Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA) is a disorder in which red blood cells are destroyed by immune system (IgG and/or IgM autoantibodies) leading to manifestations of pallor and general symptoms.

The disorder originates from the following process: auto-immune.

Presentation

The most obvious pathognomonic sign of AIHA is anemia due to hemolysis. Passage of dark-colored urine indicates presence of free hemoglobin. Hemolysis per se leads to elevated levels of bilirubin in bile and urine, with jaundice indicating disease. Patients may complain of lumbar back pain. Affected individuals which test positive for cold agglutinins, develop acrocyanosis in cold weather [12]. Abdominal pain while eating cold food occurs due to ischemia associated with agglutination of RBCs in the viscera.

A slightly enlarged spleen may be palpable. Reticulocytosis or increased number of young red blood cells likewise indicates bone marrow activity to replace the depletion of erythrocytes in peripheral circulation. Severe hemolytic anemia may lead to cardiopulmonary decompensation and angina.

Workup

The key of laboratory diagnosis in AIHA is to demonstrate the occurrence of hemolysis and to determine the presence of autoantibodies and complement. Clinical laboratory techniques include:

  • Differential blood count
  • Complete blood count
  • Reticulocyte counts
  • Serum haptoglobin level
  • Lactate dehydrogenase (LDH)
  • Bilirubin
  • Coombs test

Microscopy of stained peripheral blood films will reveal the presence of red and white blood cells and their relative numbers. Damaged red cells release LDH confirming hemolysis, likewise bilirubin from hemoglobin.

Presence of immunoglobulins G and M, and C3d from the surface of RBCs can be demonstrated with the use of homologous monoclonal antibodies. Normally warm antibody AIHA (WAIHA) is readily detectable in RBCs coated with IgG or IgG + complement; if only with C3d, the antibody may be a cold antibody. A cold agglutinin titre of > 1:512 is required for the precise diagnosis of cold antibody AIHA (CAIHA). Inconclusive results e.g., negative antiglobulin test, low titre cold antibodies, or presence of Donath-Landsteiner antibodies should be referred to a specialized laboratory for confirmation.

Diagnosis of secondary AIHA includes evaluation of patient's status, onset of illness, possible predisposing factors such as infections, drug intake, transfusion, vaccination, and other immune diseases. Other causes of hemolytic anemia should be ruled out. Complete abdominal CT scan may be needed to detect malignancies and splenomegaly. Bone marrow aspirate is recommended.

Treatment

The rationale of treatment of AIHA lies in alleviating symptoms and in averting a hemolytic crisis by sudden decrease of red blood cells. Short-term and long-term effects of intervention may be anticipated. The treatment modality follows whether AIHA is primary or secondary, warm or cold antibody-mediated.

Transfusion may be needed depending upon the patient's condition and the aforementioned considerations. For warm antibody-mediated hemolytic anemia, blood group antigens are involved and RBC can be transfused safely except those obtained from an allogenic donor. Steroids should be administered immediately in WAIHA. For cold antibody-mediated hemolytic anemia, donor's blood is prewarmed with commercial warming coils.

Treatment of primary WAIHA

First-line treatment: Glucocorticoid is the drug of choice administered, per orem (prednisone or PDN), or parenteral methylprednisolone), at a dose of 1mg/kg/day. With this initial dose, hematocrit greater than 30% and hemoglobin level greater than 10g/dL should be expected in three weeks. Otherwise, a second-line treatment should be considered in lieu of steroids [13]. As soon the treatment goal is achieved, PDN is lowered to 20-30 mg/d within a few weeks, then, the dose is tapered slowly to 2.5-5 mg/d per month, or on alternate days to offset the deleterious side effects of prolonged steroid use. Meanwhile, hemoglobin and reticulocyte counts are closely monitored. Steroid therapy may be discontinued after 3-4 months when the patient is in remission at 5 mg PDN/day. Supplementation with calcium, vitamin D, bisphosphonates, and folic acid is recommended. About 80% of patients recover partially or completely after PDN therapy.

Second-line treatment: The following patients qualify under this option:

  1. Patients who did not respond well to initial steroid treatment and required more than 15 mg/day PDN maintenance dose.
  2. Patients who required between 15 and 0.1 mg/kg/day PDN may be advised to take this option.
  3. Patients who respond well to PDN at 0.1 mg/kg/day or less may continue treatment with low-dose PDN.

In any case, benefit versus risk should be weighed for each treatment option. Rituximab and splenectomy are the only second-line alternatives with proven short-term efficacy. Splenectomy is the next best choice, because of high short-term efficacy and minimal surgical risk. Prior to surgery, patients should be vaccinated against pneumococci, meningococci and hemophilus. Pneumococci vaccination should be repeated every 5 years. Patients should be advised on the risk for venous thromboembolism and to consult a doctor for antibiotic therapy in case of fever or infection.

Laparoscopic splenectomy has been successful in almost all cases of primary AIHA, as the spleen is not too large. Postoperative thromboprophylaxis using low-molecular-weight heparin is prescribed for all patients even after discharge from the hospital. Withdrawal of steroids is gradual to avoid hemolytic crises in case of recurrence. About two thirds of patients (ranging from 38-82%) experience short-term partial or complete recovery after splenectomy.

