Autoimmune hemolytic anemia is a rare disorder characterized by the premature destruction (hemolysis) of red blood cells at a rate faster than they can be replaced. Acquired hemolytic anemias are non-genetic in origin and happen when your body mistakes red blood cells as foreign substances and attacks them. Hemolytic anemia is classified as normocytic anemia with an MCV of 80 to 100 fL. It is a form of low hemoglobin due to the destruction of red blood cells, increased hemoglobin catabolism, decreased levels of hemoglobin, and an increase in efforts of bone marrow to regenerate products. It is caused by the destruction of red blood cells, increased hemoglobin catabolism, decreased levels of hemoglobin, and an increase in efforts of bone marrow to regenerate products. Idiopathic acquired autoimmune diseases occur when the body’s natural defenses against invading organisms (e.g., lymphocytes, antibodies) destroy its healthy tissues for no known reason. Normally, the red blood cells (erythrocytes) have a life span of approximately 120 days before being removed by the spleen. The severity of this type of anemia is determined by the life span of the red blood cell and by the rate at which these cells are replaced by the bone marrow.
Clinicians can determine quite accurately (Coombs test) whether or not red blood cells are carrying with them chemicals that are being incorrectly recognized as an “enemy” and therefore subject to autoimmune destruction.
Acquired autoimmune hemolytic anemia is a disorder that occurs in individuals who previously had a normal red blood cell system. The disorder may occur as the result of, or in conjunction with, some other medical condition, in which case it is “secondary” to another disorder. Less commonly, it occurs alone without a precipitating factor.
Acquired autoimmune hemolytic anemia occurs in different forms, including warm antibody hemolytic anemia and cold antibody hemolytic anemia.
In warm antibody hemolytic anemia, the self-generated antibodies (autoantibodies) attach themselves and cause the destruction of the red blood cells at temperatures above normal body temperature. In contrast, in the cases of cold antibody hemolytic anemia, the self-generated antibodies (autoantibodies) attach themselves and cause the destruction of the red blood cells at temperatures below normal body temperature.
Classification
AIHA can be classified as warm autoimmune hemolytic anemia or cold autoimmune hemolytic anemia, which includes cold agglutinin disease and paroxysmal cold hemoglobinuria. These classifications are based on the characteristics of the autoantibodies involved in the pathogenesis of the disease. Each has a different underlying cause, management, and prognosis, making classification important when treating a patient with AIHA.
Autoimmune hemolytic anemia
Warm-antibody type
- Primary
- Secondary (lymphoproliferative disorders, autoimmune disorders)
Cold-antibody type (anemia)
- Primary cold agglutinin disease
- Secondary cold agglutinin syndrome
- Associated with malignant disease
- Acute, transient, infection-associated (acute cold antibody-mediated AIHA complicating Mycoplasma pneumonia or viral infections)
- Chronic (lymphoproliferative disorders)
Paroxysmal cold hemoglobinuria
Idiopathic
- Secondary
- Acute, transient (Infections other than syphilis)
- Chronic (syphilis)
Mixed cold- and warm-antibody type
- Idiopathic
- Secondary (lymphoproliferative disorders, autoimmune disorders)
Drug-induced immune hemolytic anemia
- Autoimmune type
- Drug absorption type
- Neoantigen type
- Evidence for hemolysis
The following findings may be present:
- Increased red cell breakdown
- Elevated serum bilirubin (unconjugated)
- Excess urinary urobilinogen
- Reduced plasma haptoglobin
- Raised serum lactic dehydrogenase (LDH)
- Hemosiderinuria
- Methemalbuminemia
- Spherocytosis
Increased red cell production
- Reticulocytosis
- Erythroid hyperplasia of the bone marrow
- Specific investigations
- Positive direct Coombs test
Symptoms
Generally, symptoms of acquired autoimmune hemolytic anemia resemble those of other anemias and may include fatigue, pale color, rapid heartbeat, shortness of breath, dark urine, chills, and backache. In severe cases, yellow skin color (jaundice) may be present and the spleen may be enlarged.
AIHA can result in a wide range of symptoms, including:
- Fever.
- Tiredness.
- Weakness.
- Rapid heartbeat.
- Shortness of breath.
- Paleness.
- Jaundice (yellowing skin).
- Headaches.
- Muscle pain.
- Dark pee.
- Nausea and vomiting.
- Difficulty breathing.
- Diarrhea.
- A sore tongue.
- Heart palpitations.
Many symptoms are specific to the type of AIHA you have.
For example, warm autoimmune hemolytic anemia most commonly causes:
- Tiredness.
- Dizziness.
- Jaundice (yellowing skin).
- Heart palpitations.
Cold autoimmune hemolytic anemia symptoms often include:
- Tiredness.
- Dizziness.
- Cold hands and feet.
- Jaundice.
- Chest pain.
- Pain in the backs of your legs.
- Raynaud’s disease.
- Blue coloring in your hands and feet.
- Arrhythmia.
- Heart murmur.
- Heart failure.
If the autoimmune hemolytic anemia is secondary to another cause, the symptoms of the other cause may be most apparent.
Causes
Hemolytic anemia may be caused by any one or more of several kinds of disorders. For example, contributing factors may include:
An autoimmune response in which the patient’s immune system destroys the patient’s red blood cells. The disorder is more common among people who already have an autoimmune disorder such as lupus. The taking of certain types of medication by certain people. Among such medications are penicillin, quinine, methyldopa, and sulfonamides.
Inherited enzyme deficiencies inside red blood cells may cause the cells to become fragile and subject to destruction. Most commonly, low levels of the enzymes pyruvate kinase or glucose-6-phosphate dehydrogenase are the culprits. Hemoglobin disorders such as sickle cell anemia or thalassemias (blood disorders that affect the cell’s ability to produce hemoglobin). Abnormalities of the cell membrane cause the red blood cells to take on a shape other than the normal disc shape. Such red blood cells may show up as spheres or ellipses or cup-like.
