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Cited by 1,261Systemic Lupus Erythematosus ResearchBlood Coagulation and Thrombosis MechanismsVenous Thromboembolism Diagnosis and Management

EULAR recommendations for the management of antiphospholipid syndrome in adults

Open access
Tektonidou, Maria G, Andreoli, Laura, Limper, Marteen, Amoura, Zahir, Cervera, Ricard, Costedoat-Chalumeau, Nathalie, Cuadrado, Maria Jose, Dörner, Thomas +16 more·2019·Annals of the Rheumatic Diseases
DOI 10.1136/annrheumdis-2019-215213PMC PMC11034817
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Abstract

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.

AI snapshot

Written from the paper’s full text.

TL;DR

This paper presents EULAR evidence-based recommendations for managing antiphospholipid syndrome (APS) in adults, covering risk stratification, thromboprophylaxis, obstetric APS, and catastrophic APS. The recommendations are based on a systematic literature review and expert consensus, with limited high-quality evidence.

Key findings

  • High-risk antiphospholipid antibody (aPL) profiles—lupus anticoagulant, double/triple aPL positivity, or persistently high titres—are associated with greater thrombotic and obstetric risk. Low-dose aspirin (LDA) 75–100 mg daily is recommended for asymptomatic aPL carriers, patients with SLE without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high-risk aPL profiles. A meta-analysis of seven observational studies of 460 asymptomatic aPL carriers found first thrombosis risk reduced by half with LDA; in women with obstetric APS without SLE, pooled OR for first thrombosis with LDA was 0.25 (95% CI 0.10 to 0.62).
  • For definite APS and first unprovoked venous thrombosis, long-term vitamin K antagonists (VKA) with target INR 2–3 are recommended. For first arterial thrombosis, VKA with INR 2–3 or INR 3–4 is recommended, considering individual bleeding/thrombosis risk. Rivaroxaban should not be used in patients with triple aPL positivity due to excess thromboembolic events in the TRAPS trial. For 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 obstetric APS, women with prior obstetric APS should receive combination LDA and prophylactic-dose heparin during pregnancy. In recurrent pregnancy complications despite LDA and prophylactic heparin, increasing heparin to therapeutic dose, adding hydroxychloroquine, or adding low-dose prednisolone in the first trimester may be considered. In women with thrombotic APS, LDA plus therapeutic-dose heparin is recommended; observational studies reported live births in 79% of pregnancies on average. For catastrophic APS, combination glucocorticoids, heparin, and plasma exchange or IVIG is recommended first-line; rituximab or eculizumab may be considered for refractory cases.
  • The task force developed 3 overarching principles and 12 recommendations. The systematic literature review yielded 7534 articles plus 15 hand-searched articles; after title/abstract review, 670 articles underwent full-text review, 249 underwent data abstraction, 61 were excluded, and 188 were finally considered relevant.

Methods

  • The project followed the updated EULAR standardised operating procedure and used the AGREE II tool. The task force included members from 11 European countries: 12 specialists in rheumatology or internal medicine, 2 obstetricians, 2 physicians from vascular medicine/thrombosis centres, 1 healthcare professional, and 2 patient representatives. Thirty-one research questions were formulated using PICO and voted by Delphi method.
  • Data sources were PubMed, Embase, and the Cochrane Library, searched for English-language articles from inception through 31 January 2018; one RCT published after this date (TRAPS) was included for safety results. Titles/abstracts were reviewed independently by two literature reviewers; full texts were reviewed independently by three persons. Data abstraction was performed by two reviewers and independently double-checked by the convenor and methodologist.
  • Evidence was tabulated with summary of findings tables and pooled estimates where applicable. Draft recommendations were prepared, reviewed, discussed in working groups, and voted at a second task force meeting on 3 September 2018. Levels of evidence and grades of recommendation used Oxford Centre for Evidence-Based Medicine standards; anonymous level of agreement was rated 0–10.

