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Name
Immune-Mediated Hemolytic Anemia, Canine
Short Description
Immune-mediated hemolytic anemia, autoimmune hemolytic anemia, IMHA,
AIHA
Affected Animals: Dogs of all ages may be affected with
immune-mediated hemolytic anemia. Young to middle-aged female dogs
are thought to be affected more commonly with immune-mediated
disease than their male counterparts. Older dogs often have
underlying or concurrent problems when IMHA develops. In some dogs,
IMHA can precede the identification of cancer or other serious
systemic diseases. Breeds including cocker spaniels, poodles, Old
English sheepdogs, Lhasa apsos, and Shih-tzus may have a higher
incidence of IMHA than other breeds.
Young dogs, especially beagles, Basenjis, and English springer
spaniels, may have specific red blood cell enzyme abnormalities that
result in hemolytic anemia at an early age; however, this anemia is
not mediated by the immune system.
Overview: Immune-mediated hemolytic anemia, or IMHA, is a
relatively common syndrome in dogs. The immune system normally helps
to protect the body from outside invaders. However, it can become
active against normal cells or parts of the body, or against normal
cells that have been altered by exposure to infectious agents,
medications, or other disease processes in the body. Although a
variety of factors may be associated with the development of IMHA,
in most situations it occurs without an identifiable trigger or
underlying cause. This is referred to as idiopathic immune-mediated
hemolytic anemia. Affected dogs show the symptoms common to anemia
due to any cause -- lethargy, weakness, increased respiratory rate,
and pallor, or pale mucous membranes. In situations where the anemia
develops rapidly, signs can be severe, with some animals actually
presenting to the veterinarian in shock. In other cases, especially
when the targeted red blood cells are in the bone marrow rather than
in circulation in the blood vessels, the onset can be very slow and
gradual.
There is no single test that is absolutely
diagnostic for immune-mediated hemolytic anemia. It is usually
diagnosed based on suspicion and the absence of any other specific
causes for anemia. Bloodwork, x-rays, ultrasound, bone marrow
examinations, and other diagnostic tests are part of the evaluation
of an anemic dog. These studies are helpful in ruling out underlying
or associated conditions, identifying additional abnormalities that
require treatment, and in monitoring complications of the disease
and its treatment.
Treatment of immune-mediated hemolytic anemia is aimed at restoring
red blood cell numbers and trying to stop the ongoing destruction of
additional red blood cells. Underlying causes or predisposing
factors, when present, need to be addressed. If medications were
being used prior to the diagnosis, they are usually stopped, in case
they may have triggered hemolysis in the affected dog. Transfusions
may be needed in severely ill dogs, but are generally useful only as
a temporary measure unless the underlying cause of the red cell
destruction is arrested. A large number of drugs have been used to
suppress the immune response in dogs with IMHA. The cornerstone of
treatment is prednisone. Only an attempt at treatment will provide
an answer about the outcome for an individual patient with IMHA.
There is an extremely wide range of severity of the condition, as
well as an unpredictable response to treatment. Some animals are
saved with relatively non-aggressive treatment and monitoring, while
others succumb despite almost heroic efforts, either to the disease
itself, complications like pulmonary blood clot formation, or side
effects from the medications used to treat the disease.
Clinical Signs: The common signs associated with anemia include
lethargy and pallor. Many patients with immune-mediated hemolytic
anemia have a recent history of nonspecific signs that can include
anorexia and vomiting. Changes in breathing patterns are common, and
can range from panting to dyspnea, especially if pulmonary
thromboembolism, or blood clots to the lungs, has occurred. The
presence of jaundice in an anemic animal is highly suggestive of
immune-mediated hemolysis as a cause of the anemia. Dogs with IMHA
may present to the veterinarian collapsed or in shock.
