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Non-Thrombotic Hematologic Manifestations in APS

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Antiphospholipid Antibody Syndrome

Part of the book series: Rare Diseases of the Immune System ((RDIS))

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Abstract

Non-thrombotic hematologic manifestations of antiphospholipid syndrome (APS) comprise immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and immune neutropenia, at present not included in APS diagnostic criteria. These cytopenias have been largely reported in APS and share the same underlying pathogenic mechanism mediated by antibodies against blood cells. Thrombocytopenia (platelets <100 × 109/L), the most frequent manifestation (20–40 %), is usually mild, although cases with severe bleeding are reported for platelets <5–10 × 109/L. According to published guidelines of primary ITP, treatment is recommended for platelets <25–30 × 109/L, provided that no other bleeding factors are present. First-line treatment includes steroids and intravenous immunoglobulins (IVIG), and second-line treatments of primary ITP splenectomy, rituximab, immunosuppressors, and thrombopoietin (TPO) agonists. However, in APS-associated ITP, immunosuppressors, such as azathioprine, are often the first choice, IVIG are used as second-line treatment, splenectomy is controversial, and TPO agonists are not used. AIHA occurs in about 10 % of APS patients and is clinically heterogeneous, from mild to fulminant life-threatening forms. Conventional therapy of warm AIHA includes corticosteroids as first-line therapy, while immunosuppressive drugs, rituximab, and IVIG are used as second line; steroids are poorly effective in cold forms, whereas rituximab is now recommended as first-line therapy. Last option treatments for refractory cases include plasmapheresis, alemtuzumab, bortezomib, and eculizumab. Both primary ITP and AIHA are associated with thromboembolic events, which should be carefully considered, particularly in the context of APS. The association between leukopenia and antiphospholipid (aPL) antibodies is reported only in few studies, and neutropenia is more frequent in APS secondary to systemic lupus erythematosus.

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References

  1. Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, Jacobsen S, Lakos G, Tincani A, Kontopoulou-Griva I, Galeazzi M, Meroni PL, Derksen RH, de Groot PG, Gromnica-Ihle E, Baleva M, Mosca M, Bombardieri S, Houssiau F, Gris JC, Quéré I, Hachulla E, Vasconcelos C, Roch B, Fernández-Nebro A, Boffa MC, Hughes GR, Ingelmo M, Euro-Phospholipid Project Group (2002) Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 46(4):1019–1027

    Article  PubMed  Google Scholar 

  2. Hughes GR (1993) The antiphospholipid syndrome: ten years on. Lancet 342(8867):341–344

    Article  CAS  PubMed  Google Scholar 

  3. Cuadrado MJ, Mujic F, Muñoz E, Khamashta MA, Hughes GR (1997) Thrombocytopenia in the antiphospholipid syndrome. Ann Rheum Dis 56(3):194–196

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Galli M, Finazzi G, Barbui T (1996) Thrombocytopenia in the antiphospholipid syndrome. Br J Haematol 93(1):1–5

    Article  CAS  PubMed  Google Scholar 

  5. Italian Registry of Antiphospholipid Antibodies [IR-APA]. Thrombosis and thrombocytopenia in antiphospholipid syndrome [idiopathic and secondary to SLE]: first report from the Italian Registry (1993). Haematologica 78(5):313–8

    Google Scholar 

  6. Uthman I, Godeau B, Taher A, Khamashta M (2008) The hematologic manifestations of the antiphospholipid syndrome. Blood Rev 22(4):187–194

    Article  PubMed  Google Scholar 

  7. Lechner K, Pabinger-Fasching I (1985) Lupus anticoagulants and thrombosis. A study of 25 cases and review of the literature. Haemostasis 15(4):254–262

    CAS  PubMed  Google Scholar 

  8. Cuker A, Cines DB (2010) Immune thrombocytopenia. Hematology Am Soc Hematol Educ Program 2010:377–384

    Article  PubMed  Google Scholar 

  9. Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA, American Society of Hematology (2011) The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 117(16):4190–4207

