Clinical and Experimental Medicine

, Volume 17, Issue 3, pp 257–267 | Cite as

The antiphospholipid syndrome: from pathophysiology to treatment

  • Simone Negrini
  • Fabrizio Pappalardo
  • Giuseppe Murdaca
  • Francesco Indiveri
  • Francesco Puppo
Review Article

Abstract

Antiphospholipid antibody syndrome (APS) is an autoimmune acquired thrombophilia characterized by recurrent thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). APS can be primary, if it occurs in the absence of any underlying disease, or secondary, if it is associated with another autoimmune disorder, most commonly systemic lupus erythematosus. The exact pathogenetic mechanism of APS is unknown, but different, not mutually exclusive, models have been proposed to explain how anti-PL autoantibodies might lead to thrombosis and pregnancy morbidity. Diagnosis of APS requires that a patient has both a clinical manifestation (arterial or venous thrombosis and/or pregnancy morbidity) and persistently positive aPL, but the clinical spectrum of the disease encompasses additional manifestations which may affect every organ and cannot be explained exclusively by a prothrombotic state. Treatment for aPL-positive patients is based on the patient’s clinical status, presence of an underlying autoimmune disease, and history of thrombotic events. In case of aPL positivity without previous thrombotic events, the treatment is mainly focused on reduction of additional vascular risk factors, while treatment of patients with definite APS is based on long-term anticoagulation. Pregnancy complications are usually managed with low-dose aspirin in association with low molecular weight heparin. Refractory forms of APS could benefit from adding hydroxychloroquine and/or intravenous immunoglobulin to anticoagulation therapy. Promising novel treatments include anti-B cell monoclonal antibodies, new-generation anticoagulants, and complement cascade inhibitors. The objective of this review paper is to summarize the recent literature on APS from pathogenesis to current therapeutic options.

Keywords

Antiphospholipid syndrome Lupus anticoagulant Anticardiolipin antibody Anti-β2 glycoprotein-1 antibody Pregnancy morbidity Thrombosis 

References

  1. 1.
    Hughes GR. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J (Clin Res Ed). 1983;287(6399):1088–9.CrossRefGoogle Scholar
  2. 2.
    Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002;46(4):1019–27.PubMedCrossRefGoogle Scholar
  3. 3.
    Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295–306.PubMedCrossRefGoogle Scholar
  4. 4.
    Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA. Antiphospholipid syndrome. Lancet. 2010;376(9751):1498–509.PubMedCrossRefGoogle Scholar
  5. 5.
    Asherson RA. The catastrophic antiphospholipid syndrome. J Rheumatol. 1992;19(4):508–12.PubMedGoogle Scholar
  6. 6.
    Asherson RA, Bucciarelli S, Gómez-Puerta JA, Cervera R. History, classification, and subsets of the antiphospholipid syndrome. In: Cervera R, Reverter JC, Khamashta M, editors. Handbook of systemic autoimmune diseases, vol. 10. Elsevier; 2009. p. 1–11.Google Scholar
  7. 7.
    Hughes GR, Khamashta MA. Seronegative antiphospholipid syndrome. Ann Rheum Dis. 2003;62(12):1127.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Mackworth-Young CG, Loizou S, Walport MJ. Primary antiphospholipid syndrome: features of patients with raised anticardiolipin antibodies and no other disorder. Ann Rheum Dis. 1989;48(5):362–7.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Asherson RA. A “primary” antiphospholipid syndrome? J Rheumatol. 1988;15(12):1742–6.PubMedGoogle Scholar
  10. 10.
    Petri M. Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun. 2000;15(2):145–51.PubMedCrossRefGoogle Scholar
  11. 11.
    Cervera R, Asherson RA, Acevedo ML, et al. Antiphospholipid syndrome associated with infections: clinical and microbiological characteristics of 100 patients. Ann Rheum Dis. 2004;63(10):1312–7.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Gomez-Puerta JA, Cervera R, Espinosa G, et al. Antiphospholipid antibodies associated with malignancies: clinical and pathological characteristics of 120 patients. Semin Arthritis Rheum. 2006;35(5):322–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Fields RA, Toubbeh H, Searles RP, Bankhurst AD. The prevalence of anticardiolipin antibodies in a healthy elderly population and its association with antinuclear antibodies. J Rheumatol. 1989;16(5):623–5.PubMedGoogle Scholar
  14. 14.
