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Cited by 0Systemic Lupus Erythematosus ResearchBlood Coagulation and Thrombosis MechanismsVenous Thromboembolism Diagnosis and Management

Hydroxychloroquine as an Adjunct Therapy for Secondary Thrombosis Prevention in Primary Antiphospholipid Syndrome: A Systematic Review and Meta-analysis

Open access
de Carvalho, Jozélio Freire, Hautz, Elizabeth, Cervera, Ricard·2026·Rheumatology and Therapy
DOI 10.1007/s40744-026-00858-xPMC PMC13407784
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Abstract

INTRODUCTION: Patients with primary antiphospholipid syndrome (PAPS) remain at significant risk of recurrent thrombosis despite long-term anticoagulation. Hydroxychloroquine (HCQ) has demonstrated antithrombotic and immunomodulatory effects in systemic lupus erythematosus and experimental models of antiphospholipid syndrome, but its role in thrombotic PAPS remains incompletely defined. This study aimed to systematically review and quantitatively synthesize the available clinical evidence evaluating hydroxychloroquine as adjunctive therapy for secondary thrombosis prevention in non-pregnant patients with primary antiphospholipid syndrome. METHODS: A systematic search of PubMed/MEDLINE, EMBASE, Web of Science, and Scopus was conducted from inception through March 2026, following PRISMA 2020 guidelines. Eligible studies included adult patients with thrombotic PAPS comparing HCQ plus standard antithrombotic therapy versus standard therapy alone. Obstetric APS, systemic lupus erythematosus-associated APS, and primary prevention studies were excluded. The primary outcome was recurrent arterial or venous thrombosis. A qualitative synthesis was performed, followed by an exploratory random-effects meta-analysis using time-to-event or incidence-based effect estimates. RESULTS: Three studies met the inclusion criteria, comprising 164 patients with thrombotic PAPS (82 receiving HCQ and 82 controls), with a cumulative follow-up of approximately 380 patient-years. Across studies, adjunctive HCQ therapy was consistently associated with lower rates of recurrent thrombosis. Absolute risk reductions ranged from 30 to 100%, depending on study design and follow-up duration. The pooled analysis demonstrated a relative risk reduction of approximately 65-70%, corresponding to a summary effect estimate equivalent to a hazard ratio of ~ 0.33, favoring HCQ. No increase in major bleeding or serious adverse events was reported. CONCLUSIONS: In non-pregnant patients with thrombotic primary antiphospholipid syndrome, adjunctive hydroxychloroquine therapy was associated with a substantial reduction in recurrent thrombotic events when added to standard anticoagulation. Although based on limited evidence and small studies, the consistency and magnitude of the observed effect support further adequately powered randomized trials and suggest that HCQ may represent a rational adjunctive strategy in selected high-risk PAPS patients.

AI snapshot

Written from the paper’s full text.

TL;DR

In non-pregnant adults with thrombotic primary antiphospholipid syndrome, adjunctive hydroxychloroquine plus standard antithrombotic therapy was associated with lower recurrent thrombosis across three studies (164 patients). The exploratory pooled estimate suggested a ~65–70% relative risk reduction (summary HR ≈ 0.33), with no reported increase in major bleeding or serious adverse events.

Key findings

  • Three studies comprising 164 patients with thrombotic PAPS (82 HCQ, 82 controls) and ~380 patient-years of follow-up found consistently lower recurrent thrombosis with adjunctive HCQ; absolute risk reductions ranged from 30% to 100%.
  • The random-effects exploratory meta-analysis showed a relative risk reduction of ~65–70%, corresponding to a summary HR of ~0.33, with low-to-moderate heterogeneity.
  • Study-level results: Kravvariti et al. reported incidence rates of 0.001 vs. 0.007 events per patient-year (~86% relative reduction) and adjusted HR 0.09 (95% CI 0.01–1.26); Nuri et al. reported annual recurrence 1.16% vs. 1.71% (~32% relative risk reduction) and no arterial recurrences in the HCQ group; Schmidt-Tanguy et al. reported 0/20 vs. 6/20 recurrent venous thromboses (30% in controls), log-rank p < 0.01.
  • No study reported increased major bleeding or serious adverse events attributable to HCQ; minor bleeding rates were similar in the only study reporting bleeding outcomes.

