Pediatrics

Autoimmune Hemolytic Anemia

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Autoimmune Hemolytic Anemia? What are the typical findings for this disease?

Autoimmune Hemolytic Anemia (AIHA) is characterized by antibody-induced erythrocyte destruction. The patient's own antibodies are directed against antigens on their own red blood cells resulting in hemolysis and anemia.

AIHA is commonly separated into either Primary AIHA or Secondary AIHA (secondary to an underlying systemic illness such as an infection, Systemic Lupus Erythematosus, or malignancy; or secondary to drug exposure). See Table I.

Table I.

Classification of Autoimmune Hemolytic Anemia (AIHA) in Children
Primary AIHA Secondary AIHA
Warm-reactive antibodies, usually IgG + complement Immmunodeficiency (e.g., CVID, ALPS)
Paroxysmal Cold Hemoglobinuria (PCH), usually IgM + complement Infection (Mycoplasma, EBV)
Cold-agglutinin disease, usually IgM + complement Malignancy (lymphomas)
Systemic Autoimmune Disease (e.g., Lupus)
Drug-induced

The patient's symptoms will be proportional to the degree of physiologic stress which is determined by the severity of anemia, the rapidity of fall of the red cell mass, and the patient's underlying health.

When there is brisk hemolysis, especially in Primary AIHA, symptoms may be acute in onset with pallor, jaundice, splenomegaly and hemoglobinuria. Jaundice and/or hemoglobinuria are strongly suggestive of intravascular hemolysis, most common in cold agglutinin IgM-mediated AIHA and in Paroxysmal Cold Hemoglobinuria (PCH).

In other cases where hemolysis is less acute, symptoms may be more insidious with fatigue and mild pallor being the only findings as in cases of Secondary AIAH. A detailed history of prior illnesses, drug exposures, or evidence of an underlying illness are critical. If AIHA is secondary to an underlying disease or drug, the signs and symptoms may be more related to the primary condition than to the anemia itself.

The absence of jaundice and/or hemoglobinuria may suggest "warm" or IgG complement mediated immune hemolytic disease.

Marked adenopathy or hepatosplenomegaly suggests an underlying primary disorder with the AIHA being a secondary manifestation.

What other disease/condition shares some of these symptoms?

The conditions most likely to be confused with AIHA are:

1. Hereditary Spherocytosis and other RBC membrane defects

Hereditary Spherocytosis (HS) is a congenital, usually familial, disorder often manifested by hyperbilirubinemia in the newborn. A family history of HS, individuals who have undergone early splenectomy, or gall bladder disease may be suggestive.

Splenomegaly is present in 30% of patients with HS. Microspherocytes are present on the smear, and a reticulocytosis is expected. Classically, AIHA has a higher percentage of microspherocytes seen, but this is variable. The incubated osmotic fragility test detects the presence of microspherocytes, but does not determine the cause. The DAT is negative in HS, while almost always positive in AIHA.

2. Disseminated Intravascular Coagulopathy (DIC)

DIC is classically seen with very ill children. Microangiopathic changes on the peripheral blood smear are far more prominent in DIC than the mere presence of spherocytes as seen in AIHA. Thrombocytopenia of some degree is routine. Coagulation abnormalities – increased aPTT, PT, INR – as well as elevated D-dimer and decreased fibrinogen are expected. The DAT is negative.

3. Enzyme Deficiency Congenital Hemolytic Anemias: G6PD deficiency, pyruvate kinase deficiency, and others

AIHA could be confused with a hemolytic crisis in patients with G-6-PD deficiency, pyruvate kinase (PK) deficiency, or another more rare congenital enzymopathy. The smear should be fairly conclusive to a trained observer. Again, the family and personal history should be suggestive. The DAT should, again, be negative.

4. Hemolytic Uremic Syndrome (HUS)

Both HUS and thrombotic thrombocytopenia purpura (TTP) are characterized by microangiopathic changes on the peripheral smear, thrombocytopenia and renal dysfunction. The DAT is negative.

Hemolytic anemia may be due to other immune mediated mechanisms such as with ABO incompatibility (in the neonate) or with transfusion reactions but these conditions are not likely to be confused with AIHA.

What caused this disease to develop at this time?

In infants and toddlers primary AIHA occurs most commonly following a viral respiratory infection. Often the antibodies are of the IgG class.

