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CONTINUING EDUCATION

HEMATOLOGY

Immune-Mediated
Hemolytic Anemia
Andrew Mackin, BVMS, MVS, DVSc, DACVIM
Mississippi State University College of Veterinary Medicine

Immune-mediated hemolytic anemia (IMHA) is Secondary IMHA: Associative IMHA has been
one of the more commonly encountered causes strongly linked with organisms that infect red
of anemia in dogs and cats. IMHA can affect blood cells (RBCs) (e.g., Babesia species in dogs
animals of any age, but it most commonly affects and Mycoplasma haemofelis in cats) and much
young adult and middle-aged dogs and cats. more speculatively with feline leukemia virus
infection, medications (particularly sulfur drugs
The condition can either be primary in dogs and antithyroid medications in cats),
(nonassociative), in which the immune disease recent vaccination, or neoplasia.1 Suspected
has no known causative trigger, or secondary secondary IMHA may also follow bee stings and
(associative), in which the trigger or cause is an elapid snake bites.2,3 However, for many of these
underlying condition.1 Practically speaking, proposed potential triggers, causation has not
although a cause for secondary IMHA can often been definitively established.
be suspected on the basis of a temporal
association with drug administration or
underlying disease, proving causation is usually PATHOPHYSIOLOGY
impossible. Although primary and secondary IMHA in dogs and cats is an antibody-mediated
IMHA occurs in dogs and cats, primary IMHA disease. It’s a classic example of a cytotoxic
is more common in dogs and secondary IMHA (type II) immune-mediated reaction in which
is more common in cats. antibody and complement attachment to the
surface of RBCs leads to hemolysis. Hemolysis
Primary IMHA: Although it has no obvious can be extravascular (antibody-coated RBCs are
identifiable cause, primary IMHA is associated recognized and phagocytosed by macrophages in
with an inherited predisposition in dogs, most organs such as the spleen) or intravascular
commonly cocker spaniels, springer spaniels, and (antibody and complement on the RBC surface
poodles. lead to direct cell lysis within the circulation).

THE GOOD FIGHT

The mortality rate among dogs with immune-mediated
hemolytic anemia is high, but long-term prognosis
after survival of the first months of treatment is fair.

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Extravascular hemolysis: With the more common inflammation associated with IMHA leads to a
extravascular hemolysis, hemoglobin is released inside functional iron deficiency (anemia of chronic disease).4
macrophages and eventually metabolized to bilirubin.
Excessive bilirubin production can sometimes
overwhelm hepatobiliary metabolic pathways, leading CLINICAL PRESENTATION
to hyperbilirubinemia and jaundice (FIGURE 1). Many Most commonly, dogs and cats with IMHA exhibit
patients with IMHA, however, never become clinically clinical features suggestive of moderate to severe
jaundiced. anemia: pale mucous membranes, lethargy, exercise
intolerance, and collapse. Physical examination will
Intravascular hemolysis: With the less common often reveal tachycardia, tachypnea, and strong
intravascular hemolysis, intracellular hemoglobin is (bounding) pulses associated with the sympathetic
released directly into the circulation, leading to stimulation triggered by local tissue hypoxia. Patients
hemoglobinemia, hemoglobinuria, and potentially with severe anemia often have a grade 1 to grade 2
kidney damage caused by hemoglobinuric nephrosis. systolic left-sided (hemic) murmur. Some patients with
extravascular hemolysis will exhibit mild to marked
Intuitively, because hemolysis involves peripheral jaundice, and patients with intravascular hemolysis will
destruction of RBCs, resultant anemia would be have hemoglobinemia (red-pink serum) and
expected to be highly regenerative as the marrow hemoglobinuria (dark “port wine” urine) (FIGURE 2).
responds (within 3 to 5 days) by maximizing
production of new RBCs. However, some cases of Some patients also show signs consistent with enhanced
IMHA are actually poorly regenerative, either because inflammatory and mononuclear phagocytic processes,
antibodies against RBCs are also directed against including inappetence, a low-grade fever, mild
marrow erythroid precursors or because the lymphadenopathy, and palpable splenomegaly. Such
signs are often erroneously interpreted as evidence of
infection. Occasionally, affected animals will have
Evans syndrome, a combination of IMHA and
immune-mediated thrombocytopenia; these patients
may exhibit bleeding in the form of cutaneous and
mucosal petechiae and ecchymoses, melena, and
hematuria. A common complication of IMHA is
pulmonary thromboembolism; affected patients will
often exhibit acute onset of dyspnea.