Methods

  • PRISMA 2020 systematic search of PubMed/MEDLINE, EMBASE, Web of Science, and Scopus from inception through March 2026; eligible studies included adults with thrombotic PAPS comparing HCQ plus standard antithrombotic therapy vs. standard therapy alone, excluding obstetric APS, SLE-associated APS, and primary prevention.
  • Three studies met inclusion criteria: one open-label randomized prospective pilot trial, one retrospective multicenter propensity score-matched cohort, and one prospective non-randomized controlled study; the primary outcome was recurrent objectively confirmed arterial or venous thrombosis.
  • A qualitative synthesis was followed by an exploratory random-effects (DerSimonian–Laird) meta-analysis pooling hazard ratios or incidence-based relative risks; analyses used JASP 0.95.4, and subgroup analyses and formal publication-bias tests were not performed because only three studies were included.

Limitations

  • The paper states: only three studies with few patients and thrombotic events were available; only one study was randomized, and it was open-label and underpowered; observational studies remained susceptible to residual confounding and confounding by indication; heterogeneous effect measures and incomplete event-level data required an exploratory meta-analysis; arterial and venous events were inconsistently reported, precluding high-quality subgroup analyses; all studies were European, limiting generalizability.
  • The text also makes evident: HCQ dose, duration of exposure, adherence monitoring, and concomitant antiplatelet therapy were variably or incompletely reported; no formal assessment of publication bias was performed; and the pooled estimate is explicitly hypothesis-generating.

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

Integrity signals

Registry

Crossref · 10.1007/s40744-026-00858-x

Cites

11 of 11 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

14 of 41 cited sources checked · 5 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    In patients with systemic lupus erythematosus, long-term exposure to hydroxychloroquine is associated with a reduction in both first and recurrent thrombotic events, particularly in those with persistent antiphospholipid antibody positivity.

    “In patients with SLE, long-term exposure to HCQ has consistently been associated with a reduction in both first and recurrent thrombotic events, particularly in those with persistent aPL positivity [6, 7].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [6] Ruiz-Irastorza G, Egurbide MV, Pijoan JI, Garmendia M, Villar I, Martinez-Berriotxoa A, et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus. 2006;15(9):577–83. https://doi.org/10.1177/0961203306071872. source
    • cites [7] Zuo Y, Fan J, Sarode R, Zhang S, Makris UE, Karp DR, et al. Identifying additional risk factors for thrombosis and pregnancy morbidities among antiphospholipid antibodies carriers. Clin Appl Thromb Hemost. 2018;24(6):980–5. https://doi.org/10.1177/1076029618755946. (Epub 2018 Feb 22). source

      The Results and Discussion report thrombotic risk factors among persistently aPL-positive patients, but do not address whether hydroxychloroquine reduces first or recurrent events in patients with SLE. Searches for “hydroxychloroquine,” “HCQ,” and recurrent thrombosis with protective treatment found no passage assessing that association. The cited copy does not verify the claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Premisecitation

    Patients with thrombotic primary antiphospholipid syndrome remain at substantial risk of recurrent thrombotic events despite long-term anticoagulation, with cumulative recurrence rates approaching 20% at 5 years in observational cohorts.

    “Despite long-term anticoagulation with vitamin K antagonists, patients with thrombotic PAPS remain at substantial risk of recurrent thrombotic events, with cumulative recurrence rates approaching 20% at 5 years in observational cohorts [2].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [2] Pengo V, Ruffatti A, Legnani C, Gresele P, Barcellona D, Erba N, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost. 2010;8(2):237–42. https://doi.org/10.1111/j.1538-7836.2009.03674.x. source

      The Thromboembolic events during the followup period section (page unavailable) reports 36 recurrent events among 123 patients receiving long-term oral anticoagulation, supporting the risk despite treatment. But its 5-year cumulative incidence is 26.1% for the entire high-risk APS cohort, not a rate approaching 20% specifically among anticoagulated patients with thrombotic primary APS. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Findingcitation

    In Schmidt-Tanguy et al., time-to-event analysis demonstrated a statistically significant difference between groups, with log-rank p values < 0.01.