Cold agglutinin disease is most commonly noted after either mycoplasma or EBV infection. The antibodies are usually of the IgM class and are associated with complement fixation on the the RBC causing hemolysis.

Secondary AIHA is more commonly seen in teenagers, particularly in association with an underlying autoimmune disorder.

Common drugs that are associated with AIHA are listed in Table II.

Table II.

Common drugs that are associated with AIHA
Drugs Commonly Associated with AIHA Other drugs that can cause AIHA
Cephalosporins Probenecid
Penicillin and/or Penicillin Derivative Levafloxacin
NSAIDS Carboplatin
Quinine and/or Quinidine

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Laboratory studies necessary for diagnosis include: CBC, platelet count, peripheral blood smear, reticulocyte count, Direct and Indirect Antiglobulin test (Coombs test), LDH, Haptoglobin, Urine analysis.

CBC with platelet count, RBC indices and peripheral blood smear for RBC morphology:

-Hemoglobin and hematocrit will be low.

-MCV is usually normal but the RDWs often elevated.

-Red cell morphology on review of the peripheral blood smear may demonstrate microspherocytes and polychromasia which are suggestive of a reactive reticulocytosis. RBC agglutination on the smear suggest cold-reactive (IgM) AIHA, with the IgM binding cells together.

-The presence of thrombocytopenia and poikilocytosis may suggest DIC.

Reticulocyte count:

-The reticulocyte is classically elevated. It may be normal or decreased if the underlying immune process also results in reticulocyte destruction in the marrow.

Direct and indirect antiglobulin or Coombs tests (DAT and IAT):

-Direct antiglobulin test (DAT, or direct Coombs) is usually positive. Specialized laboratory evaluation:

-The most important test is the direct antiglobulin test (DAT or direct Coombs test), which demonstrates the presence of antibody and/or complement on the erythrocyte surface. A positive DAT is followed by more specific testing with different antisera to distinquish between IgG, IgM and complement on the RBC. The presence of complement alone (no IgG) on the RBC suggests an IgM antibody which binds complement but elutes from the erythrocyte at higher temperatures. Further testing for an IgM antibody or the unique Donath -Landsteiner antibody should be considered. Specialized laboratory evaluation for drug-induced AIHA is usually needed.

The DAT can be negative in some cases of AIHA since the threshold for detection of IgG on the erythrocyte by this method can be greater than the amount of IgG needed to cause hemolysis. In this case, more sensitive tests ("micro Coombs") are available in some laboratories and may be needed for diagnosis.

The indirect antiglobulin test (IAT or indirect Coombs) detects antibody present in the patient's serum (i.e. free circulating antibody which is not bound to red cells). If the antibody is of high affinity that is strongly adherent to the red cells, the IAT may be negative while the DAT is positive.

LDH:

-Usually elevated.

Haptoglobin:

-Decreased with intravascular hemolysis.

Urine analysis:

-When hemolysis has been acute and brisk the patient may have hemoglobinuria.

Specialized laboratory evaluation:

-Screening for underlying disease, such as testing an ANA for SLE, is indicated for older children and those with a clinical history or exam suggesting secondary AIHA.

Would imaging studies be helpful? If so, which ones?

Imaging studies are not generally necessary and are only indicated if the history and exam suggest an underlying disease associated with AIHA (e.g. mycoplasma pneumonia) and/or complications of AIHA are suspected (e.g. high output heart failure with severe anemia).

If you are able to confirm that the patient has Autoimmune Hemolytic Anemia, what treatment should be initiated?

Therapy is aimed at: 1) stabilizing the patient's hemodynamic status, 2) decreasing the destruction and removal of antibody- and complement-coated red cells by the reticuloendothelial system using corticorsteriods, IVIG, or splenectomy, (3) decreasing circulating antibody levels by exchange transfusion or plasmapheresis, or (4) decreasing antibody production using rituximab, chemotherapy, and perhaps IVIG and splenectomy (see Table III).

Table III.

Treatment Modalities for AIHA
Treatment Dose
Red blood cell transfusions 5-10 cc PRBC/kg; Goal = Hgb 6-8 gm%
Corticosteroids 1-2 mg/kg gbh
IVIG 1 gm/kg/day for 1-5 days
Splenectomy
Rituximab 375 mg/m² IV Weekly x 8

The need to urgently treat a patient with AIHA depends upon the severity and rapidity with which anemia develops. Relatively mild anemia (9-12 gm % hemoglobin) may only require observation and close follow-up. If the antibodies causing hemolysis are cold-reactive, the patient should be kept in a warm environment and exposure to the cold avoided. More severe anemia (6-9 gm % hemoglobin) or rapidly falling hemoglobin levels frequently requires acute intervention. For marked intravascular hemolysis, maintenance of renal perfusion and urine output is critical.