Symptoms: Most anemic dogs act weak or tired. Their mucous
membranes and skin may appear to be pale or jaundiced, with yellow
discoloration. Many dogs with IMHA have symptoms like vomiting or
loss of appetite that may precede or accompany the onset of their
anemia. Respiratory symptoms are often present. Panting is the most
common respiratory sign in anemia, but since some dogs with IMHA
have problems with blood clots in the vessels supplying their lungs,
severe respiratory difficulty may be seen. Some animals may present
with very sudden onset of shock-like symptoms in severe cases of
IMHA
Description: In immune-mediated hemolytic anemia, red blood
cells are removed from circulation by interactions between
components of the immune system and cells called macrophages, which
essentially "eat up" the altered red blood cells. Veterinarians
believe that antigens, or foreign substances, alter red blood cell
membranes and stimulate formation of immune system antibodies. The
antibodies in turn form an immune complex with the affected RBCs by
attaching to the antigen. Circulating macrophages, or immune-system
"scavenger" cells, are attracted to the immune complexes.
Macrophages engulf the red blood cells with the complexes and
destroy them.
This process occurs outside the blood vessels, especially in the
spleen, and is termed extravascular hemolysis. Less commonly, immune
complexes attach to the red blood cells in circulation, causing
intravascular rupture or hemolysis. If no trigger mechanism or
antigen is recognized, then the process is attributed to an
exuberant or defective immune system that fails to recognize the
dog's normal red blood cells as "self." Antibody molecules are
produced against the normal or unchanged red blood cells.
Diagnosis: Anemia is diagnosed by documenting the presence
of decreased red blood cells. This is most commonly done in the
hospital with measurement of a packed cell volume, or PCV.
Measurement of a hematocrit is usually done in a reference
laboratory. Once anemia has been documented there are many tests
that are useful in further classifying the anemia. Anemias may be classified as regenerative and
nonregenerative. Regenerative anemias arise from factors that
generally do not suppress the bone marrow, the normal source of red
blood cells. Nonregenerative anemias occur as a result of bone
marrow-suppressing events. Reticulocytes are immature, developing
red blood cells. A reticulocyte count tells how many immature red
blood cells are in circulation. Most dogs with immune-mediated
hemolytic anemia show a regenerative response, with increased
reticulocyte counts or large numbers of nucleated red blood cells in
circulation. The most common causes of regenerative anemias are
blood loss and hemolysis, or red blood cell breakdown. Hemolysis
should be suspected if there is a regenerative anemia with no
evidence of internal or external blood loss. Not all forms of
immune-mediated anemia are associated with increased numbers of
reticulocytes. When the immune-mediated injury is directed at cells
in the marrow, the reticulocyte count is decreased. This form of
immune-mediated, non-regenerative anemia, is sometimes referred to
as pure red cell aplasia.
Additional red blood cell features are helpful in classifying anemia
as regenerative or nonregenerative. Red blood cell size is often
increased and color is often less intense than normal in
regenerative anemias. Nucleated red blood cells, which are released
early from the bone marrow when demand is high, are often elevated
in regenerative anemia. The most specific red blood cell change in
IMHA is the formation of spherocytes. A spherocyte is a
round-looking red blood cell that lacks the typical zone of paleness
in its center when examined on a blood smear. It is thought that
spherocytes are only seen with immune-mediated injury.
Red blood cell agglutination, or clumping, may be noted when blood
is collected from dogs with IMHA. The presence of agglutination is
usually thought to be specific for immune-mediated anemia, but its
absence does not rule it out. Agglutination may be either
macroscopic, which means visible to the naked eye, or microscopic,
indicating it can only be noted when drops of blood are examined
under a microscope.
When IMHA is suspected, a direct antibody, or
Coombs test is usually performed. This test looks for antibodies
against red blood cells. Although many dogs with IMHA will have a
positive Coombs test, some do not. A negative Coombs test does not
rule out the possibility of IMHA. Coombs test results should always
be interpreted in light of other clinical and laboratory findings.