    “Time-to-event analysis demonstrated a statistically significant difference between groups, with log-rank p values < 0.01, supporting a clinically meaningful reduction in recurrence associated with adjunctive HCQ [10].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost. 2013;11(10):1927–9. https://doi.org/10.1111/jth.12363. source
  • Premisecitation

    In systemic lupus erythematosus, multiple observational studies have consistently shown that long-term antimalarial use reduces both first and recurrent thrombotic events, particularly among those with persistent antiphospholipid antibodies.

    “Multiple observational studies have consistently shown that long-term antimalarial use reduces both first and recurrent thrombotic events in patients with SLE, particularly among those with persistent antiphospholipid antibodies [6, 7].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [6] Ruiz-Irastorza G, Egurbide MV, Pijoan JI, Garmendia M, Villar I, Martinez-Berriotxoa A, et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus. 2006;15(9):577–83. https://doi.org/10.1177/0961203306071872. source
    • cites [7] Zuo Y, Fan J, Sarode R, Zhang S, Makris UE, Karp DR, et al. Identifying additional risk factors for thrombosis and pregnancy morbidities among antiphospholipid antibodies carriers. Clin Appl Thromb Hemost. 2018;24(6):980–5. https://doi.org/10.1177/1076029618755946. (Epub 2018 Feb 22). source

      The Results and Discussion (page unavailable) examine thrombotic risk factors in people with persistent antiphospholipid antibodies, but do not report whether antimalarial use reduces thrombosis in SLE. Searches for antimalarial, hydroxychloroquine, and chloroquine found no passage addressing long-term use or prevention of first and recurrent events. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The absence of a bleeding signal attributable to hydroxychloroquine in any of the included studies supports its favorable risk-benefit profile.

    “The absence of a bleeding signal attributable to HCQ in any of the included studies further supports its favorable risk–benefit profile [8–10].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [8] Kravvariti E, Koutsogianni A, Samoli E, Sfikakis PP, Tektonidou MG. The effect of hydroxychloroquine on thrombosis prevention and antiphospholipid antibody levels in primary Antiphospholipid Syndrome: a pilot open-label randomized prospective study. Autoimmun Rev. 2020;19(4):102491. https://doi.org/10.1016/j.autrev.2020.102491. (Epub 2020 Feb 19). source
    • cites [9] Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A, et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res. 2017;65(1):17–24. https://doi.org/10.1007/s12026-016-8812-z. source
    • cites [10] Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost. 2013;11(10):1927–9. https://doi.org/10.1111/jth.12363. source
    • Rests on an assumption: Hydroxychloroquine has a long-standing safety record in rheumatology, with low rates of serious adverse events when appropriately monitored, minimal interaction with anticoagulants, and low cost.
  • Classified as probably not a substantial claim. 11
  • May combine two claims. 24

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

    Findingcitation

    The majority of patients had experienced venous thromboembolism as the index event, while arterial thrombosis accounted for a smaller but clinically relevant proportion of cases.

    “The majority of patients had experienced venous thromboembolism as the index event, while arterial thrombosis accounted for a smaller but clinically relevant proportion of cases.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [8] Kravvariti E, Koutsogianni A, Samoli E, Sfikakis PP, Tektonidou MG. The effect of hydroxychloroquine on thrombosis prevention and antiphospholipid antibody levels in primary Antiphospholipid Syndrome: a pilot open-label randomized prospective study. Autoimmun Rev. 2020;19(4):102491. https://doi.org/10.1016/j.autrev.2020.102491. (Epub 2020 Feb 19). source
    • cites [9] Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A, et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res. 2017;65(1):17–24. https://doi.org/10.1007/s12026-016-8812-z. source
    • cites [10] Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost. 2013;11(10):1927–9. https://doi.org/10.1111/jth.12363. source

      The Abstract says all 40 patients had previous venous thrombosis and no arterial event, except for strokes in two patients. It also says the study investigated venous, not arterial, thrombosis. The paper therefore does not describe a subgroup whose index thrombosis was arterial. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Three clinical studies met inclusion criteria, comprising 164 adult patients with thrombotic primary antiphospholipid syndrome, of whom 82 received hydroxychloroquine and 82 received standard therapy alone.

