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Antiphospholipid syndrome

Obstetric antiphospholipid syndrome combines persistent antiphospholipid antibodies with pregnancy loss or placental complications. Standard treatment combines low-dose aspirin and a low molecular weight heparin, and a proportion of pregnancies fail despite it. The work of Arsène Mekinian, carried out with French and European cohorts, addresses those failures, the presentations that lack conventional antibodies, and the treatments added to standard care.

Antiphospholipid syndrome (APS) is an autoimmune disease combining persistent antiphospholipid antibodies with thrombotic or obstetric manifestations, or with both.

Its obstetric form may be responsible for pregnancy loss, fetal death, pre-eclampsia, placental insufficiency, fetal growth restriction and prematurity.

Unlike many situations of unexplained reproductive failure, APS is a defined clinical and laboratory entity for which specific management is established. Arsène Mekinian's work addresses mainly refractory obstetric forms, atypical laboratory profiles and the assessment of additional treatment strategies.

What establishes his expertise in this field

What he coordinates or directs.

  • He is a co-author of the protocole national de diagnostic et de soins (French national diagnosis and care protocol) for antiphospholipid syndrome, 17th of 22 named authors, in alphabetical order; he is not its coordinator. Source: French National Diagnostic and Care Protocol for antiphospholipid syndrome in adults and children, La Revue de médecine interne, 2023, DOI 10.1016/j.revmed.2023.08.004.
  • Since 2024 he has directed the diplôme d'université d'immunologie de la reproduction (university diploma in reproductive immunology) of Sorbonne Université.
  • He is last author of the work from the French prospective multicentre registry FALCO, NCT05557201, on hydroxychloroquine in recurrent pregnancy loss, published in Human Reproduction in 2024.

His position in the publications cited here. Of the 20 references cited at the end of this page, Arsène Mekinian is first author of 8, last author of 3, and corresponding author of 10.

Two cited references are not his, the systematic review by Hooper et al. in 2023 and the HYPATIA protocol by Schreiber et al. in 2017: they appear in the section on what remains to be shown, to situate the state of knowledge beyond his own work.

In biomedical research, the first author is generally the person who carried out the work day to day, and the last author the one who designed and supervised the study. The literature describes this as an informal practice rather than a rule: international recommendations leave the order of authors to the authors themselves, and reading seniority from position becomes unreliable as the list of authors grows. [How to read author position](/en/method/author-position/)

An autoimmune disease with vascular and obstetric expression

The conventional antiphospholipid antibodies comprise:

  • the lupus anticoagulant;
  • anticardiolipin antibodies;
  • anti-beta-2-glycoprotein I antibodies.

The lupus anticoagulant, despite its name, is not an anticoagulant medicine but an abnormality observed on coagulation tests. When all three antibodies are present at the same time, this is called triple positivity. The persistence of these antibodies, their profile and their association with clinical manifestations all contribute to characterising risk: in the European multicentre study devoted to refractory obstetric forms, a lupus anticoagulant was present in 76% of the 49 patients and triple positivity in 45% 9.

APS may be primary or associated with another autoimmune disease, in particular with systemic lupus. It may present with thromboses, that is clots in the arteries or veins, with obstetric complications, or with both together.

The obstetric form is the one that affects pregnancy: recurrent miscarriage, fetal death, preterm delivery related to pre-eclampsia or to placental insufficiency. The European prospective follow-up of 134 children born to mothers with the disease, examined at 3, 9 and 24 months and then at 5 years, gives an idea of the prognosis of these pregnancies when they are followed: 16% had been born before 37 weeks (22 children), 14% weighed less than 2,500 g at birth (19 children), 18 (13%) had a neonatal complication. No thrombosis and no lupus were observed during the five years of follow-up, and four children showed behavioural or developmental abnormalities. Antibodies were detectable at birth in some of them, IgG anticardiolipin in 18 (16%), IgG anti-beta-2-glycoprotein I in 16 (15%), and persisted in 10% of the children. Arsène Mekinian is first author and corresponding author of this work, published in 2013 in Annals of the Rheumatic Diseases 2.

