S Miyakis, M D Lockshin, T Atsumi, D W Branch, R L Brey, R Cervera, R H W M Derksen, P G DE Groot, T Koike, P L Meroni, G Reber, Y Shoenfeld, A Tincani, P G Vlachoyiannopoulos, S A Krilis
International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).
J Thromb Haemost. 2006 Feb;4(2):295-306. doi: 10.1111/j.1538-7836.2006.01753.x.
Abstract/Text
New clinical, laboratory and experimental insights, since the 1999 publication of the Sapporo preliminary classification criteria for antiphospholipid syndrome (APS), had been addressed at a workshop in Sydney, Australia, before the Eleventh International Congress on antiphospholipid antibodies. In this document, we appraise the existing evidence on clinical and laboratory features of APS addressed during the forum. Based on this, we propose amendments to the Sapporo criteria. We also provide definitions on features of APS that were not included in the updated criteria.
Maria G Tektonidou, Laura Andreoli, Marteen Limper, Zahir Amoura, Ricard Cervera, Nathalie Costedoat-Chalumeau, Maria Jose Cuadrado, Thomas Dörner, Raquel Ferrer-Oliveras, Karen Hambly, Munther A Khamashta, Judith King, Francesca Marchiori, Pier Luigi Meroni, Marta Mosca, Vittorio Pengo, Luigi Raio, Guillermo Ruiz-Irastorza, Yehuda Shoenfeld, Ljudmila Stojanovich, Elisabet Svenungsson, Denis Wahl, Angela Tincani, Michael M Ward
EULAR recommendations for the management of antiphospholipid syndrome in adults.
Ann Rheum Dis. 2019 Oct;78(10):1296-1304. doi: 10.1136/annrheumdis-2019-215213. Epub 2019 May 15.
Abstract/Text
The objective was to develop evidence-based recommendations for the management of antiphospholipid syndrome (APS) in adults. Based on evidence from a systematic literature review and expert opinion, overarching principles and recommendations were formulated and voted. High-risk antiphospholipid antibody (aPL) profile is associated with greater risk for thrombotic and obstetric APS. Risk modification includes screening for and management of cardiovascular and venous thrombosis risk factors, patient education about treatment adherence, and lifestyle counselling. Low-dose aspirin (LDA) is recommended for asymptomatic aPL carriers, patients with systemic lupus erythematosus without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high-risk aPL profiles. Patients with APS and first unprovoked venous thrombosis should receive long-term treatment with vitamin K antagonists (VKA) with a target international normalised ratio (INR) of 2-3. In patients with APS with first arterial thrombosis, treatment with VKA with INR 2-3 or INR 3-4 is recommended, considering the individual's bleeding/thrombosis risk. Rivaroxaban should not be used in patients with APS with triple aPL positivity. For patients with recurrent arterial or venous thrombosis despite adequate treatment, addition of LDA, increase of INR target to 3-4 or switch to low molecular weight heparin may be considered. In women with prior obstetric APS, combination treatment with LDA and prophylactic dosage heparin during pregnancy is recommended. In patients with recurrent pregnancy complications, increase of heparin to therapeutic dose, addition of hydroxychloroquine or addition of low-dose prednisolone in the first trimester may be considered. These recommendations aim to guide treatment in adults with APS. High-quality evidence is limited, indicating a need for more research.
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
R Cervera, M-C Boffa, M A Khamashta, G R V Hughes
The Euro-Phospholipid project: epidemiology of the antiphospholipid syndrome in Europe.
Lupus. 2009 Sep;18(10):889-93. doi: 10.1177/0961203309106832.
