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Antiphospholipid syndrome

Nature Reviews Disease Primers volume 4, Article number: 17103 (2018) Cite this article

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A Correction to this article was published on 25 January 2018

Abstract

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies, such as lupus anticoagulant, anticardiolipin antibodies and anti-β2-glycoprotein 1 antibodies. APS can present with a variety of clinical phenotypes, including thrombosis in the veins, arteries and microvasculature as well as obstetrical complications. The pathophysiological hallmark is thrombosis, but other factors such as complement activation might be important. Prevention of thrombotic manifestations associated with APS includes lifestyle changes and, in individuals at high risk, low-dose aspirin. Prevention and treatment of thrombotic events are dependent mainly on the use of vitamin K antagonists. Immunosuppression and anticomplement therapy have been used anecdotally but have not been adequately tested. Pregnancy morbidity includes unexplained recurrent early miscarriage, fetal death and late obstetrical manifestation such as pre-eclampsia, premature birth or fetal growth restriction associated with placental insufficiency. Current treatment to prevent obstetrical morbidity is based on low-dose aspirin and/or low-molecular-weight heparin and has improved pregnancy outcomes to achieve successful live birth in >70% of pregnancies. Although hydroxychloroquine and pravastatin might further improve pregnancy outcomes, prospective clinical trials are required to confirm these findings.

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Figure 1: Pathophysiology of antiphospholipid antibody-associated thrombosis.
Figure 2: Effect of antiphospholipid antibodies on trophoblasts.
Figure 3: Clinical manifestation of antiphospholipid syndrome.

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References

  1. Ruiz-Irastorza, G., Crowther, M., Branch, W. & Khamashta, M. A. Antiphospholipid syndrome. Lancet 376, 1498–1509 (2010).

    CAS  Google Scholar 

  2. 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). This paper outlines the current APS classification criteria, commonly referred to as ‘Miyakis criteria’.

    CAS  Google Scholar 

  3. Ruiz-Irastorza, G. et al. 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 20, 206–218 (2011).

    CAS  Google Scholar 

  4. Radin, M. & Sciascia, S. Infodemiology of systemic lupus erythematous using Google Trends. Lupus 26, 886–889 (2017).

    CAS  Google Scholar 

  5. Tripodi, A. et al. Variability of cut-off values for the detection of lupus anticoagulants: results of an international multicenter multiplatform study. J. Thromb. Haemost. 15, 1180–1190 (2017).

    CAS  Google Scholar 

  6. Durcan, L. & Petri, M. Epidemiology of the Antiphospholipid Syndrome (Elsevier, 2016).

    Google Scholar 

  7. Rodriguez-Pinto, I. et al. Catastrophic antiphospholipid syndrome (CAPS): Descriptive analysis of 500 patients from the International CAPS Registry. Autoimmun. Rev. 15, 1120–1124 (2016).

    CAS  Google Scholar 

  8. Mehrani T. & Petri, M. in Handbook of Systemic Autoimmune Diseases Vol. 10 (eds Cervera, R., Reverter, J. C. & Khamashta, M. ) 13–34 (Elsevier, 2009).

    Google Scholar 

  9. Meroni, P. L. et al. Anti-beta 2 glycoprotein I antibodies in centenarians. Exp. Gerontol. 39, 1459–1465 (2004).

    CAS  Google Scholar 

  10. Andreoli, L. et al. Estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature. Arthritis Care Res. 65, 1869–1873 (2013).

    CAS  Google Scholar 

  11. Urbanus, R. T. et al. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study. Lancet Neurol. 8, 998–1005 (2009).

    CAS  Google Scholar 

  12. Martinez-Zamora, M. A. et al. Risk of thromboembolic events after recurrent spontaneous abortion in antiphospholipid syndrome: a case-control study. Ann. Rheum. Dis. 71, 61–66 (2012).

    Google Scholar 

  13. Gris, J. C. et al. Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study. Blood 119, 2624–2632 (2012).

    CAS  Google Scholar 

  14. Quenby, S., Farquharson, R. G., Dawood, F., Hughes, A. M. & Topping, J. Recurrent miscarriage and long-term thrombosis risk: a case-control study. Hum. Reprod. 20, 1729–1732 (2005).

    CAS  Google Scholar 

  15. Alijotas-Reig, J. et al. The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): a survey of 247 consecutive cases. Autoimmun. Rev. 14, 387–395 (2015).

    Google Scholar 

  16. Abou-Nassar, K., Carrier, M., Ramsay, T. & Rodger, M. A. The association between antiphospholipid antibodies and placenta mediated complications: a systematic review and meta-analysis. Thromb. Res. 128, 77–85 (2011).

    CAS  Google Scholar 

  17. Silver, R. K. M. et al. Comparative trial of prednisone plus aspirin versus aspirin alone in the treatment of anticardiolipin antibody-positive obstetric patients. Am. J. Obstetr. Gynecol. 169, 1411–1417 (1993).

    CAS  Google Scholar 

  18. Page, J. M. et al. Diagnostic tests for evaluation of stillbirth: stillbirth collaborative research network. Obstet. Gynecol. 129, 699–706 (2017).

    CAS  Google Scholar 

  19. Tektonidou, M. G., Laskari, K., Panagiotakos, D. B. & Moutsopoulos, H. M. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Rheum. 61, 29–36 (2009).

    Google Scholar 

  20. Biggioggero, M. & Meroni, P. L. The geoepidemiology of the antiphospholipid antibody syndrome. Autoimmun. Rev. 9, A299–A304 (2010).

    Google Scholar 

  21. Shrivastava, A., Dwivedi, S., Aggarwal, A. & Misra, R. Anti-cardiolipin and anti-beta 2 glycoprotein I antibodies in Indian patients with systemic lupus erythematosus: association with the presence of seizures. Lupus 10, 45–50 (2001).

    CAS  Google Scholar 

  22. Mok, M. Y. C. et al. Antiphospholipid antibody profiles and their clinical associations in Chinese patients with systemic lupus erythematosus. J. Rheumatol. 32, 622–628 (2005).

    CAS  Google Scholar 

  23. Cruz-Tapias, P., Blank, M., Anaya, J. M. & Shoenfeld, Y. Infections and vaccines in the etiology of antiphospholipid syndrome. Curr. Opin. Rheumatol. 24, 389–393 (2012).

    CAS  Google Scholar 

  24. de Laat, B. et al. Immune responses against domain I of β2-glycoprotein I are driven by conformational changes: domain I of β2-glycoprotein I harbors a cryptic immunogenic epitope. Arthritis Rheum. 63, 3960–3968 (2011).