Serum biochemical profile abnormalities are common in IMHA, but none
of the commonly seen changes are specific for the diagnosis. Serum
bilirubin levels are increased due to excessive red blood cell
breakdown. Liver enzymes may be elevated; this occurs when anemia
causes the liver to receive a decreased amount of oxygen. Protein
levels are usually normal to increased in hemolytic anemia. This is
a key point in distinguishing hemolysis from blood loss, since
protein levels are usually decreased in whole blood loss situations.
Changes in the white blood cell and platelet counts may be seen in
addition to red blood cell count abnormalities on a complete blood
count. Some dogs with IMHA have marked increases in their white
blood cell counts. This occurs when all cell lines within the bone
marrow are excessively stimulated. Other dogs with IMHA may have
decreased platelet counts, particularly if the immune-mediated
injury involves platelets as well as red blood cells. This is called
Evan's syndrome, and may be associated with a worse outcome in most
patients than with IMHA alone.
A complete blood count will also help reveal
underlying causes for hemolytic anemia. Red blood cell parasites
that can cause hemolysis may sometimes be seen on evaluation of a
blood smear. Although rarely seen, Heinz body formation in dogs can
occur from onion ingestion or from acetaminophen overdose. Heinz
bodies are structures composed of denatured hemoglobin that can also
be seen in some dogs with hemolytic anemia.
Other diagnostic tests may also help identify an underlying cause
for hemolytic anemia. These tests may help differentially diagnose
IMHA from non-immune-related hemolytic anemias. Chest and abdominal
x-rays and abdominal ultrasound may be used to screen for evidence
of cancer in older dogs with suspected IMHA. Cancer, especially
lymphosarcoma, is often associated with immune-system abnormalities.
Abdominal x-rays may also be useful in identifying zinc-containing
foreign objects like coins, which can induce hemolytic anemia in
dogs. Tests for tick-borne infectious diseases may need to be
considered as well. Geography influences the incidence of such
diseases; many tick-borne diseases occur more commonly in the
southern and the southeastern parts of the United States. Bone
marrow evaluation may be recommended if the CBC reveals unusually
low platelet and white blood cell counts, or if the anemia is
nonregenerative. This is done primarily to rule out the presence of
diseases like leukemia within the bone marrow itself, and to further
document the marrow's ability to respond to the demand for new blood
cells.
When IMHA has been tentatively diagnosed, when no likely underlying
cause has been identified by additional testing, and when there is
no history of recent drug or vaccine exposure that may have
triggered the event, the condition is often referred to as
autoimmune hemolytic anemia, or AIHA. It is assumed in these cases
that for unknown reasons, the immune system targets otherwise normal
red blood cells, and tries to remove them from circulation.
Prognosis: Immune-mediated hemolytic anemia is a very
serious disease. While overall about 20 to 40 percent of patients
with IMHA are thought to die either from the disease itself or from
its complications or treatment, this figure may be as high as 80
percent for the most severely affected dogs. Many studies have
looked at possible factors that play a role in prognosis. Some
factors that may be associated with greater likelihood of a poor
outcome include a marked elevation of serum bilirubin, lower packed
cell volumes at the time of presentation, the need for multiple
transfusions, and the occurrence of pulmonary blood clots. Only an
attempt at treatment will help determine the outcome in an
individual dog. Those dogs that respond rapidly and favorably to
treatment may do very well. Other dogs may require hospitalization
for days to weeks before it becomes clear if they will survive or
not.
Transmission or Cause: Hemolytic anemia may occur secondary to an
underlying trigger or cause. Such causes can include red blood cell
parasites, tick-borne infectious diseases, exposure to vaccines or
other biologic products, medications, bee stings, toxins like zinc
or onions, and cancer. In some specific breeds, inherited red blood
cell enzyme abnormalities can trigger hemolytic anemia. Although the
underlying cause of anemia in these instances is hemolysis, or red
blood cell breakdown, not all of these cases are due to hemolysis
that is immune system-related.
