Abstract
Antiphospholipid antibodies (aPL) are both diagnostic markers for, and pathogenic drivers of, antiphospholipid syndrome (APS). Although the presence of aPL is a necessary pre-condition, APS-associated clotting is seemingly triggered by an additional 'second hit', frequently related to innate inflammatory immune responses. β2 glycoprotein I (β2GPI)-dependent aPL, the most important subset of these antibodies, mediate several—not necessarily alternative—thrombogenic mechanisms, mainly on the basis of their reactivity with β2GPI expressed on the membrane of cells that participate in the coagulation cascade. Recurrent pregnancy complications associated with aPL cannot be explained solely by thrombosis, and alternative pathogenic mechanisms have been reported. Although one in vivo model of fetal loss suggests a mechanism of aPL-mediated acute placental inflammation, other models and the histopathological examination of APS placentae do not support a widespread inflammatory signature. β2GPI-dependent aPL are thought to recognize their antigen on placental tissues, inhibit the growth and differentiation of trophoblasts, and eventually cause defective placentation. Why antibodies with similar antigen specificity produce different clinical manifestations is not clear. Characterization of the molecular basis of the pathogenic mechanisms involved, including the putative second hits and the role of complement activation, might offer an answer to this question.
Key Points
-
Antiphospholipid antibodies (aPL) are autoantibodies that are diagnostic of, and pathogenic in, antiphospholipid syndrome (APS)
-
aPL mediate several procoagulant mechanisms that can explain their thrombogenic effect in animal models, and their epidemiological association with APS in clinical studies
-
Whereas evidence shows that a second hit (usually an inflammatory event) is required for thrombus formation in APS, this requirement is less clear for fetal loss
-
In addition to placental thrombosis, other mechanisms for direct effects of aPL on placental tissues have been proposed
-
β2 glycoprotein I (β2GPI)-dependent autoantibodies seem to be the main pathogenic subpopulation of aPL
-
More information about the epitope specificity of anti-β2GPI aPL, as well as about the tissue expression of the target molecule, might help to better understand the pathogenesis of APS
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Miyakis, S. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J. Thromb. Haemost. 4, 295–306 (2006).
Giannakopoulos, B., Passam, F., Rahgozar, S. & Krilis, S. A. Current concepts on the pathogenesis of the antiphospholipid syndrome. Blood 109, 422–430 (2007).
Pierangeli, S. S. et al. Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms. Semin. Thromb. Hemost. 34, 236–250 (2008).
de Laat, B., Mertens, K. & de Groot. P. G. Mechanisms of disease: antiphospholipid antibodies—from clinical association to pathologic mechanism. Nat. Clin. Pract. Rheumatol. 4, 192–199 (2008).
Krone, K. A., Allen, K. L. & McCrae, K. R. Impaired fibrinolysis in the antiphospholipid syndrome. Curr. Rheumatol. Rep. 12, 53–57 (2010).
Shoenfeld, Y., Meroni, P. L. & Toubi, E. Antiphospholipid syndrome and systemic lupus erythematosus: are they separate entities or just clinical presentations on the same scale? Curr. Opin. Rheumatol. 21, 495–500 (2009).
Katzav, A., Shoenfeld, Y. & Chapman, J. The pathogenesis of neural injury in animal models of the antiphospholipid syndrome. Clin. Rev. Allergy Immunol. 38, 196–200 (2010).
Pierangeli, S. S., Liu, S. W., Anderson, G., Barker, J. H. & Harris, E. N. Thrombogenic properties of murine anti-cardiolipin antibodies induced by β2 glycoprotein 1 and human immunoglobulin G antiphospholipid antibodies. Circulation 94, 1746–1751 (1996).
Jankowski, M. et al. Thrombogenicity of β2-glycoprotein I-dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster. Blood 101, 157–162 (2003).
Ramesh, S. et al. Antiphospholipid antibodies promote leukocyte–endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via β2GPI and apoER2. J. Clin. Invest. 121, 120–131 (2011).
Fischetti, F. et al. Thrombus formation induced by antibodies to β2-glycoprotein I is complement dependent and requires a priming factor. Blood 10 6, 2340–2346 (2005).