Limitations

  • The paper states that the main challenge was low certainty of evidence. Many studies included mixed clinical features and did not provide stratified data for arterial versus venous thrombosis or for different types of obstetric APS, resulting in indirect evidence for many treatment decisions. Meta-analyses also pooled heterogeneous patient groups, and RCTs commonly had high risk of bias and low power due to the rarity of the syndrome.
  • The paper states that a significant number of recommendations necessarily relied more, or only, on low-quality evidence or expert opinion. It also notes that cost and availability are not barriers to implementation except for IVIG and plasmapheresis, which were recommended first-line only in catastrophic APS, occurring in less than 1% of patients.
  • Evident from the text: several recommendations were based on expert opinion or lacked direct studies, including treatment duration after provoked first venous thrombosis, continuation of prophylactic heparin for 6 weeks postpartum, and management of recurrent pregnancy complications despite LDA and prophylactic heparin. Some supporting evidence came from small observational studies or case series.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1136/annrheumdis-2019-215213

Cites

69 of 69 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

27 of 77 cited sources checked · 13 supported · 6 flagged · accuracy not yet measured

  • Findingcitation

    In women with systemic lupus erythematosus and prior obstetric antiphospholipid syndrome, the protective effect of low-dose aspirin is supported by three retrospective studies that included a minority of patients with systemic lupus erythematosus.

    “Studies of women with SLE and prior obstetric APS are scarce, but the protective effect of LDA was supported by three retrospective studies that included a minority of patients with SLE.18–20”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [18] Erkan, 2001, High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin, Arthritis Rheum source
    • cites [19] Forastiero, 2005, A prospective study of antibodies to beta2-glycoprotein I and prothrombin, and risk of thrombosis, J Thromb Haemost source
    • cites [20] Ruffatti, 2011, Risk factors for a first thrombotic event in antiphospholipid antibody carriers: a prospective multicentre follow-up study, Ann Rheum Dis source

      Split into 2 atoms — 0 confirmed, 0 partially supported, 2 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Findingcitation

    In patients with antiphospholipid syndrome and first venous thrombosis, there is no additional benefit of a vitamin K antagonist target INR of 3-4 versus 2-3, based on an RCT and pooled data from five studies that included a majority with venous events.

    “Data from an RCT21 reporting exclusively on patients with venous events and pooled data from five studies that included a majority with venous events21–25 showed no additional benefit of a target INR of 3–4 vs INR of 2–3.”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [21] Crowther, 2003, A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome, N Engl J Med source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [22] Finazzi, 2005, A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS), J Thromb Haemost source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [23] Rosove, 1992, Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients, Ann Intern Med source
    • cites [24] Khamashta, 1995, The management of thrombosis in the antiphospholipid-antibody syndrome, N Engl J Med source

      Split into 2 atoms — 0 confirmed, 0 partially supported, 2 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [25] Ames, 2005, Bleeding and re-thrombosis in primary antiphospholipid syndrome on oral anticoagulation: an 8-year longitudinal comparison with mitral valve replacement and inherited thrombophilia, Thromb Haemost source
  • Premisecitation

    Pooled data from one RCT in women with first-trimester losses and eight observational studies not exclusively early losses indicated higher likelihood of live births with LDA plus prophylactic heparin versus LDA alone.

    “Pooled data from one RCT including only patients with a history of first trimester losses46 and eight supporting observational studies47–54 that did not exclusively study women with early pregnancy losses indicated a higher likelihood of live births with combination treatment with LDA and heparin at prophylactic dosage versus LDA alone.”
    Quote in the paperSubstantial claim3 of 9 sources checked
    • cites [46] Rai, 1997, Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies), BMJ source
    • cites [47] Lima, 1996, A study of sixty pregnancies in patients with the antiphospholipid syndrome, Clin Exp Rheumatol
    • cites [48] Muñoz-Rodriguez, 1999, Clinical study and follow-up of 100 patients with the antiphospholipid syndrome, Semin Arthritis Rheum source
    • cites [49] Naru, 2010, Pregnancy outcome in women with antiphospholipid syndrome on low-dose aspirin and heparin: a retrospective study, East Mediterr Health J source