An other option for second line treatment is rituximab, a monoclonal antibody against CD20 which is found on the surface of B cells of the adaptive immune system. The standard IV regimen is 375 mg/m2 on days 1, 8, 15, 22 as 4 doses. Patients on steroid therapy should continue taking steroids until the first signs of response to rituximab become evident.

The short-term benefit-to-risk ratio for rituximab is high and it is recommended for patients who can not undergo splenectomy because of high risk for venous thromboembolism, obesity, and presence of untreated hepatitis B virus infection. Second-line therapy often consists of high-dose immunoglobulin after or concurrent with PDN since the efficacy is considered high and the risk of side effects is reduced.

Treatment in patients with refractory/recurrent disease following splenectomy or rituximab: Patients in this category may undergo retreatment with low doses of PDN and, if both alternatives fail, splenectomy is the only other option.

Treatment in secondary WAIHA

  • WAIHA associated with systemic lupus erythematosus: The preferred first-line treatments are steroids, prescribed as in primary AIHA, and with high rate of success. Recurrence rate was low (3-4/100 patient-years) in patients treated with a maintenance dose of 5-20 mg PDN (in some patients, with azathioprine or cyclophosphamide).
  • CLL-associated WAIHA: Chronic lymphocytic leukemia (CLL)–associated WAIHA. CLL-associated WAIHA may be either “spontaneous” or drug-induced. The stage and clinical course of illness with CLL will affect treatment. Patients are older than those with primary AIHA, are at a greater risk of infection and with higher comorbidity rates. Steroids are considered appropriate for patients with early nonprogressive CLL although the efficacy of steroid monotherapy has yet to be established by controlled studies. Steroid monotherapy has been successful in the treatment of fludarabine-induced CLL-associated AIHA. In AIHA associated with untreated “active” CLL long-term steroid treatment with chlorambucil has been successful, with 84% CR/PR, and 54% of the patients in CR are relapse-free after 5 years. Toxicity is tolerable. Multidrug therapy has been tried with good results in patients with steroid-refractory AIHA in CLL. The treatment in this kind of patients is a combination of rituximab, dexamethasone and cyclophosphamide or rituximab, cyclophosphamide, vincristine, and PDN or and rituximab and cyclosporine, an effective immunomodulatory agent. Rituximab monotherapy was found to be less active and more toxic in CLL-WAIHA than in primary AIHA [14]. Data on long-term benefits and efficacy of rituximab are lacking.
  • WAIHA in non-Hodgkin lymphoma: Intensive antilymphoma chemotherapy with or without rituximab is indicated for B-cell lymphoma, follicular lymphoma, angioimmunoblastic T-cell lymphoma, and other T-cell lymphomas.
  • Drug-related WAIHA: AIHA may occur during or after exposure to drugs. Drug related AIHA has been linked to treatment of CLL with fludarabine and other antileukemic drugs. Fludarabine-triggered AIHA may be potentially fatal. This type of disorder responds to steroids although only 50% of patients go on remission without steroids. Interferon treatment likewise presdiposes to WAIHA especially in hepatitis C patients. Recovery from WAIHA follows after withdrawal of interferon.

Treatment of CAIHA

All cases of cold autoantibody hemolytic anemia (CAIHA) are presumably secondary. The underlying disorders in most cases are lymphoproliferative disorders, including IgM–monoclonal gammopathy, and less frequently, autoimmune disorders, infections, and rarely drugs.

  • Primary chronic cold agglutinin disease:Anemia is often mild and chronic. Only 50% of patients require treatment with drugs. Patients need to avoid exposure to cold weather. CAIHA does not respond well to steroids and/or removal of spleen. The drug of choice is rituximab given at a standard dose for lymphoma.
  • Secondary CAIHA: Chronic cold agglutinin AIHA may occur in indolent and aggressive B- and T-cell lymphoma. Antilymphoma chemotherapy is prescribed.

Prognosis

Except in the elderly and patients with cardiovascular disease, there is spontaneous recovery in AIHA. AIHA is a rare disorder and, in any case, mortality rates are generally low. Prognosis is good in secondary AIHA when co-existing disease conditions are recognized and eliminated clinically.

Etiology

Autoimmune hemolytic anemia is triggered by the attachment of autoantibodies and C3 complement to erythrocytes. Warm or cold autoantibody types, but rarely mixed types are present [5] [6] [7]. Warm autoantibodies are self-generated immunoglobulins that adhere to the erythrocytes at body temperatures above normal. This occurs in warm antibody hemolytic anemia. In contrast, self-generated cold immunoglobulins are active at temperatures below normal, as in cold antibody hemolytic anemia. Erythrocytes that are coated with autoantibodies and complement rupture easily and are phagocytosed by macrophages in the liver and spleen.

Unable to recognize the RBC as "self", antibodies and complement are part of the immune system's reaction to a foreign body that needs to be eliminated. The presence of antibodies and complement can be demonstrated by direct Coombs test or direct antiglobulin test (DAT).