    Mehrani T, Petri M. Epidemiology of the antiphospholipid syndrome. In: Cervera R, Reverter JC, Khamashta M, editors. Handbook of systemic autoimmune diseases, vol. 10. Elsevier; 2009. p. 13–34Google Scholar
  15. 15.
    Biggioggero M, Meroni PL. The geoepidemiology of the antiphospholipid antibody syndrome. Autoimmun Rev. 2010;9(5):A299–304.PubMedCrossRefGoogle Scholar
  16. 16.
    Andreoli L, Chighizola CB, Banzato A, Pons-Estel GJ, Ramire de Jesus G, Erkan D. 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 (Hoboken). 2013;65(11):1869–73.CrossRefGoogle Scholar
  17. 17.
    Yetman DL, Kutteh WH. Antiphospholipid antibody panels and recurrent pregnancy loss: prevalence of anticardiolipin antibodies compared with other antiphospholipid antibodies. Fertil Steril. 1996;66(4):540–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Clark EA, Silver RM, Branch DW. Do antiphospholipid antibodies cause preeclampsia and HELLP syndrome? Curr Rheumatol Rep. 2007;9(3):219–25.PubMedCrossRefGoogle Scholar
  19. 19.
    Mok CC, Tang SS, To CH, Petri M. Incidence and risk factors of thromboembolism in systemic lupus erythematosus: a comparison of three ethnic groups. Arthritis Rheum. 2005;52(9):2774–82.PubMedCrossRefGoogle Scholar
  20. 20.
    Tubach F, Hayem G, Marchand JL, et al. IgG anti-beta2-glycoprotein I antibodies in adult patients with systemic lupus erythematosus: prevalence and diagnostic value for the antiphospholipid syndrome. J Rheumatol. 2000;27(6):1437–43.PubMedGoogle Scholar
  21. 21.
    Sebastiani GD, Passiu G, Galeazzi M, Porzio F, Carcassi U. Prevalence and clinical associations of anticardiolipin antibodies in systemic lupus erythematosus: a prospective study. Clin Rheumatol. 1991;10(3):289–93.PubMedCrossRefGoogle Scholar
  22. 22.
    Rai R, Swetha T. Association of anti-phospholipid antibodies with connective tissue diseases. Indian Dermatol Online J. 2015;6(2):89–91.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Tektonidou MG, Laskari K, Panagiotakos DB, Moutsopoulos HM. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Rheum. 2009;61(1):29–36.PubMedCrossRefGoogle Scholar
  24. 24.
    Habe K, Wada H, Matsumoto T, et al. Presence of antiphospholipid antibodies as a risk factor for thrombotic events in patients with connective tissue diseases and idiopathic thrombocytopenic purpura. Intern Med. 2016;55(6):589–95.PubMedCrossRefGoogle Scholar
  25. 25.
    Uthman IW, Gharavi AE. Viral infections and antiphospholipid antibodies. Semin Arthritis Rheum. 2002;31(4):256–63.PubMedCrossRefGoogle Scholar
  26. 26.
    Sene D, Piette JC, Cacoub P. Antiphospholipid antibodies, antiphospholipid syndrome and viral infections. Rev Med Intern. 2009;30(2):135–41.CrossRefGoogle Scholar
  27. 27.
    Gharavi EE, Chaimovich H, Cucurull E, et al. Induction of antiphospholipid antibodies by immunization with synthetic viral and bacterial peptides. Lupus. 1999;8(6):449–55.PubMedCrossRefGoogle Scholar
  28. 28.
    Galli M, Barbui T, Zwaal RF, Comfurius P, Bevers EM. Antiphospholipid antibodies: involvement of protein cofactors. Haematologica. 1993;78(1):1–4.PubMedGoogle Scholar
  29. 29.