Abstract/Text
The Euro-Phospholipid project started in 1999 with a multicentre, consecutive and prospective design. A total cohort of 1000 patients with antiphospholipid syndrome (APS), derived from 13 countries (Belgium, Bulgaria, Denmark, France, Germany, Greece, Hungary, Israel, Italy, the Netherlands, Portugal, Spain and United Kingdom), has been followed since then. This project allowed the identification of the prevalence and characteristics of the main clinical and immunological manifestations at the onset and during the evolution of APS and demonstrated that it is possible to recognize more homogeneous subsets of clinical significance. Patients with APS associated with systemic lupus erythematosus (SLE) had more episodes of arthritis, livedo reticularis and more frequently exhibited thrombocytopenia and leucopenia. Female patients had more episodes of arthritis and livedo reticularis - both connected with the higher prevalence of migraine and SLE-related APS in women, while male patients had more myocardial infarction, epilepsy and lower limb arterial thrombosis. Childhood onset patients presented more episodes of chorea and jugular vein thrombosis, whereas older onset patients were more frequently male and had more strokes and angina pectoris, but less frequently livedo reticularis.
Doruk Erkan, Melanie J Harrison, Roger Levy, Margaret Peterson, Michelle Petri, Lisa Sammaritano, Aynur Unalp-Arida, Veronica Vilela, Yusuf Yazici, Michael D Lockshin
Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody-positive individuals.
Arthritis Rheum. 2007 Jul;56(7):2382-91. doi: 10.1002/art.22663.
Abstract/Text
OBJECTIVE: To determine the efficacy of a daily dose of 81 mg aspirin in primary thrombosis prevention in asymptomatic, persistently antiphospholipid antibody (aPL)-positive individuals (those with positive aPL but no vascular and/or pregnancy events).
METHODS: The Antiphospholipid Antibody Acetylsalicylic Acid (APLASA) study was a multicenter, randomized, double-blind, placebo-controlled clinical trial in which asymptomatic, persistently aPL-positive individuals were randomized to receive a daily dose of 81 mg of aspirin or placebo. In a separate observational and parallel study, asymptomatic, persistently aPL-positive individuals who were taking aspirin or declined randomization were followed up prospectively.
RESULTS: In the APLASA study, 98 individuals were randomized to receive aspirin or placebo (mean +/- SD followup period 2.30 +/- 0.95 years), of whom 48 received aspirin and 50 received placebo. In the observational study, 74 nonrandomized individuals were followed up prospectively (mean +/- SD followup period 2.46 +/- 0.76 years); 61 received aspirin and 13 did not. In the APLASA study, the acute thrombosis incidence rates were 2.75 per 100 patient-years for aspirin-treated subjects and 0 per 100 patient-years for the placebo-treated subjects (hazard ratio 1.04, 95% confidence interval 0.69-1.56) (P = 0.83). Similarly, in the observational study, the acute thrombosis incidence rates were 2.70 per 100 patient-years for aspirin-treated subjects and 0 per 100 patient-years for those not treated with aspirin. All but 1 patient with thrombosis in either study had concomitant thrombosis risk factors and/or systemic autoimmune disease at the time of thrombosis.
CONCLUSION: Our results suggest that asymptomatic, persistently aPL-positive individuals do not benefit from low-dose aspirin for primary thrombosis prophylaxis, have a low overall annual incidence rate of acute thrombosis, and develop vascular events when additional thrombosis risk factors are present.
Doruk Erkan, Cassyanne L Aguiar, Danieli Andrade, Hannah Cohen, Maria J Cuadrado, Adriana Danowski, Roger A Levy, Thomas L Ortel, Anisur Rahman, Jane E Salmon, Maria G Tektonidou, Rohan Willis, Michael D Lockshin
14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends.
Autoimmun Rev. 2014 Jun;13(6):685-96. doi: 10.1016/j.autrev.2014.01.053. Epub 2014 Jan 24.