Obstetric APS and placental involvement

The mechanisms responsible for the obstetric complications are not limited to thrombosis.

Antiphospholipid antibodies may act through mechanisms involving the trophoblast, the endothelium, complement and placental inflammatory pathways, contributing to impaired placentation.

This immunological and placental dimension explains why obstetric APS is an important model for studying the interactions between autoimmunity, inflammation and pregnancy.

Complement was the subject of a registry study in which he took part. Published in 2023 in Placenta, an analysis of the European registry covering 1,048 women shows that the 223 of them (21.3%) with low complement during pregnancy have a shorter pregnancy (median 33 weeks against 35; p = 0.022) and fewer live births (67.7% against 74.4%; p = 0.045). He is 8th of 33 named authors there 16.

Conventional treatment and refractory forms

Conventional management of obstetric APS rests mainly on the combination of low-dose aspirin and a low molecular weight heparin, adapted to the patient's clinical and thrombotic profile.

This strategy has considerably improved obstetric prognosis. Nevertheless, some patients have a further complication despite correctly conducted conventional treatment.

The European registry of obstetric antiphospholipid syndrome, launched online in 2010 and fed by thirty European hospitals, documents this in 1,000 women and 3,553 episodes in its 2019 publication: miscarriage is the most frequent manifestation (386 cases, 38.6%), early pre-eclampsia and early growth restriction concern respectively 181 (18.1%) and 161 (16.1%) women, and the live birth rate is 85% in the 448 women (44.8%) who received the recommended treatment, against 72.4% where treatment was outside the recommended regimen and 49.6% with no treatment. Arsène Mekinian is 6th of 36 named authors there 12.

These so-called refractory situations are one of the main lines of research. Their frequency is not settled: his own texts estimate it at between 20 and 39% in the 2017 French review published in Gynécologie Obstétrique Fertilité et Sénologie, of which he is first author and corresponding author 8, and at between 20 and 30% in the 2025 review in La Revue de médecine interne of which he is last author 18. Both figures are his, and this page does not settle between them.

The aim is to identify better the factors associated with failure of conventional treatment and to assess the possible value of additional strategies. The 2017 review lists the treatments tried in small open studies, corticosteroids, intravenous immunoglobulins, plasma exchange and hydroxychloroquine, none of them established 8. He has also published what fails: a 2015 letter in La Presse Médicale, of which he is second author and corresponding author, reports the inefficacy of plasma exchange combined with rituximab in a refractory obstetric form 5.

The European study devoted to refractory forms, published in 2017 in Autoimmunity Reviews, covers 49 patients, median age 27 years (23 to 32), recruited in 8 European centres between December 2015 and June 2016, all of whom had an obstetric event despite aspirin and heparin and at least one subsequent pregnancy. The form was purely obstetric in 71% of them and both obstetric and thrombotic in 26%. A pregnancy loss occurred in 71% of cases, at a median gestational age of 11 weeks (8 to 21). On multivariable analysis, only a history of disease-related prematurity, the use of corticosteroids during pregnancy and an isolated anticardiolipin antibody profile were associated with a live birth. The authors conclude that corticosteroids might be effective in this profile and that prospective studies are needed. He is first author of 19 named authors and corresponding author 9.

An earlier European study, from 2014, covering 196 pregnancies in 156 patients, finds an effect of additional treatments only in the subgroup combining thrombosis and triple positivity, with an odds ratio of 9.7 whose 95% confidence interval runs from 1.1 to 88.9; he is 9th of 20 named authors there 3.

Lines of research

The work of Arsène Mekinian and of the French and European collaborations has developed around several questions.

Refractory obstetric APS

Characterising the patients who have a recurrence despite conventional treatment and looking for clinical or laboratory factors associated with prognosis. This is the subject of the 2017 European study of 49 patients, of which he is first author 9, and of the 2017 French review 8.

