The immune system is a marvelous defense network of white blood cells,
antibodies, and other substances used to fight off infections and
reject foreign proteins. It is a police force patrolling the body,
designed to recognize "self" cells from "non-self" cells by markers
found on the surface of every cell in the body. It is this ability that
causes the body to reject skin grafts, blood transfusions, and organ
transplants. Like anything else, the immune system can fail, either by
not doing its job or by doing it too well.
Autoimmune disease (immune-mediated disease) is essentially an immune
system failure. In this situation, the ability of the immune system to
recognize the "self" marker is lost, and it begins to attack and reject
the body's own tissue as foreign. One specific tissue type such as red
blood cells may be affected, or a generalized illness such as systemic
lupus may result.
What causes the immune system to short circuit and start rejecting
normal body tissue? Many theories exist, but the ultimate answer is "We
something as threatening as a major disease emerges, it is natural to
ask why it occurred. Unfortunately, if the patient is a dog, there is a
good chance that there will be no answer to this question. Depending on
which of several studies are examined, 60-75% of IMHA cases do not have
theories include environmental pollutants, food additives and even
vaccines that over-stimulate the immune system. There is strong
evidence for a genetic predisposition in the development of autoimmune
in many species. Other causative factors include hormonal influences,
infections and stress.
The following is a list of some of the documented
potential causes of immune-mediated disease. Please note that not every
animal that meets these criteria will develop immune-mediated disease.
In fact MOST animals will NOT develop this condition.
Viral: transient or persistent upper respiratory or
gastrointestinal viral diseases. In cats, feline leukemia virus infection has been implicated.
hemobartonellosis, other various acute infections (e.g., abscess, pyometra,
babesiosis, leishmaniasis, dirofilariasis,
ehrlichiosis, intestinal parasites. In cats, infection with a red blood
cell parasite called Mycoplasma hemofelis (previously known as
Hemobartonella felis) is a known cause.
Solid tumors such as hemagiosarcoma
Insect bites or stings
American Cocker Spaniel (1/3 of all cases)
Old English Sheepdog
appear slightly predisposed, even when spayed.
There are 2 common types of immune-mediated disease seen in dogs and cats.Immune-Mediated Hemolytic Anemia (IMHA) and Immune-Mediated Thrombocytopenia
(ITP). These diseases can have similar origins and treatments, but are
best discussed spearately because of their differences.
Occasionally immune-mediated hemolytic anemia and immune-mediated
thrombocytopenia occur together. This is called Evan's Syndrome.
This disease was formerly known as Autoimmune Hemolytic Anemia.
"Autoimmune" literally means immunity against the self. "Hemolytic" is
the destruction of red blood cells. "Anemia" is defined as a decrease
in the number of red blood cells resulting in a decrease in the oxygen-
carrying capacity of the blood.
In IMHA, markers called antibodies, stick to the red blood
cells and cause the body to believe the red blood cells are a
"foreign invader". This causes the immune system to attack
the red blood cells and destroy them. The mechanism by which the immune
system mistakes the red blood cells for a "foreign invader" varies
somewhat according to the cause. It usually involves adherence of the
offending agent (parasite, drug or toxin) to the surface of the red
blood cells. The immune system attacks the offending agent,
but manages to injure the red blood cells as well. When the spleen and
the rest of the immune system is working to rid the body of the old,
diseased or damaged red blood cells, it is doing its job properly.
However, when a large percentage of the cells are affected, and they
are removed faster then they are replaced, IMHA results.
blood cells have a natural life span from the time they are released
from the bone marrow to the end of their oxygen-carrying days. When the red blood cell is no longer
functional, the body has a system to destroy it and recycle its
When old red blood cells circulate through the
spleen, liver, and bone marrow, they are plucked from circulation and
destroyed, a process called extravascular hemolysis. Their iron is sent
to the liver in the form of a yellow pigment called bilirubin for
recycling. The proteins inside the cell are broken down into amino
acids and used for other things. The spleen uses immunological cues on the surface of red
blood cells to determine which cells need to be plucked out of circulation. In
this way, red cells parasitized by infectious agents are removed
from circulation along with the old, damaged red cells. When the immune
system marks too many cells for removal, problems begin.