    Article  CAS  PubMed  Google Scholar 

  10. Ghanima W, Godeau B, Cines DB, Bussel JB (2012) How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment. Blood 120(5):960–969

    Article  CAS  PubMed  Google Scholar 

  11. Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A (2001) Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood 97(9):2549–2554

    Article  CAS  PubMed  Google Scholar 

  12. Enger C, Bennett D, Forssen U, Fogarty PF, McAfee AT (2010) Comorbidities in patients with persistent or chronic immune thrombocytopenia. Int J Hematol 92(2):289–295

    Article  PubMed  Google Scholar 

  13. Nørgaard M, Jensen AØ, Engebjerg MC, Farkas DK, Thomsen RW, Cha S, Zhao S, Sørensen HT (2011) Long-term clinical outcomes of patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. Blood 117(13):3514–3520

    Article  PubMed  Google Scholar 

  14. Kim KJ, Baek IW, Yoon CH, Kim WU, Cho CS (2013) Thrombotic risk in patients with immune thrombocytopenia and its association with antiphospholipid antibodies. Br J Haematol 161(5):706–714

    Article  CAS  PubMed  Google Scholar 

  15. Bevers EM, Smeets EF, Comfurius P, Zwaal RF (1994) Physiology of membrane lipid asymmetry. Lupus 3(4):235–240

    Article  CAS  PubMed  Google Scholar 

  16. Pierangeli SS, Chen PP, Raschi E, Scurati S, Grossi C, Borghi MO, Palomo I, Harris EN, Meroni PL (2008) Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms. Semin Thromb Hemost 34(3):236–250

    Article  CAS  PubMed  Google Scholar 

  17. Galli M, Daldossi M, Barbui T (1994) Anti-glycoprotein Ib/IX and IIb/IIIa antibodies in patients with antiphospholipid antibodies. Thromb Haemost 71(5):571–575

    CAS  PubMed  Google Scholar 

  18. Fabris F, Steffan A, Cordiano I, Borzini P, Luzzatto G, Randi ML, Girolami A (1994) Specific antiplatelet autoantibodies in patients with antiphospholipid antibodies and thrombocytopenia. Eur J Haematol 53(4):232–236

    Article  CAS  PubMed  Google Scholar 

  19. Macchi L, Rispal P, Clofent-Sanchez G, Pellegrin JL, Nurden P, Leng B, Nurden AT (1997) Anti-platelet antibodies in patients with systemic lupus erythematosus and the primary antiphospholipid antibody syndrome: their relationship with the observed thrombocytopenia. Br J Haematol 98(2):336–341

    Article  CAS  PubMed  Google Scholar 

  20. Godeau B, Piette JC, Fromont P, Intrator L, Schaeffer A, Bierling P (1997) Specific antiplatelet glycoprotein autoantibodies are associated with the thrombocytopenia of primary antiphospholipid syndrome. Br J Haematol 98(4):873–879

    Article  CAS  PubMed  Google Scholar 

  21. Harris EN, Gharavi AE, Hegde U, Derue G, Morgan SH, Englert H, Chan JK, Asherson RA, Hughes GR (1985) Anticardiolipin antibodies in autoimmune thrombocytopenic purpura. Br J Haematol 59(2):231–234

    Article  CAS  PubMed  Google Scholar 

  22. Stasi R, Stipa E, Masi M, Oliva F, Sciarra A, Perrotti A, Olivieri M, Zaccari G, Gandolfo GM, Galli M (1994) Prevalence and clinical significance of elevated antiphospholipid antibodies in patients with idiopathic thrombocytopenic purpura. Blood 84(12):4203–4208

    CAS  PubMed  Google Scholar 

  23. Diz-Küçükkaya R, Hacihanefioğlu A, Yenerel M, Turgut M, Keskin H, Nalçaci M, Inanç M (2001) Antiphospholipid antibodies and antiphospholipid syndrome in patients presenting with immune thrombocytopenic purpura: a prospective cohort study. Blood 98(6):1760–1764

    Article  PubMed  Google Scholar 

  24. Cines DB, Liebman H, Stasi R (2009) Pathobiology of secondary immune thrombocytopenia. Semin Hematol 46(1 Suppl 2):S2–S14