    CAS  Google Scholar 

  25. van Os, G. M. et al. Induction of anti-β2 -glycoprotein I autoantibodies in mice by protein H of Streptococcus pyogenes. J. Thromb. Haemost. 9, 2447–2456 (2011).

    CAS  Google Scholar 

  26. Pengo, V. et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood 118, 4714–4718 (2011).

    CAS  Google Scholar 

  27. Exner, T., Barber, S., Kronenberg, H. & Rickard, K. A. Familial association of the lupus anticoagulant. Br. J. Haematol. 45, 89–96 (1980).

    CAS  Google Scholar 

  28. Matthey, F., Walshe, K., Mackie, I. J. & Machin, S. J. Familial occurrence of the antiphospholipid syndrome. J. Clin. Pathol. 42, 495–497 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Jolidon, R. M., Knecht, H., Humair, L. & de Torrente, A. Different clinical presentations of a lupus anticoagulant in the same family. Klin. Wochenschr. 69, 340–344 (1991).

    CAS  Google Scholar 

  30. Sebastiani, G. D., Iuliano, A., Cantarini, L. & Galeazzi, M. Genetic aspects of the antiphospholipid syndrome: an update. Autoimmun. Rev. 15, 433–439 (2016).

    CAS  Google Scholar 

  31. Cervera, R. S. et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann. Rheum. Dis. 74, 1011–1018 (2015).

    CAS  Google Scholar 

  32. Lijfering, W. M., Flinterman, L. E., Vandenbroucke, J. P., Rosendaal, F. R. & Cannegieter, S. C. Relationship between venous and arterial thrombosis: a review of the literature from a causal perspective. Semin. Thromb. Hemost. 37, 885–896 (2011).

    Google Scholar 

  33. de Groot, P. G., Urbanus, R. T. & Derksen, R. H. Pathophysiology of thrombotic APS: where do we stand? Lupus 21, 704–707 (2012).

    CAS  Google Scholar 

  34. 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).

    CAS  Google Scholar 

  35. 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 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Fischetti, F. et al. Thrombus formation induced by antibodies to β2-glycoprotein I is complement dependent and requires a priming factor. Blood 106, 2340–2346 (2005).

    CAS  Google Scholar 

  37. Pericleous, C. et al. Proof-of-concept study demonstrating the pathogenicity of affinity-purified IgG antibodies directed to domain I of β2-glycoprotein I in a mouse model of anti-phospholipid antibody-induced thrombosis. Rheumatology 54, 722–727 (2015).

    CAS  Google Scholar 

  38. 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).

    CAS  Google Scholar 

  39. Agar, C., de Groot, P. G., Marquart, J. A. & Meijers, J. C. Evolutionary conservation of the lipopolysaccharide binding site of β2-glycoprotein I. Thromb. Haemost. 106, 1069–1075 (2011).

    CAS  Google Scholar 

  40. 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).

    CAS  Google Scholar 

  41. Haj-Yahia, S. et al. Anti-prothrombin antibodies cause thrombosis in a novel qualitative ex-vivo animal model. Lupus 12, 364–369 (2003).

    CAS  Google Scholar 

  42. Manukyan, D. et al. Cofactor-independent human antiphospholipid antibodies induce venous thrombosis in mice. J. Thromb. Haemost. 14, 1011–1020 (2016).

    CAS  Google Scholar 

  43. Forastiero, R., Martinuzzo, M., de Larranaga, G., Vega-Ostertag, M. & Pierangeli, S. Anti-β2glycoprotein I antibodies from leprosy patients do not show thrombogenic effects in an in vivo animal model. J. Thromb. Haemost. 9, 859–861 (2011).

    CAS  Google Scholar 

  44. de Groot, P. G. & Urbanus, R. T. The significance of autoantibodies against β2-glycoprotein I. Blood 120, 266–274 (2012). This paper highlights the importance of anti-β2-glycoprotein 1 in APS.

    CAS  Google Scholar 

  45. Chaturvedi, S., Alluri, R. & McCrae, K. R. Extracellular vesicles in the antiphospholipid syndrome. Semin. Thromb. Hemost.https://doi.org/10.1055/s-0037-1599081 (2017).

    Google Scholar 

  46. Lutters, B. C. et al. Dimers of β2-glycoprotein I increase platelet deposition to collagen via interaction with phospholipids and the apolipoprotein E receptor 2’. J. Biol. Chem. 278, 33831–33838 (2003).

    CAS  Google Scholar 

  47. de Groot, P. G. & Urbanus, R. T. Cellular signaling by antiphospholipid antibodies. J. Thromb. Haemost. 12, 773–775 (2014).

    CAS  Google Scholar 

  48. Pierangeli, S. S., Vega-Ostertag, M., Liu, X. & Girardi, G. Complement activation: a novel pathogenic mechanism in the antiphospholipid syndrome. Ann. NY Acad. Sci. 1051, 413–420 (2005).

    CAS  Google Scholar 

  49. Wahl, D., Membre, A., Perret-Guillaume, C., Regnault, V. & Lecompte, T. Mechanisms of antiphospholipid-induced thrombosis: effects on the protein C system. Curr. Rheumatol Rep. 11, 77–81 (2009).

    CAS  Google Scholar 

  50. Dahlback, B. Progress in the understanding of the protein C anticoagulant pathway. Int. J. Hematol. 79, 109–116 (2004).

    Google Scholar 

  51. Feinstein, D. I. & Rapaport, S. I. Acquired inhibitors of blood coagulation. Prog. Hemost. Thromb. 1, 75–95 (1972).

    CAS  Google Scholar 

  52. Cervera, R. et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann. Rheum. Dis. 74, 1011–1018 (2015).

    CAS  Google Scholar 

  53. Derksen, R. H. W. M. & de Groot, P. G. The obstetric antiphospholipid syndrome. J. Reproductive Immunol. 77, 41–50 (2008).

    CAS  Google Scholar 

  54. Chamley, L. W., Duncalf, A. M., Mitchell, M. D. & Johnson, P. M. Action of anticardiolipin and antibodies to beta2-glycoprotein-I on trophoblast proliferation as a mechanism for fetal death. Lancet 352, 1037–1038 (1998).

    CAS  Google Scholar 

  55. Di Simone, N. et al. Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered beta2-glycoprotein I. Arthritis Rheum. 43, 140–150 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Burton, G. J., Woods, A. W., Jauniaux, E. & Kingdom, J. C. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta 30, 473–482 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Chamley, L. W., Allen, J. L. & Johnson, P. M. Synthesis of β2 glycoprotein 1 by the human placenta. Placenta 18, 403–410 (1997).

