AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 recurrent episodes was 1-20.¹⁰ 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Evans syndrome is a diagnosis of exclusion. Other causes of immune cytopenias should be excluded, such as:

SLE
IgA deficiency
Common variable immune deficiency
Acquired immune deficiency syndrome
Autoimmune lymphoproliferative syndrome
Paroxysmal nocturnal hemoglobinuria
Thrombotic thrombocytopenic purpura
Hemolytic-uremic syndrome
Kasabach-Merritt syndrome
Hypersplenism
Rosai Dorfman Disease (may be associated with autoimmune lymphoproliferative syndrome)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The CBC count and reticulocyte count reveal anemia, thrombocytopenia, neutropenia, or combined cytopenias; the reticulocyte count increases if the patient has anemia. Features of hemolysis include a raised reticulocyte count, increase in unconjugated bilirubin, and decreased haptoglobins.
• In Evans syndrome, the direct antiglobulin result (ie, Coombs test result) is almost invariably positive (often weakly) and may be positive for IgG, complement, or both. Indirect antiglobulin test findings may also be positive in 52-83% of patients.
• Prudent studies include measurement of serum immunoglobulins (to rule out such differential diagnoses as common variable immunodeficiency and IgA deficiency), serum markers for conditions such as SLE (measuring antinuclear antibody, double-stranded DNA), and peripheral blood T-cell subsets using flow cytometry (to rule out autoimmune lymphoproliferative syndrome) and bone marrow examination (to rule out infiltrative disorders).
• Various antibodies directed against RBCs and platelets (eg, antierythrocyte, antineutrophil, antiplatelet antibodies) occur in association with Evans syndrome.
• • In a study by Fagiolo of 32 adults, as many as 91% had antiplatelet antibodies demonstrated using thromboagglutination and indirect antiglobulin consumption tests.¹⁵ About 81% had leukocyte antibodies detected using cytotoxicity testing. However, variable intervals were reported between the detection of antibodies and the demonstration of leukopenia or thrombocytopenia. No relationship was shown between the leukocyte antibodies and platelet antibodies (alone or in combination) and the type of RBC antibodies.
  • Kakaiya et al reported that the antibodies directed against RBCs and platelets were different.¹⁶ Pegels et al confirmed this finding.¹⁷ In absorption and elution experiments, they found that the autoantibodies were directed against specific antigens on RBCs, platelets, and white cells, and that the autoantibodies did not cross-react. These findings lead to questions about the clinical usefulness of these tests. Pui et al found platelet antibodies in only 2 of 6 children tested.⁷ Antineutrophil antibodies were positive in 3 of 4 patients with neutropenia. Therefore, positive antibody results are useful, but negative results provide little clinical information.

Other Tests

• Lupus antibody (Lupuslike inhibitor) and antinuclear antibody tests are used to detect SLE.
• Perform T-cell and B-cell function tests for quantitative immunoglobulins to evaluate for hypogammaglobulinemia and perturbations in T-cell numbers.
• Bone marrow aspiration helps reveal aplastic anemia or an infiltrative disorder. Bone marrow aspiration may be indicated when patients initially present with pancytopenia.
• Flow cytometry of blood samples is indicated to look for double negatives.
• Gene mutation studies are used to detect known condition such as autoimmune lymphoproliferative syndrome.

Procedures

• Blood tests are typically used to determine the CBC count and reticulocyte count and to perform the Coombs test.
• Bone marrow aspiration helps in evaluating the morphology and is usually indicated in patients who present with pancytopenia to exclude infiltrative processes.
• Bone marrow examination is usually not indicated in classic cases when patients present with AIHA or immune thrombocytopenia.