The spleen enlarges as it finds itself processing far more damaged red
blood cells than it normally does. The liver is overwhelmed by large
amounts of bilirubin and the patient becomes jaundiced or icteric,
which means the tissues become colored yellow/orange.
matters worse, a protein system called the complement system is
activated by these anti-red cell antibodies. Complement proteins are
able to simply rupture red blood cells if they are adequately coated
with antibodies, a process called intravascular hemolysis. Ultimately,
there aren’t enough red blood cells left circulating to bring adequate
oxygen to the tissues and remove waste gases. A life-threatening crisis
has emerged; in fact 20 to 80% mortality (depending on the study) have
been reported with this disease.
The symptoms or clinical signs of IMHA can appear very suddenly or they may
be gradual and progressive. The most common signs are usually related to the lack
of oxygen in the blood from the anemia and manifest themselves in the following ways:
Increased heart rate and respiration rate
membranes (gums, ears, eyelids)
Icteric/jaundiced (yellow-tinged rather
than pale mucous membranes)
Vomiting and/or abdominal pain
orange/brown discoloration of urine or stool
diagnosis of IMHA is made on the basis of these clinical signs as well
as blood testing. A complete blood count (CBC) and a chemistry panel
are usually the first tests done. The chemistry panel will often show a
increase in bilirubin level (the pigment causing the yellow
discoloration of the
skin and mucous membranes). The CBC will show a dramatic decrease in
the patient's red blood cell count and hematocrit (% of red blood cells
per voume of blood). The constitutes anemia.
Anemia due to poor red blood cell production by the bone marrow is called a "non-responsive anemia". Such
anemias are caused by chronic inflammatory diseases, kidney failure,
cancer or certain drugs (especially chemotherapy). Normally when red blood cells are lost, the drop in
blood oxygen that results causes hormonal changes leading to increased
production of red blood cells by the bone marrow. These are called
responsive anemias because the bone marrow is responding. Bleeding and
immune-mediated red blood cell destruction are both “responsive
There are several ways to determine from the blood
panel results if the anemia is responsive or not. The CBC will include red blood cell count, and size, shape,
and maturity of red blood cells, as well as white blood cell types and ratios. A patient with a
responsive anemia will have a very active bone marrow. Red blood cells
will be released early leading to a variety of sizes and colors of red
blood cells. Furthermore, red blood cell precursors
called reticulocytes are released. These findings indicate the anemia is responsive. This means
either red blood cells are being lost via bleeding or they are being destroyed by the immune system.
*It should be noted that 4
to 7 days are required for the bone marrow to generate a response. If
hemolysis occurs suddenly there may not have been adequate time for a
response. When this occurs, if there is any question about the
responsive nature of the anemia, continued monitoring of the complete
blood count will show a clear response in an appropriate time period.
destruction of red blood cells often leaves recognizable cellular
debris in the blood stream. In particular, a form of damaged red blood
cell known as a spherocyte oocurs. Finding spherocytes on a blood smear almost guarantees that
some form of hemolytic anemia is occurring. Since this disorder does
not stop the production of red blood cells, there are usually immature
red blood cells in the bloodstream which can be detected on the blood
smears as well.
severe cases of immune-mediated hemolytic anemia, the immune
destruction of red cells is so blatant that the red cells clump
together (because their antibody coatings stick together) when a drop
of blood is placed on a microscope slide.
in IMHA the stimulation of the bone marrow is so strong that even the
white blood cells lines are stimulated. This leads to white blood cell counts
that are spectacularly high. Coomb’s Test (also Called a Direct Antibody Test)
is a test designed to identify antibodies coating red blood cell
surfaces. This test is the current state of the art for the diagnosis
of IMHA but, unfortunately, it is not as helpful as it might seem. It
can be erroneously positive in the presence of inflammation or
infectious disease or in the event of prior blood transfusion.
