Introduction
Autoimmune hemolytic anemia is caused by antibodies that are directed against red blood cells.
Hemolytic anemias from changes outside of the RBC
Essentially there are three mechanisms by which hemolytic anemia can occur.
1. Autoimmune hemolytic anemias (this page)
2. Traumatic hemolytic anemia (link accessible under “Related Topics” below)
3. Splenomegaly and Hypersplenism (link accessible under “Related Topics” below)
When antibodies destroy the body’s own cell material they are called “auto”-immune antibodies. It is due to a misdirected immune response, which takes place in the spleen. Normally the spleen removes destroyed and aged red blood cells, but occasionally, in susceptible people, it can get sensitized against surface antigens of red blood cells. Two types of these autoimmune antibodies have been characterized. The one type destroys red blood cells at temperatures above 37 degrees C (warm antibody hemolytic anemia). The other type is due to antibodies that hemolyze red blood cells in temperatures below 37 degrees C (cold agglutinin disease).
Warm antibody hemolytic anemia is more common in women and is often associated with lupus, chronic lymphatic leukemia or lymphoma. However, certain drugs can also induce warm antibody hemolytic anemia. For instance levodopa that is used against Parkinson’s disease or alpha-methyldopa, which used to be a popular antihypertensive medication in the past, both interact with the Rh antigen on the red blood cell surface. Some antibiotics (high doses of cephalosporins or penicillin) will form a complex with the red blood cell membrane against which autoantibodies can be formed. This autoantibody production took place via a hapten mechanism where the haptens are stable. There are other haptens that are unstable as is the case with sulfonamides or with quinidine. There is a long list of unstable haptens that can cause warm antibody hemolytic anemia with well known names: hydrochlorothiazide (diuretic for high blood pressure), diclofenac (for arthritis), isoniacide (for tuberculosis), doxepin (an antidepressant) and many more. With warm antibody hemolytic anemia the hemolysis occurs mainly in the spleen. The antibodies are of the IgG type. Patients get sick very fast and the disease process can worsen rapidly and many of the patients die.
Cold agglutinin disease (or cold antibody disease) develops often during the course of infections, typically during mononucleosis or in a patient with mycoplasma pneumonia. Certain blood disorders, particularly involving the lymphatic tissues, can also cause this. In 50% of the cases the cause is unknown, which is termed “idiopathic cold agglutinin disease”. This form is commonly encountered in the older population and is more chronic. Cold agglutinin disease is mediated by IgM antibodies. With infection induced cold agglutinin disease the clinical course is more acute.
Paroxysmal cold hemoglobinuria is a rare form of cold agglutinin disease, which occurs mostly in children. It is also known by Donath-Landsteiner syndrome according to the researchers who developed a biphasic hemolysin test in 1904, which is still used today. Essentially they have shown that there is an IgG autohemolysin (Donath-Landsteiner antibody) that is formed by cold exposure in the skin or by drinking ice water, which coats red blood cells. When they warm up to body temperature as they circulate in the blood vessels they cause an acute hemolysis. This can happen 2 to 3 weeks following a viral infection. In the past it also was observed in the tertiary stage of syphilis, but nowadays this form of VD no longer exists as syphilis is treated much earlier. Nowadays it presents rarely in children, particularly following measles, mumps, influenza, and infectious mononucleosis.
Symptoms
The first sign may be symptoms of anemia. If the course of the disease is severe, there will be a fever, chest pains and heart failure as well. The hands and feet may be cyanotic in cold agglutinin disease and there may be Raynaud disease like changes in finger tips or toes from closed small arteries. With paroxysmal cold hemoglobinuria there can be severe back pains, vomiting, and headaches, the finding of a large liver and spleen as well as the passage of dark brown urine.
Diagnostic Tests
There is an anemia present when the CBC is taken and the mean corpuscular hemoglobin concentration (MCHC) is high. The blood smear will show many spherocytes. All of this will suggest to the physician that there is a hemolytic anemia present. More specific tests such as the Coombs’ test (antiglobulin tests) will now be ordered, which will determine with a sensitivity of about 98% whether autoimmune hemolytic anemia is present. Once this is established, further tests will show whether there are warm antibodies or cold agglutinins present. Several further immunological tests are available to the hematologist. Paroxysmal cold hemoglobinuria can be proven by a positive Donath-Landsteiner antibody test.
Treatment
Depending on what type of autoimmune hemolytic anemia is present, treatment will differ. Offending drugs will have to be discontinued in the case of warm antibody hemolytic anemia. Sometimes immunoglobulins are infused. In the warm antibody idiopathic type corticosteroids are used by the hematologist between 10 to 20 weeks, then the dosage is gradually reduced while repeat blood tests ensure that the hemolytic anemia stays controlled. Those cases that cannot be controlled this way may need splenectomy, which is successful in achieving control in 30 to 50% of the corticosteroid resistant patients. The others may respond to immunosuppressants like cyclosporine even after corticosteroids and splenectomy have failed. Cold agglutinin disease is treated largely supportive as it is self-limiting. The underlying precipitating disease should be treated first. Unfortunately splenectomy is not helping and immunosuppressive treatments are also ineffective. Paroxysmal cold hemoglobinuria is also not responding to these measures. However, strictly avoiding exposure to cold may be sufficient to improve and stabilize this condition. Sometimes a missed case of syphilis will be detected with special blood tests and appropriate treatment for this condition may cure the paroxysmal cold hemoglobinuria.
References:
1. Merck Manual (Home edition): Anemia
2. Noble: Textbook of Primary Care Medicine, 3rd ed., Mosby Inc. 2001
3. Goldman: Cecil Medicine, 23rd ed., Saunders 2007: Chapter 162 – APPROACH TO THE ANEMIAS