    Article  PubMed Central  PubMed  Google Scholar 

  25. Park SH, Kim JY, Kim SK, Choe JY, Kim SG, Ryoo HM (2010) Regulatory T-cells in systemic lupus erythematosus-associated thrombocytopenia: a comparison with idiopathic thrombocytopenic purpura. Lupus 19(7):888–889

    Article  PubMed  Google Scholar 

  26. Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, Chong BH, Cines DB, Gernsheimer TB, Godeau B, Grainger J, Greer I, Hunt BJ, Imbach PA, Lyons G, McMillan R, Rodeghiero F, Sanz MA, Tarantino M, Watson S, Young J, Kuter DJ (2010) International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 115(2):168–186

    Article  CAS  PubMed  Google Scholar 

  27. Galindo M, Khamashta MA, Hughes GR (1999) Splenectomy for refractory thrombocytopenia in the antiphospholipid syndrome. Rheumatology (Oxford) 38(9):848–853

    Article  CAS  Google Scholar 

  28. Boyle S, White RH, Brunson A, Wun T (2013) Splenectomy and the incidence of venous thromboembolism and sepsis in patients with immune thrombocytopenia. Blood 121(23):4782–4790

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Matzdorff A, Beer JH (2013) Immune thrombocytopenia patients requiring anticoagulatio--aneuvering between Scylla and Charybdis. Semin Hematol 50(Suppl 1):S83–S88

    Google Scholar 

  30. Cheng Y, Wong RS, Soo YO et al (2003) Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med 349(9):831–836

    Article  CAS  PubMed  Google Scholar 

  31. Mazzucconi MG, Fazi P, Bernasconi S et al (2007) Therapy with high-dose dexamethasone [HDDXM] in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood 109(4):1401–1407

    Article  CAS  PubMed  Google Scholar 

  32. Ruiz-Irastorza G, Crowther M, Branch W et al (2010) Antiphospholipid syndrome. Lancet 376:1498–1509

    Article  CAS  PubMed  Google Scholar 

  33. Giannakopoulos B, Krilis SA (2013) The pathogenesis of the antiphospholipid syndrome. N Engl J Med 368:1033–1044

    Article  CAS  PubMed  Google Scholar 

  34. Hall S, McCormick JL Jr, Greipp PR, Michet CJ Jr, McKenna CH (1985) Splenectomy does not cure the thrombocytopenia of systemic lupus erythematosus. Ann Intern Med 102(3):325–328

    Article  CAS  PubMed  Google Scholar 

  35. Kokori SI, Ioannidis JP, Voulgarelis M, Tzioufas AG, Moutsopoulos HM (2000) Autoimmune hemolytic anemia in patients with systemic lupus erythematosus. Am J Med 108(3):198–204

    Article  CAS  PubMed  Google Scholar 

  36. Sultan SM, Begum S, Isenberg DA (2003) Prevalence, patterns of disease and outcome in patients with systemic lupus erythematosus who develop severe haematological problems. Rheumatology (Oxford) 42(2):230–234

    Article  CAS  Google Scholar 

  37. Hazeltine M, Rauch J, Danoff D et al (1998) Antiphospholipid antibodies in systemic lupus erythematosus: evidence of an association with positive Coombs and hypocomplementemia. J Rheumatol 15:80–86

    Google Scholar 

  38. Del Papa N, Meroni PL, Barcellini W, Borghi MO, Fain C, Khamashta M, Tincani A, Balestrieri G, Hughes GR (1992) Antiphospholipid antibodies cross-reacting with erythrocyte membranes. A case report. Clin Exp Rheumatol 10(4):395–399

    PubMed  Google Scholar 

  39. Rottem M, Krause I, Fraser A, Stojanovich L, Rovensky J, Shoenfeld Y (2006) Autoimmune hemolytic anaemia in the antiphospholipid syndrome. Lupus 15(7):473–477