Hydroxychloroquine

Assessing its potential value as an additional treatment in high-risk or refractory obstetric forms. Two 2015 texts published in Autoimmunity Reviews carry his name in first position, one asking the question 4, the other providing the observational data on 30 patients and 35 pregnancies 6.

Antiphospholipid profiles

Studying the influence of the antibody profile, in particular of the lupus anticoagulant and of multiple positivity profiles, on obstetric risk, as in the 2014 European study of patients combining thrombosis and triple positivity 3.

Non-criteria or seronegative forms

Studying the patients who have a suggestive clinical phenotype without a complete conventional laboratory profile, and assessing the meaning of certain non-conventional antiphospholipid antibodies: 57 case records in 2012 1, 96 patients in 2016 7, 187 seronegative women compared with 285 seropositive women in 2020 14.

Prognostic biomarkers

Exploring other determinants of risk, in particular complement activation, measured in 1,048 women from the European registry 16, and the markers liable to characterise high-risk pregnancies better, including the European activity score validated in 2026 19.

Hydroxychloroquine and refractory obstetric APS

Hydroxychloroquine has several properties that may be relevant in APS, in particular immunomodulatory, anti-inflammatory and antithrombotic effects.

French and European cohorts in which Arsène Mekinian has taken part have reported encouraging results when hydroxychloroquine was added to conventional treatment in certain high-risk patients.

Two 2015 articles in Autoimmunity Reviews carry his name in first position and both deal with hydroxychloroquine in this disease. They do not say the same thing and are not of the same kind, and it is useful to distinguish them. The first, published online on 30 August 2014 and appearing in the January 2015 issue, is a narrative review: it studies no patient, it gathers the biological arguments in favour of the molecule, its anti-inflammatory, antiplatelet and immunoregulatory properties, and it concludes explicitly that clinical data on its use in the primary form of the disease are lacking and that prospective studies are needed. He is first author of 15 named authors and corresponding author 4. The second, published online on 21 January 2015 and appearing in the June 2015 issue, is the European multicentre series itself: 30 patients and 35 pregnancies treated with hydroxychloroquine are analysed there. Comparing these pregnancies with the same women's previous pregnancies on standard treatment, pregnancy losses fall from 81% to 19% (p < 0.05), with no difference in the accompanying treatments. Univariable analysis identifies as factors linked to outcome previous fetal deaths and the higher dose of hydroxychloroquine, 400 mg per day. In the 14 patients with a refractory obstetric form, of whom 5 had a form that was both obstetric and thrombotic and 9 a purely obstetric form, all having lost a previous pregnancy on treatment, aspirin and heparin in 11 cases and heparin alone in 3 cases, the addition of hydroxychloroquine is accompanied by a live birth in 11 cases out of 14, that is 78% (p < 0.05). The authors write that this result calls for prospective studies to confirm this preliminary work. He is first author of 19 named authors and corresponding author 6.

In a 2018 European multicentre study covering 194 high-risk pregnancies followed in 20 tertiary centres, hydroxychloroquine is associated with a live birth rate higher than that of the other oral treatments in the group of women who had had a refractory pregnancy, with an advantage for the 400 mg dose over 200 mg (p = 0.036) and for administration started before pregnancy rather than during it (p = 0.021); he is 24th of 29 named authors there 10.

These data nevertheless remain essentially observational and do not allow a causal effect of treatment to be formally established. A study of which he is last author, published in 2024 in Human Reproduction from the French prospective FALCO registry, points the other way in a neighbouring situation: 100 pregnancies exposed to hydroxychloroquine in 74 women with at least three early miscarriages, mean age 34.2 years, median of 5 previous miscarriages; 62% of the pregnancies ended before 12 weeks and 38% continued beyond, and the only predictive factor found on multivariable analysis is having had at most four previous miscarriages (adjusted odds ratio 3.13, confidence interval 1.31 to 7.83; p = 0.01). The authors write that exposure to hydroxychloroquine in early pregnancy does not appear to prevent further miscarriages, and they themselves flag the absence of a control group 17. The situation studied there is not obstetric antiphospholipid syndrome but unexplained recurrent miscarriage, and the two are not the same thing. The 2025 review in La Revue de médecine interne, of which he is last author, recalls the experimental data in vitro and in mice showing that the molecule limits the deleterious effect of the antibodies on trophoblast invasion, writes that no randomised controlled trial has assessed the addition of hydroxychloroquine to conventional treatment of the refractory obstetric form, and adds that current data do not support its use in unexplained recurrent miscarriage 18.

