Thrombosis and Anti-phospholipid Syndrome: a 5-Year Update on Treatment

  • Cecilia Beatrice ChighizolaEmail author
  • Pier Luigi Meroni
Systemic Lupus Erythematosus (G Tsokos, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Systemic Lupus Erythematosus


Purpose of Review

The aim of this review is to provide an update of the therapeutic tools for thrombotic anti-phospholipid syndrome (APS), focusing on the last 5 years.

Recent Findings

Early studies appointed anticoagulation at moderate intensity as the mainstay of treatment of thrombotic APS; in the last 5 years, the strategy has not much mutated. Some uncertainties regarding the role of direct oral anticoagulants and the optimal regimen for arterial thrombotic APS still persist: high-intensity anticoagulation, anticoagulation plus anti-platelet agent, and double anti-platelet agents being the possible alternatives. Several drugs have been proposed as effective additional tools for the management of thrombotic APS: hydroxychloroquine, statins, vitamin D, and sirolimus might be beneficial when added on the top of anticoagulation. Pregnant women with thrombotic APS should be switched to low-dose aspirin plus low molecular weight heparin at therapeutic dose. Despite adequate treatment, APS patients display a significant rate of recurrences; rituximab, eculizumab, and intravenous immunoglobulins are among the options to be considered for these patients.


From 2013 to date, the kaleidoscope of therapeutic options in thrombotic APS has been enriched, but tangible improvements in the management of patients are still awaited.


Anti-phospholipid antibodies Anti-phospholipid syndrome Thrombosis Treatment Update 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Recently published papers of particular interest have been highlighted as: • Of importance •• Of major importance

