Advertisement

Background, Presentation and Pathophysiology of Autoimmune Hemolytic Anemia

  • Shawki Qasim
Chapter

Abstract

Autoimmune hemolytic anemia (AIHA) is an acquired disorder characterized by the production of autoantibodies with high affinity for autologous erythrocyte antigens causing red blood cell (RBC) destruction and a resultant wide spectrum of symptomatology and laboratory findings. The severity of presentation highly depends on the autoantibody type, concentration, affinity, antigen type, expression level, and antibody-antigen thermodynamics. Although AIHA is a relatively rare disorder with an estimated incidence of 1–3 cases per 100,000 per year, basic understanding of its manifestations and standard diagnostics is essential for healthcare providers in various clinical settings, as severe forms of the disease can be life-threatening. Early recognition and initiation of appropriate treatment are critical to achieving a positive outcome. Additionally, autoimmune hemolysis is frequently the presenting manifestation of a myriad of underlying autoimmune, infectious and/or neoplastic processes, and awareness of such association allows for earlier diagnosis and management of these disorders. On the other hand, even isolated subclinical immune hemolysis can sometimes complicate the interpretability of common laboratory tests and standard blood banking procedures.

Keywords

Autoimmune Hemolysis Autoantibodies Warm Cold Intravascular Extravascular Agglutinin 