The HYDROSAPL trial, NCT04275778, sponsored by AP-HP, had been designed to assess this question in a randomised double-blind placebo-controlled trial. The study was in the end withdrawn without a single inclusion, in the context of the changing classification criteria for APS. It therefore produced no efficacy data.

On the trial he was to conduct, this page must be clear. The HYDROSAPL trial, registered under the number NCT04275778, sponsor AP-HP, a randomised double-blind placebo-controlled phase II trial, was designed to assess adding hydroxychloroquine to usual care in order to obtain an uncomplicated term pregnancy in primary obstetric antiphospholipid syndrome. Its protocol was published in 2018 in Gynécologie Obstétrique Fertilité et Sénologie, a text of which he is first author of six named authors and corresponding author 11. The trial itself did not take place. Its public entry, consulted on 8 September 2026, carries the status withdrawn, an actual enrolment of zero participants and the following reason, reported as it is written: the study was terminated following revisions to the diagnostic criteria defining the target pathology, revisions which significantly changed the study design. The entry was submitted for update on 31 March 2026 and posted on 6 April 2026, and Arsène Mekinian appears on it as principal investigator. The exact acronym is HYDROSAPL; the spelling HYDROAPS, which is sometimes encountered, is wrong and corresponds to no registered trial. No data were produced by this trial.

The exact place of hydroxychloroquine in refractory obstetric APS therefore remains a question for clinical research, with no answer from a French randomised trial.

Non-criteria forms and seronegative APS

Some patients have strongly suggestive obstetric manifestations without meeting the conventional laboratory criteria for APS. This is what is called a seronegative, or non-criteria, form, and it is ground on which treatment decisions rest on few data.

His first work on the subject addresses precisely those situations that the diagnostic criteria leave aside. In 2012, in the Journal of Reproductive Immunology, he retrospectively compared the records of 57 women referred between 2003 and 2010 for unexplained obstetric complications with an antiphospholipid antibody assay: 25 had a syndrome confirmed by the Sapporo criteria, 32 had the same complications with an antibody titre below the intermediate threshold. The number of obstetric events per patient was very close in the two groups before treatment, 3 [1 to 8] and 3 [1 to 6], and it falls significantly after treatment in both groups, 0 [0 to 2] in each (p < 0.05). The authors conclude that properly designed treatment trials would be needed to demonstrate the benefit of these treatments. He is first author and corresponding author 1.

Work carried out in French and European cohorts has studied various non-conventional antiphospholipid antibodies and the clinical features of these so-called non-criteria or seronegative forms. In 2016, in Seminars in Arthritis and Rheumatism, he measured, in women meeting the clinical criteria for the disease, so-called non-conventional antibodies, anti-phosphatidylethanolamine, anti-prothrombin and phosphatidylserine, anti-annexin V: 65 patients out of 96, that is 68%, carry at least one and are classified as a non-conventional form, against 83 patients with confirmed disease and 31 with no antibody at all. Of the 474 pregnancies analysed, 136 (29%) were treated, and treatment is accompanied by a markedly higher live birth rate, 72% against 26% in the untreated (p < 0.0001). He is first author of 10 named authors and corresponding author 7.