    Nayfe R, Uthman I, Aoun J, Saad Aldin E, Merashli M, Khamashta MA. Seronegative antiphospholipid syndrome. Rheumatology (Oxford). 2013;52(8):1358–67.CrossRefGoogle Scholar
  30. 30.
    Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RF. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost. 1991;66(6):629–32.PubMedGoogle Scholar
  31. 31.
    Galli M, Comfurius P, Maassen C, et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet. 1990;335(8705):1544–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Oosting JD, Derksen RH, Bobbink IW, Hackeng TM, Bouma BN, de Groot PG. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism? Blood. 1993;81(10):2618–25.PubMedGoogle Scholar
  33. 33.
    Arvieux J, Darnige L, Caron C, Reber G, Bensa JC, Colomb MG. Development of an ELISA for autoantibodies to prothrombin showing their prevalence in patients with lupus anticoagulants. Thromb Haemost. 1995;74(4):1120–5.PubMedGoogle Scholar
  34. 34.
    Sorice M, Arcieri P, Griggi T, et al. Inhibition of protein S by autoantibodies in patients with acquired protein S deficiency. Thromb Haemost. 1996;75(4):555–9.PubMedGoogle Scholar
  35. 35.
    Kaburaki J, Kuwana M, Yamamoto M, Kawai S, Ikeda Y. Clinical significance of anti-annexin V antibodies in patients with systemic lupus erythematosus. Am J Hematol. 1997;54(3):209–13.PubMedCrossRefGoogle Scholar
  36. 36.
    Salle V, Maziere JC, Smail A, et al. Anti-annexin II antibodies in systemic autoimmune diseases and antiphospholipid syndrome. J Clin Immunol. 2008;28(4):291–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Hunt J, Krilis S. The fifth domain of beta 2-glycoprotein I contains a phospholipid binding site (Cys281–Cys288) and a region recognized by anticardiolipin antibodies. J Immunol. 1994;152(2):653–9.PubMedGoogle Scholar
  38. 38.
    Amengual O, Atsumi T, Khamashta MA, Hughes GR. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome. Thromb Haemost. 1998;79(2):276–81.PubMedGoogle Scholar
  39. 39.
    Pierangeli SS, Chen PP, Raschi E, et al. Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms. Semin Thromb Hemost. 2008;34(3):236–50.PubMedCrossRefGoogle Scholar
  40. 40.
    Jimenez S, Tassies D, Espinosa G, et al. Double heterozygosity polymorphisms for platelet glycoproteins Ia/IIa and IIb/IIIa increases arterial thrombosis and arteriosclerosis in patients with the antiphospholipid syndrome or with systemic lupus erythematosus. Ann Rheum Dis. 2008;67(6):835–40.PubMedCrossRefGoogle Scholar
  41. 41.
    Robbins DL, Leung S, Miller-Blair DJ, Ziboh V. Effect of anticardiolipin/beta2-glycoprotein I complexes on production of thromboxane A2 by platelets from patients with the antiphospholipid syndrome. J Rheumatol. 1998;25(1):51–6.PubMedGoogle Scholar
  42. 42.
    Sikara MP, Routsias JG, Samiotaki M, Panayotou G, Moutsopoulos HM, Vlachoyiannopoulos PG. {beta}2 Glycoprotein I ({beta}2GPI) binds platelet factor 4 (PF4): implications for the pathogenesis of antiphospholipid syndrome. Blood. 2010;115(3):713–23.PubMedCrossRefGoogle Scholar
  43. 43.
    Zucker MB, Katz IR. Platelet factor 4: production, structure, and physiologic and immunologic action. Proc Soc Exp Biol Med. 1991;198(2):693–702.PubMedCrossRefGoogle Scholar
  44. 44.
    Rand JH, Wu XX, Andree HA, et al. Pregnancy loss in the antiphospholipid-antibody syndrome—a possible thrombogenic mechanism. N Engl J Med. 1997;337(3):154–60.PubMedCrossRefGoogle Scholar
  45. 45.
