eMedicine Specialties > Pediatrics: General Medicine > Hematology

Evans Syndrome

Author: Prasad Mathew, MBBS, DCh, Director, Hemostasis and Hematology Program, Professor of Pediatrics, University of New Mexico
Contributor Information and Disclosures

Updated: Nov 19, 2009

Introduction

Background

In 1951, Evans and colleagues described a group of patients whose clinical course was characterized by immune thrombocytopenia and autoimmune hemolytic anemia (AIHA).1 The anemia and thrombocytopenia varied in time of onset, course, and duration. Spontaneous remission and exacerbation were common, and a few patients had neutropenia.

Evans syndrome is the coexistence of simultaneous or sequential direct Coombs-positive AIHA in conjunction with immune-mediated thrombocytopenia, with no known underlying etiology. The typical clinical course is chronic and relapsing, and therapy is generally progressive and poor. Although Evans syndrome seems to be a disorder of immune regulation, the exact pathophysiology is unknown. Autoantibodies targeted at different antigenic determinants on red cells and platelets are assumed to cause isolated episodes of hemolytic anemia and thrombocytopenia, respectively.

Pathophysiology

The etiology of Evans syndrome is unknown. Noncrossreacting autoantibodies are directed against antigens specific to red cells, platelets, or neutrophils. Wang et al demonstrated decreased levels of serum immunoglobulin (Ig) G, IgM, and IgA in these patients.2,3 The cytopenias that occur with Evans syndrome may be related to T-cell abnormalities because decreased T-helper cells and increased T-suppressor cells were noted in these patients.

Savasan et al observed that more than half of the patients with Evans syndrome had evidence of lymphoid hyperactivity.4  Teachey et al demonstrated that numerous patients (58%) with Evans syndrome may have autoimmune lymphoproliferative syndrome , a novel finding that may have important therapeutic implications.5

Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and defective expression of either Fas or Fas ligand results in marked overaccumulation of mature lymphocytes and autoimmune disease in mice. The results of recent studies suggest that defective lymphocyte apoptosis caused by mutations of the Fas gene can result in a severe autoimmune lymphoproliferative syndrome in humans. 

Teachey et al screened 12 children using flow cytometry for CD4/CD8 (double-negative) T cells and using the definitive test for autoimmune lymphoproliferative syndrome (ie, defective in vitro Fas-mediated apoptosis).5  Six patients had elevated numbers of these double negative T cells and defective Fas-mediated apoptosis and one patient had borderline elevation; this suggests that 7 patients with Evans syndrome (58%) had evidence suggestive of autoimmune lymphoproliferative syndrome. This finding suggests Evans syndrome and autoimmune lymphoproliferative syndrome may have some overlap.

Frequency

United States

Evans syndrome is an uncommon but not rare condition; its exact frequency is unknown. Familial occurrence is rare.

Pirofsky estimated the minimal annual incidence of immune hemolytic anemia to be one case per 80,000 US residents (mostly adults).6 In a combined series of 1064 patients with childhood immune thrombocytopenia, only 9 had autoimmune hemolytic anemia associated with immune thrombocytopenia; however, thrombocytopenia occurs relatively often in patients with autoimmune hemolytic anemia. Frequencies of 1.6-59.4% have been reported in adults.

Pui et al first described 7 children with Evans syndrome out of 164 cases of immune thrombocytopenia and 15 cases of AIHA.7 Habibi et al observed that 10 of 46 children with prolonged chronic AIHA had thrombocytopenia.8

International

In a report from Malaysia by Ng, Evans syndrome was diagnosed in 12 of 220 adult patients with immune thrombocytopenia and 102 with AIHA.9

Mortality/Morbidity

Evans syndrome has a chronic, relapsing, and sometimes fatal course.