    “Three clinical studies met the inclusion criteria, comprising a total of 164 adult patients with thrombotic primary antiphospholipid syndrome (PAPS), of whom 82 received hydroxychloroquine (HCQ) in addition to standard antithrombotic therapy and 82 received standard therapy alone [8–10].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [8] Kravvariti E, Koutsogianni A, Samoli E, Sfikakis PP, Tektonidou MG. The effect of hydroxychloroquine on thrombosis prevention and antiphospholipid antibody levels in primary Antiphospholipid Syndrome: a pilot open-label randomized prospective study. Autoimmun Rev. 2020;19(4):102491. https://doi.org/10.1016/j.autrev.2020.102491. (Epub 2020 Feb 19). source
    • cites [9] Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A, et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res. 2017;65(1):17–24. https://doi.org/10.1007/s12026-016-8812-z. source
    • cites [10] Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost. 2013;11(10):1927–9. https://doi.org/10.1111/jth.12363. source

      The study description (Abstract) reports 40 adults with primary APS: 20 received hydroxychloroquine plus oral anticoagulation, and 20 received anticoagulation alone. This supports the paper’s contribution to the cited group of studies, but the paper does not establish the pooled totals of three studies, 164 patients, or 82 patients per treatment group. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Across included studies, patients were predominantly female (approximately 70-80% when reported) and all had a documented history of objectively confirmed thrombosis fulfilling APS classification criteria.

    “Across studies, patients were predominantly female (approximately 70–80% women, when reported), and all had a documented history of objectively confirmed thrombosis fulfilling APS classification criteria.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [8] Kravvariti E, Koutsogianni A, Samoli E, Sfikakis PP, Tektonidou MG. The effect of hydroxychloroquine on thrombosis prevention and antiphospholipid antibody levels in primary Antiphospholipid Syndrome: a pilot open-label randomized prospective study. Autoimmun Rev. 2020;19(4):102491. https://doi.org/10.1016/j.autrev.2020.102491. (Epub 2020 Feb 19). source
    • cites [9] Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A, et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res. 2017;65(1):17–24. https://doi.org/10.1007/s12026-016-8812-z. source
    • cites [10] Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost. 2013;11(10):1927–9. https://doi.org/10.1111/jth.12363. source

      The paper’s Abstract (page unavailable) says its 40 patients met primary APS criteria and had a history of venous thrombosis. It does not report that approximately 70–80% were women, and a single study cannot establish the statement about patients across studies. The passage describing imaging confirmation concerns thrombosis diagnosis but does not explicitly say every prior event was objectively confirmed. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    The three included studies were a randomized prospective trial in Greece, a retrospective multicenter propensity score-matched cohort in Italy, and a prospective non-randomized controlled study in France.

    “One study was a randomized prospective trial conducted in Greece [8], one a retrospective multicenter propensity score-matched cohort from Italy [9], and one a prospective non-randomized controlled study from France [10].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [8] Kravvariti E, Koutsogianni A, Samoli E, Sfikakis PP, Tektonidou MG. The effect of hydroxychloroquine on thrombosis prevention and antiphospholipid antibody levels in primary Antiphospholipid Syndrome: a pilot open-label randomized prospective study. Autoimmun Rev. 2020;19(4):102491. https://doi.org/10.1016/j.autrev.2020.102491. (Epub 2020 Feb 19). source
    • cites [9] Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A, et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res. 2017;65(1):17–24. https://doi.org/10.1007/s12026-016-8812-z. source
    • cites [10] Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost. 2013;11(10):1927–9. https://doi.org/10.1111/jth.12363. source

      The Abstract (page unavailable) identifies this as a prospective, non-randomized study and describes a control group, supporting the study-design description attached to [10]. The passages in our copy do not identify France as the study location, so that part is unverified. The Greece and Italy descriptions are attached to other citations, not this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Study design and conductcitation

    The systematic review and meta-analysis were conducted in accordance with the PRISMA 2020 statement.