In 2020, in RMD Open, he is last author, 29th of 29, and corresponding author of the European study comparing 187 women with a seronegative form, recruited in 14 centres in Austria, Spain, Italy, Slovenia and France, with 285 women with a seropositive form. The seronegative forms are more obstetric than thrombotic, with only 6% venous thromboses. The cumulative incidence of obstetric events was comparable between the two groups, with, in the seropositive women, more intrauterine fetal deaths (15% against 5%, p = 0.03) and an earlier gestational age at birth (36 ± 3 against 38 ± 3 weeks, p = 0.04), together with a significant difference in pre-eclampsia (7% against 16%, p = 0.048) whose direction the published abstract does not allow to be established. Treatment significantly improves the cumulative incidence of events in the seronegative women, with no difference between aspirin alone and the combination of aspirin and heparin. The authors' conclusion is that the detection of non-criteria antibodies might prompt discussion of management similar to that of seropositive forms, but that well designed controlled studies are needed 14. The 2020 publication from the European registry points the same way: it compares 1,000 women meeting the Sydney criteria with 640 women having antibody-related obstetric complications without meeting them, and shows that the laboratory profiles differ markedly between the two groups whereas the fetal and maternal outcomes are comparable when the women are treated. He is 6th of 34 named authors there 13.

These observations suggest the existence of phenotypes clinically close to conventional APS, but their definition remains debated. The search for non-conventional antibodies and their use to guide a treatment decision do not have the same level of validation as the conventional markers.

A disease whose criteria are changing

The classification criteria for APS have recently changed, in order to obtain more homogeneous populations for research.

The European work in which Arsène Mekinian takes part shows that applying the new criteria substantially changes the population classified as obstetric APS. In 2026, in the European Journal of Obstetrics and Gynecology and Reproductive Biology, he co-authored the reanalysis of the 1,200 women of the European registry classified under the Sydney criteria, revisited in the light of the 2023 ACR/EULAR classification criteria: applying the obstetric clinical domain alone would exclude 816 cases (68%), the rule on IgM would remove 46 more, bringing the total excluded to 862 (71.83%), and the threshold of 40 units would set aside a further 86 women whose antibodies nevertheless exceed the 99th percentile; in all, of the 1,200 cases, only 256 (21.33%) would remain classifiable. The authors write that the clinical and research consequences of this reduction need to be assessed in prospective studies. He is 7th of 29 named authors there 20.

He is finally one of the twenty-four members of the European working group that built and validated in 2026 the disease activity score known as the EAPSDAS, comprising 24 items for the thrombotic and microvascular domain and 6 items for the obstetric domain, of which the authors write that it requires further prospective validation 19.

It is essential to distinguish classification from clinical diagnosis: classification criteria are designed mainly to make the populations included in studies homogeneous and do not replace the individual assessment of a patient. A woman who cannot be classified is not for that reason a woman without the disease.

This change is also an important methodological issue for comparing older and future studies.

Multidisciplinary organisation

The management of obstetric APS brings together internal medicine, obstetrics, reproductive medicine, haemostasis and laboratory immunology.

The work is developed within the department of internal medicine and clinical immunology at Saint-Antoine Hospital, AP-HP, Sorbonne Université, in collaboration with several French and European obstetric and laboratory teams.

The MEDLINE records of his publications carry the label "service de médecine interne" of Saint-Antoine Hospital (AP-HP, Sorbonne Université), in the medical and university department devoted to inflammation, immunopathology and biotherapies, designated DHU i2B until about 2019 then DMU 3iD and DMU i3 in the affiliations of his publications. His 2025 and 2026 publications also mention, in his affiliation, a reference centre attached to Saint-Antoine, whose acronym is written CEREMAIAA on one record and CEREMAIIA on the other.

The follow-up of these pregnancies is multidisciplinary by construction, and the composition of his publication teams shows it: obstetrics at Jean Verdier Hospital in Bondy, at Armand-Trousseau Hospital and at Tenon Hospital for the follow-up of pregnancies and for assisted reproduction, immunology laboratories at Bichat Hospital and Saint-Antoine Hospital for antibody testing and monitoring, and the biostatistics department at Saint-Antoine for the analysis of the cohorts. Complex or refractory situations may be the subject of a multidisciplinary team meeting and of referral to an expert centre, and treatments given intravenously are delivered in the day hospital.