  • According to Mathew et al, the course of Evans syndrome is characterized by recurrences of thrombocytopenia in 60% of patients; the number of reported 10 AIHA recurred in 31% of patients; the number of episodes was 1-8. Neutropenia recurred in 15% of patients.
  • In a median follow-up study of 42 patients (aged 4 m to 18.9 y) that spanned 3 years, 3 patients (7%) had died, 20 (48%) had active disease and remained on some treatment, and 5 (12%) had persistent disease but were not receiving any treatment.10 The remaining 14 (33%) had no evidence of disease for 1.5 months to 5 years (median 1 y). Fourteen (33%) had no evidence of disease for 1.5 months to 5 years (median 1 year).

Race

  • Of 42 patients reported in a national survey, 29 were white, 7 were black, and 6 had other racial backgrounds.10 This distribution could suggest a preponderance among whites or a reporting bias.
  • As individual conditions, AIHA and immune thrombocytopenia have no racial predilection.

Sex

  • No predilection is known in Evans syndrome; AIHA affects boys more frequently than girls at a ratio of 1.4:1.
  • Among adults, AIHA affects women more often than men. In one study from Genty et al, 67% of cases occurred in women.11

Age

Evans syndrome occurs in individuals of all ages.

  • In a 1997 survey of North American pediatric hematologists, the median reported age at diagnosis was 7.7 years (range 0.2-26.6 y).10 This late presentation age may indicate the disease was undiagnosed until the second presentation of cytopenia, which was usually months to years after the first presentation.
  • Evans syndrome in adults has been anecdotally reported.

Clinical

History

  • In a national survey, thrombocytopenia was the presenting feature in 76% of patients with Evans syndrome, and anemia was the presenting feature in 67% of these patients.10
  • In addition, 24% of patients had neutropenia, and 14% had pancytopenia.

Physical

Evans syndrome is a diagnosis of exclusion. Confounding disorders, such as infections, rheumatologic diseases, and malignancies can present with autoimmune cytopenias, must be ruled out.

  • Signs of thrombocytopenia include purpura, petechiae, and ecchymoses.
  • Signs of anemia include pallor, fatigue, and light-headedness.
  • Jaundice may indicate hemolysis.

Causes

The etiology of Evans syndrome remains unknown .

  • Autoantibodies are directed against antigens specific to red cells, platelets, or neutrophils, but these autoantibodies do not cross-react.
  • Many patients have associated disorders (eg, systemic lupus erythematosus [SLE] and other autoimmune diseases, chronic lymphadenopathy, hypogammaglobulinemia).
  • Acquired cytopenias occur in association with sex-linked agammaglobulinemia, common variable immunodeficiency, and IgA deficiency.
  • Evans syndrome has been diagnosed in one child with insulin-dependent diabetes mellitus,12  in another after an autologous bone marrow transplant for recurrent Hodgkin disease,13 and in one child with Celiac disease.14
  • Most patients with Evans syndrome have decreased levels of serum IgG, IgM, and IgA and decreased in vitro synthesis of IgG and/or IgM.
  • Decreased T-helper lymphocyte populations and increased T-suppressor lymphocyte populations that are similar to levels found in congenital hypoplastic anemia and amegakaryocytic thrombocytopenia have been observed. This finding has led to speculation that the cytopenias in Evans syndrome may relate to T-cell abnormalities.
  • Teachey et al demonstrated that numerous patients with Evans syndrome may have autoimmune lymphoproliferative syndrome.5
  • The role of childhood immunizations in the development of Evans syndrome has been investigated, but specific associations have not been reported. However, case reports suggest that immunizations may trigger the development of this disease in susceptible individuals.

More on Evans Syndrome

Overview: Evans Syndrome
Differential Diagnoses & Workup: Evans Syndrome
Treatment & Medication: Evans Syndrome
Follow-up: Evans Syndrome
References
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References

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  2. Wang W, Herrod H, Pui CH. Immunoregulatory abnormalities in Evans syndrome. Am J Hematol. Dec 1983;15(4):381-90. [Medline].