    Rand JH, Wu XX, Quinn AS, et al. Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug. Blood. 2010;115(11):2292–9.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Pierangeli SS, Girardi G, Vega-Ostertag M, Liu X, Espinola RG, Salmon J. Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia. Arthritis Rheum. 2005;52(7):2120–4.PubMedCrossRefGoogle Scholar
  47. 47.
    Girardi G, Berman J, Redecha P, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest. 2003;112(11):1644–54.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Versteeg HH, Ruf W. Thiol pathways in the regulation of tissue factor prothrombotic activity. Curr Opin Hematol. 2011;18(5):343–8.PubMedCrossRefGoogle Scholar
  49. 49.
    de Groot PG, Derksen RH. Pathophysiology of the antiphospholipid syndrome. J Thromb Haemost. 2005;3(8):1854–60.PubMedCrossRefGoogle Scholar
  50. 50.
    Cesarman-Maus G, Rios-Luna NP, Deora AB, et al. Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid syndrome. Blood. 2006;107(11):4375–82.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Meroni PL, Tincani A, Sepp N, et al. Endothelium and the brain in CNS lupus. Lupus. 2003;12(12):919–28.PubMedCrossRefGoogle Scholar
  52. 52.
    Di Simone N, Meroni PL, de Papa N, et al. Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered beta2-glycoprotein I. Arthritis Rheum. 2000;43(1):140–50.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Di Simone N, Raschi E, Testoni C, et al. Pathogenic role of anti-beta 2-glycoprotein I antibodies in antiphospholipid associated fetal loss: characterisation of beta 2-glycoprotein I binding to trophoblast cells and functional effects of anti-beta 2-glycoprotein I antibodies in vitro. Ann Rheum Dis. 2005;64(3):462–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Barteneva NS, Fasler-Kan E, Bernimoulin M, et al. Circulating microparticles: square the circle. BMC Cell Biol. 2013;14:23.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    van der Pol E, Boing AN, Harrison P, Sturk A, Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev. 2012;64(3):676–705.PubMedCrossRefGoogle Scholar
  56. 56.
    Beyer C, Pisetsky DS. The role of microparticles in the pathogenesis of rheumatic diseases. Nat Rev Rheumatol. 2010;6(1):21–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Horstman LL, Jy W, Minagar A, et al. Cell-derived microparticles and exosomes in neuroinflammatory disorders. Int Rev Neurobiol. 2007;79:227–68.PubMedCrossRefGoogle Scholar
  58. 58.
    Dignat-George F, Camoin-Jau L, Sabatier F, et al. Endothelial microparticles: a potential contribution to the thrombotic complications of the antiphospholipid syndrome. Thromb Haemost. 2004;91(4):667–73.PubMedGoogle Scholar
  59. 59.
    Pericleous C, Clarke LA, Brogan PA, et al. Endothelial microparticle release is stimulated in vitro by purified IgG from patients with the antiphospholipid syndrome. Thromb Haemost. 2013;109(1):72–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Nagahama M, Nomura S, Kanazawa S, Ozaki Y, Kagawa H, Fukuhara S. Significance of anti-oxidized LDL antibody and monocyte-derived microparticles in anti-phospholipid antibody syndrome. Autoimmunity. 2003;36(3):125–31.PubMedCrossRefGoogle Scholar
  61. 61.
    Pereira J, Alfaro G, Goycoolea M, et al. Circulating platelet-derived microparticles in systemic lupus erythematosus. Association with increased thrombin generation and procoagulant state. Thromb Haemost. 2006;95(1):94–9.PubMedGoogle Scholar
  62. 62.
    Vikerfors A, Mobarrez F, Bremme K, et al. Studies of microparticles in patients with the antiphospholipid syndrome (APS). Lupus. 2012;21(7):802–5.PubMedCrossRefGoogle Scholar
  63. 63.
    Niccolai E, Emmi G, Squatrito D, et al. Microparticles: bridging the gap between autoimmunity and thrombosis. Semin Thromb Hemost. 2015;41(4):413–22.PubMedCrossRefGoogle Scholar
  64. 64.