      This paper is a retrospective observational study, but its Abstract concludes that aspirin alone and aspirin plus heparin were equally efficacious in women with antiphospholipid syndrome and recurrent miscarriage. Its Introduction reports that other randomized trials favored combination treatment; it does not present its own study as supporting a higher likelihood of live birth with heparin. (LLM, conf=0.84)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [50] Cohn, 2010, Recurrent miscarriage and antiphospholipid antibodies: prognosis of subsequent pregnancy, J Thromb Haemost source
    • cites [51] Mohamed, 2014, Enoxaparin and aspirin therapy for recurrent pregnancy loss due to anti-phospholipid syndrome (APS), Middle East Fertil Soc J source
    • cites [52] Ruffatti, 2014, Treatment strategies and pregnancy outcomes in antiphospholipid syndrome patients with thrombosis and triple antiphospholipid positivity. a European multicentre retrospective study, Thromb Haemost source
    • cites [53] Franklin, 2002, Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique APA positive population, Hum Reprod source
    • cites [54] Laskin, 2009, Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA trial, J Rheumatol source

      The Objectives section says the HepASA trial included women with losses before 32 weeks, and Table 1 (Discussion) records participants with histories of losses after 14 weeks. It was therefore not restricted to first-trimester losses. The Abstract reports no live-birth advantage for heparin plus aspirin over aspirin alone in this trial; the eight observational studies are cited separately in the claiming sentence. (LLM, conf=0.92)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Findingcitation

    Pooled data from two retrospective studies and two RCTs showed no statistically significant difference in thrombosis recurrences between vitamin K antagonist target INR 3-4 and INR 2-3 (relative risk 0.46 (0.06-3.52)).

    “Pooled data from two retrospective studies and two RCTs21–24 showed that there was no statistically significant difference in thrombosis recurrences between treatment with VKA with a target INR of 3–4 and treatment with INR of 2–3 (relative risk (RR) 0.46 (0.06–3.52)).”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [21] Crowther, 2003, A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome, N Engl J Med source
    • cites [22] Finazzi, 2005, A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS), J Thromb Haemost source

      The Study design and Results sections (page not specified) establish that WAPS is one of the randomized trials comparing high- and conventional-intensity treatment and found no statistically significant difference in recurrent thrombosis. But its pooled analysis includes only WAPS and the Crowther trial; it does not report a pooled analysis of two retrospective studies and two RCTs or the stated RR of 0.46 (0.06–3.52). (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [23] Rosove, 1992, Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients, Ann Intern Med source
    • cites [24] Khamashta, 1995, The management of thrombosis in the antiphospholipid-antibody syndrome, N Engl J Med source

      Table 3 (p. 995) reports fewer recurrent events during warfarin treatment at INR ≥3 than at INR <3: 0.015 versus 0.23 events per patient-year. The Discussion (p. 996) says INR 2–3 did not prevent thrombotic events and recommends maintaining INR above 3, contrary to the claimed finding of no significant difference. This paper does not report the pooled RR of 0.46; its Table 3 relative risks compare each treatment with no treatment, not the two INR targets with each other. (LLM, conf=0.86)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Findingcitation

    A recent RCT of rivaroxaban versus warfarin in antiphospholipid syndrome patients with triple antiphospholipid antibody positivity was prematurely terminated because of an excess of thromboembolic events, mostly arterial, in the rivaroxaban arm.

    “A recent RCT of rivaroxaban versus warfarin in patients with APS with triple aPL positivity was prematurely terminated due to an excess of thromboembolic events (mostly arterial) in the rivaroxaban arm.7”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Pengo, 2018, Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome, Blood source
  • May combine two claims. 15
  • Classified as probably not a substantial claim. 8
  • The quote only partly states this claim. 2

  • May combine two claims.

    Premisecitation

    IVIG was not associated with a higher proportion of live births compared with conventional treatment in three small observational studies, though confounding by indication may have occurred.