    CAS  Google Scholar 

  58. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Mulla, M. J. et al. Antiphospholipid antibodies limit trophoblast migration by reducing IL-6 production and STAT3 activity. Am. J. Reprod. Immunol. 63, 339–348 (2010).

    CAS  Google Scholar 

  60. Carroll, T. Y. et al. Modulation of trophoblast angiogenic factor secretion by antiphospholipid antibodies is not reversed by heparin. Am. J. Reprod. Immunol. 66, 286–296 (2011).

    CAS  Google Scholar 

  61. Alvarez, A. M., Mulla, M. J., Chamley, L. W., Cadavid, A. P. & Abrahams, V. M. Aspirin-triggered lipoxin prevents antiphospholipid antibody effects on human trophoblast migration and endothelial cell interactions. Arthritis Rheumatol. 67, 488–497 (2015).

    CAS  Google Scholar 

  62. Ulrich, V. et al. ApoE receptor 2 mediation of trophoblast dysfunction and pregnancy complications induced by antiphospholipid antibodies in mice. Arthritis Rheumatol. 68, 730–739 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Holers, V. M. et al. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J. Exp. Med. 195, 211–220 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Girardi, G. et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J. Clin. Invest. 112, 1644–1654 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 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).

    CAS  Google Scholar 

  66. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Gelber, S. E. et al. Prevention of defective placentation and pregnancy loss by blocking innate immune pathways in a syngeneic model of placental insufficiency. J. Immunol. 195, 1129–1138 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Girardi, G., Redecha, P. & Salmon, J. E. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat. Med. 10, 1222–1226 (2004). This study supports the role of the complement system in antiphospholipid antibody-related pregnancy morbidity in a murine model.

    CAS  Google Scholar 

  69. 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, 167.e1–167.e5 (2007).

    Google Scholar 

  70. Cohen, D. et al. Classical complement activation as a footprint for murine and human antiphospholipid antibody-induced fetal loss. J. Pathol. 225, 502–511 (2011).

    CAS  Google Scholar 

  71. Viall, C. A. & Chamley, L. W. Histopathology in the placentae of women with antiphospholipid antibodies: a systematic review of the literature. Autoimmun. Rev. 14, 446–471 (2015).

    CAS  Google Scholar 

  72. Salmon, J. E. et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 8, e1001013 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Oku, K. et al. Complement activation in patients with primary antiphospholipid syndrome. Ann. Rheum. Dis. 68, 1030–1035 (2009).

    CAS  Google Scholar 

  74. Breen, K. A. et al. Complement activation in patients with isolated antiphospholipid antibodies or primary antiphospholipid syndrome. Thromb. Haemost. 107, 423–429 (2012).

    CAS  Google Scholar 

  75. Ritis, K. et al. A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J. Immunol. 177, 4794–4802 (2006).

    CAS  Google Scholar 

  76. Kupferminc, M. J., Peaceman, A. M., Wigton, T. R., Rehnberg, K. A. & Socol, M. L. Tumor necrosis factor-α is elevated in plasma and amniotic fluid of patients with severe preeclampsia. Am. J. Obstetr. Gynecol. 170, 1752–1759 (1994).

    CAS  Google Scholar 

  77. Tosun, M. et al. Maternal and umbilical serum levels of interleukin-6, interleukin-8, and tumor necrosis factor-alpha in normal pregnancies and in pregnancies complicated by preeclampsia. J. Matern. Fetal Neonatal Med. 23, 880–886 (2010).

    CAS  Google Scholar 

  78. Pijnenborg, R. et al. Immunolocalization of tumour necrosis factor-α (TNF-α) in the placental bed of normotensive and hypertensive human pregnancies. Placenta 19, 231–239 (1998).

    CAS  Google Scholar 

  79. Yalavarthi, S. et al. Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome. Arthritis Rheumatol. 67, 2990–3003 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Marder, W. et al. Placental histology and neutrophil extracellular traps in lupus and pre-eclampsia pregnancies. Lupus Sci. Med. 3, e000134 (2016).

    PubMed  PubMed Central  Google Scholar 

  81. Giannakopoulos, B., Passam, F., Ioannou, Y. & Krilis, S. A. How we diagnose the antiphospholipid syndrome. Blood 113, 985–994 (2009).

    CAS  Google Scholar 

  82. Pengo, V. et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J. Thromb. Haemost. 7, 1737–1740 (2009). This publication outlines the current SSC-ISTH guidelines for the detection of antiphospholipid antibodies.

    CAS  Google Scholar 

  83. Devreese, K. M. et al. Testing for antiphospholipid antibodies with solid phase assays: guidance from the SSC of the ISTH. J. Thromb. Haemost. 12, 792–795 (2014).

    CAS  Google Scholar 

  84. Devreese, K. M. Standardization of antiphospholipid antibody assays. Where do we stand? Lupus 21, 718–721 (2012).

    CAS  Google Scholar 

  85. Devreese, K. M. No more mixing tests required for integrated assay systems in the laboratory diagnosis of lupus anticoagulants? J. Thromb. Haemost. 8, 1120–1122 (2010).

    CAS  Google Scholar 

  86. Devreese, K. M. & de Laat, B. Mixing studies in lupus anticoagulant testing are required at least in some type of samples. J. Thromb. Haemost. 13, 1475–1478 (2015).

    CAS  Google Scholar 

  87. Tripodi, A. & Pengo, V. More on: laboratory investigation of lupus anticoagulants: mixing studies are sometimes required. J. Thromb. Haemost. 9, 2126–2127 (2011).

    CAS  Google Scholar 

  88. Devreese, K. M. J. Antiphospholipid antibody testing and standardization. Int. J. Lab. Hematol. 36, 352–363 (2014).

    CAS  Google Scholar 

  89. Hoxha, A., Banzato, A., Ruffatti, A. & Pengo, V. Detection of lupus anticoagulant in the era of direct oral anticoagulants. Autoimmun. Rev. 16, 173–178 (2017).

    CAS  Google Scholar 

  90. Moore, G. W. Combining Taipan snake venom time/Ecarin time screening with the mixing studies of conventional assays increases detection rates of lupus anticoagulants in orally anticoagulated patients. Thromb. J. 5, 12 (2007).

    PubMed  PubMed Central  Google Scholar 

  91. Devreese, K. M. Antiphospholipid antibody testing and standardization. Int. J. Lab. Hematol. 36, 352–363 (2014).

    CAS  Google Scholar 

  92. Galli, M. et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 335, 1544–1547 (1990).

    CAS  Google Scholar 

  93. Van Hoecke, F., Persijn, L., Decavele, A. S. & Devreese, K. Performance of two new, automated chemiluminescence assay panels for anticardiolipin and anti-beta2-glycoprotein I antibodies in the laboratory diagnosis of the antiphospholipid syndrome. Int. J. Lab. Hematol. 34, 630–640 (2012).