The Coomb’s test can be erroneously negative for a number of reasons as
well. If the clinical picture fits with IMHA, often the Coomb’s test is
Other Causes of Hemolysis
Remember, not all causes of hemolysis (red blood cell
destruction) are immune-mediated. Onions in large amounts (and possibly
garlic as well) will cause a toxic hemolysis. Zinc toxicity,
usually from swallowing a penny minted after 1983, or from licking off
a zinc oxide ointment applied to the skin, will cause hemolysis as
well. In a young animal, a genetic red blood cell malformation might be
Once there is a diagnosis of immune mediated hemolytic anemia,
efforts to determine an underlying cause should be made. Any or all of
the following tests should be performed:
Radiographs of the chest and abdomen to look for tumors or zinc foreign objects
Tests for tick-borne infectious agents such as Ehrlichia, Anaplasma, and Babesia
Fecal Analysis to rule out intestinal parasites
patient with IMHA is often unstable. If the hematocrit has dropped to a
dangerously low level then blood transfusion is needed. It is not
unusual for a severely affected patient to require many transfusions.
supportive care is needed to maintain the patient’s fluid balance and
nutritional needs. Most importantly, the hemolysis must be stopped by
suppressing the immune system’s rampant red blood cell destruction.
There are several products that may be helpful in
treating IMHA. If the patient is in a crisis and needs immediate
therapy, artificial blood may be a good choice. Artificial blood
(Oxyglobin®) is made from hemoglobin harvested from cow’s blood.
Because the patient does not receive actual red blood cells, the
artificial blood does not further stimulate the immune system. The
disadvantage of artificial blood is that it does not last in the body
like a well-matched blood transfusion does. The body begins removing
artificial blood immediately so that the entire transfusion is probably
gone in 48 hours or so. In IMHA, this may buy some time but since IMHA
tends to have a long treatment course, it is likely that the patient
will end up right where they started. If a compatible
donor is not readily available, sometimes an artificial blood
transfusion buys enough time to find a compatible donor.
whole blood or packed red blood cells (a unit of whole blood with the plasma
mostly removed leaving only a concentrated solution of red blood cells)
may last longer. Compatible blood can last a good 3-4 weeks in the
recipient’s body. The problem, of course, with IMHA is that even the
patient’s own red blood cells are being destroyed so what chance do
donated cells have? For this reason, it is not unusual for several
transfusions to become necessary to treat the condition.
Corticosteroid hormones in high doses are the cornerstone of immune
suppression. Prednisone and dexamethasone
are the most popular medications selected. These hormones are directly
toxic to lymphocytes, the cells that produce antibodies. Remember, in
patients with IMHA, the red blood cells have been inappropriately
coated with anitbodies. The body then attempts to destroy the antibody
coated cells. Stopping antibody production is an
important part of therapy.
Corticosteroids may be the only
immune suppressive medication the patient needs. The problem is that
if they are withdrawn too soon, the hemolysis will begin all over
again. The patient is likely to be on high doses of corticosteroids for
weeks or months before the dose is tapered down and there will be
regular monitoring blood tests. Expect your pet to require steroid
therapy for at least 4 months; many pets require lifelong treatment with a low dose to prevent
Corticosteroids in high doses produce excessive
thirst, excessive urination, increased hunger, re-distribution of body fat, thin skin, panting, a predisposition
for urinary tract infections and other signs
This is an unfortunate consequence of long-term steroid use, but in the
case of IMHA, there is no way around it. It is important to remember
that the undesirable steroid effects will diminish as the dosage
More Immune Suppression
no response at all is seen with corticosteroids, supplementation with
stronger immune suppressive agents is necessary. The two most common
medications used in this case are azathiaprine and cyclophosphamide.
These are serious drugs reserved for serious diseases.
Cyclosporine is an immune-modulator, made popular in organ transplantation
technology. It has the advantage over azathioprine and cyclophosphamide of not
being suppressive to the bone marrow cells. It has been a promising
adjunctive therapy in IMHA but can be costly and requires blood level monitoring to
ensure that the dosage is appropriate.
Thromboembolic Disease This
particular complication is the leading cause of death for dogs with
IMHA (between 30-80% of dogs that die of IMHA die due to thromboembolic
disease). A thrombus is a large blood clot that occludes a blood
vessel. Embolism refers to smaller
blood clots, spitting off the surface of a larger thrombus. These
mini-clots travel and occlude smaller vessels thus interfering with
circulation. The inflammatory reaction that normally ensues to dissolve
errant blood clots can be disastrous if the embolic events are
occurring throughout the body.