References

  1. 1.
    Morgagni G, Alexander B. The seats and causes of diseases investigated by anatomy; in five books, containing a great variety of dissections, with remarks. To which are added very accurate and copious indexes of the principal things and names therein contained. London: Printed for A. Millar, and T. Cadell; 1769.Google Scholar
  2. 2.
    Freedman J. Autoimmune hemolysis: a journey through time. Transfus Med Hemother. 2015;42(5):278–85.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Andral G. Essai d'hématologie pathologique. Paris: Fortin, Masson et Cie; 1843.Google Scholar
  4. 4.
    Major RH. Classic descriptions of disease. Springfield, IL: C. C. Thomas; 1939.Google Scholar
  5. 5.
    Vanlair C, Masius J. De la microcythémia. Bull Acad R Med Belg. 1871;5:515–612.Google Scholar
  6. 6.
    Mackenzie S. Paroxysmal haemoglobinuria, with remarks on its nature. Lancet. 1879;II:116–7.CrossRefGoogle Scholar
  7. 7.
    Minkowski O. Ueber eine hereditäre, unter dem Bilde eines chronischen Icterus mit Urobilinurie, Splenomegalie und Nierensiderosis verlaufende Affection. Verh Krong Inn Med. 1900;1(18):316–21.Google Scholar
  8. 8.
    Hayem G. Sur une variete particuliere d’ictere chronique. Ictere infectieux chronique splenomegalique. Presse Méd. 1898;1(6):121–5.Google Scholar
  9. 9.
    Landsteiner K. Zur Kentniss der antifermentativen, lytischen und agglutinierenden Wirkungen des Blutserums und der Lymphe. Zbl Bakt. 1900;1(27):357–62.Google Scholar
  10. 10.
    Donath JLK. Über paroxysmale Hämoglobinurie. Münch Med Wochenschr. 1904;1(51):1590–5.Google Scholar
  11. 11.
    Chauffard M. Pathogénie de l’ictère congenital de l’adulte. Semaine Med. 1907;1(27):25–9.Google Scholar
  12. 12.
    Chauffard M, Troissier J. Anémie grave avec hémolysinique dans le sérum; ictère hémolysiniqe. Semaine Med. 1908;1(28):345.Google Scholar
  13. 13.
    Chauffard M, Vincent C. Hémoglobinurie hémolysinique avec ictère polycholique aigu. Semaine Med. 1909;1(29):601–4.Google Scholar
  14. 14.
    Micheli F. Unmittelbare Effekte der Splenektomie bei einem Fall von erworbenem hämolytischen splenomegalischen Ikterus Typus Hayem-Widal (spleno-hämolytischer Ikterus). Wien Klin Wochenschr. 1911;1(24):1269–74.Google Scholar
  15. 15.
    Banti G. La esplanomegalia hemolitica. Semaine Med. 1912;1(32):265–8.Google Scholar
  16. 16.
    Witts LJ. The paroxysmal haemoglobinurias. Lancet. 1936;II:115–20.CrossRefGoogle Scholar
  17. 17.
    Dameshek W, Schwartz SO. The presence of hemolysins in acute hemolytic anemia. New Engl J Med. 1938;218:75–80.CrossRefGoogle Scholar
  18. 18.
    Weiner AS. A new test (blocking test) for Rh sensitization. Proc Soc Exp Biol NY. 1944;56(2):173–6.CrossRefGoogle Scholar
  19. 19.
    Race RR. An ‘incomplete’ antibody in human serum. Nature. 1944;153(3895):771–2.CrossRefGoogle Scholar
  20. 20.
    Coombs RR, Mourant AE, Race RR. A new test for the detection of weak and incomplete Rh agglutinins. Br J Exp Pathol. 1945;26:255–66.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Evans RS, Duane RT. Acquired hemolytic anemia; the relation of erythrocyte antibody production to activity of the disease; the significance of thrombocytopenia and leukopenia. Blood. 1949;4(11):1196–213.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Iafusco F, Buffa V. Autoimmune hemolytic anemia in a newborn infant. Pediatria. 1962;70:1256–64.PubMedGoogle Scholar
  23. 23.
    Pirofsky B. The hemolytic anemias—historical review and classification. The hemolytic anemias—historical review and classification. 1. Baltimore, MA: Williams & Wilkins; 1969. p. 3–21.Google Scholar
  24. 24.
    Schubothe H. Current problems of chronic cold hemagglutinin disease. Annals NY Acad Sci. 1965;124(2):484–90.CrossRefGoogle Scholar
  25. 25.
    Dacie JV. Aetiology of the auto-immune haemolytic anaemias. Haematologia. 1971;5(4):351–7.PubMedGoogle Scholar
  26. 26.
    Rosse WF. The autinglobulin test in autoimmune hemolytic anemia. Annu Rev Med. 1975;26:331–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Schreiber AD, Frank MM. Role of antibody and complement in the immune clearance and destruction of erythrocytes. I. In vivo effects of IgG and IgM complement-fixing sites. J Clin Invest. 1972;51(3):575–82.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Engelfriet CP, Borne AE, Beckers D, Van Loghem JJ. Autoimmune haemolytic anaemia: serological and immunochemical characteristics of the autoantibodies; mechanisms of cell destruction. Ser Haematol. 1974;7(3):328–47.PubMedGoogle Scholar
  29. 29.
    von dem Borne AE, Beckers D, Engelfriet CP. Mechanisms of red cell destruction mediated by non-complement binding IgG antibodies: the essential role in vivo of the Fc part of IgG. Br J Haematol. 1977;36(4):485–93.CrossRefGoogle Scholar