    CAS  Google Scholar 

  94. de Moerloose, P., Reber, G., Musial, J. & Arnout, J. Analytical and clinical performance of a new, automated assay panel for the diagnosis of antiphospholipid syndrome. J. Thromb. Haemost. 8, 1540–1546 (2010).

    CAS  Google Scholar 

  95. Kelchtermans, H., Pelkmans, L., de Laat, B. & Devreese, K. M. IgG/IgM antiphospholipid antibodies present in the classification criteria for the antiphospholipid syndrome: a critical review of their association with thrombosis. J. Thromb. Haemost. 14, 1530–1548 (2016).

    CAS  Google Scholar 

  96. Pericleous, C. et al. Measuring IgA anti-β2-glycoprotein I and IgG/IgA anti-domain I antibodies adds value to current serological assays for the antiphospholipid syndrome. PLoS ONE 11, e0156407 (2016).

    PubMed  PubMed Central  Google Scholar 

  97. Bertolaccini, M. L. et al. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun. Rev. 13, 917–930 (2014).

    Google Scholar 

  98. Favaloro, E. J., Wheatland, L., Jovanovich, S., Roberts-Thomson, P. & Wong, R. C. Internal quality control and external quality assurance in testing for antiphospholipid antibodies: Part I−-Anticardiolipin and anti-beta2-glycoprotein I antibodies. Semin. Thromb. Hemost 38, 390–403 (2012).

    CAS  Google Scholar 

  99. Pelkmans, L. et al. Variability in exposure of epitope G40-R43 of domain i in commercial anti-beta2-glycoprotein I IgG ELISAs. PLoS ONE 8, e71402 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Devreese, K. M. et al. A multicenter study to assess the reproducibility of antiphospholipid antibody results produced by an automated system. J. Thromb. Haemost. 15, 91–95 (2017).

    CAS  Google Scholar 

  101. Devreese, K. M. Antiphospholipid antibodies: evaluation of the thrombotic risk. Thromb. Res. 130 (Suppl. 1), S37–S40 (2012).

    Google Scholar 

  102. Devreese, K., Peerlinck, K. & Hoylaerts, M. F. Thrombotic risk assessment in the antiphospholipid syndrome requires more than the quantification of lupus anticoagulants. Blood 115, 870–878 (2010).

    CAS  Google Scholar 

  103. Devreese, K., Peerlinck, K. & Hoylaerts, M. F. Diagnostic test combinations associated with thrombosis in lupus anticoagulant positive patients. Thromb. Haemost. 105, 736–738 (2011).

    CAS  Google Scholar 

  104. Pengo, V. et al. Antibody profiles for the diagnosis of antiphospholipid syndrome. Thromb. Haemost. 93, 1147–1152 (2005).

    CAS  Google Scholar 

  105. Pengo, V. et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J. Thromb. Haemost. 8, 237–242 (2010).

    CAS  Google Scholar 

  106. Pengo, V. Four good reasons to appreciate triple positivity. Pol. Arch. Med. Wewn 126, 7–8 (2016).

    Google Scholar 

  107. Mustonen, P., Lehtonen, K. V., Javela, K. & Puurunen, M. Persistent antiphospholipid antibody (aPL) in asymptomatic carriers as a risk factor for future thrombotic events: a nationwide prospective study. Lupus 23, 1468–1476 (2014).

    CAS  Google Scholar 

  108. Pengo, V. et al. Confirmation of initial antiphospholipid antibody positivity depends on the antiphospholipid antibody profile. J. Thromb. Haemost. 11, 1527–1531 (2013).

    CAS  Google Scholar 

  109. Pengo, V. et al. APS — diagnostics and challenges for the future. Autoimmun. Rev. 15, 1031–1033 (2016).

    CAS  Google Scholar 

  110. Devreese, K. & Hoylaerts, M. F. Challenges in the diagnosis of the antiphospholipid syndrome. Clin. Chem. 56, 930–940 (2010).

    CAS  Google Scholar 

  111. Rodriguez-Garcia, V., Ioannou, Y., Fernandez-Nebro, A., Isenberg, D. A. & Giles, I. P. Examining the prevalence of non-criteria anti phospholipid antibodies in patients with anti phospholipid syndrome: a systematic review. Rheumatology 54, 2042–2050 (2015).

    CAS  Google Scholar 

  112. de Laat, B., Derksen, R. H., Urbanus, R. T. & de Groot, P. G. IgG antibodies that recognize epitope Gly40-Arg43 in domain I of β2-glycoprotein I cause LAC, and their presence correlates strongly with thrombosis. Blood 105, 1540–1545 (2005).

    CAS  Google Scholar 

  113. 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).

    CAS  Google Scholar 

  114. Mahler, M. et al. Autoantibodies to domain 1 of beta 2 glycoprotein I determined using a novel chemiluminescence immunoassay demonstrate association with thrombosis in patients with antiphospholipid syndrome. Lupus 25, 911–916 (2016).

    CAS  Google Scholar 

  115. De Craemer, A. S., Musial, J. & Devreese, K. M. Role of anti-domain 1-β2 glycoprotein I antibodies in the diagnosis and risk stratification of antiphospholipid syndrome. J. Thromb. Haemost. 14, 1779–1787 (2016).

    CAS  Google Scholar 

  116. Pengo, V. et al. Antiphospholipid syndrome: antibodies to Domain 1 of β2-glycoprotein 1 correctly classify patients at risk. J. Thromb. Haemost. 13, 782–787 (2015).

    CAS  Google Scholar 

  117. Meneghel, L. et al. Detection of IgG anti-domain I β2 glycoprotein I antibodies by chemiluminescence immunoassay in primary antiphospholipid syndrome. Clin. Chim. Acta 446, 201–205 (2015).

    CAS  Google Scholar 

  118. Mondejar, R. et al. Role of antiphospholipid score and anti-β2-glycoprotein I domain I autoantibodies in the diagnosis of antiphospholipid syndrome. Clin. Chim. Acta 431, 174–178 (2014).

    CAS  Google Scholar 

  119. Zhang, S. et al. Evaluation of the diagnostic potential of antibodies to β2-glycoprotein 1 domain 1 in Chinese patients with antiphospholipid syndrome. Sci. Rep. 6, 23839 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Iwaniec, T., Kaczor, M. P., Celinska-Lowenhoff, M., Polanski, S. & Musial, J. Clinical significance of anti-domain 1 β2-glycoprotein I antibodies in antiphospholipid syndrome. Thromb. Res. 153, 90–94 (2017).