    Article  CAS  PubMed  Google Scholar 

  40. Lang B, Straub RH, Weber S, Röther E, Fleck M, Peter HH (1997) Elevated anticardiolipin antibodies in autoimmune haemolytic anaemia irrespective of underlying systemic lupus erythematosus. Lupus 6(8):652–655

    Article  CAS  PubMed  Google Scholar 

  41. Pullarkat V, Ngo M, Iqbal S, Espina B, Liebman HA (2002) Detection of lupus anticoagulant identifies patients with autoimmune haemolytic anaemia at increased risk for venous thromboembolism. Br J Haematol 118(4):1166–1169

    Article  PubMed  Google Scholar 

  42. Hendrick AM (2003) Auto-immune haemolytic anaemia—a high-risk disorder for thromboembolism? Hematology 8(1):53–56

    Article  CAS  PubMed  Google Scholar 

  43. Cabral AR, Cabiedes J, Alarcón-Segovia D (1990) Haemolytic anaemia related to an IgM autoantibody to phosphatidylcholine that binds in vitro to stored and to bromelain-treated human erythrocytes. J Autoimmun 3(6):773–787

    Article  CAS  PubMed  Google Scholar 

  44. Petz LD, Garratty G (2004) Immune hemolytic anemias, 2nd edn. Churchill Livingstone, Philadelphia

    Google Scholar 

  45. Barcellini W, Clerici G, Montesano R, Taioli E, Morelati F, Rebulla P, Zanella A (2000) In vitro quantification of anti-red blood cell antibody production in idiopathic autoimmune haemolytic anaemia: effect of mitogen and cytokine stimulation. Br J Haematol 111:452–460

    Article  CAS  PubMed  Google Scholar 

  46. Valent P, Lechner K (2008) Diagnosis and treatment of autoimmune haemolytic anaemias in adults: a clinical review. Wien Klin Wochenschr 120(5–6):136–151

    Article  PubMed  Google Scholar 

  47. Alba P, Karim MY, Hunt BJ (2003) Mycophenolate mofetil as a treatment for autoimmune haemolytic anaemia in patients with systemic lupus erythematosus and antiphospholipid syndrome. Lupus 12:633–635

    Article  CAS  PubMed  Google Scholar 

  48. Kotb R, Pinganaud C, Trichet C, Lambotte O, Dreyfus M, Delfraissy JF et al (2005) Efficacy of mycophenolate mofetil in adult refractory auto-immune cytopenias: a single center preliminary study. Eur J Haematol 75:60–64

    Article  CAS  PubMed  Google Scholar 

  49. Barcellini W, Zanella A (2011) Rituximab therapy for autoimmune haematological diseases. Eur J Intern Med 22:220–229

    Article  CAS  PubMed  Google Scholar 

  50. Barcellini W, Zaja F, Zaninoni A, Imperiali FG, Di Battista ML, Bona E et al (2012) Low-dose rituximab in adult patients with idiopathic autoimmune hemolytic anemia: clinical efficacy and biological studies. Blood 119:3691–3697

    Article  CAS  PubMed  Google Scholar 

  51. Barcellini W, Zaja F, Zaninoni A, Imperiali FG, Di Bona E, Fattizzo B et al (2013) Sustained response to low-dose rituximab in idiopathic autoimmune hemolytic anemia. Eur J Haematol 91:546–551

    Article  CAS  PubMed  Google Scholar 

  52. Barros MM, Blajchman MA, Bordin JO (2010) Warm autoimmune hemolytic anemia: recent progress in understanding the immunobiology and the treatment. Trans Med Rev 24:195–210

    Article  Google Scholar 

  53. Flores G, Cunningham-Rundles C, Newland AC, Bussel JB (1993) Efficacy of intravenous immunoglobulin in the treatment of autoimmune hemolytic anemia: results in 73 patients. Am J Hematol 44:237–242

    Article  CAS  PubMed  Google Scholar 

  54. Lechner K, Jager U (2010) How I treat autoimmune hemolytic anemias in adults. Blood 16:1831–1838

    Article  Google Scholar 

  55. Crowther M, Chan YL, Garbett IK, Lim W, Vickers MA, Crowther MA (2011) Evidence-based focused review of the treatment of idiopathic warm immune hemolytic anemia in adults. Blood 118:4036–4040

