Detection of anti-cardiolipin and anti-β2glycoprotein I antibodies differs between platforms without influence on association with clinical symptoms

Background: The anti-phospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with persistent presence of anti-phospholipid antibodies (aPL). Laboratory criteria include aPL detection by coagulation tests for lupus anticoagulant (LAC) or solid phase assays measuring anti-beta 2 glycoprotein I (a beta 2GPI) or anticardiolipin (aCL) immunoglobulin (Ig) G/IgM antibodies. External quality control programs illustrate that commercially available aPL assays produce variable results. Objective: We aimed to investigate the agreement and diagnostic accuracy of solid phase assays. Materials and Methods: In thismulti-centre study, 1,168 patient samples were tested on one site for aCL and a beta 2GPI IgG/IgM antibodies by four solid phase test systems. Samples included APS patients, controls and monoclonal antibodies (MoAB) against different epitopes of beta 2GPI. LAC was determined by the local centre. Results: aCL IgM assays resulted in the most discrepancies (60%), while aCL IgG and a beta 2GPI IgM assays resulted in lower discrepancies (36%), suggesting better agreement. Discrepant samples displayed lower median aPL titers. Dependent on the solid phase test system, odds ratios (ORs) for thrombosis and pregnancy morbidity ranged from 1.98 to 2.56 and 3.42 to 4.78, respectively. Three platforms showed lower sensitivity for MoAB directed against the glycine (Gly) 40-arginine (Arg) 43 epitope of domain I of beta 2GPI. Conclusion: Poor agreement was observed between different commercially available aCL and a beta 2GPI IgG/IgM assays, hampering uniformity in the identification of aPL-positive patients. Clinical association was globally concordant between solid phase test systems considering results of the four aPL together. An assay sensitive in detecting the MoAB against Gly40-Arg43 of domain I of beta 2GPI reached the highest OR for thrombosis

Proposal of new clinical and laboratory criteria in the determination of thrombotic risk in antiphospholipid patients

Le syndrome des anticorps antiphospholipides (SAPL) est caractérisé par une atteinte auto-immune systémique à l’origine d’événements cliniques thrombotiques ou obstétricaux en présence d’anticorps antiphospholipides (aPL) persistants sur 2 prélèvements. Ce travail de thèse s’est intéressé à des manifestations cliniques et des tests biologiques dont le but est d’évaluer le risque thrombotique dans ce syndrome. En premier lieu, le risque de valvulopathie associé aux aPL chez les patients lupiques a été étudié. L’existence d’une telle association faisait l’objet d’une controverse non résolue. En ayant recours à une revue systématique de la littérature et à une méta-analyse d’études observationnelles, les fréquences des valvulopathies chez les patients lupiques en fonction de la présence ou non d’aPL ont été comparées. Le résultat principal est, qu’en présence d’aPL chez les patients lupiques, ce risque est multiplié par 3. En second lieu, la valeur pronostique sur le risque de thrombose des thromboses veineuses superficielles (TVS) a été étudiée chez les patients atteints d’un SAPL. Une étude de cohorte prospective monocentrique a montré que la présence d’un antécédent de TVS était prédictive du risque de thrombose ultérieure. D’autre part, l’apport de nouveaux marqueurs biologiques, les anticorps spécifiquement dirigés contre le domaine I de la [bêta]2-Glycoprotéine I ainsi que les paramètres de thrombinographie prenant en compte la sensibilité à la protéine C activée ont été étudiés. Les résultats montrent que ces 2 tests sont prédictifs du risque thrombotique incident. Enfin, les données de qualité de vie d’une cohorte multicentrique de patients atteints de lupus et/ou porteurs d’aPL, ont été analysées. Les résultats montrent que la présence d’un antécédent de thrombose artérielle était associée à une altération de toutes les dimensions de la qualité de vie évaluée par un auto-questionnaire généraliste (MOS-SF36) en comparaison à des patients atteints de maladie auto-immune sans ce type de thrombose. Ces résultats pourront avoir un impact significatif dans la réflexion sur l’évolution des critères de classification de ce syndromeAntiphospholipid syndrome (APS) is characterized by an auto-immune disorder with thrombotic and obstetrical morbidity in the presence of persistant antiphospholipid antibodies (aPL). This work studied clinical manifestations and laboratory assays for the determination of thrombotic risk in APS patients. Firstly, the risk of heart valve disease associated with aPL in systemic lupus erythematosus (SLE) patients was studied. Since 20 years, data regarding this association yielded conflicting results. A systematic review and a meta-analysis were performed to compare frequencies of heart valve disease in SLE patients with and without aPL. Main result concluded that the presence of aPL in SLE patients is associated with a 3-fold increased risk for heart valve disease in comparison with SLE patients without these antibodies. Secondly, prognostic significance of superficial vein thrombosis (SVT) was studied in APS patients. A prospective cohort study was performed and showed that SVT was predictive of thrombotic events overtime in this population. Moreover, the contribution of new laboratory assays were studied (antibodies directed against the domain I of [beta]2-Glycoprotein I and thrombin generation assay assessing sensitivity to activated protein C). Results demonstrated that these two assays were predictive of thrombotic events in APS patients. Finally, health-related quality of life was assessed in a multicentric cohort study of patients with aPL and/or SLE. Results showed that the presence of a history of arterial thrombosis was significantly associated with an impairment of all dimensions scores assessed by the MOS-SF36 questionnaire in comparison with patients with an auto-immune disease but without arterial thrombosis. This work provides new insights in the field of APS and may have an impact in the evolution leading to new classification criteria for definite APS