Abstract/Text
Antiphospholipid Syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity occurring in patients with persistent antiphospholipid antibodies (aPL). The primary objective of the APS Treatment Trends Task Force, created as part of the 14th International Congress on aPL, was to systematically review the potential future treatment strategies for aPL-positive patients. The task force chose as future clinical research directions: a) determining the necessity for controlled clinical trials in venous thromboembolism with the new oral direct thrombin or anti-factor Xa inhibitors pending the results of the ongoing rivaroxaban in APS (RAPS) trial, and designing controlled clinical trials in other forms of thrombotic APS; b) systematically analyzing the literature as well as aPL/APS registries, and creating specific registries for non-warfarin/heparin anticoagulants; c) increasing recruitment for an ongoing primary thrombosis prevention trial, and designing secondary thrombosis and pregnancy morbidity prevention trials with hydroxychloroquine; d) determining surrogate markers to select patients for statin trials; e) designing controlled studies with rituximab and other anti-B-cell agents; f) designing mechanistic and clinical studies with eculizumab and other complement inhibitors; and g) chemically modifying peptide therapy to improve the half-life and minimize immunogenicity. The report also includes recommendations for clinicians who consider using these agents in difficult-to-manage aPL-positive patients.
Copyright © 2014 Elsevier B.V. All rights reserved.
Maria G Tektonidou, Katerina Laskari, Demosthenes B Panagiotakos, Haralampos M Moutsopoulos
Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies.
Arthritis Rheum. 2009 Jan 15;61(1):29-36. doi: 10.1002/art.24232.
Abstract/Text
OBJECTIVE: Antiphospholipid antibodies (aPL), namely anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC), have been associated with an increased risk of thrombosis in systemic lupus erythematosus (SLE). We examined additional thrombosis risk factors (aPL profile, SLE-related, and traditional risk factors) and the primary thrombosis prevention in SLE patients with and without aPL.
METHODS: All SLE patients with positive aPL but without previous thrombotic manifestations who were regularly followed up at our department (n = 144) and 144 age- and sex-matched SLE patients with negative aPL were included in this study. The median followup times were 104 and 112 months, respectively. The demographic, clinical, laboratory, and treatment characteristics and the traditional thrombosis risk factors were recorded.
RESULTS: The thrombosis rate was 29 per 144 aPL-positive patients (20.1%) and 11 per 144 aPL-negative patients (7.6%; P = 0.003). In multiadjusted analysis, significant predictors of thrombosis were male sex (hazard ratio [HR] 6.25, P < 0.01), LAC (HR 3.48, P = 0.04), and constantly positive aCL (HR 5.87, P = 0.01) for aPL-positive patients, while male sex (HR 7.14, P = 0.03) and hypertension were predictors for aPL-negative patients (HR 6.49, P = 0.03). Additionally, the duration of low-dose aspirin treatment played a protective role against thrombosis in aPL-positive patients (HR per month 0.98, P = 0.05), as did the duration of hydroxychloroquine in both aPL-positive (HR per month 0.99, P = 0.05) and aPL-negative patients (HR per month 0.98, P = 0.04).
CONCLUSION: Independent predictors of thrombosis for aPL-positive patients were male sex, LAC, and constantly positive aCL, and for aPL-negative patients were male sex and hypertension. The duration of low-dose aspirin use played a protective role against thrombosis in aPL-positive patients as did the duration of hydroxychloroquine in both groups.
Laurent Arnaud, Alexis Mathian, Amelia Ruffatti, Doruk Erkan, Maria Tektonidou, Ricard Cervera, Ricardo Forastiero, Vittorio Pengo, Marc Lambert, Maria Angeles Martinez-Zamora, Juan Balasch, Stephane Zuily, Denis Wahl, Zahir Amoura
Efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies: an international and collaborative meta-analysis.
Autoimmun Rev. 2014 Mar;13(3):281-91. doi: 10.1016/j.autrev.2013.10.014. Epub 2013 Nov 2.
