosis continues to be elucidated, we have observed no decline in antiphospholipid antibody levels in a span of one year in our patient. Importantly, there has been no recurrent thrombosis during this time. Our case suggests that eculizumab may have a role as a therapeutic option in refractory thrombosis in APS. Chronology of Events:Eculizumab initiated on 9/5/2019. No evidence of venous or arterial thrombosis since 10/2019 to present. Figure Disclosures Tarantino: Pfizer:Other;Genentech:Membership on an entity's Board of Directors or advisory committees;Octapharma:Membership on an entity's Board of Directors or advisory committees;Dova:Membership on an entity's Board of Directors or advisory committees;CDC:Membership on an entity's Board of Directors or advisory committees;Grifols:Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Amgen:Membership on an entity's Board of Directors or advisory committees;Biomarin:Membership on an entity's Board of Directors or advisory committees;NovoNordisk:Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Takeda:Research Funding;HRSA:Membership on an entity's Board of Directors or advisory committees;Spark:Membership on an entity's Board of Directors or advisory committees;Sobi:Membership on an entity's Board of Directors or advisory committees.McCrae:Rigel:Consultancy;Novartis:Honoraria;Momenta Pharmaceuticals:Consultancy;Dova:Consultancy.Chaturvedi:Sanofi:Honoraria, Membership on an entity's Board of Directors or advisory committees;Alexion:Honoraria, Membership on an entity's Board of Directors or advisory committees.Roberts:Octapharma:Consultancy, Speakers Bureau;uniQure:Consultancy;Sanofi:Consultancy, Speakers Bureau;Novo Nordisk:Consultancy, Speakers Bureau;Pfizer:Consultancy;Takeda:Consultancy, Research Funding, Speakers Bureau. OffLabel Disclosure: eculizumab for treatment of refractory thrombosis in antiphospholipid syndrome

Effectiveness and Safety of the Direct Oral Anticoagulants in Low-Risk Antiphospholipid Syndrome: A Case Series

Introduction: Thrombotic Antiphospholipid syndrome (TAPS) is an autoimmune condition where venous thromboembolism (VTE) and/or arterial thromboembolism (ATE) occurs in the presence of antiphospholipid antibodies (aPLs). TAPS is traditionally managed with long-term anticoagulation with vitamin K antagonists (VKA). Over the past decade, direct oral anticoagulants (DOACs) have been increasingly replacing VKAs as the oral anticoagulant of choice given their lower risk of bleeding, fixed dosing, and no requirement for routine monitoring. However, recent evidence has demonstrated inferiority of DOACs compared to VKAs in TAPS patients with high risk (triple positive) aPL profiles or previous arterial events. It remains unclear whether TAPS patients with low risk aPL profiles (single positive), and without previous ATE, can be treated effectively and safely with DOACs. Objectives: To assess the effectiveness and safety of DOACs at preventing recurrent VTE or ATE in TAPS patients with a low risk aPL profile, and without prior ATE. Methods: We conducted a retrospective review of all TAPS patients with a low risk aPL profile, without prior ATE, who were anticoagulated with a DOAC at two tertiary care hospitals in Toronto, Canada from January 2010 to July 2020. All patients with any positive aPL test results were first identified through the laboratory information system. This list was cross referenced with patients seen in specific thrombosis clinics and confirmed through individual electronic chart review. TAPS was defined as persistent (&amp;gt;12 weeks apart) lupus anticoagulant (LA) positivity, anti-cardiolipin titre (ACA) &amp;gt;40 GPL, or anti-2-glycoprotein 1 titre (a2GP1) &amp;gt;40 GPL, with a preceding thrombotic event. Patients were excluded if any of the aPLs were deemed to be simultaneously positive or if there was a history of previous ATE. a2GP1 was not systematically tested in all patients. Patient outcomes were assessed throughout the duration of anticoagulation with a DOAC. Recurrent VTE included deep vein thrombosis, pulmonary embolism, or VTE of atypical location, and required objective confirmation with appropriate diagnostic imaging. ATE included ischemic stroke, transient ischemic attack (TIA), myocardial infarction, or other systemic arterial embolism. Major bleeding (MB) and clinically relevant non major bleeding (CRNMB) were defined by International Society on Thrombosis and Hemostasis criteria. Results: 1195 patients were identified with at least one instance of single positive aPL who had been seen in one of the thrombosis clinics. Patients were excluded for the following reasons: 858 for non-persistent aPL positivity, 70 for simultaneous aPL positivity, 20 for a likely false positive LA due to DOAC therapy, 93 due to an absence of preceding VTE, 45 for history of previous ATE, and 59 due to no prior DOAC therapy. After exclusions, 50 patients were included in the analysis, encompassing 157.2 years of patient-follow up. The study population was comprised of 24 women and 26 men with a mean age of 49.6 (standard deviation (SD) 16.3)years at the start of DOAC therapy (Table 1). The mean duration of DOAC treatment was 37.7 (SD 23.8) months. Fifteen (30%) patients had prior diagnosis of systemic lupus erythematosus (SLE), while 4 (8%) had other systemic autoimmune disease diagnoses. Only 1 patient met criteria for obstetric APS, on the basis of 3 consecutive fetal losses before 10 weeks gestation. None of the patients had documented valvular disease or thrombocytopenia. All patients were treated initially with therapeutic dose rivaroxaban, although 6 (12%) patients were switched to therapeutic dose apixaban due to increased bruising or menorrhagia. Five patients on rivaroxaban and 3 patients on apixaban were switched to a reduced dose DOAC. No patient had recurrent VTE. One patient had a possible ATE as a TIA, presenting with an episode of loss of sight for 15 minutes while on reduced dose apixaban. None of the patients experienced MB. Two patients experienced CRNMB, both severe menorrhagia, one on therapeutic dose of rivaroxaban and the other patient on reduced dose of rivaroxaban. Conclusions: In our retrospective case series of 50 patients with TAPS, a low risk aPL profile and no previous ATE, DOACs were effective and safe in the secondary prevention of thrombotic events with no MB. Larger, prospective controlled studies are required to confirm these findings. Disclosures No relevant conflicts of interest to declare.