    “This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [11].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. https://doi.org/10.1136/bmj.n71. source

      The Abstract identifies this paper as the PRISMA 2020 statement, a reporting guideline applicable to systematic reviews and meta-analyses. The Scope of the guideline section explicitly says PRISMA 2020 is not intended to guide systematic review conduct. It therefore supports the identification of the statement, but not the implication that it is a standard for how the citing authors conducted their review. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    In Schmidt-Tanguy et al., 40 patients with venous thrombotic primary antiphospholipid syndrome were equally divided between hydroxychloroquine plus oral anticoagulation (n=20) and oral anticoagulation alone (n=20), with a 3-year follow-up.

    “The prospective non-randomized study by Schmidt-Tanguy et al. included 40 patients with venous thrombotic PAPS, equally divided between HCQ plus oral anticoagulation (n = 20) and oral anticoagulation alone (n = 20), with a 3-year follow-up [10].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost. 2013;11(10):1927–9. https://doi.org/10.1111/jth.12363. source

  • May combine two claims.

    Findingcitation

    In Schmidt-Tanguy et al., six recurrent venous thromboses (30%) occurred in the control group, whereas no thrombotic recurrences were observed in the hydroxychloroquine-treated group, despite excellent anticoagulation control (time in therapeutic range ~98% in both arms).

    “Six recurrent venous thromboses (30%) occurred in the control group, whereas no thrombotic recurrences were observed in the HCQ-treated group, despite excellent anticoagulation control (time in therapeutic range ~ 98% in both arms).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost. 2013;11(10):1927–9. https://doi.org/10.1111/jth.12363. source

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

    Findingcitation

    High-risk antiphospholipid antibody profiles (lupus anticoagulant positivity and/or double antiphospholipid antibody positivity) were frequent, although reporting of triple positivity was heterogeneous.

    “High-risk antiphospholipid antibody profiles (lupus anticoagulant positivity and/or double aPL positivity) were frequent, although reporting of triple positivity was heterogeneous [8–10].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [8] Kravvariti E, Koutsogianni A, Samoli E, Sfikakis PP, Tektonidou MG. The effect of hydroxychloroquine on thrombosis prevention and antiphospholipid antibody levels in primary Antiphospholipid Syndrome: a pilot open-label randomized prospective study. Autoimmun Rev. 2020;19(4):102491. https://doi.org/10.1016/j.autrev.2020.102491. (Epub 2020 Feb 19). source
    • cites [9] Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A, et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res. 2017;65(1):17–24. https://doi.org/10.1007/s12026-016-8812-z. source
    • cites [10] Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost. 2013;11(10):1927–9. https://doi.org/10.1111/jth.12363. source

      The Results passage in our copy (labeled Abstract; page unavailable) reports lupus anticoagulant positivity in four of six patients with recurrent thrombosis and double aPL positivity in two, with no triple positivity among those patients. This supports frequent high-risk profiles among patients with recurrences, but does not establish their frequency across the full cohort or show heterogeneous reporting of triple positivity. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    In Kravvariti et al., recurrent thrombotic events occurred far less frequently in the hydroxychloroquine group, with an incidence rate of 0.001 events per patient-year versus 0.007 events per patient-year in controls, representing an approximate 86% relative reduction.

    “Recurrent thrombotic events occurred far less frequently in the HCQ group, with an incidence rate of 0.001 events per patient-year, compared with 0.007 events per patient-year in controls. This represents an approximate 86% relative reduction in thrombotic recurrence.”
    • Also stated in: § Discussion · hedged
      “In the randomized pilot trial by Kravvariti et al., HCQ use resulted in an approximately 85–90% reduction in thrombotic incidence, with a multivariable-adjusted hazard ratio strongly favoring HCQ, albeit with wide confidence intervals due to limited power [8].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Kravvariti E, Koutsogianni A, Samoli E, Sfikakis PP, Tektonidou MG. The effect of hydroxychloroquine on thrombosis prevention and antiphospholipid antibody levels in primary Antiphospholipid Syndrome: a pilot open-label randomized prospective study. Autoimmun Rev. 2020;19(4):102491. https://doi.org/10.1016/j.autrev.2020.102491. (Epub 2020 Feb 19). source

  • May combine two claims.