  1. 1.
    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;4:295–306.CrossRefPubMedGoogle Scholar
  2. 2.
    Sciascia S, Sanna G, Khamashta MA, Cuadrado MJ, Erkan D, Andreoli L, et al. The estimated frequency of antiphospholipid antibodies in young adults with cerebrovascular events: a systematic review. Ann Rheum Dis. 2015;74:2028–33.CrossRefPubMedGoogle Scholar
  3. 3.
    Cervera R, Khamashta MA, Shoenfeld Y, Camps MT, Jacobsen S, Kiss E, et al. Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2009;68:1428–32.CrossRefPubMedGoogle Scholar
  4. 4.
    Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002;46:1019–27.CrossRefPubMedGoogle Scholar
  5. 5.
    Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, 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. 2003;349:1133–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Finazzi G, Marchioli R, Brancaccio V, et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost. 2005;3:848–53.CrossRefPubMedGoogle Scholar
  7. 7.
    •• Bala MM, Celinska-Lowenhoff M, Szot W, et al. Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome. Cochrane Database Syst Rev. 2017;10:doi: This is a 2017 Cochrane review assessing the beneficial effects of anti-platelet agents and anticoagulation in anti-phospholipid syndrome.
  8. 8.
    Chighizola CB, Ubiali T, Meroni PL. Treatment of thrombotic antiphospholipid syndrome: the rationale of current management—an insight into future approaches. J Immunol Res. 2015; 951424;2015:1–20.CrossRefGoogle Scholar
  9. 9.
    Ruiz-Irastorza G, Hunt BJ, Khamashta MA. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum. 2007;57:1487–95.CrossRefPubMedGoogle Scholar
  10. 10.
    Silva FF, Carvalho JF. Intensity of anticoagulation in the treatment of thrombosis in the antiphospholipid syndrome: a meta-analysis. Rev Bras Reumatol. 2015;55:159–66.CrossRefPubMedGoogle Scholar
  11. 11.
    • Sciascia S, Coloma-Bazán E, Radin M, et al. Can we withdraw anticoagulation in patients with antiphospholipid syndrome after seroconvertion? Autoimmun Rev. 2017;16:1109–14. This recent review discusses the available evidence on the potential withdrawal of anticoagulation in patients who turn negative for anti-phospholipid antibodies. CrossRefPubMedGoogle Scholar
  12. 12.
    Criado-García J, Fernández-Puebla RA, Jiménez LL, et al. Anticoagulation treatment withdrawal in primary antiphospholipid syndrome when anticardiolipin antibodies become negative. Rev Clin Esp. 2008;208:135–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Comarmond C, Jego P, Veyssier-Belot C, Marie I, Mekinian A, Elmaleh-Sachs A, et al. Cessation of oral anticoagulants in antiphospholipid syndrome. Lupus. 2017;26:1291–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Coloma Bazán E, Donate López C, Moreno Lozano P, Cervera R, Espinosa G. Discontinuation of anticoagulation or antiaggregation treatment may be safe in patients with primary antiphospholipid syndrome when antiphospholipid antibodies became persistently negative. Immunol Res. 2013;56:358–61.CrossRefPubMedGoogle Scholar
  15. 15.
    Medina G, Briones-García E, Cruz-Domínguez MP, Flórez-Durante OI, Jara LJ. Antiphospholipid antibodies disappearance in primary antiphospholipid syndrome: thrombosis recurrence. Autoimmun Rev. 2017;16:352–4.CrossRefPubMedGoogle Scholar
  16. 16.
    •• Chighizola CB, Andreoli L, Gerosa M, Tincani A, Ruffatti A, Meroni PL. The treatment of anti-phospholipid syndrome: a comprehensive clinical approach. J Autoimmun. 2018; This is a recently published review that extensively reports all the possible treatment strategies for anti-phospholipid syndrome, critically appointed by experts of the field.
  17. 17.
    Burnett AE, Mahan CE, Vazquez SR, Oertel LB, Garcia DA, Ansell J. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis. 2016;41:206–32.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Mekaj YH, Mekaj AY, Duci SB, Miftari EI. New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag. 2015;11:967–77.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Woller SC, Stevens SM, Kaplan DA, Rondina MT. Protocol modification of apixaban for the secondary prevention of thrombosis among patients with antiphospholipid syndrome study. Clin Appl Thromb Hemost. 2018;24:192.CrossRefPubMedGoogle Scholar
  20. 20.
    Jackson WG, Oromendia C, Unlu O, Erkan D, DeSancho M, Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking. Recurrent thrombosis in patients with antiphospholipid antibodies and arterial thrombosis on antithrombotic therapy. Blood Adv. 2017;1:2320–4.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost. 2013;11:1927–9.PubMedGoogle Scholar
  22. 22.
    Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A, et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res. 2017;65:17–24.CrossRefPubMedGoogle Scholar
  23. 23.
    Erkan D, Willis R, Murthy VL, Basra G, Vega JA, Ruiz-Limón P, et al. A prospective open-label pilot study of fluvastatin on proinflammatory and prothrombotic biomarkers in antiphospholipid antibody positive patients. Ann Rheum Dis. 2014;73:1176–80.CrossRefPubMedGoogle Scholar
  24. 24.
    Riancho-Zarrabeitia L, Cubería M, Muñoz P, López-Hoyos M, García-Canale S, García-Unzueta M, Hernández JL, Martínez-Taboada VM Vitamin D and antiphospholipid syndrome: a retrospective cohort study and meta-analysis. Semin Arthritis Rheum 2017;
  25. 25.
    Agmon-Levin N, Blank M, Zandman-Goddard G, Orbach H, Meroni PL, Tincani A, et al. Vitamin D: an instrumental factor in the antiphospholipid syndrome by inhibition of tissue factor expression. Ann Rheum Dis. 2011;70:145–50.CrossRefPubMedGoogle Scholar
  26. 26.
    Piantoni S, Andreoli L, Allegri F, Meroni PL, Tincani A. Low levels of vitamin D are common in primary antiphospholipid syndrome with thrombotic disease. Reumatismo. 2012;64:307–13.CrossRefPubMedGoogle Scholar
  27. 27.
    Canaud F, Bienaimé F, Tabarin Bataillon G, et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med. 2014;371:303–12.CrossRefPubMedGoogle Scholar
  28. 28.
    Mora-Ramírez M, González-Pacheco H, Amezcua-Guerra LM. Stents coated with mammalian target of rapamycin inhibitors (mTOR) appear to be the best choice in patients with antiphospholipid syndrome and myocardial infarction. J Clin Rheumatol. 2016;22:281.CrossRefPubMedGoogle Scholar
  29. 29.
    Taraborelli M, Reggia R, Dall'Ara F, et al. Longterm outcome of patients with primary antiphospholipid syndrome: a retrospective multicenter study. J Rheumatol. 2017;44:1165–72.CrossRefPubMedGoogle Scholar
  30. 30.
    Chighizola CB, Raimondo MG, Meroni PL. Management of thrombotic antiphospholipid syndrome. Semin Thromb Hemost 2017;
  31. 31.
    Pérez-De-Lis M, Retamozo S, Flores-Chávez A, Kostov B, Perez-Alvarez R, Brito-Zerón P, et al. Autoimmune diseases induced by biological agents. A review of 12,731 cases (BIOGEAS Registry). Exp Op Drug Saf. 2017;16:1255–71.CrossRefGoogle Scholar
  32. 32.
    Erkan D, Vega J, Ramón G, Kozora E, Lockshin MD. A pilot open-label phase II trial of rituximab for non-criteria manifestations of antiphospholipid syndrome. Arthritis Rheum. 2013;65:464–71.CrossRefPubMedGoogle Scholar
  33. 33.
    Erkan D, Aguiar CL, Andrade D, Cohen H, Cuadrado MJ, Danowski A, et al. 14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev. 2014;13:685–96.CrossRefPubMedGoogle Scholar
  34. 34.
    Sciascia S, Giachino O, Roccatello D. Prevention of thrombosis relapse in antiphospholipid syndrome patients refractory to conventional therapy using intravenous immunoglobulin. Clin Exp Rheumatol. 2012;30:409–13.PubMedGoogle Scholar
  35. 35.
    Tenti S, Cheleschi S, Guidelli GM, Galeazzi M, Fioravanti A. Intravenous immunoglobulins and antiphospholipid syndrome: how, when and why? A review of the literature. Autoimmun Rev. 2016;15:226–35.CrossRefPubMedGoogle Scholar
  36. 36.
    Meroni PL, Macor P, Durigutto P, de Maso L, Gerosa M, Ferraresso M, et al. Complement activation in antiphospholipid syndrome and its inhibition to prevent rethrombosis after arterial surgery. Blood. 2016;127:365–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Andreoli L, Bertsias GK, Agmon-Levin N, Brown S, Cervera R, Costedoat-Chalumeau N, 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. 2017;76:476–85.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Lawley CM, Lain SJ, Algert CS, Ford JB, Figtree GA, Roberts CL. Prosthetic heart valves in pregnancy: a systematic review and meta-analysis protocol. Syst Rev. 2014;3:8.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med. 2010;35:64–101.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Cecilia Beatrice Chighizola
    • 1
    • 2
    • 3
    Email author
  • Pier Luigi Meroni
    • 2
  1. 1.Department of Clinical Sciences and Community HealthUniversity of MilanMilanItaly
  2. 2.Experimental Laboratory of Immunological and Rheumatologic ResearchesIRCCS Istituto Auxologico ItalianoCusano MilaninoItaly
  3. 3.Unit of Immunology, Allergology and RheumatologyIRCCS Istituto Auxologico ItalianoMilanItaly

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