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Anemia
Howard A. Liebman, MA, MD*, Ilene C. Weitz, MS, MD
KEYWORDS
Anemia Hemolysis Autoantibodies
KEY POINTS
Autoimmune hemolytic anemia results from antibody-mediated destruction of red blood
cells.
It can be a primary disorder or associated with other immune and nonimmune disorders.
In most cases, immune modulation is required for treatment.
INTRODUCTION
Jane Anne Nohl Division of Hematology, Department of Medicine, Keck School of Medicine,
University of Southern California, Los Angeles, CA, USA
* Corresponding author. Jane Anne Nohl Division of Hematology, USC Norris Cancer Hospital,
1441 Eastlake Avenue, Suite 3466, Los Angeles, CA 90033.
E-mail address: liebman@usc.edu
Patients with AIHA can have a highly variable clinical presentation.14 Patients may
describe symptoms related to their anemia such as fatigue, weakness, dyspnea
Table 1
Serologic types of autoimmune hemolytic anemia
Box 1
Secondary forms of autoimmune hemolytic anemia
Autoimmune Disorders
Lupus erythematosus (SLE)
Rheumatoid arthritis (RA)
Antiphospholipid syndrome
Inflammatory bowel disease (Crohn disease and ulcerative colitis)
Primary biliary cirrhosis
Autoimmune thyroid disease
Evan syndrome
Immunodeficiency disorders
Common variable immunodeficiency (CVID)
Autoimmune lymphoproliferative syndrome (ALPS)
IgA deficiency
Post-transplant (solid organ and autologous bone marrow transplant)
Lymphoproliferative
Chronic lymphocytic leukemia (CLL)
Non-Hodgkin lymphoma (NHL)
Hodgkin lymphoma
Angioimmunoblastic lymphadenopathy
Waldenstrom macroglobulinemia
Infections
Epstein Barr virus
Cytomegalovirus
Human immunodeficiency virus
Hepatitis C
Mycoplasma pneumonia
Rare: Varicella, Rubella, Parvo B19
Table 2
Drugs frequently reported to be associated with autoimmune hemolytic anemia (>10 reports)
Drug Mechanism
Penicillins Membrane absorptionhaptene
Cephalosporin-first generation Nonimmune protein absorption
Cephalosporin second -third generation Immune complex
Alpha methyl dopaimmune hemolytic anemia Drug-dependent autoantibodies
Fludarabine Drug-dependent autoantibodies
Oxaliplatinum Drug-dependent autoantibodies
354 Liebman & Weitz
autoantibodies. In patients with acquired hemolytic anemia with blood smears consis-
tent with AIHA, but a negative DAT, more specialized studies are needed to determine
if hemolysis is due to a low concentration or low affinity IgG, an IgA, or monomeric
IgM.8
TREATMENT
The correct serologic diagnosis of a patient with AIHA is essential before initiating ther-
apy. The therapeutic approach to warm hemolytic anemia is significantly different from
patients with cold agglutinin hemolysis. In patients with secondary AIHA, consider-
ation must be given to the effect of treatment on the associated disorder. Other
comorbidities such as diabetes, atherosclerotic and coronary vascular disease, renal
disease, the presence of venous thrombosis, and other cytopenias may require mod-
ifications in or additions to the therapeutic approach to the AIHA.