Heparin, a natural anticoagulant,
may be used in hospitalized patients (or in patients with predisposing
factors for embolism) as a preventive.
A platelet is a cloud-shaped blood cell, neither related to the red
blood cell line nor the white blood cell line. Platelets assist in the
clotting of blood by seeking out damaged areas of blood
vessels. When a damaged vessel is found the platelets aggregate there, piling onto each other and
binding together to form a small plug to seal the hole in the leaking blood
vessel. While piled on each other, they release assorted biochemicals
that initiate a more permanent fibrous seal of the tear. Of course,
large tears are too big for platelets to seal, but when it comes to
small bleeds and normal blood vessel wear and tear, platelets are the
star of the show.
small bleed unstaunched by a platelet aggregation quickly becomes a
large bruise. Spontaneous bruising is a sign of reduced
platelet numbers or poor platelet function.
Platelets come from the bone marrow where a
large cell called a megakaryocyte splits off little active pieces
of itself. These pieces are platelets, ready to enter the circulation
where they will live for an average of 8 to 12 days in a dog or 6 to 8
days in a human before a bleeding capillary calls them to their
destiny. At any given time some 200,000 to 500,000 platelets are on
patrol in circulatory system, though only about 20,000 to 50,000 are
considered the bare minimum to prevent spontaneous bruising and
bleeding. About 1/3 of the circulating platelets are stored in the
spleen, like boats in a harbor, ready to mobilize if necessary. When
platelets become too old to be useful, the spleen has cells called
phagocytes that essentially eat old cells and recycle their inner
reasons unknown, platelets can be mistaken by the immune system as
invaders. When this happens, antibodies coat the platelets and the
spleen’s phagocytes remove them in numbers up to 10 times greater than
the normal platelet removal rate. The megakaryocytes in the bone marrow
respond by getting larger and growing in numbers so that they may
increase their production of platelets. The platelets produced under
these circumstances tend to be larger and more effective than normal
platelets and are called stress platelets. The bone marrow attempts to
overcome the accelerated platelet destruction rate; unfortunately, as
immune-mediated destruction is occurring, a platelet can expect
to survive only one to two days in the circulation instead of its normal 8 to 12
days. If antibody levels are very high, a platelet may survive only
minutes or hours after its release from the bone marrow and, making
matters worse, the antibody coated platelets still circulating do not
many cases, a cause for the immune-mediated thrombocytopenia is never found; however, in most cases a primary
reaction in the immune system precedes the platelet destruction. Keep
in mind that the immune system responds to the shapes of proteins
present on a cell’s surface. These shapes are similar to ID cards. The
immune system recognizes shapes defined as “self” and does not attack
but when it sees a cell expressing protein shapes that are “non-self,”
it will respond.
the immune system is responding to a blood parasite, tumor, drug, or
other cell type (as in lupus or immune-mediated hemolytic anemia),
it will be producing antibodies against enemy shapes. Some of these
shapes may, unfortunately, resemble some “self” shapes such as some of
the shapes on the surface of the platelets. The platelets are then
misidentified as the enemy and are attacked.
reduction in platelet numbers is almost always caused by
immune-mediated destruction, though certain tick-borne blood parasites
could also be responsible: Ehrlichiosis or Neorickettsia rickettsii (Rocky Mountain Spotted Fever) are the most common. If
an infectious agent such as one of these is responsible for the
immune-mediated platelet destruction, obviously specific therapy
against the infection is warranted in addition to therapy for the
Very low platelet counts can also occur in
response to the suppression of megakaryocytes within the bone marrow.