    “Use of IVIG was not associated with a higher proportion of live births compared with conventional treatment in three small observational studies58–60 that directly addressed this question, although confounding by indication may have occurred.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [58] Diejomaoh, 2002, A favorable outcome of pregnancies in women with primary and secondary recurrent pregnancy loss associated with antiphospholipid syndrome, Arch Gynecol Obstet source
    • cites [59] Jeremic, 2005, Comparison of two therapeutic protocols in patients with antiphospholipid Antibodies and recurrent miscarriages, Vojnosanit Pregl source
    • cites [60] Heilmann, 2008, Pregnancy outcome in women with antiphospholipid antibodies: report on a retrospective study, Semin Thromb Hemost source

      The Abstract reports a higher observed proportion of live births with added IVIG than with standard therapy (83.7% versus 74.3%), contrary to the claim as worded. The Patients section supports the concern about confounding by indication: IVIG was given to women whose standard treatment had failed. The paper does not establish whether the live-birth difference was statistically significant. (LLM, conf=0.78)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Antiphospholipid syndrome patients with arterial thrombosis have a higher risk of recurrence compared with those with venous thrombosis, and a tendency for recurrences in the same vascular bed.

    “Patients with APS with arterial thrombosis have a higher risk of recurrence compared with those with venous thrombosis, and a tendency for recurrences in the same vascular (arterial) bed.34”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [34] Tektonidou, 2000, Prognostic factors and clustering of serious clinical outcomes in antiphospholipid syndrome, QJM source

      The ‘Clustering of similar clinical events’ section reports a tendency for subsequent thromboses to occur in the same vascular bed as the presenting thrombosis. It does not establish that patients presenting with arterial thrombosis have a higher overall recurrence risk than those presenting with venous thrombosis; its odds ratios measure same-type clustering against other presentations, not arterial-versus-venous recurrence risk. Page numbers were not supplied in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The project followed the updated European League Against Rheumatism standardised operating procedure and used the Appraisal of Guidelines for Research & Evaluation II tool.

    “We followed the updated European League Against Rheumatism (EULAR) standardised operating procedure5 and used the Appraisal of Guidelines for Research & Evaluation II tool.6”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [5] van der Heijde, 2015, 2014 update of the EULAR standardised operating procedures for EULAR-endorsed recommendations, Ann Rheum Dis source
    • cites [6] Brouwers, 2010, Agree II: advancing Guideline Development, reporting and evaluation in health care, CMAJ source

  • May combine two claims.

    Findingcitation

    In one trial that provided data specifically on patients with arterial thrombosis, there was no difference in recurrences between those treated to a target INR of 2-3 or INR of 3-4 but without statistical significance (HR 3.1 (0.3-30.0)), although the sample was small and achievement of a target INR of 3-4 was low.

    “In one trial that provided data specifically on patients with arterial thrombosis, there was no difference in recurrences between those treated to a target INR of 2–3 or INR of 3–4 but without statistical significance (HR 3.1 (0.3–30.0)), although the sample was small and the achievement of a target INR of 3–4 was low.21”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [21] Crowther, 2003, A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome, N Engl J Med source

  • May combine two claims.

    Premisecitation

    Data from one placebo-controlled RCT in six women with SLE and three low-quality studies in women without SLE found no difference in live birth prevalence with LDA use.

    “Data from one placebo-controlled RCT of LDA in six women with SLE42 and data from three low-quality studies (two RCTs, one retrospective cohort)43–45 of women without SLE found no difference in the prevalence of live births with use of LDA.”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [42] Kaaja, 1993, Production of prostacyclin and thromboxane in lupus pregnancies: effect of Small dose of aspirin, Obstet Gynecol source
    • cites [43] Cowchock, 1997, Do low-risk pregnant women with antiphospholipid antibodies need to be treated? organizing group of the antiphospholipid antibody treatment trial, Am J Obstet Gynecol source
    • cites [44] Kahwa, 2006, Anticardiolipin antibodies in Jamaican primiparae, J Obstet Gynaecol source
    • cites [45] Del Ross, 2013, Treatment of 139 pregnancies in antiphospholipid-positive women not fulfilling criteria for antiphospholipid syndrome: a retrospective study, J Rheumatol source