    Gysler SM, Mulla MJ, Guerra M et al. Antiphospholipid antibody-induced miR-146a-3p drives trophoblast interleukin-8 secretion through activation of Toll-like receptor 8. Mol Hum Reprod. 2016. doi:10.1093/molehr/gaw027
  65. 65.
    Pengo V, Bison E, Denas G, Jose SP, Bracco A, Banzato A. The paradox of the lupus anticoagulant: history and perspectives. Semin Thromb Hemost. 2014;40(8):860–5.PubMedCrossRefGoogle Scholar
  66. 66.
    Bertolaccini ML, Hughes GR, Khamashta MA. Revisiting antiphospholipid antibodies: from targeting phospholipids to phospholipid binding proteins. Clin Lab. 2004;50(11–12):653–65.PubMedGoogle Scholar
  67. 67.
    de Laat B, Pengo V, Pabinger I, et al. The association between circulating antibodies against domain I of beta2-glycoprotein I and thrombosis: an international multicenter study. J Thromb Haemost. 2009;7(11):1767–73.PubMedCrossRefGoogle Scholar
  68. 68.
    Meroni PL, Chighizola CB, Rovelli F, Gerosa M. Antiphospholipid syndrome in 2014: more clinical manifestations, novel pathogenic players and emerging biomarkers. Arthritis Res Ther. 2014;16(2):209.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Mirrakhimov AE, Hill NS. Primary antiphospholipid syndrome and pulmonary hypertension. Curr Pharm Des. 2014;20(4):545–51.PubMedCrossRefGoogle Scholar
  70. 70.
    Ruiz-Irastorza G, Hunt BJ, Khamashta MA. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum. 2007;57(8):1487–95.PubMedCrossRefGoogle Scholar
  71. 71.
    Pengo V, Ruffatti A, Legnani C, et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood. 2011;118(17):4714–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Pengo V, Ruffatti A, Legnani C, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost. 2010;8(2):237–42.PubMedCrossRefGoogle Scholar
  73. 73.
    Nalli C, Andreoli L, Casu C, Tincani A. Management of recurrent thrombosis in antiphospholipid syndrome. Curr Rheumatol Rep. 2014;16(3):405.PubMedCrossRefGoogle Scholar
  74. 74.
    Cohen D, Berger SP, Steup-Beekman GM, Bloemenkamp KW, Bajema IM. Diagnosis and management of the antiphospholipid syndrome. BMJ. 2010;340:c2541.PubMedCrossRefGoogle Scholar
  75. 75.
    Diz-Kucukkaya R, Hacihanefioglu A, Yenerel M, et al. Antiphospholipid antibodies and antiphospholipid syndrome in patients presenting with immune thrombocytopenic purpura: a prospective cohort study. Blood. 2001;98(6):1760–4.PubMedCrossRefGoogle Scholar
  76. 76.
    Uthman I, Godeau B, Taher A, Khamashta M. The hematologic manifestations of the antiphospholipid syndrome. Blood Rev. 2008;22(4):187–94.PubMedCrossRefGoogle Scholar
  77. 77.
    Emmi G, Silvestri E, Squatrito D, et al. An approach to differential diagnosis of antiphospholipid antibody syndrome and related conditions. Sci World J. 2014;2014:341342.Google Scholar
  78. 78.
    Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168–86.PubMedCrossRefGoogle Scholar
  79. 79.
    Rottem M, Krause I, Fraser A, Stojanovich L, Rovensky J, Shoenfeld Y. Autoimmune hemolytic anaemia in the antiphospholipid syndrome. Lupus. 2006;15(7):473–7.PubMedCrossRefGoogle Scholar
  80. 80.
    Sthoeger Z, Sthoeger D, Green L, Geltner D. The role of anticardiolipin autoantibodies in the pathogenesis of autoimmune hemolytic anemia in systemic lupus erythematosus. J Rheumatol. 1993;20(12):2058–61.PubMedGoogle Scholar
  81. 81.