  3. Wang WC. Evans syndrome in childhood: pathophysiology, clinical course, and treatment. Am J Pediatr Hematol Oncol. Winter 1988;10(4):330-8. [Medline].

  4. Savasan S, Warrier I, Ravindranath Y. The spectrum of Evans' syndrome. Arch Dis Child. Sep 1997;77(3):245-8. [Medline].

  5. Teachey DT, Manno CS, Axsom KM, et al. Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS). Blood. Mar 15 2005;105(6):2443-8. [Medline].

  6. Pirofsky B. Immune haemolytic disease: the autoimmune haemolytic anaemias. Clin Haematol. Feb 1975;4(1):167-89.

  7. Pui CH, Wilimas J, Wang W. Evans syndrome in childhood. J Pediatr. Nov 1980;97(5):754-8. [Medline].

  8. Habibi B, Homberg JC, Schaison G, Salmon C. Autoimmune hemolytic anemia in children. A review of 80 cases. Am J Med. Jan 1974;56(1):61-9. [Medline].

  9. Ng SC. Evans syndrome: a report on 12 patients. Clin Lab Haematol. 1992;14(3):189-93. [Medline].

  10. Mathew P, Chen G, Wang W. Evans syndrome: results of a national survey. J Pediatr Hematol Oncol. Sep-Oct 1997;19(5):433-7. [Medline].

  11. Genty I, Michel M, Hermine O, Schaeffer A, Godeau B, Rochant H. [Characteristics of autoimmune hemolytic anemia in adults: retrospective analysis of 83 cases]. Rev Med Interne. Nov 2002;23(11):901-9. [Medline].

  12. Franklin VL, Torrance T, Peebles M, Wilkie R, Greene S. Life-threatening autoimmunity with diabetes: management with an insulin pump. Pediatr Diabetes. Sep 2003;4(3):151-4. [Medline].

  13. Keung YK, Cobos E, Bolanos-Meade J, et al. Evans syndrome after autologous bone marrow transplant for recurrent Hodgkin's disease. Bone Marrow Transplant. Dec 1997;20(12):1099-101. [Medline].

  14. Yarali, Nese; Demirceken, Fulya; Kondolat, Meda; Ozkasap, Serdar; Kara, Abdurrahman; Tunc, et al. A Rare Condition Associated With Celiac Disease: Evans Syndrome. Journal of Pediatric Hematology/Oncology. September 2007;29 (9):633-635.

  15. Fagiolo E. Platelet and leukocyte antibodies in autoimmune hemolytic anemia. Acta Haematol. 1976;56(2):97-106. [Medline].

  16. Kakaiya RM, Sherman LA, Miller WV, Katz AJ. Nature of platelet antibody in Evans syndrome: a case report. Ann Clin Lab Sci. Nov-Dec 1981;11(6):511-5. [Medline].

  17. Pegels JG, Helmerhorst FM, van Leeuwen EF. The Evans syndrome: characterization of the responsible autoantibodies. Br J Haematol. Jul 1982;51(3):445-50. [Medline].

  18. Blanchette VS, Kirby MA, Turner C. Role of intravenous immunoglobulin G in autoimmune hematologic disorders. Semin Hematol. Jul 1992;immunology(3 Suppl 2):72-82. [Medline].

  19. Nuss R, Wang W. Intravenous gamma globulin for thrombocytopenia in children with Evans syndrome. Am J Pediatr Hematol Oncol. Summer 1987;9(2):164-7. [Medline].

  20. Galor A, O'Brien T. Rituximab treatment for relapsed autoimmune hemolytic anemia in Evans syndrome. Int J Hematol. Nov 2003;78(4):335-6. [Medline].

  21. Mantadakis E, Danilatou V, Stiakaki E, Kalmanti M. Rituximab for refractory Evans syndrome and other immune-mediated hematologic diseases. Am J Hematol. Nov 2004;77(3):303-10. [Medline].

