Pathogenesis of the antiphospholipid syndrome revisited: time to challenge the dogma
Open accessAbstract
For more than a decade the antiphospholipid syndrome (APS) has been reported to be caused mainly by antiphospholipid antibodies (aPL), which are not directed against phospholipids but against a complex of phospholipids and phospholipid binding proteins, so called cofactors (e.g. β2-glycoprotein I [β2GPI]). In fact, many researchers propose that the only relevant antigens in the APS are the cofactors themselves, with β2GPI being the most important. Antibodies that bind to phospholipids in a cofactor-independent manner are considered insignificant for the pathogenesis of the APS. We review the evidence for this current pathophysiologic concept and argue that it has never been proven and is now clearly no longer tenable. First, there is undisputable evidence that cofactor-independent aPL are pathogenic and present in the blood of APS patients. Second, available epidemiologic and clinical studies do not support a dominant pathogenic role for anti-β2GPI.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
These results add to the growing body of evidence that shows inconsistent associations between aPL-associated autoantibodies and anamnestic thrombotic risk.
“These results confirm and validate several previous reports that have implicated these antibodies in the pathogenesis of APS [9, 10, 12, 13, 29, 30], but they also add to the growing body of evidence that shows inconsistent associations between aPL-associated autoantibodies and anamnestic thrombotic risk [3, 16].”
From Cardiovascular risk factors are major determinants of thrombotic risk in patients with the lupus anticoagulant (2017) · cites this paper as [16]
Cites
MIYAKIS, S., LOCKSHIN, M. D., ATSUMI, T., BRANCH, D. W., BREY, R. L., CERVERA, R., DERKSEN, R. H. W. M., DE GROOT, P. G., KOIKE, T., MERONI, P. L., et al. (2006) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2006.01753.x · Cited by 7,203 · see citing works
McNeil, H. P., Simpson, R. J., Chesterman, C. N., & Krilis, S. A. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.11.4120 · Cited by 1,595 · see citing works
Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor
Galli, M., Barbui, T., Comfurius, P., Maassen, C., Hemker, H. C., Zwaal, R. F. A., Bevers, E. M., Baets, M. H. D., & Vriesman, P. J. C. V. B. (1990) · The Lancet · doi:10.1016/0140-6736(90)91374-j · Cited by 1,266 · see citing works
Galli, M., Luciani, D., Bertolini, G., & Barbui, T. (2003) · Blood · doi:10.1182/blood-2002-02-0441 · Cited by 974 · see citing works
The Pathogenesis of the Antiphospholipid Syndrome
Giannakopoulos, B., & Krilis, S. A. (2013) · New England Journal of Medicine · doi:10.1056/nejmra1112830 · Cited by 682 · see citing works
Heparin prevents antiphospholipid antibody–induced fetal loss by inhibiting complement activation
Girardi, G., Redecha, P. B., & Salmon, J. E. (2004) · Nature Medicine · doi:10.1038/nm1121 · Cited by 680 · see citing works
Pathogenesis of antiphospholipid syndrome: understanding the antibodies
Meroni, P. L., Borghi, M. O., Raschi, E., & Tedesco, F. (2011) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2011.52 · Cited by 620 · see citing works
Galli, M., Luciani, D., Bertolini, G., & Barbui, T. (2003) · Blood · doi:10.1182/blood-2002-11-3334 · Cited by 413 · see citing works
Heterogeneity of anticardiolipin antibodies defined by the anticardiolipin cofactor
Matsuura, E., Igarashi, Y., Fujimoto, M., Ichikawa, K., Suzuki, T., Sumida, T., Yasuda, T., & Koike, T. (1992) · The Journal of Immunology · doi:10.4049/jimmunol.148.12.3885 · Cited by 322 · see citing works
Reynaud, Q., Lega, J.-C., Mismetti, P., Chapelle, C., Wahl, D., Cathébras, P., & Laporte, S. (2014) · Autoimmunity Reviews · doi:10.1016/j.autrev.2013.11.004 · Cited by 179 · see citing works
Arad, A., Proulle, V., Furie, R. A., Furie, B. C., & Furie, B. (2011) · Blood · doi:10.1182/blood-2010-08-300715 · Cited by 140 · see citing works
Pengo, V., Ruffatti, A., Tonello, M., Cuffaro, S., Banzato, A., Bison, E., Denas, G., & Padayattil Jose, S. (2015) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.12865 · Cited by 126 · see citing works
Pierangeli, S. S., Liu, X. W., Anderson, G., Barker, J. H., & Harris, E. N. (1996) · Circulation · doi:10.1161/01.cir.94.7.1746 · Cited by 118 · see citing works
Prinz, N., Clemens, N., Strand, D. J., Pütz, I., Lorenz, M., Daiber, A., Stein, P., Degreif, A., Radsak, M. P., Schild, H., et al. (2011) · Blood · doi:10.1182/blood-2011-01-330639 · Cited by 115 · see citing works