  30. 30.
    Berentsen S, Randen U, Tjonnfjord GE. Cold agglutinin-mediated autoimmune hemolytic anemia. Hematol Oncol Clin North Am. 2015;29(3):455–71.CrossRefPubMedGoogle Scholar
  31. 31.
    Engelfriet CP, Overbeeke MA, von dem Borne AE. Autoimmune hemolytic anemia. Semin Hematol. 1992;29(1):3–12.PubMedGoogle Scholar
  32. 32.
    Naik R. Warm autoimmune hemolytic anemia. Hematol Oncol Clin North Am. 2015;29(3):445–53.CrossRefPubMedGoogle Scholar
  33. 33.
    Quist E, Koepsell S. Autoimmune hemolytic anemia and red blood cell autoantibodies. Arch Pathol Lab Med. 2015 Nov;139(11):1455–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Segel GB, Lichtman MA. Direct antiglobulin (“Coombs”) test-negative autoimmune hemolytic anemia: a review. Blood Cells Mol Dis. 2014;52(4):152–60.CrossRefPubMedGoogle Scholar
  35. 35.
    Shanbhag S, Spivak J. Paroxysmal cold hemoglobinuria. Hematol Oncol Clin North Am. 2015;29(3):473–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Shulman IA, Branch DR, Nelson JM, Thompson JC, Saxena S, Petz LD. Autoimmune hemolytic anemia with both cold and warm autoantibodies. Jama. 1985;253(12):1746–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Kaplan M, Hammerman C, Vreman HJ, Wong RJ, Stevenson DK. Direct antiglobulin titer strength and hyperbilirubinemia. Pediatrics. 2014;134(5):e1340–4.CrossRefPubMedGoogle Scholar
  38. 38.
    Zantek ND, Koepsell SA, Tharp DR Jr, Cohn CS. The direct antiglobulin test: a critical step in the evaluation of hemolysis. Am J Hematol. 2012;87(7):707–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Habibi B, Homberg JC, Schaison G, Salmon C. Autoimmune hemolytic anemia in children. A review of 80 cases. Am J Med. 1974;56(1):61–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Barker RN, Hall AM, Standen GR, Jones J, Elson CJ. Identification of T-cell epitopes on the rhesus polypeptides in autoimmune hemolytic anemia. Blood. 1997;90(7):2701–15.PubMedGoogle Scholar
  41. 41.
    Liebman HA, Weitz IC. Autoimmune hemolytic anemia. Med Clin North Am. 2017;101(2):351–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Petz LD, Fudenberg HH. Coombs-positive hemolytic anemia caused by penicillin administration. N Engl J Med. 1966;274(4):171–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Garratty G. Drug-induced immune hemolytic anemia. Hematology/the Education Program of the American Society of Hematology American Society of Hematology Education Program. 2009;73–9.CrossRefGoogle Scholar
  44. 44.
    Ahmad E, Elgohary T, Ibrahim H. Naturally occurring regulatory T cells and interleukins 10 and 12 in the pathogenesis of idiopathic warm autoimmune hemolytic anemia. J Investig Allergol Clin Immunol. 2011;21(4):297–304.PubMedGoogle Scholar
  45. 45.
    Visco C, Barcellini W, Maura F, Neri A, Cortelezzi A, Rodeghiero F. Autoimmune cytopenias in chronic lymphocytic leukemia. Am J Hematol. 2014;89(11):1055–62.CrossRefPubMedGoogle Scholar
  46. 46.
    De Angelis V, Biasinutto C, Pradella P, Vaccher E, Spina M, Tirelli U. Clinical significance of positive direct antiglobulin test in patients with HIV infection. Infection. 1994;22(2):92–5.CrossRefPubMedGoogle Scholar
  47. 47.
    Rosse WF. Fixation of the first component of complement (C’la) by human antibodies. J Clin Invest. 1969;47(11):2430–45.CrossRefPubMedGoogle Scholar
  48. 48.
    Ravetch JV. Fc receptors. Curr Opin Immunol. 1997;9(1):121–5.CrossRefPubMedGoogle Scholar
  49. 49.
    Schur PH. IgG subclasses—a review. Ann Allergy. 1987;58(2):89–96.PubMedGoogle Scholar
  50. 50.
    Garratty G, Arndt P, Domen R, Clarke A, Sutphen-Shaw D, Clear J, et al. Severe autoimmune hemolytic anemia associated with IgM warm autoantibodies directed against determinants on or associated with glycophorin A. Vox Sang. 1997;72(2):124–30.CrossRefPubMedGoogle Scholar
  51. 51.
    Sachs UJ, Roder L, Santoso S, Bein G. Does a negative direct antiglobulin test exclude warm autoimmune haemolytic anaemia? A prospective study of 504 cases. Br J Haematol. 2006;132(5):655–6.CrossRefPubMedGoogle Scholar
  52. 52.
    Lau P, Haesler WE, Wurzel HA. Positive direct antiglobulin reaction in a patient population. Am J Clin Pathol. 1976;65(3):368–75.CrossRefPubMedGoogle Scholar
  53. 53.
    Keeling DM, Isenberg DA. Haematological manifestations of systemic lupus erythematosus. Blood Rev. 1993;7(4):199–207.CrossRefPubMedGoogle Scholar
  54. 54.
    Jeffries M, Hamadeh F, Aberle T, Glenn S, Kamen DL, Kelly JA, et al. Haemolytic anaemia in a multi-ethnic cohort of lupus patients: a clinical and serological perspective. Lupus. 2008;17(8):739–43.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Iordache L, Launay O, Bouchaud O, Jeantils V, Goujard C, Boue F, et al. Autoimmune diseases in HIV-infected patients: 52 cases and literature review. Autoimmun Rev. 2014;13(8):850–7.CrossRefPubMedGoogle Scholar