Venous Thromboembolic Disease in Children Associated with COVID-19

Venous thromboembolism (VTE) in children is rare and VTE in association with antiphospholipid antibodies (lupus anticoagulant, cardiolipin antibodies and beta-2 glycoprotein I) is even rarer. The development of these antibodies can be due to an acute infection or an autoimmune disease. Recently, these antibodies have been noted to be present in conjunction with SARS-CoV-2 in adult patients with VTE.We report 5 cases of VTE associated with presence of antiphospholipid antibodies in children over a short period during the coronavirus 19 pandemic. One child had SARS-CoV-2 PCR positive on nasopharyngeal swab while 2 had positive antibodies (IgM) to SARS-CoV-2. One adolescent female had features of Multi-Inflammatory System in Children (MIS-C) a few weeks before presenting with multiple pulmonary emboli and DVT. Thrombotic events included DVT of lower extremity (3 patients), multiple PE (2 patients), orbital vein thrombosis (1 patient) and upper extremity DVT (1 patient). Two of these patients had both DVT and PE. All patients had one or more antiphospholipid antibody present. Two adolescent females had new onset of systemic lupus erythematous. All patients were treated with systemic anticoagulation with heparin (initially with unfractionated heparin if clinically unstable and later changed to low molecular weight heparin).We report a cluster of adolescents with unusual thrombotic complications with antiphospholipid antibody positivity during the coronavirus 19 pandemic, 3 with positive virologic criteria, one with delayed presentation after MIS-C like features and one with close family member exposure. We hypothesize that VTE in children is likely due to development of antiphospholipid antibodies when associated with SARS-CoV-2 infection.DisclosuresNo relevant conflicts of interest to declare.

Increased eryptosis in patients with primary antiphospholipid syndrome (APS): a new actor in the pathogenesis of APS

Antiphospholipid syndrome (APS) is an autoimmune disease characterised by a hypercoagulable state and the presence of antiphospholipid antibodies (aPL). During the mechanism of red blood cells (RBCs) death, called eryptosis, RBCs can adhere to vascular wall participating in the development of a pro-thrombotic state. It is known that enhanced eryptosis contributes to several pathological conditions but the role of this process in APS has not been investigated yet. We analysed spontaneous eryptosis in a cohort of APS patients and aPL carriers (asymptomatic subjects with positive aPL tests). The effect on eryptosis of antibodies (Abs) purified from serum of APS patients and aPL carriers was also investigated. In this study, 30 patients with primary APS (PAPS) and 17 aPL carriers were recruited. Twenty healthy donors (HD) and 13 patients affected by autoimmune haemolytic anaemia (AHIA) were also recruited. RBCs were incubated with PAPS and aPL carriers Abs, purified by ammonium sulfate precipitation. Levels of eryptosis were analysed by flow cytometry. In vitro Abs from APS patients induced eryptosis in RBCs isolated from HD after 4 h of culture. On the contrary, Abs from aPL carriers had no effect on the percentage of phosphatidylserine-exposing RBCs. Ex vivo, APS patients showed higher levels of spontaneous eryptosis compared to HD and aPL carriers. In this study, we demonstrated a potential new aspect of APS pathogenesis based on the ability of Abs isolated from APS patients, not identified in aPL carriers, to stimulate eryptosis suggesting a possible contribution of this process in the clinical manifestations of APS.