    CAS  Google Scholar 

  121. Sciascia, S. et al. Anti-prothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies and the risk of thrombosis in the antiphospholipid syndrome. A systematic review. Thromb. Haemost. 111, 354–364 (2014).

    CAS  Google Scholar 

  122. Cervera, R. et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 46, 1019–1027 (2002).

    Google Scholar 

  123. Ruiz-Irastorza, G., Hunt, B. J. & Khamashta, M. A. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum. 57, 1487–1495 (2007).

    Google Scholar 

  124. Khamashta, M., Taraborelli, M., Sciascia, S. & Tincani, A. Antiphospholipid syndrome. Best Pract. Res. Clin. Rheumatol. 30, 133–148 (2016).

    CAS  Google Scholar 

  125. Mekinian, A. L. et al. European registry of babies born to mothers with antiphospholipid syndrome. Ann. Rheum. Dis. 72, 217–222 (2013).

    Google Scholar 

  126. Fredi, M. et al. Multicenter evaluation of obstetric and maternal outcome in prospectively followed pregnant patients with confirmed positivity for antiphospholipid antibodies (aPL) [abstract]. Arthritis Rheumatol. 67 (suppl 10), 2530 (2015).

    Google Scholar 

  127. Yelnik, C. M. et al. Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPL-positive patients: validation of PROMISSE study results. Lupus Sci. Med. 3, e000131 (2016).

    PubMed  PubMed Central  Google Scholar 

  128. Carbillon, L., Uzan, M. & Uzan, S. Pregnancy, vascular tone, and maternal hemodynamics: a crucial adaptation. Obstet. Gynecol. Surv. 55, 574–581 (2000).

    CAS  Google Scholar 

  129. Le Thi Huong, D. W. et al. The second trimester Doppler ultrasound examination is the best predictor of late pregnancy outcome in systemic lupus erythematosus and/or the antiphospholipid syndrome. Rheumatology 45, 332–338 (2006).

    CAS  Google Scholar 

  130. Stone, S. H., B. J., Khamashta, M. A., Bewley, S. J. & Nelson-Piercy, C. Primary antiphospholipid syndrome in pregnancy: An analysis of outcome in a cohort of 33 women treated with a rigorous protocol. Editorial comment. Obstet. Gynecol. Surv. 60, 501–503 (2005).

    Google Scholar 

  131. Andreoli, L. et al. EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann. Rheum. Dis. 76, 476–485 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Rodrigues, C. E., Carvalho, J. F. & Shoenfeld, Y. Neurological manifestations of antiphospholipid syndrome. Eur. J. Clin. Invest. 40, 350–359 (2010).

    Google Scholar 

  133. Shoenfeld, Y. et al. Features associated with epilepsy in the antiphospholipid syndrome. J. Rheumatol 31, 1344–1348 (2004).

    Google Scholar 

  134. Soltesz, P., Szekanecz, Z., Kiss, E. & Shoenfeld, Y. Cardiac manifestations in antiphospholipid syndrome. Autoimmun. Rev. 6, 379–386 (2007).

    CAS  Google Scholar 

  135. Ziporen, L. et al. Libman-Sacks endocarditis in the antiphospholipid syndrome: immunopathologic findings in deformed heart valves. Lupus 5, 196–205 (1996).

    CAS  Google Scholar 

  136. Cervera, R. et al. Task Force on Catastrophic Antiphospholipid Syndrome (APS) and Non-criteria APS Manifestations (I): catastrophic APS, APS nephropathy and heart valve lesions. Lupus 20, 165–173 (2011).

    CAS  Google Scholar 

  137. Nesher, G., Ilany, J., Rosenmann, D. & Abraham, A. S. Valvular dysfunction in antiphospholipid syndrome: prevalence, clinical features, and treatment. Semin. Arthritis Rheum. 27, 27–35 (1997).

    CAS  Google Scholar 

  138. Shoenfeld, Y. et al. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation 112, 3337–3347 (2005).

    Google Scholar 

  139. Krause, I. et al. The association of thrombocytopenia with systemic manifestations in the antiphospholipid syndrome. Immunobiology 210, 749–754 (2005).

    CAS  Google Scholar 

  140. Rottem, M. et al. Autoimmune hemolytic anaemia in the antiphospholipid syndrome. Lupus 15, 473–477 (2006).

    CAS  Google Scholar 

  141. Stojanovich, L. et al. Pulmonary events in antiphospholipid syndrome: influence of antiphospholipid antibody type and levels. Scand. J. Rheumatol 41, 223–226 (2012).

    CAS  Google Scholar 

  142. Frances, C. et al. Dermatologic manifestations of the antiphospholipid syndrome: two hundred consecutive cases. Arthritis Rheum. 52, 1785–1793 (2005).

    Google Scholar 

  143. Frances, C. et al. Sneddon syndrome with or without antiphospholipid antibodies. A comparative study in 46 patients. Med. (Baltimore) 78, 209–219 (1999).

    CAS  Google Scholar 

  144. Toubi, E. & Shoenfeld, Y. Livedo reticularis as a criterion for antiphospholipid syndrome. Clin. Rev. Allergy Immunol. 32, 138–144 (2007).

    CAS  Google Scholar 

  145. Tektonidou, M. G. Identification and treatment of APS renal involvement. Lupus 23, 1276–1278 (2014).

    CAS  Google Scholar 

  146. Chaturvedi, S., Brandao, L., Geary, D. & Licht, C. Primary antiphospholipid syndrome presenting as renal vein thrombosis and membranous nephropathy. Pediatr. Nephrol. 26, 979–985 (2011).

    Google Scholar 

  147. Asherson, R. A. et al. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 12, 530–534 (2003).

    CAS  Google Scholar 

  148. Tektonidou, M. G., Ioannidis, J. P., Boki, K. A., Vlachoyiannopoulos, P. G. & Moutsopoulos, H. M. Prognostic factors and clustering of serious clinical outcomes in antiphospholipid syndrome. QJM 93, 523–530 (2000).

    CAS  Google Scholar 

  149. Danowski, A., de Azevedo, M. N., de Souza Papi, J. A. & Petri, M. Determinants of risk for venous and arterial thrombosis in primary antiphospholipid syndrome and in antiphospholipid syndrome with systemic lupus erythematosus. J. Rheumatol. 36, 1195–1199 (2009).

