Autoimmune Hemolytic AnemiaIntroduction: Autoimmune
hemolytic anemia is caused by antibodies that are directed against red blood cells.
As
they 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.
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