Espinola, R. G. et al. E-Selectin mediates pathogenic effects of antiphospholipid antibodies. J. Thromb. Haemost. 1, 843–848 (2003).
Vega-Ostertag, M. E. et al. Role of p38 mitogen-activated protein kinase in antiphospholipid antibody-mediated thrombosis and endothelial cell activation. J. Thromb. Haemost. 5, 1828–1834 (2007).
Romay-Penabad, Z. et al. Apolipoprotein E receptor 2 is involved in the thrombotic complications in a murine model of the antiphospholipid syndrome. Blood 117, 1408–1414 (2010).
Pierangeli, S. S. et al. Toll-like receptor and antiphospholipid mediated thrombosis: in vivo studies. Ann. Rheum. Dis. 66, 1327–1333 (2007).
De Laat, B. et al. An international multicentre-laboratory evaluation of a new assay to detect specifically lupus anticoagulants dependent on the presence of anti-β2-glycoprotein autoantibodies. J. Thromb. Haemost. 9, 149–153 (2011).
Vega-Ostertag, M., Liu, X., Kwan-Ki, H., Chen, P. & Pierangeli, S. A human monoclonal antiprothrombin antibody is thrombogenic in vivo and upregulates expression of tissue factor and E-selectin on endothelial cells. Br. J. Haematol. 135, 214–219 (2006).
Chen, P. P. & Giles, I. Antibodies to serine proteases in the antiphospholipid syndrome. Curr. Rheumatol. Rep. 12, 45–52 (2010).
Atsumi, T. et al. Association of autoantibodies against the phosphatidylserine–prothrombin complex with manifestations of the antiphospholipid syndrome and with the presence of lupus anticoagulant. Arthritis Rheum. 43, 1982–1993 (2000).
Bertolaccini, M. L., Atsumi, T., Koike, T., Hughes, G. R. & Khamashta, M. A. Antiprothrombin antibodies detected in two different assay systems. Prevalence and clinical significance in systemic lupus erythematosus. Thromb. Haemost. 93, 289–297 (2005).
Galli, M., Luciani, D., Bertolini, G. & Barbui, T. Anti-β2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood 102, 2717–2723 (2003).
Galli, M. et al. Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the antiphospholipid syndrome) study. Blood 110, 1178–1183 (2007).
Meroni, P. L. Pathogenesis of the antiphospholipid syndrome: an additional example of the mosaic of autoimmunity. J. Autoimmun. 30, 99–103 (2008).
Tincani, A. et al. The anti-β2-glycoprotein I activity in human anti-phospholipid syndrome sera is due to monoreactive low-affinity autoantibodies directed to epitopes located on native β2-glycoprotein I and preserved during species' evolution. J. Immunol. 157, 5732–5738 (1996).
Nevinsky, G. A. & Buneva, V. N. Natural catalytic antibodies in norm, autoimmune, viral, and bacterial diseases. ScientificWorldJournal 10, 1203–1233 (2010).
Yang, Y. H. et al. Identification of anti-prothrombin antibodies in the anti-phospholipid syndrome that display the prothrombinase activity. Rheumatology (Oxford) 49, 34–42 (2010).
Passam, F. H. et al. β2 glycoprotein I is a substrate of thiol oxidoreductases. Blood 1 16, 1995–1997 (2010).
Meroni, P. L. et al. Anti-phospholipid antibody mediated fetal loss: still an open question from a pathogenic point of view. Lupus 1 9, 453–456 (2010).
Peaceman, A. M. & Rehnberg, K. A. The effect of immunoglobulin G fractions from patients with lupus anticoagulant on placental prostacyclin and thromboxane production. Am. J. Obstet. Gynecol. 169, 1403–1406 (1993).
Nayar, R. & Lage, J. M. Placental changes in a first trimester missed abortion in maternal systemic lupus erythematosus with antiphospholipid syndrome; a case report and review of the literature. Hum. Pathol. 27, 201–206 (1996).
Rand, J. H., Wu, X. X., Quinn, A. S. & Taatjes, D. J. The annexin A5-mediated pathogenic mechanism in the antiphospholipid syndrome: role in pregnancy losses and thrombosis. Lupus 19, 460–469 (2010).