    CAS  Google Scholar 

  150. Erkan, D. et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody-positive individuals. Arthritis Rheum. 56, 2382–2391 (2007).

    CAS  Google Scholar 

  151. Arnaud, L. et al. Efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies: an international and collaborative meta-analysis. Autoimmun. Rev. 13, 281–291 (2014).

    CAS  Google Scholar 

  152. Antithrombotic Trialists, C. et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373, 1849–1860 (2009).

    Google Scholar 

  153. Wallace, D. J., Gudsoorkar, V. S., Weisman, M. H. & Venuturupalli, S. R. New insights into mechanisms of therapeutic effects of antimalarial agents in SLE. Nat. Rev. Rheumatol. 8, 522–533 (2012).

    CAS  Google Scholar 

  154. Bertolaccini, M. L. et al. Complement inhibition by hydroxychloroquine prevents placental and fetal brain abnormalities in antiphospholipid syndrome. J. Autoimmun. 75, 30–38 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. US National Library of Medicine. ClinicalTrials.govhttp://www.clinicaltrials.gov/ct2/show/NCT01784523 (2017).

  156. Erkan, D. et al. High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin. Arthritis Rheum. 44, 1466–1467 (2001).

    CAS  Google Scholar 

  157. Bertsias, G. et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann. Rheum. Dis. 67, 195–205 (2008).

    CAS  Google Scholar 

  158. Cohen, H., Efthymiou, M., Gates, C. & Isenberg, D. Direct oral anticoagulants for thromboprophylaxis in patients with antiphospholipid syndrome. Semin. Thromb. Hemost.https://doi.org/10.1055/s-0036-1597902 (2017).

    Google Scholar 

  159. Lim, W., Crowther, M. A. & Eikelboom, J. W. Management of antiphospholipid antibody syndrome: a systematic review. JAMA 295, 1050–1057 (2006).

    CAS  Google Scholar 

  160. Finazzi, G. et al. A randomized clinical trial of high-intensity warfarin versus conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J. Thromb. Haemost. 3, 848–853 (2005).

    CAS  Google Scholar 

  161. Crowther, M. A. et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N. Engl. J. Med. 349, 1133–1138 (2003).

    CAS  Google Scholar 

  162. Cohen, H. et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 3, e426–436 (2016). This is the first RCT of DOACs versus warfarin in APS.

    PubMed  PubMed Central  Google Scholar 

  163. Arachchillage, D. R. et al. Rivaroxaban limits complement activation compared with warfarin in antiphospholipid syndrome patients with venous thromboembolism. J. Thromb. Haemost. 14, 2177–2186 (2016).

    CAS  Google Scholar 

  164. US National Library of Medicine. ClinicalTrials.govhttp://www.clinicaltrials.gov/ct2/show/NCT02926170 (2016).

  165. US National Library of Medicine. ClinicalTrials.govhttp://www.clinicaltrials.gov/ct2/show/NCT02157272 (2017).

  166. US National Library of Medicine. ClinicalTrials.govhttp://www.clinicaltrials.gov/ct2/show/NCT02295475 (2017).

  167. Crowley, M. P., Cuadrado, M. J. & Hunt, B. J. Catastrophic antiphospholipid syndrome on switching from warfarin to rivaroxaban. Thromb. Res. 153, 37–39 (2017).

    CAS  Google Scholar 

  168. Schaefer, J. K. et al. Failure of dabigatran and rivaroxaban to prevent thromboembolism in antiphospholipid syndrome: a case series of three patients. Thromb. Haemost. 112, 947–950 (2014).

    Google Scholar 

  169. Win, K. & Rodgers, G. M. New oral anticoagulants may not be effective to prevent venous thromboembolism in patients with antiphospholipid syndrome. Am. J. Hematol. 89, 1017 (2014).

    CAS  Google Scholar 

  170. Levine, S. R. et al. Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA 291, 576–584 (2004).

    CAS  Google Scholar 

  171. Molad, Y. et al. Protective effect of hydroxychloroquine in systemic lupus erythematosus. Prospective long-term study of an Israeli cohort. Lupus 11, 356–361 (2002).

    CAS  Google Scholar 

  172. Ruiz-Irastorza, G. et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus 15, 577–583 (2006). This study emphasizes the antithrombotic effect of antimalarials in individuals with SLE.

    CAS  Google Scholar 

  173. Schmidt-Tanguy, A. et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J. Thromb. Haemost. 11, 1927–1929 (2013).

    CAS  Google Scholar 

  174. Schreiber, K. et al. The effect of hydroxychloroquine on haemostasis, complement, inflammation and angiogenesis in patients with antiphospholipid antibodies. Rheumatologyhttps://doi.org/10.1093/rheumatology/kex378 (2017). This paper suggests that hydroxychloroquine reduces soluble tissue factor in patients with APS.

    Google Scholar 

  175. Cervera, R. & Group, C. R. P. Catastrophic antiphospholipid syndrome (CAPS): update from the ‘CAPS Registry’. Lupus 19, 412–418 (2010).

    CAS  Google Scholar 

  176. Cervera, R. et al. Task Force on Catastrophic Antiphospholipid Syndrome (APS) and Non-criteria APS Manifestations (II): thrombocytopenia and skin manifestations. Lupus 20, 174–181 (2011).

    CAS  Google Scholar 

  177. Bazzan, M. et al. Patients with antiphosholipid syndrome and thrombotic recurrences: A real world observation (the Piedmont cohort study). Lupus 25, 479–485 (2016).

    CAS  Google Scholar 

  178. Mak, A., Cheung, M. W., Cheak, A. A. & Ho, R. C. Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology 49, 281–288 (2010).

    CAS  Google Scholar 

  179. Bramham, K. et al. Pregnancy outcome in different clinical phenotypes of antiphospholipid syndrome. Lupus 19, 58–64 (2010).

    CAS  Google Scholar 

  180. Fischer-Betz, R. S., C., Brinks, R. & Schneider, M. Pregnancy outcome in patients with antiphospholipid syndrome after cerebral ischaemic events: an observational study. Lupus 21, 1183–1189 (2012).

    CAS  Google Scholar 

  181. Sliwa, K. et al. Pulmonary hypertension and pregnancy outcomes: data from the Registry Of Pregnancy and Cardiac Disease (ROPAC) of the European Society of Cardiology. Eur. J. Heart Fail. 18, 1119–1128 (2016).

    Google Scholar 

  182. Bouvier, S. et al. Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study. Blood 123, 404–413 (2014).

    CAS  Google Scholar 

  183. Rai, R., Cohen, H., Dave, M. & Regan, L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 314, 253–257 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Kutteh, W. H. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am. J. Obstet. Gynecol. 174, 1584–1589 (1996).