    Findingcitation

    In Nuri et al., arterial thrombotic recurrences occurred exclusively in the control group, whereas no arterial events were observed among hydroxychloroquine-treated patients during follow-up.

    “Notably, arterial thrombotic recurrences occurred exclusively in the control group, whereas no arterial events were observed among HCQ-treated patients during follow-up.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A, et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res. 2017;65(1):17–24. https://doi.org/10.1007/s12026-016-8812-z. source

  • May combine two claims.

    Findingcitation

    In Kravvariti et al., 50 patients with thrombotic primary antiphospholipid syndrome were randomized to hydroxychloroquine plus standard antithrombotic therapy (n=25) or standard therapy alone (n=25) and followed for a mean of 2.6 years.

    “In the open-label randomized prospective trial by Kravvariti et al., 50 patients with thrombotic PAPS were randomized to receive HCQ plus standard antithrombotic therapy (n = 25) or standard therapy alone (n = 25) and followed for a mean of 2.6 years [8].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Kravvariti E, Koutsogianni A, Samoli E, Sfikakis PP, Tektonidou MG. The effect of hydroxychloroquine on thrombosis prevention and antiphospholipid antibody levels in primary Antiphospholipid Syndrome: a pilot open-label randomized prospective study. Autoimmun Rev. 2020;19(4):102491. https://doi.org/10.1016/j.autrev.2020.102491. (Epub 2020 Feb 19). source

  • May combine two claims.

    Findingown data

    All participants received long-term oral anticoagulation, predominantly with vitamin K antagonists, and no study evaluated hydroxychloroquine as monotherapy.

    “All participants received long-term oral anticoagulation, predominantly with vitamin K antagonists, and no study evaluated HCQ as monotherapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In Nuri et al., among patients with prior thrombosis, the annual incidence of thrombotic recurrence was 1.16% in the hydroxychloroquine group versus 1.71% in the control group, corresponding to a relative risk reduction of approximately 32%.

    “Among patients with prior thrombosis, the annual incidence of thrombotic recurrence was 1.16% in the HCQ group versus 1.71% in the control group, corresponding to a relative risk reduction of approximately 32%.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A, et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res. 2017;65(1):17–24. https://doi.org/10.1007/s12026-016-8812-z. source

  • May combine two claims.

    Findingown data

    Between-study heterogeneity was low to moderate, consistent with the uniform direction of effect observed across all included studies.

    “Between-study heterogeneity was low to moderate, consistent with the uniform direction of effect observed across all included studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    In Nuri et al., 57 hydroxychloroquine-treated patients with primary antiphospholipid syndrome were matched to 57 controls without hydroxychloroquine exposure and followed longitudinally.

    “In the multicenter retrospective propensity score-matched cohort by Nuri et al., 57 HCQ-treated patients with PAPS were matched to 57 controls without HCQ exposure and followed longitudinally [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A, et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res. 2017;65(1):17–24. https://doi.org/10.1007/s12026-016-8812-z. source

  • May combine two claims.

    Findingcitation

    In Nuri et al., hydroxychloroquine exposure was associated with a statistically significant reduction in IgG anticardiolipin and anti-β2-glycoprotein I antibody titers, whereas antibody levels remained largely unchanged in controls.

    “In parallel, HCQ exposure was associated with a statistically significant reduction in IgG anticardiolipin and anti-β2-glycoprotein I antibody titers, whereas antibody levels remained largely unchanged in controls [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A, et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res. 2017;65(1):17–24. https://doi.org/10.1007/s12026-016-8812-z. source

  • May combine two claims.

    Findingown data

    The combined effect corresponded to an overall relative risk reduction of approximately 65-70%, with a pooled effect estimate equivalent to a summary hazard ratio of approximately 0.33.