Corticosteroids
Corticosteroids are the primary therapeutic agent for the treatment of warm antibody
AIHA. However, there are no prospective trials on the optimal use of corticosteroids in
patients with AIHA. An analysis of 6 studies, comprising 301 patients with warm AIHA,
evaluated the initial use of corticosteroids for the treatment of AIHA.22 Most patients
were initially treated with prednisone 1 mg to 1.5/kg/d until hemoglobin stabilized
and then were often treated with lower doses (<10 mg/d) for 3 to 6 months. A good
response was reported in 248 (82%) patients. However, only 15% to 20% of patients
achieved a long-term remission upon withdrawal of corticosteroids.2224 Long-term
outcome data from patients with AIHA treated with corticosteroids alone are sadly
lacking since up to 50% of patients require longer-term low-dose corticosteroid
maintenance.2224
Standard doses of corticosteroids are often less effective in some patients with sec-
ondary AIHA.2527 This can be particularly true for patients with chronic lymphocytic
leukemia (CLL) and AIHA. In refractory CLL patients, the use of high-dose methylpred-
nisolone or pulse dexamethasone appears to be more effective, often combined with
cyclophosphamide and rituximab.2527 Standard doses of prednisone are relatively
ineffective in cold agglutinin hemolytic anemia. However, pulse doses of dexametha-
sone (40 mg/d for 4 days), as used in multiple myeloma, can be effective in patients
with cold agglutinin disease, but are usually combined with either rituximab or
cyclophosphamide.
Splenectomy
Prior to the advent of corticosteroid therapy, splenectomy was the only effective treat-
ment for warm antibody AIHA. In an early study of 34 patients with primary AIHA, 27
patients (79%) were treated with a splenectomy.28 Although the subsequent long-term
outcome of the splenectomized patients was not reported, 18 of the 34 (53%) primary
AIHA patients died of their disease.28 Splenectomy is not effective in cold antibody he-
molytic anemia.
Most contemporary reports on the use of splenectomy for the treatment of AIHA
report a 40% to 80% initial response, with up to a 20% long-term remission.2931
The advent of laparoscopic splenectomy combined with postsurgical antibiotic and
thrombotic prophylaxis has significantly reduced surgery-related morbidity and mor-
tality.32 However, a long-term increased risk of overwhelming sepsis remains even
with appropriate immunizations.24,33 The risk of severe infection is approximately
3% to 7%, with a nearly 50% mortality.33,34 In addition, a long-term increased risk
356 Liebman & Weitz
of venous thromboembolism has been observed in patients treated for immune throm-
bocytopenia with splenectomy.24,35
Immunosuppressive Drugs
It was only 3 years after Robert Schwartz and William Dameshek demonstrated the
ability of 6-mercaptopurine to induce immune tolerance in rabbits that the drug was
found to be effective in the treatment of AIHA.36,37 The drug and its prodrug, azathio-
prine, remain among the most effective second-line treatments for steroid refractory
and steroid-dependent patients with warm antibody AIHA. The reported responses
are 40% to 60%, with 10% to 20% of patients obtaining a complete response.30,38
The usual treatment dose azathioprine is 2 to 3 mg/kg/d (100250 mg). The drugs ma-
jor benefit is in its ability to allow a reduction in corticosteroid dosing.30,38 The long-
term use of azathioprine appears to be well tolerated by most patients.
Cyclophosphamide has also been shown to be an effective therapy in both warm
antibody and cold agglutinin AIHA.16,30,38,39 Initial responses in warm antibody AIHA
range from 40% to 60%, but durable response occurs in only 20% to 30% treated pa-
tients. Treatment doses range from daily low dose oral (50 mg to 100 mg/d) to high-
dose intravenous doses (50 mg/kg for 4 days). Combination treatment with rituximab
and corticosteroids appears to be most effective in treating warm and cold agglutinin
AIHA associated with lymphoproliferative malignancies.27 Toxicities of cyclophospha-
mide treatment include nausea, bone marrow suppression with neutropenia frequently
observed, male and female sterility, hemorrhagic cystitis, and long-term use bladder
fibrosis. Treatment-related myelodysplasia and leukemia are rare, but significant
late complications.
Patients who fail to respond to standard second-line therapy cytotoxic agents such
as azathioprine or cyclophosphamide may respond to treatment with other immune-
modulating agents such as cyclosporine, mycophenolate mofetil, or sirolimus.30,3843
However, the few case reports that document responses to these second-line thera-
pies provide few long-term outcome data on responding patients.
SUMMARY
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