    CAS  Google Scholar 

  185. Farquharson, R. G., Quenby, S. & Greaves, M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet. Gynecol. 100, 408–413 (2002).

    CAS  Google Scholar 

  186. Laskin, C. A. S. et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial. J. Rheumatol. 36, 279–287 (2009).

    CAS  Google Scholar 

  187. Noble, L. S. K., W. H., Lashey, N., Franklin, R. D. & Herrada, J. Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin. Fertil. Steril. 83, 684–690 (2005).

    CAS  Google Scholar 

  188. Fouda, U. M. et al. Enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome. Int. J. Gynaecol. Obstet. 112, 211–215 (2011).

    CAS  Google Scholar 

  189. Empson, M., Lassere, M., Craig, J. & Scott, J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev. 2, CD002859 (2005).

    Google Scholar 

  190. National Collaborating Centre for Women's and Children's Health (UK). Hypertension in Pregnancy: The Management of Hypertensive Disorders During Pregnancy (RCOG Press, 2010).

  191. Henderson, J. T. et al. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann. Intern. Med. 160, 695–703 (2014).

    Google Scholar 

  192. Lausman, A., Kingdom, J. & Maternal Fetal Medicine, C. Intrauterine growth restriction: screening, diagnosis, and management. J. Obstet. Gynaecol. Can. 35, 741–748 (2013).

    Google Scholar 

  193. Bramham, K., Thomas, M., Nelson-Piercy, C., Khamashta, M. & Hunt, B. J. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood 117, 6948–6951 (2011).

    CAS  Google Scholar 

  194. Triolo, G. et al. Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies. Arthritis Rheum. 48, 728–731 (2003).

    CAS  Google Scholar 

  195. Branch, D. W. et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. Am. J. Obstet. Gynecol. 182, 122–127 (2000).

    CAS  Google Scholar 

  196. Tincani, A., Scarsi, M., Franceschini, F. & Cattaneo, R. Intravenous immunoglobulin in pregnancy: a chance for patients with an autoimmune disease. Isr. Med. Assoc. J. 9, 553–554 (2007).

    Google Scholar 

  197. Lefkou, E. et al. Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy. J. Clin. Invest. 126, 2933–2940 (2016). This case-control study highlights the potential role of pravastatin in refractory obstetrical APS.

    PubMed  PubMed Central  Google Scholar 

  198. Sciascia, S. et al. The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies. Am. J. Obstet. Gynecol. 214, 273.e1–273.e8 (2016). This paper highlights the possible role of hydroxychloroquine in improving antiphospholipid antibody-related pregnancy outcomes.

    CAS  Google Scholar 

  199. Mekinian, A. et al. The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: data from a European multicenter retrospective study. Autoimmun. Rev. 14, 498–502 (2015).

    CAS  Google Scholar 

  200. Schreiber, K. et al. HYdroxychloroquine to improve pregnancy outcome in women with AnTIphospholipid Antibodies (HYPATIA) protocol: a multinational randomized controlled trial of hydroxychloroquine versus placebo in addition to standard treatment in pregnant women with antiphospholipid syndrome or antibodies. Semin. Thromb. Hemost. 43, 562–571 (2017).

    CAS  Google Scholar 

  201. van Hoorn, M. E. et al. 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. 197, 168–173 (2016).

    CAS  Google Scholar 

  202. Rodger, M. A. et al. Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial. Lancet 384, 1673–1683 (2014).

    CAS  Google Scholar 

  203. van Korlaar, I. M. et al. The impact of venous thrombosis on quality of life. Thromb. Res. 114, 11–18 (2004).

    CAS  Google Scholar 

  204. Balitsky, A. K. et al. Thrombovascular events affect quality of life in patients with systemic lupus erythematosus. J. Rheumatol 38, 1017–1019 (2011).

    Google Scholar 

  205. Georgopoulou, S., Efraimidou, S., MacLennan, S. J., Ibrahim, F. & Cox, T. Antiphospholipid (Hughes) syndrome: description of population and health-related quality of life (HRQoL) using the SF-36. Lupus 24, 174–179 (2015).

    CAS  Google Scholar 

  206. Georgopoulou, S., Efraimidou, S., MacLennan, S. J., Ibrahim, F. & Cox, T. The relationship between social support and health-related quality of life in patients with antiphospholipid (hughes) syndrome. Mod. Rheumatol.https://doi.org/10.1080/14397595.2017.1317319 (2017).

    Google Scholar 

  207. Alarcon-Segovia, D., Perez-Vazquez, M. E., Villa, A. R., Drenkard, C. & Cabiedes, J. Preliminary classification criteria for the antiphospholipid syndrome within systemic lupus erythematosus. Semin. Arthritis Rheum. 21, 275–286 (1992).

    CAS  Google Scholar 

  208. Erkan, D. & Lockshin, M. D. Non-criteria manifestations of antiphospholipid syndrome. Lupus 19, 424–427 (2010).

    CAS  Google Scholar 

  209. Abreu, M. M. et al. The relevance of “non-criteria” clinical manifestations of antiphospholipid syndrome: 14th International Congress on Antiphospholipid Antibodies Technical Task Force Report on Antiphospholipid Syndrome Clinical Features. Autoimmun. Rev. 14, 401–414 (2015).

    Google Scholar 

  210. Sciascia, S., Bertolaccini, M. L., Roccatello, D. & Khamashta, M. A. Independent validation of the antiphospholipid score for the diagnosis of antiphospholipid syndrome. Ann. Rheum. Dis. 72, 142–143 (2013). This paper outlines the development of the GAPSS.

    Google Scholar 

  211. Sciascia, S. S. et al. The global anti-phospholipid syndrome score in primary APS. Rheumatology 54, 134–138 (2015).

    CAS  Google Scholar 

  212. Sciascia, S. et al. Thrombotic risk assessment in systemic lupus erythematosus: validation of the global antiphospholipid syndrome score in a prospective cohort. Arthritis Care Res. 66, 1915–1920 (2014).

    Google Scholar 

  213. Zuily, S. et al. Validity of the global anti-phospholipid syndrome score to predict thrombosis: a prospective multicentre cohort study. Rheumatology 54, 2071–2075 (2015).

    CAS  Google Scholar 

  214. Oku, K. et al. An independent validation of the Global Anti-Phospholipid Syndrome Score in a Japanese cohort of patients with autoimmune diseases. Lupus 24, 774–775 (2015).