    “The combined effect corresponded to an overall relative risk reduction of approximately 65–70%, with a pooled effect estimate equivalent to a summary HR of approximately 0.33 (random-effects model).”
    • Also stated in: § Discussion · plain
      “When pooled in a random-effects meta-analysis, these concordant findings translated into an overall relative risk reduction of approximately 65–70%, corresponding to a summary effect estimate equivalent to a hazard ratio of around 0.33.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mean or median follow-up duration ranged from 2.6 years to 3 years, yielding an estimated cumulative follow-up of approximately 380 patient-years across all studies.

    “Mean or median follow-up duration ranged from 2.6 years in the randomized trial to 3 years in the prospective and retrospective cohorts, yielding an estimated cumulative follow-up of approximately 380 patient-years across all studies.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A systematic search of PubMed/MEDLINE, EMBASE, Web of Science, and Scopus was conducted from inception through March 2026.

    “A comprehensive electronic literature search was performed in PubMed/MEDLINE, EMBASE, Web of Science (Core Collection), and Scopus, from inception through March 2026.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Subgroup analyses and formal tests for publication bias were not performed because only three studies were included.

    “Given the small number of included studies (n = 3), subgroup analyses and formal tests for publication bias (e.g., funnel plots) were not performed, and the meta-analysis was considered hypothesis-generating.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Risk of bias was assessed independently by two reviewers using the Cochrane Risk of Bias 2 tool for the randomized trial and the Newcastle-Ottawa Scale for observational studies.

    “Risk of bias was assessed independently by two reviewers. The randomized controlled trial was evaluated using the Cochrane Risk of Bias 2 (RoB 2) tool, while observational studies were assessed using the Newcastle–Ottawa Scale.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Experimental studies show that hydroxychloroquine interferes with the binding of antiphospholipid antibody-β2-glycoprotein I complexes to phospholipid surfaces, reverses antiphospholipid antibody-induced thrombogenicity, reduces platelet activation, downregulates endothelial tissue factor expression, modulates complement activation and improves endothelial function.

    “Experimental studies have shown that HCQ interferes with the binding of aPL–β2-glycoprotein I complexes to phospholipid surfaces, reverses aPL-induced thrombogenicity, reduces platelet activation, downregulates endothelial tissue factor expression, modulates complement activation and improves endothelial function [3–5].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Belizna C. Hydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome. Autoimmun Rev. 2015;14(4):358–62. https://doi.org/10.1016/j.autrev.2014.12.006. source
    • cites [4] Rand JH, Wu XX, Quinn AS, Chen PP, Hathcock JJ, Taatjes DJ. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-β2-glycoprotein I complexes to phospholipid bilayers. Blood. 2008;112(5):1687–95. https://doi.org/10.1182/blood-2008-03-144204. (Epub 2008 Jun 24). source
    • cites [5] Edwards MH, Pierangeli S, Liu X, Barker JH, Anderson G, Harris EN. Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation. 1997;96(12):4380–4. https://doi.org/10.1161/01.cir.96.12.4380. source

  • May combine two claims.

    Interpretationreasoning

    Evidence supporting hydroxychloroquine use specifically in primary antiphospholipid syndrome, independent of systemic lupus erythematosus, is limited and less systematically appraised.

    “In contrast, evidence supporting HCQ use specifically in primary APS, independent of SLE, is limited and less systematically appraised.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Observational research, although strengthened by methods like propensity score matching, is still susceptible to remaining confounding and confounding by indication.

    “Observational research, although strengthened by methods like propensity score matching, is still susceptible to remaining confounding and confounding by indication.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The small number of studies and incomplete reporting of treatment-related variables should be considered when interpreting the pooled estimates.

    “Additionally, the small number of studies and incomplete reporting of treatment-related variables, including HCQ exposure characteristics and concomitant therapies, should be considered when interpreting the pooled estimates.”
    Quote in the paperSubstantial claim

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

    Interpretationown data

    Since all studies were performed in European cohorts, the generalizability of the findings to other populations should be reconfirmed.

    “Last, since all studies were performed in European cohorts, the generalizability of the findings to other populations should be reconfirmed.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Funnel plot analysis and formal statistical assessment of publication bias were not performed due to the limited number of studies.

    “Owing to the limited number of studies, funnel plot analysis and formal statistical assessment of publication bias were not performed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The heterogeneity of reported effect measures and inadequate reporting of event-level data limited the accuracy of quantitative synthesis and required an exploratory meta-analytic approach.