Risque de valvulopathie associé aux anticorps antiphospholipides chez les patients atteints de lupus érythémateux systémique (méta-analyse des études échographiques)

L atteinte valvulaire est fréquente dans le syndrome des antiphospholipides (SAPL) indépendamment du lupus érythémateux systémique (LES) mais le rôle des antiphospholipides (aPL) est controversé. Notre objectif était d étudier l aasociation entre les aPl et les vulvopathies chez patients atteints de LES. Nous avons réalisé une méta-analyse des études échographiques sélectionnées grâce aux bases de données Pubmed, Embase et Cochrane Libray à partir des mots-clés suivants : Antiphospholipid Syndrome ; Antibodies ; Antiphospholipids : beta 2-Glycoprotein I ; Cardiolipins ; Lupus Erythematosus Systemic ; Heart Valve Diseases : Endocarditis ; Heart Valves. A partir des données de 23 études représentant 1656 patients, les fréquences des valvulopathies et des aPL chez les patients atteints de LES étaient respectivement de 30.7% et 40.3%. Le risque des valvulopathie associéaux aPL chez les patients atteints de LES était de 3.13 [IC 95% : 2.31-4.24], sans hétérogénéité (p=0.11). Le Funnel plot ne suggérait pas de biais de publication. Le risque de valvulopathie différait selon le type d aPL : 5.88 [IC 95% : 2.92-11.84) pour l anticoagulant circulant (LA). 3.28 [IC 95% : 2.06-5.22] pour les anticardiolipides (aCL), ainsi que 5.63 [IC 95% : 3.53-8.97] et 1.67 [IC 95% : 0.46-6.05] pour les aCL et IgG et IgM respectivement. Le score de qualité variait de 19 à 53% avec un bon agrément inter-juges (ICC [0.56-0.84]). Au total, la présence d aPL chez les patients atteints de LES est significativement associé à un risque augmenté de valvulopathie. Ce risque différe selon le type d aPL. En pratique clinique, ces résultats peuvent pmotiver la réalisations d échocardiographies systématiques chez les personnes atteints de LES et porteurs d aPL, même en l absence d antécédent de valvulopathie.NANCY1-Bib. numérique (543959902) / SudocSudocFranceF

Direct oral anticoagulants in antiphospholipid syndrome: Meta-analysis of randomized controlled trials