Rand, J. H. et al. Reduction of annexin-V (placental anticoagulant protein-I) on placental villi of women with antiphospholipid antibodies and recurrent spontaneous abortion. Am. J. Obstet. Gynecol. 171, 1566–1572 (1994).
Park, A. L. in Hughes' Syndrome (ed. Khamashta, M. A.) Ch. 28 Placental pathology in antiphospholipid syndrome, 362–374 (Springer-Verlag, London, 2006).
Chaouat, G. The Th1/Th2 paradigm: still important in pregnancy? Semin. Immunopathol. 29, 95–113 (2007).
Holers, V. M. et al. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J. Exp. Med. 195, 211–220 (2002).
Girardi, G. et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J. Clin. Invest. 112, 1644–1654 (2003).
Berman, J., Girardi, G. & Salmon, J. E. TNF-α is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J. Immunol. 174, 485–490 (2005).
Thurman, J. M. et al. A novel inhibitor of the alternative complement pathway prevents antiphospholipid antibody-induced pregnancy loss in mice. Mol. Immunol. 42, 87–97 (2005).
Girardi, G., Yarilin, D., Thurman, J. M., Holers, V. M. & Salmon, J. E. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J. Exp. Med. 203, 2165–2175 (2006).
Redecha, P. et al. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury. Blood 110, 2423–2431 (2007).
Redecha, P., Franzke, C. W., Ruf, W., Mackman, N. & Girardi, G. Neutrophil activation by the tissue factor/Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome. J. Clin. Invest. 118, 3453–3461 (2008).
Seshan, S. V. et al. Role of tissue factor in a mouse model of thrombotic microangiopathy induced by antiphospholipid antibodies. Blood 114, 1675–1683 (2009).
Girardi, G., Redecha, P. & Salmon, J. E. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat. Med. 10, 1222–1226 (2004).
Martinez de la Torre, Y. et al. Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6. Proc. Natl Acad. Sci. USA 104, 2319–2324 (2007).
Cowchock, F. S., Reece, E. A., Balaban, D., Branch, D. W. & Plouffe, L. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am. J. Obstet. Gynecol. 166, 1318–1323 (1992).
Ruiz-Irastorza, G., Crowther, M., Branch, W. & Khamashta, M. A. Antiphospholipid syndrome. Lancet 376, 1498–1509 (2010).
Shamonki, J. M., Salmon, J. E., Hyjek, E. & Baergen, R. N. Excessive complement activation is associated with placental injury in patients with antiphospholipid antibodies. Am. J. Obstet. Gynecol. 196, e1–e5 (2007).
Cavazzana, I. et al. Complement activation in anti-phospholipid syndrome: a clue for an inflammatory process? J. Autoimmun. 28, 160–164 (2007).
Gerosa, M. et al. Complement involvement in antiphospholipid-mediated placental damage: prospective study in APS pregnant women [abstract THU0120] Ann. Rheum. Dis. 68 (Suppl. 3), 210 (2009).
Martinez de la Torre, Y. et al. Pregnant naïve mice are protected from aPL-induced fetal loss by the injection of a synthetic peptide (TIFI) mimicking the β2GPI PL-binding site [abstract 644]. Arthritis Rheum. 58, S404 (2008).
Francis, J. et al. Impaired expression of endometrial differentiation markers and complement regulatory proteins in patients with recurrent pregnancy loss associated with antiphospholipid syndrome. Mol. Hum. Reprod. 12, 435–442 (2006).
Borghi, M. O. et al. Antiphospholipid antibodies reactivity with human decidual cells: an additional mechanism of pregnancy complications in APS and a potential target for innovative therapeutic intervention [abstract OP-0119]. Ann. Rheum. Dis. 68 (Suppl. 3), 109 (2009).
Di Simone, N. et al. Pathogenic role of anti-β2-glycoprotein I antibodies in antiphospholipid-associated fetal loss: characterisation of β2-glycoprotein I binding to trophoblast cells and functional effects of anti-β2-glycoprotein I antibodies in vitro. Ann. Rheum. Dis. 64, 462–467 (2005).
Ostertag, M. V., Liu, X., Henderson, V. & Pierangeli, S. S. A peptide that mimics the Vth region of β2-glycoprotein I reverses antiphospholipid-mediated thrombosis in mice. Lupus 15, 358–365 (2006).