Transfusion is indicated if there is a demonstrable physiologic effect of the anemia resulting in presence or risk of tissue hypoxia and/or tissue damage. Because of the antibodies present in the patient's circulation, fully compatible unit(s) of packed erythrocytes may be impossible to obtain. Therefore, when transfusion is required, the best available unit(s) should be cautiously administered with the goal in mind of stabilizing the patient, rather than achieving normal laboratory values.

For the acute management of severe anemia (< 5 gm % hemoglobin ), transfusion with the “least incompatible” unit(s) of packed erythrocytes is indicated. The goal is hemodynamic stability of the patient, not normalization of the patient's hemoglobin. Thus, transfusion of 5-10 cc/kg – perhaps repeatedly - is usually adequate. Transfusion should not be withheld for fear that it “will make things worse.” A slow initial infusion rate, while monitoring for free hemoglobin in the plasma and hemoglobinuria is prudent. In cases of cold-reactive AIHA, the blood must be warmed at the bedside.

For moderately severe warm-mediated AIHA, short-term therapy with corticosteroids at doses of 1-2mg/kg/every 6 hours may stabilize the hemoglobin and hematocrit levels.

Corticosteroids, commonly methylprednisolone 4mg/kg/day or equivalent, is the mainstay of therapy and is particularly suitable for treatment of IgG mediated disease.

IVIG and exchange transfusion are occasionally indicated. Other options include splenectomy, plasmapheresis, and chemotherapy. Each of these options should be considered in consultation with a pediatric hematologist.

If therapy with IVIG, rituximab, splenectomy, and/or chemotherapy is considered, it is best done in consultation with a pediatric hematologist.

For secondary AIHA, vigorous evaluation and expeditious treatment of the underlying disease is critical.

What are the adverse effects associated with each treatment option?

The most common adverse effects of the potential therapies are listed:

1) Corticosteroids - weight gain, hypertension, hyperglycemia, immune suppression, mood disturbances, effects on growth and bone density.

2) IVIG - allergic reaction, fever, headache.

3) Rituximab - immune suppresion, allergic reaction, rare malignancy

4) Splenectomy - surgical and post-operative complications, increased infection risk with encapsulated bacteria.

5) Chemotherapy - myelosuppresion, immune suppression, nausea and vomiting.

What are the possible outcomes of Autoimmune Hemolytic Anemia?

The prognosis is good for most children with AIHA. Buchanan found 77% of pediatric patients with AIHA have a brief disorder. Young children with cold agglutinin disease (IgM) in general have a better long-term outcome than those with warm antibodies (IgG). The IgM mediated disease is usually brief and self-limited, but may require aggressive clinical support initially. In contrast, IgG mediated disease is more often chronic, with recurrent remission and relapses, and these patients may require more long-term therapy.

Overall mortality is less than 10%, mostly occurring in older children with chronic refractory disease.

What causes this disease and how frequent is it?

Primary AIHA is not rare, estimated to be 1 in 80,000 persons in the general population. This incidence places it between aplastic anemia (rare) and ITP (common) as a cause of hematologic disease in children.

The underlying pathophysiology of AIHA was significantly elucidated with the 1945 report of Coombs and co-workers with the use of rabbit antihuman globulin to detect Rh agglutinins on red cells. These were later determined to be gamma globulin, and that IgG warm-reactive antibodies were the cause of the most common forms of AIHA.

Subsequent research determined the roles of complement, IgG and IgG subtypes, IgM, and the reticuloendothelial system in AIHA.

AIHA can be classified according to several characteristics, such as the thermal sensitivity or isotype of the antibodies. However, the most useful approach is commonly to separate AIHA into a primary versus a secondary process. In primary AIHA, the hemolytic anemia is the sole definable abnormality, with no evidence of an underlying systemic illness. In some cases, a recent viral-like illness may be identified. Warm-reactive antibodies, classically IgG, attach to red blood cells (RBC) and cause extravascular hemolysis in the reticuloendothelial system.