    Frances C, Niang S, Laffitte E, Pelletier F, Costedoat N, Piette JC. Dermatologic manifestations of the antiphospholipid syndrome: two hundred consecutive cases. Arthritis Rheum. 2005;52(6):1785–93.PubMedCrossRefGoogle Scholar
  82. 82.
    Pinto-Almeida T, Caetano M, Sanches M, Selores M. Cutaneous manifestations of antiphospholipid syndrome: a review of the clinical features, diagnosis and management. Acta Reumatol Port. 2013;38(1):10–8.PubMedGoogle Scholar
  83. 83.
    Hojnik M, George J, Ziporen L, Shoenfeld Y. Heart valve involvement (Libman–Sacks endocarditis) in the antiphospholipid syndrome. Circulation. 1996;93(8):1579–87.PubMedCrossRefGoogle Scholar
  84. 84.
    Lee JL, Naguwa SM, Cheema GS, Gershwin ME. Revisiting Libman–Sacks endocarditis: a historical review and update. Clin Rev Allergy Immunol. 2009;36(2–3):126–30.PubMedCrossRefGoogle Scholar
  85. 85.
    Kanakis MA, Kapsimali V, Vaiopoulos AG, Vaiopoulos GA, Samarkos M. The lung in the spectrum of antiphospholipid syndrome. Clin Exp Rheumatol. 2013;31(3):452–7.PubMedGoogle Scholar
  86. 86.
    Barnini T, Silvestri E, Emmi G, et al. Pulmonary fibrosis and lymphocytic alveolitis associated with triple antiphospholipid antibody positivity: a diagnostic puzzle. Clin Exp Rheumatol. 2012;30(5):806.PubMedGoogle Scholar
  87. 87.
    Rodrigues CE, Carvalho JF, Shoenfeld Y. Neurological manifestations of antiphospholipid syndrome. Eur J Clin Invest. 2010;40(4):350–9.PubMedCrossRefGoogle Scholar
  88. 88.
    Katzav A, Chapman J, Shoenfeld Y. CNS dysfunction in the antiphospholipid syndrome. Lupus. 2003;12(12):903–7.PubMedCrossRefGoogle Scholar
  89. 89.
    Hughes GR. Migraine, memory loss, and “multiple sclerosis “. Neurological features of the antiphospholipid (Hughes’) syndrome. Postgrad Med J. 2003;79(928):81–3.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Tektonidou MG. Identification and treatment of APS renal involvement. Lupus. 2014;23(12):1276–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Pons-Estel GJ, Cervera R. Renal involvement in antiphospholipid syndrome. Curr Rheumatol Rep. 2014;16(2):397.PubMedCrossRefGoogle Scholar
  92. 92.
    Alchi B, Griffiths M, Jayne D. What nephrologists need to know about antiphospholipid syndrome. Nephrol Dial Transplant. 2010;25(10):3147–54.PubMedCrossRefGoogle Scholar
  93. 93.
    Sciascia S, Cuadrado MJ, Khamashta M, Roccatello D. Renal involvement in antiphospholipid syndrome. Nat Rev Nephrol. 2014;10(5):279–89.PubMedCrossRefGoogle Scholar
  94. 94.
    Asherson RA, Cervera R, de Groot PG, et al. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus. 2003;12(7):530–4.PubMedCrossRefGoogle Scholar
  95. 95.
    Asherson RA. The catastrophic antiphospholipid syndrome, 1998. A review of the clinical features, possible pathogenesis and treatment. Lupus. 1998;7(Suppl 2):S55–62.PubMedCrossRefGoogle Scholar
  96. 96.
    Espinosa G, Cervera R, Asherson RA. Catastrophic antiphospholipid syndrome and sepsis. A common link? J Rheumatol. 2007;34(5):923–6.PubMedGoogle Scholar
  97. 97.
    Asherson RA. The catastrophic antiphospholipid syndrome. J Rheumatol. 1992;19(4):508–12.PubMedGoogle Scholar
  98. 98.