Secondary AIHA may result from other illnesses, such as neoplasms, lymphoproliferative disorders, infections, and other autoimmune diseases. Sometimes AIHA may develop following an allogeneic hematopoietic stem cell transplant.

Epidemiology

The annual incidence was estimated to be 0.8 per 100,000 population [1]. An earlier estimate was 1-3 per 100,000 [8]. The prevalence is 17 cases per 100,000 population [2]. AIHA affects women more than men. Women who are affected, are usually under 50 years of age. Cold antibody hemolytic anemia is common among the elderly, while warm antibody hemolytic anemia affects all age groups.

Sex distribution
Age distribution

Pathophysiology

As it were, the precise etiology of AIHA remains to be elucidated. What is known is that warm IgG antibody hemolytic anemia is associated with the Rh blood group system [9]. IgG-coated erythrocytes are targeted and destroyed in the spleen by macrophages [10]. In cold antibody AIHA, IgM-coated RBCs are bound by complement at the level of C3 resulting in the formation of a complex with other complement proteins, which facilitate opsonization and phagocytosis by hepatic macrophages [11].

Prevention

Autoimmune hemolytic anemia can not be anticipated but one can be aware of conditions that may trigger the occurrence of the disorder.

Summary

The body's immune system is a closely coordinated network of structures and processes designed to provide protection against foreign bodies. In autoimmune diseases, as in systemic lupus erythematosus, this discriminatory function is abrogated. Hemolytic anemia is the process of premature destruction of red blood cells (RBCs). The disorder develops if the bone marrow is unable to counterbalance for the premature loss of RBCs.

The severity of anemia depends on the onset of hemolysis, be it gradual or sudden, and on the level of red cell destruction. Mild forms of hemolysis may be asymptomatic whereas severe hemolytic anemia may be critical, causing cardiopulmonary symptoms as decompensation and angina.

Autoimmune hemolytic anemia (AIHA) is a relatively rare condition. Primary or idiopathic AIHA is less frequently encountered than secondary AIHA. Further more, secondary AIHA requires that other underlying disorders be identified and treated as well. AIHA is diagnosed on the basis of laboratory tests and here substantial amounts of improvements have been made, on the other hand, treatment modalities have not advanced much [3] [4]. Meanwhile, steroids continue to be the mainstay in AIHA therapy. Splenectomy is recommended in refractory cases.

Patient Information

Autoimmune hemolytic anemia (AIHA) is a rare disorder in which the body' s immune system destroys its own red blood cells by releasing proteins that are meant to protect it from "outsiders" or so-called "non-self", such as infectious disease agents. The proteins are antibodies or immunogloblins G and M produced by the bone marrow and thymus gland, and complement, from the liver. Autoantibody and complement-coated red cells rupture or lyze and are eliminated by phagocytic while blood cells (phagocytes) in the liver and spleen. Red blood cells (erythrocytes) are killed prematurely, thus, are unable to attain their normal life span of 120 days, resulting in anemia (loss of hemoglobin) and symptoms like pallor and general debility.

The disorder affects women more than men. The exact cause of AIHA is not known, hence, it is called primary idiopathic AIHA. Secondary AIHA is usually associated with some underlying condition (infection, other autoimmune disease, malignancy, drugs) that need to be diagnosed and treated together with AIHA.

According to the type of immunoglobulin produced, AIHA is of two categories, namely:

  • Warm autoantibody hemolytic anemia (WAIHA), in which IgG (immunoglobulin G) adheres to red blood cells at temperatures equal to or above normal body temperature and
  • Cold autoantibody hemolytic anemia (CAIHA), in which immunoblobulin M (IgM) attaches to red blood cells at temperatures below normal.

AIHA patients may be asymptomatic if destruction of erythrocytes is not massive and onset is gradual. Symptoms, if any, are fatigue, weakness and pallor. CAIHA patients may experience bluish, cold hands and feet (acrocyanosis) and abdominal pain when eating cold food. Symptoms of fever and swollen, painful lymph nodes may accompany CAIHA.

The presence of young red blood cells (reticulocytes) in peripheral circulation beyond normal range indicate that the bone marrow is compensating for the loss of mature red cells. Antibodies and complement can be detected by appropriate immunological tests in serum or on the surface of erythrocytes. Routine clinical laboratory methods can confirm other hematological abnormalities.

Treatment may be deferred in asymptomatic cases. Otherwise several options are available. Initially, oral or parenteral corticosteroid can be administered in gradually diminishing doses. Second-line treatment include: IV administration of an immunoglobulin against CD20; drug combinations especially for WAIHA and CAIHA; and, finally, if chemotherapeutics fail, for some reason or another, splenectomy.

While there are surgical risks, there are also the side effects of chemotherapy to consider, the patient's status, and personal decision. Follow-up is important even after discharge from the hospital. In the case of secondary AIHA, protection against recurrence of infection and concomitant diseases must be considered.

Self-assessment

References

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Self-assessment