Intracorpuscular causes refer to abnormalities in the red blood cell itself. A red blood cell can be internally damaged when the solubility of hemoglobin is altered (hemoglobinopathy), the structure of the membrane or cytoskeleton is changed (embryopathy), or its metabolic abilities (enzymopathy) are decreased. Examples of hemoglobinopathies include sickle cell disease (SCD) and thalassemias. SCD is caused by a beta-globin gene mutation leading to polymerization of hemoglobin-S, sticking, and, therefore, hemolysis. Thalassemia is the most common cause of hereditary hemolytic anemia and is caused by a partial or complete lack of synthesis of one of the major alpha or beta globin chains of hemoglobin A.[rx]
Membranopathies include hereditary spherocytosis (HS) and hereditary elliptocytosis (HE). HS is often autosomal dominant; however, non-dominant and recessive traits have been seen. It has been seen in all racial groups. HS has been documented as a rare disease, however, due to limited knowledge as the onset and severity vary considerably, as well as, the lack of specific lab tests, make it a difficult disease to study. HE is a heterogeneous red cell membrane disordered where the autosomal dominant inheritance can lead to a spectrum of presentations from asymptomatic to life-threatening.[rx][rx]
Several RBC enzymopathies alter the shape of RBCs and cause nonspherocytic hemolytic anemias.[rx] G6PD deficiency and pyruvate kinase deficiency (PKD) both fall into this category. PK is the rate-limiting enzyme in RBC energy production, whereas G6PD is involved in the processing of carbohydrates and plays a protective role against reactive oxygen species in RBCs.[rx] G6PD deficiency is an X-linked inherited disorder, almost exclusively seen in males, that causes hemolysis often with certain medications or foods such as fava beans and aspirin.[rx]
Alternatively, extracorpuscular causes refer to defects that were influenced by external factors, including mechanical, immune-mediated, or infectious. RBC transfusions can cause both acute and delayed hemolytic reactions. Mechanical trauma to RBCs is seen with microthrombi, fibrin, or valve shearing forces. Pathogens such as malaria and babesiosis are known to destroy RBCs as well as medications like dapsone, which can be used to treat these diseases, also have deleterious effects as it has oxidant potential.
Some unusual situations may lead to the destruction of red blood cells. For example, as the cells pass through oxygenating machines during open-heart surgery, they may undergo changes that lead to hemolytic anemia.
Diagnosis
Upon suspicion of hemolytic anemia, blood will be tested to determine the proportion of immature red blood cells to mature ones. If the ratio is high, hemolytic anemia is likely. Another blood test (Coombs test) is used to determine whether the amount of certain antibodies is higher than normal. If so, the diagnosis may be autoimmune hemolytic anemia.
If your healthcare provider suspects anemia, they might order additional tests. These assessments may include:
- Peripheral smear. Your healthcare provider examines a sample of your blood under a microscope to see if your blood cells are being destroyed.
- Reticulocyte count. This test measures how many young red blood cells are in your body. If your bone marrow is making a lot more cells to replace the destroyed ones, then your reticulocyte count will be high.
- Bilirubin test. Bilirubin increases when red blood cells are destroyed.
- Coombs’ test. Your healthcare provider will run this test to determine if your body is making antibodies against red blood cells.
- Haptoglobin test. Haptoglobin is a protein that eliminates debris produced by damaged red blood cells. If your body is using up a lot of haptoglobins, your levels will be low.
- Lactate dehydrogenase (LDH). Lactate dehydrogenase is an enzyme that’s present in red blood cells. When red blood cells are destroyed, the LDH level will rise.
- Cold agglutinin titer. If your healthcare provider suspects cold autoimmune hemolytic anemia, they may perform this test. It tells your healthcare provider the level of antibodies that attack red blood cells at cold temperatures.
Treatment
When acquired autoimmune hemolytic anemia is secondary to other diseases, diagnosis and treatment of the underlying disorder usually bring marked improvement of the anemia. Mild cases may require no treatment. Individuals with more severe cases of warm antibody hemolytic anemia may be treated with oral steroids or intravenous hydrocortisone followed by divided daily oral doses of prednisone. Improvement usually occurs within five to ten days after treatment.
Medications
Corticosteroids help weaken your body’s immune response. That’s why they’re typically the first line of treatment for autoimmune hemolytic anemia. If corticosteroids don’t work, then your healthcare provider may prescribe immunosuppressants. The goal is to stop your immune system from attacking your bone marrow.
Other third-line options, that are less studied, include azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil, and bortezomib. The treatments for secondary warm AIHA are generally the same as primary warm AIHA, but with the addition of treating the underlying disease if possible
Rituximab can be combined with bendamustine to achieve a 71% overall and 40% complete response rate with an increased response seen with prolonged therapy (with a time to best response at a median of 30 months) due to the drugs’ effect on long-lived plasma cells
Splenectomy
When medications don’t work, you may need surgery to remove your spleen. Your spleen is responsible for eliminating abnormal red blood cells from your bloodstream, including those with antibodies. The spleen also houses antibody-producing cells. Splenectomy can help preserve red blood cells, reducing the risk of anemia.
Blood transfusion
In severe cases, people with AIHA may need a blood transfusion.
If the response to the steroid therapy is unsatisfactory, other therapeutic approaches must be considered. In some resistant cases, total removal of the spleen may be required. Immunosuppressive drugs such as oral azathioprine or cyclophosphamide may be administered. Blood transfusions may be required in the most severe cases.
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