This might be caused by certain medications or chemotherapy drugs, bone marrow cancer, or disseminated
intravascular coagulation (DIC) - a life-threatening, disastrous uncoupling
of normal blood clotting and clot dissolving functions in the body. One
of its hallmark signs is a drop in platelet count, along with a
constellation of other signs.
platelet numbers are normal but it is obvious that platelet function is
not, some other causes to look into might include: Von Willebrand's
disease (a hereditary clotting disorder), metabolic toxins (liver or
kidney failure), over use of aspirin or similar NSAID drugs, or
usual patient is a middle-aged dog. Poodles appear to be predisposed
although Cocker Spaniels and Old English Sheepdogs also seem to have a
higher than average incidence of this condition.
bruising is the major clinical sign. The gums and oral surfaces as well
as the whites of the eyes are obvious areas to check, as are the hairless
areas of the belly. Small spots of bruising in large conglomerations
called petechiae (pet-TEEK-ee-a) are the hallmark sign. A large, purple
expansive bruise might also be seen, which is called ecchymosis. Large
internal bleeds are not typical of platelet dysfunction, though
bleeding small amounts in urine, from the nose, or rectally may also
indicate a platelet problem.
When these sorts of signs are seen,
a platelet count is drawn, along with usually an array of clotting
parameters, red blood cell counts to assess blood loss, and other
general metabolic blood tests. Since testing to detect actual
anti-platelet antibodies is not available, the veterinarian must
determine if any other possible causes of low platelet count make sense.
a diagnosis of immune-mediated platelet destruction has been
made, the goal in therapy is to stop the phagocytes of the spleen from
removing the antibody-coated platelets and cutting off antibody
production. This, of course, means suppression of the immune system
using whatever combination of medication seems to work best for the
Prednisone or Dexamethasone
steroid hormones are the first line of defense and, often all that is
necessary to bring platelet counts back up. Unfortunately, long-term
use should be expected and this means steroid side effects are
eventually inevitable: excessive thirst, possible urinary tract
infections, panting, poor hair coat etc. The good news is that these
effects should resolve once medication is discontinued. If
side the effects are especially problematic, other medications can be
brought in to reduce the dose of steroid needed.
injectable chemotherapeutic medication is mildly immune suppressive but also seems to
stimulate a sudden burst of platelet release from the marrow
megakaryocytes. The platelets released in response to vincristine
contain a phagocyte toxin so that when they are ultimately eaten by
spleen phagocytes, the phagocytes will die. While repeated injections
of vincristine ultimately do not yield the same effect, at least a
one-time dose may be extremely helpful. Vincristine is extremely
irritating if delivered outside of the vein. It must be given IV
cleanly or the overlying tissue will slough.
Azathioprine or Cyclophosphamide
are stronger immune suppressive agents typically used in cancer
chemotherapy. If steroid side effects are unacceptable or if the
patient does not respond to steroids alone, one of these medications
may be indicated. Cyclosporine, a newer medication made popular in
organ transplantation, also may be used but expense has been
You might think that a transfusion of blood or at least
“platelet rich plasma” might be helpful in the treatment of a platelet
dysfunction. The problem is that platelets do not survive well after
removal from a blood donor. You have about 12 hours to deliver the
freshly withdrawn blood to the recipient before the platelets become
inactive. After the platelets are delivered they are likely to live
only hours. In general, most efforts are spent on establishing immune
If medication simply does not work or the condition
keeps recurring once medications are discontinued, the solution may be
to simply remove the spleen. After all, this is where the phagocytes
removing the platelets are primarily located. In humans,
immune-mediated platelet destruction is generally treated with
splenectomy first. Response in dogs has not been as predictably good
thus in veterinary medicine it is generally one of the last therapies
Prognosis for both immune-mediated hemolytic anemia and immune-mediated
thrombocytopenia is highly variable and depends on the
underlying cause if one is present, complications related to the
disease or drug therapy, and the response to treatment. The initial
phase of the disease and the animal's response to it are very important
when determining the long term prognosis. 50% of animals may not
survive the initial crisis. Keep in mind that relapses can
occur months to years after the initial episode, even if initial
responses were favorable. Overall, if there is
no severe underlying illness or significant complications and if your
pet responds to therapy, prognosis for both diseases is generally good.
If suspect your dog or cat has signs of an immune
mediated disease such as those listed above, please call the Merrick
Veterinary Group at 516-379-6200
to schedule your pet for a physical examination, bloodwork, and other
diagnostic tests today. Early detection and treatment can result in a
better outcome for your pet.