FIGURE 2. Necropsy images from a dog with severe

intravascular hemolysis, demonstrating typical “port
wine” appearance of hemoglobinuria (syringe) and dark
FIGURE 1. Severe jaundice in a schnauzer that had received discoloration of kidneys (“gun metal” kidneys) associated
multiple transfusions for IMHA. with hemoglobinuric nephrosis.

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DIAGNOSIS mimic the extreme neutrophil counts seen with

granulocytic leukemia (so-called leukemoid response).
Minimum Database
Many diagnostically helpful clues can be provided by Thrombocytopenia: Platelet counts in IMHA patients
a complete blood count (CBC), serum biochemistry, are occasionally low.
and urinalysis. ■ Mild to moderate thrombocytopenia (<150,000
platelets/µL) is common, affecting about 55%
of IMHA patients, and is most likely associated
Complete Blood Count with platelet consumption within thrombi.5
A CBC may reveal anemia, an inflammatory ■ Marked thrombocytopenia (<50,000 platelets/
leukogram, and/or thrombocytopenia. µL) is less common, affecting about 25% of IMHA
patients, and may indicate Evans syndrome.5-7
Anemia: Anemia may be mild to marked, usually with
features of a regenerative response such as anisocytosis
and polychromasia and associated RBC indices such as Serum Biochemistry
increased mean corpuscular volume and decreased Serum biochemistry will often reveal mild to marked
mean corpuscular hemoglobin concentration. hyperbilirubinemia in about 66% of IMHA patients
■ Marked autoagglutination, which is common and elevated liver enzymes in more than 50% of
in IMHA patients, can lead to inaccuracies in patients.8
hematocrit, RBC counts, and other RBC indices. ■ Bilirubinemia is not present in all IMHA patients;
■ Reticulocytes most commonly increase; however, in up it is most common in those that have severe acute
to one-third of IMHA patients, reticulocytes decrease. hemolysis or have had multiple transfusions.
■ Analysis by automated hematology analyzers should ■ Liver enzymes, particularly alanine aminotransferase
be accompanied by direct examination of a stained (ALT), will often be mildly to moderately
blood smear for diagnostically useful features (e.g., elevated, possibly caused by hepatic hypoxia.
spherocytes and ghost cells) and for conditions ■ Hemoglobinemia may be noted by visual
that trigger or mimic IMHA (e.g., babesiosis, inspection of the serum of patients with
mycoplasmosis, Heinz body hemolytic anemia, and intravascular hemolysis and can interfere
microangiopathic hemolytic anemia [schistocytes]). with other serum biochemistry results.
The presence of spherocytes is strongly suggestive of ■ Serum protein levels in IMHA patients are
IMHA. Spherocytes are small spherical RBCs that typically within normal limits and, if low,
have lost their usual disk shape and central pallor. may suggest undetected bleeding rather
Spherocytes in IMHA patients are formed when than hemolysis as the cause of anemia.
phagocytes remove a piece of RBC membrane during ■ Marked hypophosphatemia may be identified as a
attempted phagocytosis. Spherocytes are readily nonimmune cause of hemolytic anemia, particularly in
recognizable among the normal larger disk-shaped patients receiving treatment for diabetic ketoacidosis
RBCs of dogs but are not easily identified in cats. or in those with suspected refeeding syndrome.
The presence of ghost cells in freshly processed
samples strongly suggests intravascular hemolysis.
Ghost cells are hollow membrane remnants of Urinalysis
RBCs that have been emptied of hemoglobin. Urinalysis results for IMHA patients are typically
However, in blood for which sample preparation within normal limits, apart from dipstick detection of
was delayed, ghost cells are a common and bilirubinuria or hemoglobinuria in some patients.
diagnostically meaningless artifact. Dipstick evaluation may lead to misinterpretation of
hemoglobinuria as hematuria, but urine sediment
Inflammatory Leukogram: A CBC will often also examination will confirm the absence of RBCs, thereby
reveal a mild to marked inflammatory leukogram ruling out hematuria.
associated with the inflammation caused by immune-
mediated RBC destruction. An inflammatory
leukogram in patients with suspected IMHA, however Diagnostic Imaging
marked, should not be misinterpreted as evidence of Diagnostic imaging (chest and abdominal radiography
infection. Neutrophilia is sometimes profound and can and abdominal ultrasonography) is not an essential

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A diagnostic tool for patients with suspected IMHA and

often reveals no significant abnormalities. The main
purpose of diagnostic imaging is to rule out conditions
that mimic or trigger IMHA (e.g., zinc toxicity) or
underlying neoplasia causing either associative IMHA
(most commonly suspected with round cell tumors) or
nonimmune microangiopathic hemolytic anemia (often
seen with hemangiosarcoma).