    Pengo V, Tripodi A, Reber G, 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. 2009;7(10):1737–40.PubMedCrossRefGoogle Scholar
  99. 99.
    Tincani A, Balestrieri G, Spatola L, Cinquini M, Meroni PL, Roubey RA. Anticardiolipin and anti-beta 2glycoprotein I immunoassays in the diagnosis of antiphospholipid syndrome. Clin Exp Rheumatol. 1998;16(4):396–402.PubMedGoogle Scholar
  100. 100.
    Bertolaccini ML, Gomez S, Pareja JF, et al. Antiphospholipid antibody tests: spreading the net. Ann Rheum Dis. 2005;64(11):1639–43.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003;101(5):1827–32.PubMedCrossRefGoogle Scholar
  102. 102.
    Martinez-Berriotxoa A, Ruiz-Irastorza G, Egurbide MV, et al. Transiently positive anticardiolipin antibodies and risk of thrombosis in patients with systemic lupus erythematosus. Lupus. 2007;16(10):810–6.PubMedCrossRefGoogle Scholar
  103. 103.
    Opatrny L, David M, Kahn SR, Shrier I, Rey E. Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a meta analysis. J Rheumatol. 2006;33(11):2214–21.PubMedGoogle Scholar
  104. 104.
    Urbanus RT, Siegerink B, Roest M, Rosendaal FR, de Groot PG, Algra A. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case–control study. Lancet Neurol. 2009;8(11):998–1005.PubMedCrossRefGoogle Scholar
  105. 105.
    Levine SR, Salowich-Palm L, Sawaya KL, et al. IgG anticardiolipin antibody titer >40 GPL and the risk of subsequent thrombo-occlusive events and death. A prospective cohort study. Stroke. 1997;28(9):1660–5.PubMedCrossRefGoogle Scholar
  106. 106.
    Naess IA, Christiansen SC, Cannegieter SC, Rosendaal FR, Hammerstroem J. A prospective study of anticardiolipin antibodies as a risk factor for venous thrombosis in a general population (the HUNT study). J Thromb Haemost. 2006;4(1):44–9.PubMedCrossRefGoogle Scholar
  107. 107.
    Ruffatti A, Tonello M, Cavazzana A, Bagatella P, Pengo V. Laboratory classification categories and pregnancy outcome in patients with primary antiphospholipid syndrome prescribed antithrombotic therapy. Thromb Res. 2009;123(3):482–7.PubMedCrossRefGoogle Scholar
  108. 108.
    Ruffatti A, Tonello M, Del Ross T, et al. Antibody profile and clinical course in primary antiphospholipid syndrome with pregnancy morbidity. Thromb Haemost. 2006;96(3):337–41.PubMedGoogle Scholar
  109. 109.
    Trenor CC 3rd, Chung RJ, Michelson AD, et al. Hormonal contraception and thrombotic risk: a multidisciplinary approach. Pediatrics. 2011;127(2):347–57.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Erkan D, Merrill JT, Yazici Y, Sammaritano L, Buyon JP, Lockshin MD. High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin. Arthritis Rheum. 2001;44(6):1466–7.PubMedCrossRefGoogle Scholar
  111. 111.
    Finazzi G, Brancaccio V, Moia M, et al. Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four-year prospective study from the Italian Registry. Am J Med. 1996;100(5):530–6.PubMedCrossRefGoogle Scholar
  112. 112.
    Wallace DJ, Linker-Israeli M, Metzger AL, Stecher VJ. The relevance of antimalarial therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE. Lupus. 1993;2(Suppl 1):S13–5.PubMedGoogle Scholar
  113. 113.
    Rand JH, Wu XX, Quinn AS, Chen PP, Hathcock JJ, Taatjes DJ. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-beta2-glycoprotein I complexes to phospholipid bilayers. Blood. 2008;112(5):1687–95.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Giannakopoulos B, Krilis SA. How I treat the antiphospholipid syndrome. Blood. 2009;114(10):2020–30.PubMedCrossRefGoogle Scholar
  115. 115.