      The Results report no statistically significant difference in pregnancy loss between the LDA and non-LDA groups, supporting the live-birth finding for this retrospective study. But the Results also identify three participants with SLE, so the study was not exclusively of women without SLE; the Discussion says its results cannot be extended to SLE. The RCTs in the citing sentence are attributed to other references, not this paper. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    An early study in older patients with strokes reported no difference in event recurrences between low-dose aspirin and warfarin, but antiphospholipid antibody was tested only once and was mainly of low titre.

    “An early study in older patients with strokes reported no difference in event recurrences between LDA and warfarin, but aPL was tested only once and was mainly of low titre in this study.33”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [33] Levine, 2004, Antiphospholipid Antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke, JAMA source

  • May combine two claims.

    Findingcitation

    In patients with systemic lupus erythematosus and a high-risk antiphospholipid antibody profile, low-dose aspirin reduces first thrombosis by almost half compared with no low-dose aspirin, without major bleeding, based on a subanalysis of eight mostly observational studies.

    “Treatment with LDA for patients with SLE and high-risk aPL profile is supported by a subanalysis of eight studies, mostly observational, in a meta-analysis.14 In this analysis, risk of first thrombosis was reduced by almost half among patients treated with LDA versus patients not treated, without major bleeding events.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Arnaud, 2014, Efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies: an international and collaborative meta-analysis, Autoimmun Rev source

  • May combine two claims.

    Findingcitation

    An earlier systematic literature review including mainly observational studies reported that recurrent events occurred more often in antiphospholipid syndrome patients treated with vitamin K antagonist target INR 2-3 compared with INR 3-4, but outcomes among patients with first arterial thrombosis were not analysed specifically.

    “An earlier SLR including mainly observational studies reported that recurrent events occurred more often in patients with APS treated with VKA with a target INR of 2–3 compared with an INR of 3–4, but outcomes among patients with first arterial thrombosis were not analysed specifically.35”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Ruiz-Irastorza, 2007, A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies, Arthritis Rheum source

  • The quote only partly states this claim.

    Study design and conductreasoning

    Evidence on vitamin K antagonist target INR 3-4 versus 2-3 in antiphospholipid syndrome venous thrombosis is limited by frequent failure to achieve the target INR in the high-intensity groups in the RCTs.

    “However, evidence is limited by the frequent failure to achieve the target INR in the high-intensity groups in the RCTs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Bleeding data were not reported specifically for patients with venous thrombosis.

    “Data on bleeding were not reported for patients with venous thrombosis specifically.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: A higher level of anticoagulation is expected to carry a higher risk of bleeding.

  • May combine two claims.

    Premisecitation

    The presence of antiphospholipid antibodies in asymptomatic individuals or in patients with systemic lupus erythematosus does not confirm antiphospholipid syndrome, but it can be associated with increased risk of thrombosis or pregnancy morbidity depending on antibody characteristics and other risk factors.

    “The presence of aPL in asymptomatic individuals or patients with SLE does not confirm the diagnosis of APS but can be associated with increased risk of thrombosis or pregnancy morbidity, depending on aPL characteristics and coexistence of other risk factors.3 4”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Ruiz-Irastorza, 2011, Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task Force at the 13th International Congress on antiphospholipid antibodies, Lupus source
    • cites [4] Garcia, 2018, Diagnosis and management of the antiphospholipid syndrome, N Engl J Med source

  • May combine two claims.

    Study design and conductown data

    Those studies included a mixture of patients with either venous or arterial thrombosis, and a minority had arterial events.

    “However, these studies included a mixture of patients with either venous or arterial thrombosis, and a minority had arterial events.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Titles and abstracts were reviewed independently by two literature reviewers, and full-text articles were reviewed independently by three persons.