Histologic Findings

• Bone marrow studies may reveal erythroid hyperplasia and, occasionally, hypoplasia if AIHA is the predominant finding.
• Normal levels or increased numbers of megakaryocytes confirm that thrombocytopenia is caused by increased destruction in the blood.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• The management of Evans syndrome is challenging. Although almost all patients require therapy at some time during the course of the disease, the search for a consistent, effective, and nontoxic therapy continues. Medical therapy continues to be the mainstay. Response to therapy varies even within the same individual, and the disease is characterized by periods of remission and exacerbation. No randomized trials have been conducted in patients with Evans syndrome, and the evidence for treatment is based on case reports, case series, and retrospective studies.
• Prednisone therapy, the most commonly used first-line therapy, often effectively controls acute episodes, although relapses may be frequent when patients are weaned off prednisone.
• Intravenous immunoglobulin (IVIG) may help patients who depend on steroids.^{18, 19}
• Other therapies effective in small series include danazol, cyclosporine, azathioprine, cyclophosphamide, and vincristine.
• Recently, rituximab (a chimeric human/mouse monoclonal antibody which targets CD20 on B lymphocytes) has been used in the management of refractory patients.^{20, 21, 22, 23, 24, 25} Responses have varied. Norton and Roberts recently reviewed the use of rituximab in 18 patients (aged 0.3-65 y).²⁶ The results were encouraging, with sustained complete remission of as long as 17 months. In a recent pediatric prospective series by Rao et al, 2 patients with Evans syndrome were treated with rituximab; one had a partial response, and one had no response.²⁵ Complications associated with rituximab in these studies have been minimal; the most common is infusion-associated reaction.
• In an acute setting, blood transfusions and/or platelet transfusions may be required to alleviate symptoms, although their use should be minimized.
• Additional therapies include splenectomy, alemtuzumab administration, and hematopoietic stem cell transplantation.
• • The role of splenectomy is not clearly established, but it may improve blood counts and reduce steroid dependence; relapses are common and, in most cases, occur within 1-2 months postsplenectomy.
  • Children with Evans syndrome appear to have a higher risk of postsplenectomy sepsis, especially children with pancytopenia.
  • Autologous and allogeneic stem cell transplantation have been used in a small number of patients (14 patients aged 5-52 y), with mixed results.²⁷
  • Alemtuzumab is a humanized IgG monoclonal antibody specific for the CD52 antigen present on T cells and B cells. Willis et al reported its use in 3 patients with Evans syndrome; although a response was seen in 2 patients, both relapsed in 3 months.²⁸

Surgical Care

Consider splenectomy in refractory cases.

• Splenectomy may improve CBC counts and decrease the steroid requirement, although relapses are common.
• According to a national survey, splenectomy provided a reported duration of response that ranged from 1 week to 5 years; however, the median response duration was just one month.¹⁰
• The risk of infection after splenectomy appears to be increased in children with pancytopenia.

Consultations

• Pediatric hematologist
• Pediatric oncologist
• Rheumatologist
• Immunologist

Diet

• Dietary restrictions are not usually required.
• Patients receiving steroid therapy should have some restrictions on their salt, sugar, and fluid intake to prevent excessive fluid retention.

Activity

• Restrict activities based on patient tolerance and the degree of anemia and bruising.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prednisone (eg, 1-2 mg/kg dose, usually divided twice or three times daily) often effectively controls acute episodes. Although some patients are successfully weaned off steroids, relapses may occur when prednisone is tapered or stopped. Use an alternate-day steroid therapy, if possible.

Patients with persistent immune cytopenia and those who require prolonged or high doses of steroids may benefit from IVIG (eg, 1-2 gm/kg/d for 1-2 d). Their thrombocytopenia is more likely than their hemolysis to respond. Long-term control of thrombocytopenia is reportedly achieved with interval doses of IVIG.

Other therapies reported in a national survey by Mathew et al included immunomodulating agents (eg, cyclosporine, danazol, azathioprine, cyclophosphamide, vincristine).¹⁰ Plasmapheresis was performed in 3 patients. One patient had transient responses, at best, to receiving the immunosuppressive agent tacrolimus (Prograf, FK506), protein A-Sepharose column plasmapheresis, whole blood exchange transfusion, and total nodal irradiation. Another patient showed some response to treatment with a combination of Rh D immunoglobulin (anti-D), methotrexate, prednisone, and folic acid (responses to these agents varied).

One pilot study showed that a multiagent approach may be effective in patients with Evans syndrome²⁹. Transfusions of RBCs and platelets were also used as adjuncts to treatment.

One of the newer agents that has been tried in refractory Evans syndrome is rituximab. However, recent reports suggest that it is being used as a second-line therapy. Rituximab is approved for the treatment of relapsed and refractory B-cell non-Hodgkin lymphoma. Binding of rituximab to cells expressing CD20 results in cell death by means of a combination of mechanisms, including antibody-dependent cell cytotoxicity, complement activation and apoptosis. Hence, it has been used in the treatment of various autoimmune disorders mediated by autoantibodies.