    CAS  Google Scholar 

  215. Glynn, R. J. et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N. Engl. J. Med. 360, 1851–1861 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Erkan, D. et al. A prospective open-label pilot study of fluvastatin on proinflammatory and prothrombotic biomarkers in antiphospholipid antibody positive patients. Ann. Rheum. Dis. 73, 1176–1180 (2014).

    CAS  Google Scholar 

  217. Unlu, O. & Erkan, D. Catastrophic antiphospholipid syndrome: candidate therapies for a potentially lethal disease. Annu. Rev. Med. 68, 287–296 (2017).

    CAS  Google Scholar 

  218. Leone, A. et al. Autologous hematopoietic stem cell transplantation in Systemic Lupus Erythematosus and antiphospholipid syndrome: a systematic review. Autoimmun. Rev. 16, 469–477 (2017).

    Google Scholar 

  219. Abrahams, V. M., Chamley, L. W. & Salmon, J. E. Emerging treatment models in rheumatology: antiphospholipid syndrome and pregnancy: pathogenesis to translation. Arthritis Rheumatol. 69, 1710–1721 (2017).

    PubMed  PubMed Central  Google Scholar 

  220. Petri, M. Epidemiology of the antiphospholipid antibody syndrome. J. Autoimmun. 15, 145–151 (2000).

    CAS  Google Scholar 

  221. Deeb, A., Hamdoun, S. & Dababo, K. Prevalence of antiphospholipid antibodies in Syrian patients with thrombosis. Iran. J. Immunol. 6, 154–159 (2009).

    Google Scholar 

  222. 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).

    CAS  Google Scholar 

  223. Ginsburg, K. S. et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann. Intern. Med. 117, 997–1002 (1992).

    CAS  Google Scholar 

  224. de Groot, P. G. et al. Lupus anticoagulants and the risk of a first episode of deep venous thrombosis. J. Thromb. Haemost. 3, 1993–1997 (2005).

    CAS  Google Scholar 

  225. Meroni, P. L. et al. Anti-beta 2 glycoprotein I antibodies and the risk of myocardial infarction in young premenopausal women. J. Thromb. Haemost. 5, 2421–2428 (2007).

    CAS  Google Scholar 

  226. [No authors listed.] Anticardiolipin antibodies and the risk of recurrent thrombo-occlusive events and death. The Antiphospholipid Antibodies and Stroke Study Group (APASS). Neurology 48, 91–94 (1997).

  227. Sciascia, S. et al. The estimated frequency of antiphospholipid antibodies in young adults with cerebrovascular events: a systematic review. Ann. Rheum. Dis. 74, 2028–2033 (2015).

    CAS  Google Scholar 

  228. Opatrny, L., David, M., Kahn, S. R., Shrier, I. & Rey, E. Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis. J. Rheumatol 33, 2214–2221 (2006).

    CAS  Google Scholar 

  229. Kumar, K. S. J., A., Prakash, M. S., Rani, H. S. & Reddy, P. P. Beta2-glycoprotein I dependent anticardiolipin antibodies and lupus anticoagulant in patients with recurrent pregnancy loss. J. Postgrad. Med. 48, 5–10 (2002).

    CAS  Google Scholar 

  230. Mtiraoui, N. et al. Prevalence of antiphospholipid antibodies, factor V G1691A (Leiden) and prothrombin G20210A mutations in early and late recurrent pregnancy loss. Eur. J. Obstet. Gynecol. Reprod. Biol. 119, 164–170 (2005).

    CAS  Google Scholar 

  231. Rolnik, D. L. et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N. Engl. J. Med. 377, 613–622 (2017).

    CAS  Google Scholar 

  232. Rey, E. et al. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. J. Thromb. Haemost. 7, 58–64 (2009).

    CAS  Google Scholar 

  233. Flint, J. et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding — part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology 55, 1693–1697 (2016).

    CAS  Google Scholar 

  234. Flint, J. et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding — part II: analgesics and other drugs used in rheumatology practice. Rheumatology 55, 1698–1702 (2016).

    Google Scholar 

  235. Royal College of Obstetricians and Gynaecologists. Reducing the Risk of Venous Thromboembolism during Pregnancy and the Puerperium. Green-top Guideline No. 37a (Royal College of Obstetricians and Gynaecologists, 2015).

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Acknowledgements

The authors thank the Guy's and St Thomas’ Charity for their support of K.S.

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Authors and Affiliations

  1. Thrombosis & Thrombophilia, Guy's and St Thomas’ Hospital NHS Foundation Trust, Westminster Bridge Road, London, SE1 7EH, UK

    Karen Schreiber & Beverley J. Hunt

  2. Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Karen Schreiber & Soren Jacobsen

  3. Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases and SCDU Nephrology and Dialysis, University of Turin, Turin, Italy

    Savino Sciascia

  4. Synapse Research Institute, Maastricht, The Netherlands

    Philip G. de Groot

  5. Department of Clinical Chemistry, Coagulation Laboratory, Microbiology and Immunology, Ghent University Hospital, Ghent, Belgium

    Katrien Devreese

  6. Department of Internal Medicine, Autoimmune Diseases Research Unit, BioCruces Health Research Institute, Hospital Universitario Cruces, University of the Basque Country, Bizkaia, Spain

    Guillermo Ruiz-Irastorza

  7. Department of Medicine, Hospital for Special Surgery, Weill Cornell Medicine, New York, New York, USA

    Jane E. Salmon

  8. Zabuldowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Israel

    Yehuda Shoenfeld & Ora Shovman

  9. Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Yehuda Shoenfeld

  10. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ora Shovman

Authors
  1. Karen Schreiber
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  2. Savino Sciascia
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  3. Philip G. de Groot
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  4. Katrien Devreese
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  5. Soren Jacobsen
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  6. Guillermo Ruiz-Irastorza
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  7. Jane E. Salmon
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  8. Yehuda Shoenfeld
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  9. Ora Shovman
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  10. Beverley J. Hunt
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Contributions

Introduction (G.R.-I.); Epidemiology (S.S.); Mechanisms/pathophysiology (J.E.S. and P.G.d.G.); Diagnosis, screening and prevention (K.D., Y.S. and O.S.); Management (K.S. and B.J.H.); Quality of life (K.S. and S.S.); Outlook (S.J.); Overview of Primer (K.S. and B.J.H.).

Corresponding author

Correspondence to Beverley J. Hunt.

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Competing interests

J.E.S. has received an investigator-initiated grant from UCB. The other authors declare no competing interests.

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Schreiber, K., Sciascia, S., de Groot, P. et al. Antiphospholipid syndrome. Nat Rev Dis Primers 4, 17103 (2018). https://doi.org/10.1038/nrdp.2017.103

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