International audienceBackground: The gold standard for secondary thromboprophylaxis in APS is long term anticoagulation with vitamin K antagonists (VKAs). Because of their widespread use and potential advantages of directs oral anticoagulants (DOACs) over VKAs, they have been prescribed in APS without definitive evidence of their safety and efficacy in this context. Recent specific randomized controlled trials (RCT) in APS and results from pivotal RCTs comparing DOACs vs VKAs are now available. Their results are conflicting but these studies have been conducted in different APS populations.Purpose of review: To summarize available data from RCT and determine risks of recurrent thrombosis and bleeding.Results: Four studies were included and 23 and 10 thrombotic events were recorded among 282 and 294 APS patients treated with DOACs and warfarin respectively. Overall recurrent thrombotic events were not significantly increased during DOACs treatment (OR = 2.22 [95% CI, 0.58-8.43]) compared to VKAs. However, when different types of thrombosis were analyzed separately, there was an increased risk of recurrent arterial thrombosis (5.17 [95% CI, 1.57-17.04]) with DOACs compared to warfarin but no significant higher risk of venous thrombosis (OR 0.69 [95% CI, 0.23-2.06). No increased risk of bleeding was found.In conclusion: In APS patients treated with DOACs compared to those treated with warfarin, no evidence of a higher risk of recurrent venous thromboembolism was found however there was a significantly increased risk of recurrent arterial thrombosis. Moreover risk of recurrent arterial thrombosis tended to be more frequent in patients with a history of arterial thrombosis. These results are in line with international guidelines which recommend not to use DOACs in APS patients with a history of arterial thrombosis but raise the question of the efficacy of DOACs to prevent venous thrombosis in a subset of APS patients without a history of arterial thrombosis

Role of antiphospholipid antibodies in the diagnosis of antiphospholipid syndrome

The diagnosis of antiphospholipid syndrome (APS) relies on the detection of antiphospholipid antibodies (aPL). Currently, lupus anticoagulant (LA), anticardiolipin (aCL), and antibeta2-glycoprotein I antibodies (a beta 2GPI) IgG or IgM are included as laboratory criteria, if persistently present. LAC measurement remains a complicated procedure with many pitfalls and interfered by anticoagulant therapy. Solid-phase assays for aCL and a beta 2GPI show interassay differences. These methodological issues make the laboratory diagnosis of APS challenging. In the interpretation of aPL results, antibody profiles help in identifying patients at risk. Other aPL, such as antibodies against the domain I of beta2-glycoprotein (aDI) and antiphosphatidylserine-prothrombin (aPS/PT) antibodies have been studied in the last years and may be useful in risk stratification of APS patients. Because of the methodological shortcomings of immunological and clotting assays, these non-criteria aPL may be useful in patients with incomplete antibody profiles to confirm or exclude the increased risk profile. This manuscript will focus on the laboratory aspects, the clinical relevance of assays and interpretation of aPL results in the diagnosis of APS

Thromboprophylaxis strategies to improve the prognosis of COVID-19

The outbreak of 2019 novel coronavirus disease (Covid-19) has deeply challenged the world population, but also our medical knowledge. Special attention has been paid early to an activation of coagulation, then to an elevated rate of venous thromboembolism (VTE) in patients hospitalized with severe COVID-19. These data suggested that anticoagulant drugs should be evaluated in the treatment of patients with COVID-19. The publication of unexpected high rates of VTE in patients hospitalized with COVID-19, despite receiving thromboprophylaxis, open the way to dedicated trials, evaluating modified regimens of thromboprophylaxis. Moreover, the further improvement in our comprehension of the disease, particularly the pulmonary endothelial dysfunction increased the hope that anticoagulant drugs may also protect patients from pulmonary thrombosis. In this comprehensive review, we cover the different situations where thromboprophylaxis standard may be modified (medically-ill inpatients, ICU inpatients, outpatients), and describe some of the current randomized controls trials evaluating new regimens of thromboprophylaxis in patients with COVID-19, including the preliminary available results. We also discuss the potential of anticoagulant drugs to target the thromboinflammation described in patients with severe COVID-19.</p