    “Second, the heterogeneity of reported effect measures and inadequate reporting of event-level data limited the accuracy of quantitative synthesis and required us to adopt an exploratory meta-analytic approach.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The quantity of available evidence is limited, including only three studies and only a few patients and thrombotic events.

    “First, the quantity of available evidence is limited, including only three studies and only a few patients and thrombotic events.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    These findings should be interpreted with caution given the limited sample size, heterogeneity in reporting, and incomplete availability of key treatment variables across studies.

    “However, these findings should be interpreted with caution, given the limited sample size, heterogeneity in reporting, and incomplete availability of key treatment variables across studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Arterial and venous thromboembolic events were inconsistently reported among the studies, which precluded high-quality subgroup analyses.

    “Third, arterial and venous thromboembolic events were inconsistently reported among the studies, which precluded us to perform high-quality subgroup analyses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hydroxychloroquine reduces platelet activation, downregulates endothelial tissue factor expression, modulates complement activation and improves endothelial function, collectively targeting multiple thrombo-inflammatory pathways central to APS pathophysiology.

    “In addition, HCQ reduces platelet activation, downregulates endothelial tissue factor expression, modulates complement activation and improves endothelial function, collectively targeting multiple thrombo-inflammatory pathways central to APS pathophysiology [3, 5].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Belizna C. Hydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome. Autoimmun Rev. 2015;14(4):358–62. https://doi.org/10.1016/j.autrev.2014.12.006. source
    • cites [5] Edwards MH, Pierangeli S, Liu X, Barker JH, Anderson G, Harris EN. Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation. 1997;96(12):4380–4. https://doi.org/10.1161/01.cir.96.12.4380. source
32 of 32

  • The paper relies on this without support.

    Hydroxychloroquine has a long-standing safety record in rheumatology, with low rates of serious adverse events when appropriately monitored, minimal interaction with anticoagulants, and low cost.

    “The drug has a long-standing safety record in rheumatology, with low rates of serious adverse events when appropriately monitored, minimal interaction with anticoagulants, and low cost.”

  • The paper relies on this without support.

    Alternative approaches to reducing recurrence risk—intensifying anticoagulation or combining anticoagulants with antiplatelet agents—are associated with increased bleeding risk and modest incremental benefit.

    “In contrast, alternative approaches to reducing recurrence risk—such as intensifying anticoagulation or combining anticoagulants with antiplatelet agents—are associated with increased bleeding risk and modest incremental benefit.”

  • The paper relies on this without support.

    Direct oral anticoagulants are not recommended in high-risk APS patients, particularly those with triple positivity, due to an increased risk of recurrent thrombosis.

    “Direct oral anticoagulants (DOACs), although initially considered attractive alternatives to vitamin K antagonists, are currently not recommended in high-risk APS patients, particularly those with triple positivity, due to an increased risk of recurrent thrombosis.”
3 of 3

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.

  • Retrospective cohort follow-up exceeds the stated range

    Minor

    The text says follow-up ranged up to 3 years in the prospective and retrospective cohorts, but Table 1 gives the retrospective cohort's follow-up as more than 3 years.

1 of 1

Cites

Flagged first, then by citations

Authors
de Carvalho, J. F., Hautz, E., & Cervera, R.
Affiliations
Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
ORCID
Venue
Rheumatology and Therapy
Publisher
Springer Science and Business Media LLC
Published
2026-05-09
Volume
13
Issue
4
Pages
985-995
ISSN
  • 2198-6576 (ISSN-L)
  • 2198-6584
DOI
10.1007/s40744-026-00858-x
PMC
PMC13407784
OpenAlex
W7160718456
Cited by
0
References
11
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Rheumatology and Therapy (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • PubMed Central (submittedVersion, cc-by-nc)
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
hydroxychloroquine, primary antiphospholipid syndrome, thromboprophylaxis, recurrent thrombosis, adjunctive therapy, anticoagulation, venous thrombosis, arterial thrombosis

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.

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Statistics and arithmetic are recomputed, not judged.

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