Self-citationPierangeli, S. S., Liu, X., Espinola, R. G., Olee, T., Zhu, M., Harris, N., & Chen, P. P. (2000) · Thrombosis and Haemostasis · doi:10.1055/s-0037-1607384 · Cited by 100 · see citing works
Pierangeli, S. S., Harris, E. N., Davis, S. A., et al. (1992) · British Journal of Haematology · doi:10.1111/j.1365-2141.1992.tb06468.x · Cited by 87 · see citing works
Forastiero, R. R., Martinuzzo, M. E., Kordich, L., & Carreras, L. O. (1996) · PubMed · Cited by 84 · see citing works
Biasiolo, A., Rampazzo, P., Brocco, T., & Pengo, V. (1999) · Thrombosis and Haemostasis · doi:10.1055/s-0037-1614453 · Cited by 76 · see citing works
Banzato, A., Pozzi, N., Frasson, R., Filippis, V. D., Ruffatti, A., Bison, E., Jose, S. P., Denas, G., & Pengo, V. (2011) · Thrombosis Research · doi:10.1016/j.thromres.2011.04.021 · Cited by 73 · see citing works
Forastiero, R. R., Martinuzzo, M. E., Kordich, L., & Carreras, L. O. (1996) · Thrombosis and Haemostasis · doi:10.1055/s-0038-1650354 · Cited by 72 · see citing works
A two‐step coagulation test to identify antiβ2‐glycoprotein I lupus anticoagulants
Pengo, V., Biasiolo, A., Pegoraro, C., & Iliceto, S. (2004) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2004.00712.x · Cited by 70 · see citing works
Müller‐Calleja, N., Köhler, A., Siebald, B., Canisius, A., Orning, C., Radsak, M. P., Stein, P., Mönnikes, R., & Lackner, K. J. (2015) · Thrombosis and Haemostasis · doi:10.1160/th14-07-0628 · Cited by 66 · see citing works
Self-citationCofactor‐independent human antiphospholipid antibodies induce venous thrombosis in mice
Manukyan, D., Müller‐Calleja, N., Jäckel, S., Luchmann, K., Mönnikes, R., Kiouptsi, K., Reinhardt, C., Jurk, K., Walter, U., & Lackner, K. J. (2016) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.13263 · Cited by 58 · see citing works
Self-citationPrinz, N., Clemens, N., Canisius, A., & Lackner, K. J. (2013) · Thrombosis and Haemostasis · doi:10.1160/th12-06-0421 · Cited by 53 · see citing works
Self-citationvon Landenberg, C., Lackner, K. J., von Landenberg, P., et al. (1999) · Journal of Autoimmunity · doi:10.1006/jaut.1999.0316 · Cited by 48 · see citing works
Self-citationGiles, I., Haley, J., Nagl, S., Isenberg, D. A., Latchman, D. S., & Rahman, A. (2003) · Seminars in Arthritis and Rheumatism · doi:10.1053/sarh.2003.49994 · Cited by 43 · see citing works
Receptors involved in cell activation by antiphospholipid antibodies
Brandt, K. J., Kruithof, E. K. O., & de Moerloose, P. (2013) · Thrombosis Research · doi:10.1016/j.thromres.2013.08.015 · Cited by 36 · see citing works
Du, V. X., Kelchtermans, H., de Groot, P. G., & de Laat, B. (2013) · Thrombosis Research · doi:10.1016/j.thromres.2013.07.023 · Cited by 35 · see citing works
Levy, R. A., de Meis, E., & Pierangeli, S. S. (2004) · Thrombosis Research · doi:10.1016/j.thromres.2004.06.032 · Cited by 28 · see citing works
Pathogenesis of the antiphospholipid syndrome revisited: time to challenge the dogma: comment
Pengo, V. (2016) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.13510 · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Posch, F., Gebhart, J., Rand, J. H., Koder, S., Quehenberger, P., Pengo, V., Ay, C., & Pabinger, I. (2017) · BMC Medicine · doi:10.1186/s12916-017-0807-7 · Cited by 25 · see citing works
“These results confirm and validate several previous reports that have implicated these antibodies in the pathogenesis of APS [9, 10, 12, 13, 29, 30], but they also add to the growing body of evidence that shows inconsistent associations between aPL-associated autoantibodies and anamnestic thrombotic risk [3, 16].”
Result
- Authors
- Lackner, K. J., & Müller‐Calleja, N.
- Affiliations
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Corresponding author
- Lackner, K.J.
- Venue
- Journal of Thrombosis and Haemostasis
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 14
- Issue
- 6
- Pages
- 1117-1120
- ISSN
- 1538-7836 (ISSN-L)
- OpenAlex
- W2305409522
- Cited by
- 24
- References
- 31
- Citations by year
- 2025: 1 · 2024: 2 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 4 · 2017: 7 · 2016: 4
- FWCI
- 6.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thrombosis and Haemostasis (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Vasculitis and related conditions
- Keywords
- antiphospholipid syndrome, pathogenesis, antiphospholipid antibodies, beta2-glycoprotein I, phospholipid-binding proteins, autoantibody pathogenicity
- MeSH terms
- Humans, Thromboembolism, Antiphospholipid Syndrome, Antibodies, Antiphospholipid, beta 2-Glycoprotein I
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.
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 ›
Are you an author, or do you see a problem with this page? Request a review