    Article  CAS  PubMed  Google Scholar 

  56. Berentsen S, Tjønnfjord GE (2012) Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev 26:107–115

    Article  CAS  PubMed  Google Scholar 

  57. Berentsen S, Randen U, Vagan AM, Hjorth-Hansen H, Vik A, Dalgaard J et al (2010) High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood 116:3180–3184

    Article  CAS  PubMed  Google Scholar 

  58. Moyo VM, Smith D, Brodsky I, Crilley P, Jones RJ, Brodsky RA (2002) High-dose cyclophosphamide for refractory autoimmune hemolytic anemia. Blood 100:704–706

    Article  CAS  PubMed  Google Scholar 

  59. Carson KR, Beckwith LG, Mehta J (2010) Successful treatment of IgM-mediated autoimmune haemolytic anemia with bortezomib. Blood 115:915

    Article  CAS  PubMed  Google Scholar 

  60. Roth A, Huttmann A, Rother RP, Duhrsen U, Philipp T (2009) Long-term efficacy of the complement inhibitor eculizumab in cold agglutinin disease. Blood 113:3485–3486

    Article  Google Scholar 

  61. Wouters D, Stephan F, Strengers P, de Haas M, Brower C, Hagenbeek A et al (2013) C1-esterase inhibitor concentrate rescues erythrocytes from complement-mediated destruction in autoimmune hemolytic anemia. Blood 121:1242–1244

    Article  CAS  PubMed  Google Scholar 

  62. Arbach O, Funck R, Seibt F, Salama A (2012) Erythropoietin may improve anemia in patients with autoimmune hemolytic anemia associated with reticulocytopenia. Transfus Med Hemother 39:221–223

    Article  PubMed Central  PubMed  Google Scholar 

  63. Snowden JA, Saccardi R, Allez M, Ardizzone S, Arnold R, Cervera R, Denton C, Hawkey C, Labopin M, Mancardi G, Martin R, Moore JJ, Passweg J, Peters C, Rabusin M, Rovira M, van Laar JM, Farge D, EBMT Autoimmune Disease Working Party [ADWP]; Paediatric Diseases Working Party [PDWP] (2012) Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 47(6):770–790

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Arvieux J, Jacob MC, Roussel B, Bensa JC, Colomb MG (1995) Neutrophil activation by anti-beta 2 glycoprotein I monoclonal antibodies via Fc gamma receptor II. J Leukoc Biol 57(3):387–394

    CAS  PubMed  Google Scholar 

  65. Cervera R, Font J, López-Soto A, Casals F, Pallarés L, Bové A, Ingelmo M, Urbano-Márquez A (1990) Isotype distribution of anticardiolipin antibodies in systemic lupus erythematosus: prospective analysis of a series of 100 patients. Ann Rheum Dis 49(2):109–113

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Vianna JL, Khamashta MA, Ordi-Ros J, Font J, Cervera R, Lopez-Soto A, Tolosa C, Franz J, Selva A, Ingelmo M et al (1994) Comparison of the primary and secondary antiphospholipid syndrome: a European Multicenter Study of 114 patients. Am J Med 96(1):3–9

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Anemia Physiopathology Unit, Onco-hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, Milan, 20122, Italy

    Wilma Barcellini MD

  2. Division of Rheumatology – Istituto Ortopedico Gaetano Pini, Department of Clinical Sciences and Community Health, University of Milan, Milan, 20122, Italy

    Carolina Artusi

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Correspondence to Wilma Barcellini MD .

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  1. Department of Rheumatology, Gaetano Pini Institute, Milan, Milano, Italy

    Pier Luigi Meroni

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Barcellini, W., Artusi, C. (2015). Non-Thrombotic Hematologic Manifestations in APS. In: Meroni, P. (eds) Antiphospholipid Antibody Syndrome. Rare Diseases of the Immune System. Springer, Cham. https://doi.org/10.1007/978-3-319-11044-8_10

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