Abdominal images of patients with primary IMHA are

often unremarkable but may sometimes reveal
splenomegaly, most likely caused by increased activity
of the mononuclear phagocytic system.
B Ultrasonography may reveal thrombus formation in the
vasculature of organs such as the spleen. Mild
abdominal effusion is sometimes noted.

For any dyspneic IMHA patient with normal or

near-normal thoracic radiographs, pulmonary
thromboembolism should be strongly suspected.
Although pulmonary thromboembolism can be
radiographically silent, sometimes enlarged pulmonary
arteries, focal interstitial or alveolar lung patterns, focal
areas of lung hyperlucency caused by reduced blood
flow distal to the thrombus (oligemia), and/or mild
pleural effusion are observed (FIGURE 3). Suspected
C pulmonary thromboembolism can be confirmed, if

FIGURE 3. (A) Right lateral, (B) left lateral, and (C)

ventrodorsal radiographs of a dog with a suspected
pulmonary thromboembolism affecting the left caudal
lung lobe. Radiographs reveal a moderate to severe diffuse
unstructured interstitial and bronchial pulmonary pattern; FIGURE 4. Red speckles caused by autoagglutination in a
the left caudal lung lobe is most severely affected (arrow). heparinized tube of blood from a dog with severe IMHA.

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needed, by use of advanced imaging techniques such as blood on a microscope slide (FIGURE 5) and the
contrast-enhanced computed tomography and sample is gently mixed by tilting the slide while
pulmonary scintigraphy. watching for gross agglutination (speckles) (FIGURE 6).
The test should be performed with saline and blood at
or above room temperature to avoid an erroneous
Immunologic Testing false-positive result caused by cold agglutination, a
Strictly speaking, diagnosis of IMHA requires result of dubious diagnostic significance. If gross
confirmation of the immune-mediated nature of the agglutination is not observed, a cover slip is placed over
disease. Although many different immunologic tests the sample and the slide is inspected microscopically
have been used over the years, 2 particular tests have for microagglutination (strongly adhered RBC clumps).
stood the test of time: in-saline agglutination testing Both gross and microscopic agglutination support a
and Coombs’ testing. diagnosis of IMHA. In-saline agglutination test
specificity can be increased by adding saline washing
In-Saline Agglutination Testing: In many patients steps before assessing for agglutination.9 Because RBC
with IMHA, particularly those with high levels of agglutination does not occur in many IMHA patients,
antibody bound to cell membranes, RBCs can be a negative in-saline agglutination test result does not
strongly adhered to each other by antibodies attached rule out IMHA.
to more than one RBC. Resultant RBC
autoagglutination is noted by visible red speckles in Coombs’ Testing: The most common send-out test
anticoagulated blood (FIGURE 4) and by rapid used to confirm a diagnosis of IMHA is the Coombs’
separation of RBCs from plasma in blood samples that test, or direct antiglobulin test (DAT), which detects
stand in tubes without mixing. This immune-mediated antibodies and/or complement bound to RBC
agglutination process is so strong that no amount of membranes. Many laboratories use a polyvalent mix of
washing with saline will separate attached RBCs, antibodies directed against IgG, IgM, and complement.
whereas rouleaux formation (another process that The end point of the DAT is RBC agglutination, and
causes RBCs to adhere to each other in sick patients addition of antibodies that bind to IgG, IgM, or
and leads to visible speckles) is readily dispersed by complement on the cell membrane increases the
saline. A positive in-saline agglutination test, therefore, number of antibodies bound to RBCs, leading to
strongly suggests a diagnosis of IMHA and is often agglutination in samples that would otherwise not have
thought to indicate a more severe disease process. true autoagglutination. Test sensitivity is therefore
increased compared with slide agglutination, albeit
The simplest in-clinic version of in-saline agglutination with potentially decreased test specificity. With use of a
testing is the slide agglutination test, in which 4 to polyvalent mix of antibodies, DAT sensitivity is
10 drops of saline are added to 1 drop of anticoagulated reported to typically range from 60% to a little over

FIGURE 5. In-saline slide agglutination test process. A drop FIGURE 6. Strong positive in-saline slide agglutination in
of EDTA anticoagulated blood has already been added to a blood from a jaundiced dog with IMHA; red speckles persist
microscope slide, and 4 drops of saline are being added. despite addition of saline.