  22. Zecca M, Nobili B, Ramenghi U, et al. Rituximab for the treatment of refractory autoimmune hemolytic anemia in children. Blood. May 15 2003;101(10):3857-61. [Medline].

  23. Shanafelt TD, Madueme HL, Wolf RC, Tefferi A. Rituximab for immune cytopenia in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and Evans syndrome. Mayo Clin Proc. Nov 2003;78(11):1340-6. [Medline].

  24. Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood. Sep 15 1997;90(6):2188-95. [Medline].

  25. Rao A, Kelly M, Musselman M, et al. Safety, efficacy, and immune reconstitution after rituximab therapy in pediatric patients with chronic or refractory hematologic autoimmune cytopenias. Pediatr Blood Cancer. Jun 14, 2007;[Epub ahead of print].

  26. Norton A, Roberts I. Management of Evans syndrome. Br J Haematol. 2006;132:125-137.

  27. Raetz E, Beatty PG, Adams RH. Treatment of severe Evans syndrome with an allogeneic cord blood transplant. Bone Marrow Transplant. Sep 1997;20(5):427-9. [Medline].

  28. Willis F, Marsh JCW, Bevan DH, et al. The effect of treatment with Campath-1H in patients with autoimmune cytopenias. Br J Haematol. 2001;114:891-898.

  29. Scaradavou A, Bussel J. Evans syndrome. Results of a pilot study utilizing a multiagent treatment protocol. J Pediatr Hematol Oncol. Nov 1995;17(4):290-5. [Medline].

  30. Grossi A, Santini V, Longo G, et al. Treatment with anti CD20 antibodies of patients with autoimmune thrombocytopenia with or without hemolytic anemia: worsening in hemoglobin level [abstract]. Blood. 2000;96:1089A.

  31. Avcin T, Jazbec J, Kuhar M, et al. Evans syndrome associated with antiphospholipid antibodies. J Pediatr Hematol Oncol. Sep 2003;25(9):755-6. [Medline].

  32. Chen RT, Pless R, DeStafano F. Epidemiology of autoimmune reactions induced by vaccinations. J Autoimmunity. 2001;16:309-318.

  33. Conley ME, Park CL, Douglas SD. Childhood common variable immunodeficiency with autoimmune disease. J Pediatr. Jun 1986;108(6):915-22. [Medline].

  34. Miller BA, Schultz Beardsley D. Autoimmune pancytopenia of childhood associated with multisystem disease manifestations. J Pediatr. Dec 1983;103(6):877-81. [Medline].

  35. Petitt RM. Thrombotic thrombocytopenic purpura: a thirty year review. Semin Thromb Hemost. 1980;6(4):350-5. [Medline].

  36. Rosse WF. Paroxysmal nocturnal hemoglobinuria: the biochemical defects and the clinical syndrome. Blood Rev. Sep 1989;3(3):192-200. [Medline].

  37. Sneller MC, Wang J, Dale JK, et al. Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood. Feb 15 1997;89(4):1341-8. [Medline].

  38. Tsudo M, Moriguchi T. [Effective cyclosporine therapy to resistant-Evans syndrome]. Rinsho Ketsueki. Nov 1996;37(11):1289-92. [Medline].

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Further Reading

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Keywords

Evans syndrome, ES, autoimmune hemolytic anemia, AIHA, idiopathic thrombocytopenia, ITP, Evans syndrome, autoimmune lymphoproliferative syndrome, ALPS, common variable immunodeficiency, IgA deficiency, diabetes mellitus, Hodgkin disease, Celiac disease, treatment, diagnosis, symptoms

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Contributor Information and Disclosures

Author

Prasad Mathew, MBBS, DCh, Director, Hemostasis and Hematology Program, Professor of Pediatrics, University of New Mexico
Prasad Mathew, MBBS, DCh is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories
Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Gary D Crouch, MD, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Associate Professor, Uniformed Services University of the Health Sciences
Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

 
 
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