Tincani, A., Rebaioli, C. B., Andreoli, L., Lojacono, A. & Motta, M. Neonatal effects of maternal antiphospholipid syndrome. Curr. Rheumatol. Rep. 11, 70–76 (2009).
Renaudineau, Y., Dugué, C., Dueymes, M. & Youinou, P. Antiendothelial cell antibodies in systemic lupus erythematosus. Autoimmun. Rev. 1, 365–372 (2002).
Alard, J. E. et al. TLR2 is one of the endothelial receptors for β2-glycoprotein I. J. Immunol. 185, 1550–1557 (2010).
Raschi, E. et al. Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies. Blood 101, 3495–3500 (2003).
Cockrell, E., Espinola, R. G. & McCrae, K. R. Annexin A2: biology and relevance to the antiphospholipid syndrome. Lupus 17, 943–951 (2008).
Wegrowski, Y. et al. Cell surface proteoglycan expression during maturation of human monocytes-derived dendritic cells and macrophages. Clin. Exp. Immunol. 144, 485–493 (2006).
Lambrianides, A. et al. Effects of polyclonal IgG derived from patients with different clinical types of the antiphospholipid syndrome on monocyte signaling pathways. J. Immunol. 184, 6622–6628 (2010).
Yang, X. V. et al. Activated protein C ligation of ApoER2 (LRP8) causes Dab1-dependent signaling in U937 cells. Proc. Natl Acad. Sci. USA 106, 274–279 (2009).
Zhou, H. et al. Annexin A2 mediates anti-β2 GPI/β2 GPI-induced tissue factor expression on monocytes. Int. J. Mol. Med. 24, 557–562 (2009).
Kaneider, N. C. et al. Expression and function of syndecan-4 in human platelets. Thromb. Haemost. 93, 1120–1127 (2005).
Cognasse, F. et al. Evidence of Toll-like receptor molecules on human platelets. Immunol. Cell Biol. 83, 196–198 (2005).
Urbanus, R. T., Pennings, M. T., Derksen, R. H. & de Groot, P. G. Platelet activation by dimeric β2-glycoprotein I requires signaling via both glycoprotein Ibα and apolipoprotein E receptor 2′. J. Thromb. Haemost. 6, 1405–1412 (2008).
Chen, C. P., Liu, S. H., Lee, M. Y. & Chen, Y. Y. Heparan sulfate proteoglycans in the basement membranes of the human placenta and decidua. Placenta 4, 309–316 (2008).
Koga, K. & Mor, G. Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy disorders. Am. J. Reprod. Immunol. 63, 587–600 (2010).
Mulla, M. J. et al. Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. Am. J. Reprod. Immunol. 62, 96–111 (2009).
Hoang, V. M. et al. Functional proteomics: examining the effects of hypoxia on the cytotrophoblast protein repertoire. Biochemistry 40, 4077–4086 (2001).
Abaskharoun, M., Bellemare, M., Lau, E. & Margolis, R. U. Glypican-1, phosphacan/receptor protein-tyrosine phosphatase-ζ/β and its ligand, tenascin-C, are expressed by neural stem cells and neural cells derived from embryonic stem cells. ASN Neuro. 2, e00039 (2010).
Tang, S. C. et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc. Natl Acad. Sci. USA 104, 13798–13803 (2007).
Myant, N. B. Reelin and apolipoprotein E receptor 2 in the embryonic and mature brain: effects of an evolutionary change in the apoER2 gene. Proc. Biol. Sci. 277, 345–351 (2010).
Chua, C. C., Rahimi, N., Forsten-Williams, K. & Nugent, M. A. Heparan sulfate proteoglycans function as receptors for fibroblast growth factor-2 activation of extracellular signal-regulated kinases 1 and 2. Circ. Res. 94, 316–323 (2004).
Satta, N. et al. The role of TLR2 in the inflammatory activation of mouse fibroblasts by human antiphospholipid antibodies. Blood 109, 1507–1514 (2007).
Romay-Penabad, Z. et al. Annexin A2 is involved in antiphospholipid antibody-mediated pathogenic effects in vitro and in vivo. Blood 114, 3074–3083 (2009).