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80%, and test specificity is generally 95% or above.10,11 IgA, and complement as well as a standard polyvalent
Modifications to the standard DAT that may increase antibody/complement mix. Because, depending on the
diagnostic value include running the test at different method used, the diagnostic accuracy of the DAT can
temperatures and a wide range of titers and using vary from mediocre to highly accurate, a patient can
individual monovalent antibodies against IgG, IgM, potentially have IMHA despite a negative DAT result.10

Anemia
(must be present)

At least 2 clues to immune-mediated process

ƒ Spherocytes (dogs)
ƒ Positive saline agglutination
ƒ Positive direct antiglobulin test (DAT)

Yes No

At least one clue to hemolysis One clue to immune-mediated process

ƒ Icterus, marked bilirubinuria, or hyperbilirubinemia ƒ Spherocytes (dogs)
(in absence of hepatic or biliary disease) ƒ Positive saline agglutination
ƒ Hemoglobinemia ƒ Positive DAT
ƒ Hemoglobinuria
ƒ Ghost cells

Yes No

Yes No

At least one clue to hemolysis

ƒ Icterus, marked bilirubinuria, or hyperbilirubinemia
(in absence of hepatic or biliary disease)
ƒ Hemoglobinemia
ƒ Hemoglobinuria
ƒ Ghost cells

Yes No

Supportive of IMHA Suspicious for IMHA

Diagnostic for
(if no other cause of (if no other cause of Not IMHA
IMHA
anemia found) anemia found)

FIGURE 7. Algorithm for diagnosis of immune-mediated hemolytic anemia (IMHA).

Modified from Garden, et al.1

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Diagnostic accuracy of the DAT may be affected by Final Diagnosis

prior corticosteroid therapy or transfusion. The American College of Veterinary Internal Medicine
(ACVIM) recently published a comprehensive
Because the DAT is typically a send-out test in which consensus statement regarding the diagnosis of IMHA
results are invariably delayed, treatment for critical in dogs and cats.1 Given that all tests can produce
patients with suspected IMHA should be based on false-positive or -negative results for patients with
clinical suspicion and not delayed until results return. IMHA, the consensus statement suggests a diagnostic
Arguably, if an in-saline slide agglutination test using algorithm based on multiple test results. The algorithm
washed RBCs is already positive, a DAT may not be for an anemic patient categorizes the likelihood of a
required. final diagnosis as diagnostic, supportive of IMHA,
suspicious for IMHA, or not IMHA (FIGURE 7).

Other Testing Definitive: Requires the presence of at least

The degree of confidence in a diagnosis of primary 2 indicators of immune-mediated destruction (positive
IMHA is largely based on how aggressively causes of slide agglutination, positive DAT, or spherocytes) and
nonimmune hemolytic anemia or secondary IMHA at least 1 indicator of hemolysis (jaundice/
have been excluded. Specific tests that may be indicated hyperbilirubinemia/marked bilirubinuria,
for selected patients are as follows. hemoglobinemia/hemoglobinuria, or ghost cells) in the
■ Testing for infectious disease absence of other obvious causes of anemia.
„ Testing of cats for retroviruses (feline leukemia

virus, feline immunodeficiency virus) Supportive: Has several indicators of immune-

„ Polymerase chain reaction (PCR) testing for mediated destruction or hemolysis but does not meet
Mycoplasma haemofelis (cats), Babesia species the strict criteria required for a definitive diagnosis.
(dogs), and, arguably, Mycoplasma haemocanis
(dogs). Serologic tests are also available to Suspected: Requires the presence of only 1 indicator of
detect babesiosis in dogs. immune-mediated destruction in the absence of
■ Testing for inherited hemolytic anemia indicators of hemolysis.
„ Genetic testing for pyruvate kinase deficiency