Galor et al reported the successful use of rituximab in a patient with Evans syndrome.²⁰ Mantadakis et al reported its successful use in a patient with long-lasting Evans syndrome refractory to standard treatments; the patient responded well to Rituximab and then responded again when relapse occurred 7 months later.²¹ In contrast, Grossi et al treated 2 patients with rituximab without success.³⁰ In fact, the patients had a worsening of their anemia. Zecca et al described the weekly use of rituximab in 5 children with Evans syndrome, all of whom were successfully treated.²² In a retrospective review of patients at the Mayo Clinic, Shanafelt reported responses in one of the cytopenias among 3 patients with Evans syndrome, but not both.²³

Drug Category: Glucocorticoids

Initial therapy for Evans syndrome. Elicits anti-inflammatory properties and cause profound and varied metabolic effects. They modify the immune response of the body to diverse stimuli.

Drug Category: Immune Globulin

This is a purified preparation of gamma globulin. It is derived from large pools of human plasma and is composed of 4 subclasses of antibodies, approximating the distribution of human serum.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients admitted for severe anemia or thrombocytopenia should have respiratory and cardiovascular functions stabilized first; receive blood transfusions, if needed, after consultation with a pediatric hematologist; and then be started on therapy with either IVIG or steroids.
• In classic cases (ie, patients who present with either AIHA or immune thrombocytopenia), bone marrow aspiration is not indicated.
• • When a patient has pancytopenia at presentation, or when diagnosis of immune thrombocytopenia is unconfirmed, bone marrow aspiration findings may help exclude an infiltrative pathology or an aplastic marrow.
  • Bone marrow examination may be indicated in unusual cases, in cases refractory to treatment, or in cases when a peripheral blood smear suggests immature myeloid cells.
• A patient may be discharged if clinically stable (eg, with rising blood counts).

Further Outpatient Care

• Weekly follow-up is recommended with blood counts and physical examinations until counts become stable or return to reference ranges.
• Subsequent follow-up care may be arranged at intervals of 2-4 weeks.
• More frequent follow-up care may be indicated for patients with clinical or laboratory signs of recurrence (eg, when steroids are tapered).

Complications

• A risk of hemorrhage with severe thrombocytopenia is noted.
• • The national survey reported hemorrhage in 29% of patients.¹⁰
  • This study reported 2 patient deaths from severe GI bleeding and a third death from an acute intracranial bleed.
• Patients with neutropenia also risk serious infection.
• • The national survey showed invasive infections in 29% of patients, including pneumonia, sepsis, and meningitis with Streptococcus pneumoniae, localized abscess, and osteomyelitis.
  • One patient died from presumed sepsis and liver failure 9 years after splenectomy.

Prognosis

• The characteristic clinical course of Evans syndrome has periods of remission and exacerbation, with variable and often disappointing responses to therapy.
• Recurrences of thrombocytopenia and anemia are common, as are episodes of hemorrhage and serious infections. Evans syndrome sometimes is fatal.
• Treatment occasionally provides complete resolution. In the national study on Evans syndrome, after a median follow-up of 3 years (range, 4 mo to 18.9 y), 48% had active disease and continued to be treated, 12% had persistent disease but were receiving no treatment, and 33% had no evidence of disease for periods ranging from 1.5-5 years (median, 1 y).¹⁰ Long-term survival data are limited. In patients followed for a median range of 3-8 years, the mortality ranged from 7-36%. Causes of death were mainly due to hemorrhage or sepsis. None of these patients developed any malignancy. 
• Patients rarely do well without treatment.
• • In the national survey, each patient received a median of 5 (range, 1-12) treatment modalities, either in combination or sequentially.¹⁰
  • Only one patient received no treatment; this patient's hemoglobin levels were 9-13.2 g/dL and platelet counts were 9-208,000/µL during follow-up examinations over 11 years.

Patient Education

• Educate patients and their families about the chronic nature of this condition, which can include periods of remission and exacerbation.
• Explain potential adverse effects of medications, especially long-term steroids, each time a steroid is used to treat an exacerbation.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Evans syndrome may not be apparent when a child presents with an isolated cytopenia. Therefore, diagnosis may be delayed until a second episode of cytopenia manifests.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Evans RS, Takahashi K, Duane RT. Primary thrombocytopenic purpura and acquired hemolytic anemia. Arch Intern Med. 1951;87:48-65.
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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].
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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.
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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].
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Article Last Updated: May 14, 2008