There are many possible triggers for the development of
immune-mediated hemolytic anemia. Sometimes IMHA is associated with
exposure to certain medications that may alter the red blood cell
membranes, or that serve as a stimulus for antibody production
themselves. Red blood cell parasites may either attach to the red
blood cell membranes or invade the red blood cells directly,
triggering an immune response. Infectious diseases like ehrlichiosis
may be associated with immune-mediated hemolysis. Some forms of
cancer, particularly lymphosarcoma, can serve as triggers for IMHA.
However, in most patients, there is no identifiable trigger or
obvious underlying, associated condition. This situation is referred
to as idiopathic immune-mediated hemolytic anemia. The exact cause
of this syndrome and the mechanisms that perpetuate it are not
completely understood. In these patients, some abnormality in the
immune system allows for the destruction of otherwise normal red
blood cells. Veterinarians believe that there may be a hereditary
predisposition to this condition. It may occur alone or in
conjunction with other immune-mediated disorders.
Treatment: Treatment is directed toward any identified
underlying causes of the hemolytic anemia and toward symptomatic
illness secondary to the IMHA itself. Emergency treatment of a
patient with IMHA frequently requires blood transfusion or the use
of synthetic hemoglobin solutions to temporarily stabilize the
patient and to permit time for other treatments to work. Packed red
blood cells from a universal or cross-matched donor are used if
available, but whole blood may also be used. It is possible that
transfused red blood cells may also be destroyed by the patient's
immune system, so the benefit from transfusion may only be
temporary.
Synthetic hemoglobin solutions have the advantage of a longer shelf
life compared to blood, so they can be used in hospitals where blood
donors are not available. However, their expense and their
interference with the ability to monitor some biochemical parameters
in patients with IMHA must be kept in mind. Plasma may also be given
to patients that are thought to have serious blood clotting
abnormalities secondary to their disease.
The main thrust of drug treatment in IMHA is the use of drugs to
suppress the immune system. Corticosteroids like prednisone,
prednisolone, and dexamethasone are most commonly used to accomplish
this goal. High doses are necessary, and therefore side effects are
common. Some side effects like increased thirst, increased
urination, increased appetite, and panting are not very serious, but
others, including the potential for gastrointestinal injury, can be
severe. When immunosuppressive doses of steroids are used, most
animals are placed on drugs to protect the gastrointestinal tract
from ulceration.
Additional drugs to suppress or modify the immune
system are commonly used to treat IMHA. It is thought that
combination therapy may be more effective in some patients, and that
it may limit side effects from over-reliance on a single class of
drugs. These drugs have the potential to cause serious side effects,
such as liver injury or bone marrow suppression, so patients must be
carefully monitored. The medications may be used on a one-time only
basis, or for longer periods of time during treatment. Examples of
these drugs include azathioprine, cyclophosphamide, and danazol.
Some very expensive medications may also be used in the fight
against IMHA. These include human intravenous immunoglobulins, and
cyclosporine, a drug commonly used in transplant recipients to
prevent organ rejection.
In some IMHA-patients that have failed to adequately respond to
medical treatment, surgical removal of the spleen may also be
considered. This invasive step is seldom performed, although there
are some reports that indicate it can be associated with a high
degree of success. Because many patients with IMHA are in such
critical condition, the risk of general anesthesia may be too high.
Despite a relatively large number of treatment options and treatment
protocols with these medications, there is no one agreed upon,
universally effective treatment for IMHA. All possible treatments
have potential side effects that need to be carefully monitored, and
once an animal is successfully managed through an initial crisis,
long-term treatment is usually necessary.
Prevention: For most dogs with immune-mediated hemolytic
anemia, there is no known means of prevention of the disease.
Modified live-virus vaccinations may trigger IMHA in some dogs.
Patients that are suspected of having had vaccine-related IMHA in
the past probably should not be given these vaccines again.