and phosphofructokinase deficiency in some Another diagnostic clue for dogs and cats that are
affected dog breeds suspected to have IMHA but do not meet initial
„ Osmotic fragility testing to detect hereditary criteria for a definitive diagnosis is an appropriate
increases in RBC fragility in affected breeds of response to immunosuppressive therapy.
cats and dogs. True IMHA, however, can also
cause increased RBC osmotic fragility.12
■ Testing for hemostasis THERAPY
„ Evaluation of prothrombin time, partial Because IMHA is an immune-mediated disease,
thromboplastin time, D-dimer, and treatment has typically been centered on suppressing
antithrombin if hemolysis is suspected to result the immune system and providing supportive care to
from microangiopathic RBC damage and an keep the patient stable until the immune-mediated
associated consumptive coagulopathy, component of the disease is controlled. Careful initial
particularly in patients for which schistocytes diagnostic evaluation is needed to ensure that the
are seen on blood smear patient does not have nonimmune hemolytic anemia or
■ Bone marrow evaluation (aspiration IMHA secondary to an underlying trigger such as
cytology and/or histopathology biopsy) babesiosis or mycoplasmosis; otherwise, standard
„ Marrow evaluation for patients with suspected therapy will probably be at best ineffective and at worst
IMHA associated with precursor-targeted dangerous.
immune-mediated anemia13,14
„ Marrow evaluation for patients with

unexplained pancytopenia (all 3 major Glucocorticoids

circulating cell lines affected) to rule out Typically, the cornerstone of IMHA treatment for dogs
concurrent hematopoietic neoplasia, which and cats is glucocorticoids. In fact, for many patients
may induce an immune-mediated anemia with IMHA, clinical remission can be attained with

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glucocorticoids alone. For dogs, the standard Many drugs have been used as a second
recommended glucocorticoid therapy is oral prednisone immunosuppressive agent for dogs with IMHA, but
or prednisolone at a starting dose of 2 mg/kg q24h (for strong evidence for efficacy is lacking. The ACVIM
large breed dogs, a lower dose of 1 to 1.5 mg/kg q24h recently published a consensus statement regarding the
or 50 to 60 mg/m2 q24h is suggested). For dogs, no treatment of IMHA in dogs and suggested
evidence indicates that twice daily dosing with consideration of azathioprine, mycophenolate mofetil,
prednisone or prednisolone is any more effective than cyclosporine, or leflunomide as reasonable choices for a
once daily dosing, and side effects tend to be more second agent.16 Although it is uncommon for cats with
pronounced with twice daily dosing.15 Cats typically IMHA to need therapy beyond glucocorticoids,
need, and tolerate, a higher dosage of glucocorticoids; mycophenolate mofetil, cyclosporine, and leflunomide
prednisolone (preferable to prednisone in cats) is (but not azathioprine) can all be used in cats with
typically commenced at 2 mg/kg PO q12h. For IMHA that is refractory to glucocorticoids.
patients that do not tolerate oral therapy, injectable
dexamethasone can be substituted, usually at
approximately one-seventh of the calculated prednisone Azathioprine
or prednisolone doses. Azathioprine, a purine synthesis inhibitor that inhibits
lymphocyte proliferation, has long been used to treat
Recommended glucocorticoid starting doses are IMHA in dogs. The recommended starting dose for
typically considered to be immunosuppressive, and dogs is 2 mg/kg PO q24h. Azathioprine is usually well
such doses are indicated for patients with acute and tolerated, but a reversible hepatopathy develops in up
severe IMHA. These starting doses, however, are poorly to 15% of treated dogs.17 For this reason, liver enzymes
tolerated over the long term and are often associated of dogs receiving azathioprine should be monitored
with numerous unacceptable side effects including regularly, and azathioprine should be discontinued if
polyuria/polydipsia, polyphagia, panting and the ALT level rapidly rises beyond that expected from
hyperventilation, muscle weakness and atrophy, glucocorticoids alone. Less common side effects include
hepatomegaly and a pot belly, alopecia, susceptibility to mild anemia and (rarely) severe neutropenia.
infection (e.g., pyoderma and urinary tract infections), Azathioprine is dangerously myelosuppressive in cats;
calcinosis cutis, poor wound healing, and increased risk therefore, its use in cats is not recommended.
for pulmonary thromboembolism. For this reason,
although starting doses of glucocorticoids are often
effective at treating initial episodes of IMHA, tapering Mycophenolate Mofetil
of starting doses should usually begin within a few Mycophenolate mofetil, another purine synthesis
weeks of commencing therapy. inhibitor, has recently gained popularity for treatment
of IMHA in dogs. The recommended starting dose is
8 to 12 mg/kg PO q12h. The most common side
Other Immunosuppressive Agents effect, which occurs in about 20% of treated dogs, is
Glucocorticoids alone may not be sufficient to control diarrhea, which can sometimes be severe and is most
immune disease in patients with severe or refractory common at doses higher than the currently
IMHA. Even when glucocorticoids are initially recommended starting dose.
effective, unacceptably high doses with associated
steroid side effects may be needed to maintain IMHA
remission. In these circumstances, a second Cyclosporine
immunosuppressive agent is often added to the Cyclosporine, a calcineurin inhibitor that inhibits T-cell
therapeutic regimen to either increase the chances of function, seems to be the most potent
initial remission or enable more rapid tapering of immunosuppressive agent standardly available for
glucocorticoid doses for patients experiencing veterinary use. The recommended starting dose for the
unacceptable steroid side effects. A second treatment of IMHA in dogs is 5 mg/kg PO q12h of the
immunosuppressive agent is much more commonly most bioavailable modified (microemulsified)
used in dogs than in cats, probably because cats are formulation of the drug. Unlike other
more likely to respond to glucocorticoid monotherapy immunosuppressive agents, cyclosporine has a
and because they also seem to be less sensitive to steroid veterinary-approved formulation, which enables
side effects. accurate dosing in smaller patients. The most common