    “All titles and abstracts of retrieved articles were first reviewed independently by the two literature reviewers. The full-text articles were then reviewed independently by three persons: one literature reviewer, convenor and methodologist.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    That review did not compare the target INR 2-3 and INR 3-4 arms within the same study, but disaggregated the arms.

    “This review did not compare the target INR 2–3 and INR 3–4 arms within the same study, but disaggregated the arms.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Each included article was graded for methodological quality and assigned to the relevant PICO question.

    “Each included article was graded for its methodological quality and assigned to the relevant PICO question by the convenor and methodologist.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Studies combined several types of pregnancy losses without specifying the proportion of non-criteria APS, and evidence is very limited.

    “Because studies combined several types of pregnancy losses without specifying on the proportion of ‘non-criteria’ APS and due to very limited evidence, this recommendation is mainly based on expert opinion.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Recommendations were voted on anonymously for level of agreement using a 0-10 rating scale.

    “was sent by the convenor to all task force members, who voted anonymously on the level of agreement (LoA). A rating scale of 0–10 (0: do not agree; 10: fully agree) was used for each recommendation.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Premisecitation

    Data from two studies showed no difference in likelihood of live births between LDA plus heparin and LDA alone in women with prior delivery before 34 weeks due to eclampsia, severe pre-eclampsia, or placental insufficiency.

    “Data from two studies (one RCT, one retrospective cohort)48 55 showed that the likelihood of live births did not differ between women treated with LDA plus heparin and those treated with LDA alone.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] Muñoz-Rodriguez, 1999, Clinical study and follow-up of 100 patients with the antiphospholipid syndrome, Semin Arthritis Rheum source
    • cites [55] van Hoorn, 2016, Low-molecular-weight heparin and aspirin in the prevention of recurrent early-onset pre-eclampsia in women with antiphospholipid antibodies: the FRUIT-RCT, Eur J Obstet Gynecol Reprod Biol source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Data abstraction was performed according to a written protocol, supervised by the methodologist, and independently double-checked by the convenor and methodologist.

    “The data abstraction was performed by the two literature reviewers according to a written protocol and supervised by the methodologist. Data abstraction was then independently double-checked by the convenor and methodologist.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The task force included members from several professional groups and two patients who actively participated in both meetings.

    “The task force included members from several professional groups covering different perspectives and also involved two patients who participated actively in both meetings.”
    Quote in the paperNot a substantial claim
20 of 20

  • The paper relies on this without support.

    A higher level of anticoagulation is expected to carry a higher risk of bleeding.

    “However, although not based on data from these studies, higher level of anticoagulation would be anticipated to also have a higher risk of bleeding.”

  • The paper relies on this without support.

    For antiphospholipid syndrome patients with provoked first venous thrombosis, the anticoagulation duration recommended for patients without antiphospholipid syndrome is appropriate.

    “The panel recommended a duration of anticoagulation according to international guidelines for patients without APS30 because the benefit of long-term anticoagulation in this population is unclear.”

  • The paper relies on this without support.

    Low-dose aspirin has a low risk of adverse events in asymptomatic antiphospholipid antibody carriers.

    “given the likelihood of benefit and low risk of adverse events of this intervention.”

  • The paper relies on this without support.

    High-risk aPL profile is associated with risk of obstetric and thrombotic complications during pregnancy.

    “The panel agreed that use of LDA should be considered in pregnant women with high-risk aPL profile due to the risk of obstetric and thrombotic complications during pregnancy associated with high-risk aPL profile.”

  • The paper relies on this without support.

    Women with a history of clinical non-criteria obstetric APS have a potential higher risk for obstetric and/or thrombotic complications during pregnancy.

    “Because of a potential higher risk for obstetric and/or thrombotic complications during pregnancy in women with a history of clinical ‘non-criteria’ obstetric APS, the panel agreed that treatment with LDA alone or in combination with heparin might be considered, based on an individual’s risk profile (aPL profile, concomitant SLE, prior live births, and additional risk factors for pregnancy loss or”

  • The paper relies on this without support.