    Erkan D, Aguiar CL, Andrade D, et al. 14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev. 2014;13(6):685–96.PubMedCrossRefGoogle Scholar
  116. 116.
    Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e691S–736S.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Levy RA, Dos Santos FC, de Jesus GR, de Jesus NR. Antiphospholipid antibodies and antiphospholipid syndrome during pregnancy: diagnostic concepts. Front Immunol. 2015;6:205.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Carmona F, Font J, Azulay M, et al. Risk factors associated with fetal losses in treated antiphospholipid syndrome pregnancies: a multivariate analysis. Am J Reprod Immunol. 2001;46(4):274–9.PubMedCrossRefGoogle Scholar
  119. 119.
    Silver RK, MacGregor SN, Sholl JS, Hobart JM, Neerhof MG, Ragin A. Comparative trial of prednisone plus aspirin versus aspirin alone in the treatment of anticardiolipin antibody-positive obstetric patients. Am J Obstet Gynecol. 1993;169(6):1411–7.PubMedCrossRefGoogle Scholar
  120. 120.
    Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol. 1992;166(5):1318–23.PubMedCrossRefGoogle Scholar
  121. 121.
    Triolo G, Ferrante A, Ciccia F, 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. 2003;48(3):728–31.PubMedCrossRefGoogle Scholar
  122. 122.
    Branch DW, Peaceman AM, Druzin M, et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol. 2000;182(1 Pt 1):122–7.PubMedCrossRefGoogle Scholar
  123. 123.
    Vaquero E, Lazzarin N, Valensise H, et al. Pregnancy outcome in recurrent spontaneous abortion associated with antiphospholipid antibodies: a comparative study of intravenous immunoglobulin versus prednisone plus low-dose aspirin. Am J Reprod Immunol. 2001;45(3):174–9.PubMedCrossRefGoogle Scholar
  124. 124.
    Ruiz-Irastorza G, Khamashta MA. Lupus and pregnancy: ten questions and some answers. Lupus. 2008;17(5):416–20.PubMedCrossRefGoogle Scholar
  125. 125.
    Bramham K, Hunt BJ, Germain S, et al. Pregnancy outcome in different clinical phenotypes of antiphospholipid syndrome. Lupus. 2010;19(1):58–64.PubMedCrossRefGoogle Scholar
  126. 126.
    Cervera R, Group CRP. Catastrophic antiphospholipid syndrome (CAPS): update from the ‘CAPS Registry’. Lupus. 2010;19(4):412–8.PubMedCrossRefGoogle Scholar
  127. 127.
    Sukara G, Baresic M, Sentic M, Brcic L, Anic B. Catastrophic antiphospholipid syndrome associated with systemic lupus erythematosus treated with rituximab: case report and a review of the literature. Acta Reumatol Port. 2015;40(2):169–75.PubMedGoogle Scholar
  128. 128.
    Gomez-Puerta JA, Cervera R. Diagnosis and classification of the antiphospholipid syndrome. J Autoimmun. 2014;48–49:20–5.PubMedCrossRefGoogle Scholar
  129. 129.
    Amigo MC. What do we know about the cardiac valve lesion in the antiphospholipid syndrome (APS)? Lupus. 2014;23(12):1259–61.PubMedCrossRefGoogle Scholar
  130. 130.
    Espinosa G, Cervera R. Current treatment of antiphospholipid syndrome: lights and shadows. Nat Rev Rheumatol. 2015;11(10):586–96.PubMedCrossRefGoogle Scholar
  131. 131.
    Bertsias GK, Tektonidou M, Amoura Z, et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis. 2012;71(11):1771–82.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Brey RL. New treatment option for the antiphospholipid antibody syndrome? More pleiotropic effects of the statin drugs. J Thromb Haemost. 2004;2(9):1556–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Internal Medicine, Clinical Immunology UnitUniversity of GenoaGenoaItaly
  2. 2.Centre of Excellence for Biomedical ResearchUniversity of GenoaGenoaItaly
  3. 3.Department of DermatologyUniversity of GenoaGenoaItaly

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