Abstract/Text
We performed a meta-analysis to determine whether aspirin has a significant protective effect on risk of first thrombosis among patients with antiphospholipid antibodies (aPL+). Observational and interventional studies identified from the Medline, Embase and Cochrane databases were selected if they assessed the incidence of first thrombosis in aPL+ patients treated with aspirin versus those without. Pooled effect estimates were obtained using a random-effects model. Of 1211 citation retrieved, 11 primary studies (10 observational and 1 interventional) met inclusion criteria, including a total of 1208 patients and 139 thrombotic events. The pooled odds ratio (OR) for the risk of first thrombosis in patients treated with aspirin (n=601) was 0.50 (95%CI: 0.27 to 0.93) compared to those without aspirin (n=607), with significant heterogeneity across studies (I(2)=46%, p=0.05). Subgroup analysis showed a protective effect of aspirin against arterial (OR: 0.48 [95%CI: 0.28-0.82]) but not venous (OR: 0.58 [95% CI: 0.32-1.06]) thrombosis, as well as in retrospective (OR: 0.23 [0.13-0.42]) but not prospective studies (OR: 0.91 [0.52-1.59]). Subgroup analysis according to underlying disease revealed a significant protective effect of aspirin for asymptomatic aPL+ individuals (OR: 0.50 [0.25-0.99]), for systemic lupus erythematosus (SLE) (OR: 0.55 [0.31-0.98]) and obstetrical antiphospholipid syndrome (APS) (OR: 0.25 [0.10-0.62]). This meta-analysis shows that the risk of first thrombotic event is significantly decreased by low dose aspirin among asymptomatic aPL individuals, patients with SLE or obstetrical APS. Importantly, no significant risk reduction was observed when considering only prospective studies or those with the best methodological quality.
© 2013.
厚生労働科学研究費補助金（難治性疾患政策研究事業）難治性血管炎に関する調査研究 針谷正祥 編：抗リン脂質抗体症候群・好酸球性多発血管炎性肉芽腫・結節性多発動脈炎・リウマトイド血管炎の治療の手引き2020．2021、診断と治療社.
日本血栓止血学会編集委員会 編：わかりやすい血栓と止血の臨床．2011、南江堂、p184-6.
循環器病の診断と治療に関するガイドライン：循環器疾患における抗凝固・抗血小板療法に関するガイドライン（2009年改訂版）.
平成27年度日本医療研究開発機構成育疾患克服等総合研究事業 「抗リン脂質抗体症候群合併妊娠の治療及び予後に関する研究」研究班 編：抗リン脂質抗体症候群合併妊娠の診療ガイドライン．2016、南山堂.
Usama M Fouda, Ahmed M Sayed, Abdel-Megid A Abdou, Dalia I Ramadan, Iman M Fouda, Mahmoud M Zaki
Enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome.
Int J Gynaecol Obstet. 2011 Mar;112(3):211-5. doi: 10.1016/j.ijgo.2010.09.010. Epub 2011 Jan 19.
Abstract/Text
OBJECTIVE: To determine whether low molecular weight heparin (LMWH) plus low-dose aspirin (LDA) is comparable in efficacy and safety to unfractionated heparin (UFH) plus LDA in the management of pregnant women with a history of recurrent spontaneous abortion secondary to antiphospholipid syndrome (APS).
METHODS: In a randomized prospective study, 60 women with a history of 3 or more consecutive spontaneous abortions and positive antiphospholipid antibodies were assigned in equal numbers to receive either UFH (5000 units, twice daily) plus LDA, or LMWH (enoxaparin 40 mg, once daily) plus LDA as soon as pregnancy was diagnosed.
RESULTS: Twenty-four women in the LMWH group (80%) and 20 women in the UFH group (66.67%) delivered a viable infant (P = 0.243). There were no significant differences in pregnancy complications or neonatal morbidity between the 2 groups. There were no incidences of excessive bleeding, thrombocytopenia, or osteoporotic fractures in either group.
CONCLUSION: LMWH plus LDA was successfully used as an alternative to UFH plus LDA in the management of recurrent abortion secondary to APS. The results highlight the need for a larger randomized controlled trial to determine whether LMWH plus LDA should be the treatment of choice for recurrent abortion secondary to APS. Clinicaltrials.gov NCT01051778.
Copyright © 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