    There is an increased risk of thrombosis at puerperium.

    “The panel suggested that in women receiving prophylactic dose heparin during pregnancy, the same dosage of heparin should be continued for 6 weeks after delivery due to an increased risk of thrombosis at puerperium.”

  • The paper relies on this without support.

    The most common practice when LDA plus prophylactic heparin fails is to increase heparin dose to therapeutic dose.

    “The most common practice if the combination of LDA and prophylactic dose heparin fails is to increase the dose of heparin to therapeutic dose, although no supporting evidence exists.”

  • The paper relies on this without support.

    Cost and availability of suggested treatments are not a barrier to implementation, except IVIG and plasmapheresis.

    “The cost and availability of suggested treatments are not a barrier to implementation of these recommendations, with the exception of IVIG and plasmapheresis.”

  • The paper relies on this without support.

    CAPS occurs in less than 1% of patients.

    “However, both treatments were recommended as first-line treatment only in CAPS which occurs in less than 1% of patients, while B cell depletion and complement inhibitors may be considered in refractory cases of CAPS.”
9 of 9

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • A cited randomized trial is counted among observational studies

    Minor

    The text describes references 47-54 as eight observational studies, but reference 54 identifies itself as a randomized, controlled trial.

1 of 1

Cites

Flagged first, then by citations

3 of the 72 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. OCEBM Levels of Evidence Working Group,. The Oxford levels of evidence 2: Oxford centre for evidence-based medicine. Available: http://www.cebm.net/index.aspx?o=5653.

Cited by

Sorted by citations

Related

Authors
Tektonidou, M. G., Andreoli, L., Limper, M., Amoura, Z., Cervera, R., Costedoat-Chalumeau, N., Cuadrado, M. J., Dörner, T., Ferrer-Oliveras, R., Hambly, K., Khamashta, M. A., King, J., Marchiori, F., Meroni, P. L., Mosca, M., Pengo, V., Raio, L., Ruiz-Irastorza, G., Shoenfeld, Y., Stojanovich, L., Svenungsson, E., Wahl, D., Tincani, A., & Ward, M. M.
Affiliations
  • National and Kapodistrian University of Athens (GR)
  • University Medical Center Utrecht (NL)
  • Sorbonne Université (FR)
  • Hospital Clínic de Barcelona (ES)
  • Inserm (FR)
  • Charité - Universitätsmedizin Berlin (DE)
  • University of Kent (GB)
  • Dubai Hospital (AE)
  • European League Against Rheumatism (CH)
  • IRCCS Istituto Auxologico Italiano (IT)
  • University of Pisa (IT)
  • University of Padua (IT)
  • University Hospital of Bern (CH)
  • Tel Aviv University (IL)
  • University of Belgrade (RS)
  • Karolinska University Hospital (SE)
  • National Institutes of Health (US)
ORCID
Venue
Annals of the Rheumatic Diseases
Publisher
Elsevier BV
Published
2019-10
Volume
78
Issue
10
Pages
1296-1304
ISSN
0003-4967 (ISSN-L)
DOI
10.1136/annrheumdis-2019-215213
PMC
PMC11034817
OpenAlex
W2946160313
Semantic Scholar
cca4d07183616eebc75996c57f7d029bd63e5bf2
Cited by
1,261
References
72
Citations by year
2026: 153 · 2025: 180 · 2024: 215 · 2023: 185 · 2022: 170 · 2021: 141 · 2020: 163 · 2019: 42 · 2017: 1
FWCI
84.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of the Rheumatic Diseases (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, cc-by-nc)
  • BORIS (University Library Bern) (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
  • Kent Academic Repository (University of Kent) (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
European League Against Rheumatism
Topics
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
Keywords
antiphospholipid syndrome, antiphospholipid antibodies, thrombosis, obstetric antiphospholipid syndrome, low-dose aspirin, vitamin K antagonists, rivaroxaban, low molecular weight heparin
MeSH terms
Adult, Anticoagulants, Female, Humans

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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