Raschi, E., Broggini, V., Borghi, M. O., Grossi, C. & Meroni, P. L. TLR-4 and Annexin A2 involvement in endothelial cell activation by anti-phospholipid antibodies: specific silencing by small interfering RNAs [abstract 1356]. Arthritis Rheum. 62 (Suppl.), S563 (2010).
Zhang, J. & McCrae, K. R. Annexin A2 mediates endothelial cell activation by antiphospholipid/anti-β2 glycoprotein I antibodies. Blood 105, 1964–1969 (2005).
Shoenfeld, Y. et al. Prevalence and clinical correlations of antibodies against six β2-glycoprotein-I-related peptides in the antiphospholipid syndrome. J. Clin. Immunol. 23, 377–383 (2003).
de Laat, B. et al. The association between circulating antibodies against domain I of β2-glycoprotein I and thrombosis: an international multicenter study. J. Thromb. Haemost. 7, 1767–1773 (2009).
Ioannou, Y. & Rahman, A. Domain I of β2-glycoprotein I: its role as an epitope and the potential to be developed as a specific target for the treatment of the antiphospholipid syndrome. Lupus 19, 400–405 (2010).
Ioannou, Y. et al. In vivo inhibition of antiphospholipid antibody-induced pathogenicity utilizing the antigenic target peptide domain I of β2-glycoprotein I: proof of concept. J. Thromb. Haemost. 7, 833–842 (2009).
Shoenfeld, Y. et al. Infectious origin of the antiphospholipid syndrome. Ann. Rheum. Dis. 65, 2–6 (2006).
Agar, C. et al. β2-Glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome. Blood 116, 1336–1343 (2010).
Tedesco, F. Biodistribution of β2GPI in naive and immunized mice and in vivo pro-thrombotic effect of an anti-β2GPI minibody isolated from human phage display library [abstract A006]. Lupus 19, 497–498 (2010).
McIntyre, J. A., Wagenknecht, D. R. & Sugi, T. Phospholipid binding plasma proteins required for antiphospholipid antibody detection—an overview. Am. J. Reprod. Immunol. 37, 101–110 (1997).
La Rosa, L. et al. β2 Glycoprotein I and placental anticoagulant protein I in placentae from patients with antiphospholipid syndrome. J. Rheumatol. 21, 1684–1693 (1994).
Pierangeli, S. S. et al. Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia. Arthritis Rheum. 52, 2120–2124 (2005).
Munakata, Y. et al. Detection of complement-fixing antiphospholipid antibodies in association with thrombosis. Thromb. Haemost. 83, 728–731 (2000).
Oku, K. et al. Complement activation in patients with primary antiphospholipid syndrome. Ann. Rheum. Dis. 68, 1030–1035 (2009).
Ziglioli, T. et al. Low complement levels during pregnancy are associated with obstetric complications in patients with primary antiphospholipid syndrome [abstract THU0129]. Ann. Rheum. Dis. 68 (Suppl. 3), 213–214 (2009).
Tedesco, F. et al. The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity. J. Exp. Med. 185, 1619–1627 (1997).
Girardi, G. Role of tissue factor in the maternal immunological attack of the embryo in the antiphospholipid syndrome. Clin. Rev. Allergy Immunol. 39, 160–165 (2010).
Author information
Authors and Affiliations
Contributions
All authors contributed equally to researching data, discussing content and writing the article, and reviewing/editing of the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Meroni, P., Borghi, M., Raschi, E. et al. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 7, 330–339 (2011). https://doi.org/10.1038/nrrheum.2011.52
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrrheum.2011.52
This article is cited by
-
A young woman with acute coronary syndrome and antiphospholipid syndrome. Is it the antiphospholipid syndrome or COVID-19 vaccination or classical risk as the risk factor? a case report
Journal of Medical Case Reports (2024)
-
An immunogenomic exome landscape of triple positive primary antiphospholipid patients
Genes & Immunity (2024)
-
Prevalence, clinical significance, and persistence of autoantibodies in COVID-19
Virology Journal (2023)
-
Antiphospholipid Syndrome: State of the Art of Clinical Management
Cardiovascular Drugs and Therapy (2023)
-
The trends in the incidence and thrombosis-related comorbidities of antiphospholipid syndrome: a 14-year nationwide population-based study
Thrombosis Journal (2022)