Cold agglutinin disease associated with IgM is more common in adults but is classically noted in children following a mycoplasma infection. In these cases the IgM binds below 37°C and fixes complement; which leads to intravascular hemolysis or immune-mediated clearance. A third less common form of primary AIHA, Paroxysmal Cold Hemoglobinuria (PCH), often affects children after viral diseases. In PCH, IgG binds to red cells at cold temperatures (<37° C), fixes complement very efficiently to red cells, and causes brisk intravascular hemolysis.

Secondary AIHAs occur in the context of definable underlying disorder, with the hemolysis being one manifestation of the systemic illness. Typical primary disorders associated with secondary AIHA include SLE and other autoimmune conditions, lymphoid cancer, immunodeficiency states, drug exposure, and specific infections. AIHA may be the presenting illness, necessitating proper evaluation for an underlying disorder. At minimum, this will require an inquiry about recent signs and symptoms, drug exposures, and commonly an ANA panel (see Table I and Table II).

How do these pathogens/genes/exposures cause the disease?

The binding of antibody, either IgG or IgM, along with complement to the erythrocyte membrane is the ultimate cause of hemolysis – the premature destruction of the erythrocyte. Two IgG molecules in close proximity on the erythrocyte surface or a single IgM can bind C1g, which leads to C3b binding. The erythrocyte coated with C3b can now be engulfed and destroyed by the spleen, liver, or other elements of the reticuloendothelial system, causing extravascular hemolysis. Although extravascular hemolysis is often primarily in the spleen, hepatic destruction may also be prominent. Extravascular hemolysis is not typically accompanied by jaundice or hemoglobinuria.

Alternatively, and most prominently with IgM related AIHA, complement cascade activation proceeds through C9, which bores a hole in the erythrocyte membrane. With the erythrocyte membrane broken, hemoglobin leaks out into the intravascular space and the erythrocyte is destroyed. Jaundice and hemoglobinuria can follow.

What complications might you expect from the disease or treatment of the disease?

Most patients with primary AIHA do well. Children between age 2-12 years who often had abrupt onset and modest reticulocyte events, often have the most favorable prognosis.

Children who are younger than 2 years of age or teenagers often have more insidious onset of symptoms, higher reticulocyte counts, and might have moderate thrombocytopenia, suggesting a broader affinity of antibodies. These patients tend to have a more protracted disease, with some having Evan’s syndrome, and many of these having underlying ALPS.

Those patients with secondary AIHA often have a protracted and relapsing course. The underlying disease state critically impacts the disease course.

Consulting a hematology specialist is indicated in cases of severe, prolonged, or chronic AIHA.

What is the evidence?

Ware, RE, Nathan, DG, Orkin, SH, Ginsburg, P, Look, AT. "Autoimmune Hemolytic Anemia in Hematology of Infancy and Childhood". Sanders. 2003.

(A general review and overview of AIHA.)

The following two papers review the natural history and overall prognosis of AIHAs:

Heisel, MA, Ortega, JA. "Factors influencing prognosis in childhood autoimmune hemolytic anemia". Am J Pediatr Hematol Oncol. vol. 5. 1983. pp. 147.

Buchanan, GR, Boxer, LA, Nathan, DG. "The acute and transient nature of idiopathic immune hemolytic anemia in childhood". J Pediatr. vol. 88. 1976. pp. 780.

Pathogenesis and laboratory studies:

Vaglio, S, Arista, MC, Perrone, MP. "Autoimmune hemolytic anemia in childhood: serologic features in 100 cases". Transfusion,. vol. 47. 2007. pp. 50-4.

Kamesaki, T, Oyamada, T, Omine, M. "Cut-off value of red-blood-cell-bound IgG for the diagnosis of Cooms-negative autoimmune hemolytic anemia". Am. J. Hematol. vol. 84. 2009. pp. 98-101.

Johnson, ST, Fueger, JT, Gottschall, JL. "One center’s experience: the serology and drugs associated with drug-induced immune hemolytic anemia – a new paradigm". Transfusion,. vol. 47. 2007. pp. 697-702.

Therapy for severe AIHA:

Motto, MD, David, G, Williams, MD, James, A, Boxer, MD, Laurence, A. "Rituximab for Refractory Childhood Autoimmune Hemolytic Anemia". IMAJ. vol. 4. 2002. pp. 1006-8.

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