  56. 56.
    Toy PT, Reid ME, Burns M. Positive direct antiglobulin test associated with hyperglobulinemia in acquired immunodeficiency syndrome (AIDS). Am J Hematol. 1985;19(2):145–50.CrossRefPubMedGoogle Scholar
  57. 57.
    Wang J, Cunningham-Rundles C. Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID). J Autoimmun. 2005;25(1):57–62.CrossRefPubMedGoogle Scholar
  58. 58.
    Neven B, Magerus-Chatinet A, Florkin B, Gobert D, Lambotte O, De Somer L, et al. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood. 2011;118(18):4798–807.CrossRefPubMedGoogle Scholar
  59. 59.
    Hamblin TJ, Oscier DG, Young BJ. Autoimmunity in chronic lymphocytic leukaemia. J Clin Pathol. 1986;39(7):713–6.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Diehl LF, Ketchum LH. Autoimmune disease and chronic lymphocytic leukemia: autoimmune hemolytic anemia, pure red cell aplasia, and autoimmune thrombocytopenia. Semin Oncol. 1998;25(1):80–97.PubMedGoogle Scholar
  61. 61.
    Garratty G, Arndt PA. An update on drug-induced immune hemolytic anemia. Immunohematology. 2007;23(3):105–19.PubMedGoogle Scholar
  62. 62.
    LoBuglio AF, Jandl JH. The nature of the alpha-methyldopa red-cell antibody. N Engl J Med. 1967;276(12):658–65.CrossRefPubMedGoogle Scholar
  63. 63.
    Worlledge SM, Carstairs KC, Dacie JV. Autoimmune haemolytic anaemia associated with alpha-methyldopa therapy. Lancet. 1966;2(7455):135–9.CrossRefPubMedGoogle Scholar
  64. 64.
    Salama A, Santoso S, Mueller-Eckhardt C. Antigenic determinants responsible for the reactions of drug-dependent antibodies with blood cells. Br J Haematol. 1991;78(4):535–9.CrossRefPubMedGoogle Scholar
  65. 65.
    Salama A, Mueller-Eckhardt C. On the mechanisms of sensitization and attachment of antibodies to RBC in drug-induced immune hemolytic anemia. Blood. 1987;69(4):1006–10.PubMedGoogle Scholar
  66. 66.
    Liesveld JL, Rowe JM, Lichtman MA. Variability of the erythropoietic response in autoimmune hemolytic anemia: analysis of 109 cases. Blood. 1987;69(3):820–6.PubMedGoogle Scholar
  67. 67.
    Dobryszycka W. Biological functions of haptoglobin—new pieces to an old puzzle. Eur J Clin Chem Clin Biochem. 1997;35(9):647–54.PubMedGoogle Scholar
  68. 68.
    Shih AW, McFarlane A, Verhovsek M. Haptoglobin testing in hemolysis: measurement and interpretation. Am J Hematol. 2014;89(4):443–7.CrossRefPubMedGoogle Scholar
  69. 69.
    Marchand A, Galen RS, Van Lente F. The predictive value of serum haptoglobin in hemolytic disease. JAMA. 1980;243(19):1909–11.CrossRefPubMedGoogle Scholar
  70. 70.
    Pollack W, Hager HJ, Reckel R, Toren DA, Singher H. A study of the forces involved in the second stage of Hemagglutination. Transfusion. 1965;5:158–83.CrossRefPubMedGoogle Scholar
  71. 71.
    Kirschfink M, Knoblauch K, Roelcke D. Activation of complement by cold agglutinins. Infusionsther Transfusionsmed. 1994;21(6):405–9.PubMedGoogle Scholar
  72. 72.
    Jenkins WJ, Marsh WL, Noades J, Tippett P, Sanger R, Race RR. The I antigen and antibody. Vox Sang. 1960;5:97–121.PubMedGoogle Scholar
  73. 73.
    Marsh WL. Anti-i: a cold antibody defining the Ii relationship in human red cells. Br J Haematol. 1961;7:200–9.CrossRefPubMedGoogle Scholar
  74. 74.
    Feizi T. Monotypic cold agglutinins in infection by mycoplasma pneumoniae. Nature. 1967;215(5100):540–2.CrossRefPubMedGoogle Scholar
  75. 75.
    Deaton JG, Skaggs H Jr, Levin WC. Acute hemolytic anemia complicating infectious mononucleosis: the mechanism of hemolysis. Tex Rep Biol Med. 1967;25(3):309–17.PubMedGoogle Scholar
  76. 76.
    Rollof J, Eklund PO. Infectious mononucleosis complicated by severe immune hemolysis. Eur J Haematol. 1989;43(1):81–2.CrossRefPubMedGoogle Scholar
  77. 77.
    Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114–21.CrossRefPubMedGoogle Scholar
  78. 78.
    Sokol RJ, Hewitt S, Stamps BK, Hitchen PA. Autoimmune haemolysis in childhood and adolescence. Acta Haematol. 1984;72(4):245–57.CrossRefPubMedGoogle Scholar
  79. 79.
    Gottsche B, Salama A, Mueller-Eckhardt C. Donath-Landsteiner autoimmune hemolytic anemia in children. A study of 22 cases. Vox Sang. 1990;58(4):281–6.CrossRefPubMedGoogle Scholar
  80. 80.
    Heddle NM. Acute paroxysmal cold hemoglobinuria. Transfus Med Rev. 1989;3(3):219–29.CrossRefPubMedGoogle Scholar
  81. 81.
    Qiao L, Chen J, Leng XM, Zhang W, Han B, Zhao Y, et al. Agranulocytosis and mixed-type autoimmune hemolytic anemia in primary sjogren’s syndrome: a case report and review of the literature. Int J Rheum Dis. 2016;19(12):1351–3.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Baylor College of Medicine, Texas Children’s HospitalHoustonUSA

Personalised recommendations