French recommendations are also given structure by a national diagnostic and care protocol devoted to antiphospholipid syndrome, published under the aegis of the Haute Autorité de santé, whose English-language version appeared in 2023 in La Revue de médecine interne. Arsène Mekinian is one of the twenty-two named authors of this text, whose signatories are listed in alphabetical order 15. This protocol recalls that a reference or competence centre specialising in autoimmune disease should be consulted for the management of severe forms, and in particular of catastrophic antiphospholipid syndrome.

What remains to be shown

Conventional treatment of obstetric APS is established. The main uncertainties now concern refractory forms and non-criteria situations.

The most important point holds in one sentence: no randomised trial has demonstrated that adding hydroxychloroquine to standard treatment improves pregnancy outcome in the refractory obstetric form. That is what the 2025 review of which he is last author states in black and white 18. The French trial that was to answer this question, HYDROSAPL, was withdrawn without including a single participant, and its public entry attributes that termination to the revision of the diagnostic criteria for the disease. The international HYPATIA trial, which asked a neighbouring question, had no results publication indexed on PubMed as at 8 September 2026: only the publication of its protocol, in 2017, appears there, and Arsène Mekinian is not a signatory of it. The question therefore remains open, and nothing on this page is to be read as a treatment recommendation.

The data of which he is first or last author are, on this subject, entirely observational and retrospective. The 2015 European series covers 30 patients and 35 pregnancies, of whom only 14 had a refractory form, and its comparison is made with the same women's previous pregnancies, which is not a control group. This type of comparison readily overestimates the effect of a treatment, because a woman who has lost several pregnancies retains, with nothing changed, a non-zero probability of carrying the next one to term, and because the decision to treat is made by the physician and not randomised. The 2017 study of refractory forms covers 49 patients recruited in 8 centres, it is retrospective and open-label, and the signal in favour of corticosteroids that it describes is the result of a multivariable analysis on a small number of patients, which its own authors say has to be confirmed by prospective studies. None of these results has been independently replicated in a controlled trial.

The very definition of what is being counted is not stable. His own texts estimate the frequency of refractory forms at between 20 and 39% in 2017 and at between 20 and 30% in 2025, and this page does not settle between the two figures. And the scope of the disease has changed: the 2026 European reanalysis he co-authored shows that applying the 2023 ACR/EULAR classification criteria would leave only 256 of the 1,200 women in the registry classifiable, that is a little more than one in five. It should be added that these criteria are classification criteria, built to constitute homogeneous groups in research, and not criteria for individual diagnosis at the bedside.

The clinical meaning of non-conventional antiphospholipid antibodies and the management of so-called seronegative forms also remain insufficiently standardised. His own conclusion of 2020 is cautious: the detection of non-criteria antibodies might prompt discussion of management similar to that of seropositive forms, but well designed controlled studies remain necessary 14. Neither the positivity threshold for these non-conventional antibodies, nor what to do when they are present alone, is the subject of consensus. Finally, one of the most recent pieces of work in which he took part is negative: in the French FALCO registry, exposure to hydroxychloroquine in early pregnancy in women with recurrent miscarriage does not appear to prevent further miscarriages, and that study too lacks a control group 17.

To place this work in the international literature, and without his being a signatory of it, a systematic review published in 2023 in the American Journal of Reproductive Immunology by Hooper, Bacal and Bedaiwy took up twelve studies on hydroxychloroquine in pregnancy in women with the primary form of the disease: three retrospective cohorts show an improvement in the live birth rate and four studies a reduction in the pregnancy loss rate, and the authors conclude that randomised trials with standardised selection criteria must be conducted to confirm these observations. This reference is not his.

It therefore remains to be determined which patients may benefit from a treatment additional to conventional antithrombotic treatment and which strategy should be preferred. The research priorities are to stratify obstetric risk better, identify prognostic biomarkers and prospectively assess additional strategies in refractory forms.

References

Published work he has taken part in, on this subject.

General information only. This page does not replace individual medical advice. Updated: 19 September 2026.