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side effects are nausea and vomiting. Because

cyclosporine has unpredictable bioavailability and
efficacy, pharmacokinetic or pharmacodynamic Unlike other immunosuppressive
therapeutic drug monitoring may be needed to ensure
effective dosing. Unlike other immunosuppressive
agents, cyclosporine has a
agents, cyclosporine has no marrow suppressive effects, veterinary-approved formulation,
making it the preferred agent for dogs with poorly
which enables accurate
regenerative IMHA.
dosing in smaller patients.
Leflunomide
Leflunomide, a pyrimidine synthesis inhibitor, has not
achieved widespread use in veterinary medicine but
seems to be well tolerated by most patients. The single first-time unmatched and untyped transfusion is
recommended starting dose is 2 mg/kg PO q24h. typically safe. For cats, blood type compatibility should
always be verified before administering transfusion, and
Regardless of the immunosuppressive drugs used, it is immunochromatographic typing kits that are not
uncommon for patients with IMHA to respond to affected by agglutination are available for this species.
therapy in fewer than 5 to 10 days. In the meantime,
aggressive supportive measures may be needed to The target post-transfusion PCV in dogs with IMHA is
maintain patient stability until immunosuppressive about 25% or greater and in cats is about 20% or
therapy takes effect. Clinicians should resist the greater. In very severely affected animals, multiple
temptation to use higher than recommended drug transfusions (up to 2 transfusions/day) for up to a week
doses or to use “triple therapy” (3 immunosuppressive or more may be needed to maintain patient stability
agents, including glucocorticoids, concurrently) until immunosuppressive therapy becomes effective.
because such measures are likely to increase the risk for
infection without adding therapeutic benefit.18
Other Therapeutic Options
For patients with IMHA that is life-threatening and
Transfusion refractory to more standard therapy, other therapeutic
Many patients with IMHA can tolerate anemia very options include splenectomy, intravenous human
well; therefore, transfusion is not indicated just because immunoglobulin, liposomal clodronate, and
of anemia. Transfusion can, however, be lifesaving for therapeutic plasma exchange. Although each of these
patients with severe anemia (packed cell volume [PCV] more advanced or expensive options certainly seems to
<15%), particularly those that show overt clinical signs benefit some individual IMHA patients, strong
of anemia such as tachycardia, tachypnea, lethargy, and evidence to support their routine use is minimal. Some
mental dullness. Transfusion adds more RBCs to a clinicians also recommend oral melatonin as an
process that already involves excessive consumption of adjunctive therapy for management of IMHA.
RBCs and therefore carries an associated risk of
“fueling the fire.” Transfusion should not, however, be In cats, because IMHA commonly occurs secondary to
withheld from profoundly anemic patients. M. haemofelis infection and because this organism can
be hard to identify on blood smears, treatment with
For IMHA patients, packed RBC products, which doxycycline or pradofloxacin, in addition to
provide RBCs without unnecessary plasma, are glucocorticoids, is often commenced at presentation
preferable to whole blood, although whole blood is while confirmatory PCR results are pending.
acceptable in an emergency. Fresh or recently stored
(for fewer than 10 days) products are preferable to
long-stored blood products.19,20 Ideally, donor–patient PREVENTING PULMONARY
compatibility matching via cross-match or blood typing THROMBOEMBOLISM
should be performed before administering transfusion In dogs with IMHA, pulmonary thromboembolism is a
to dogs but may not be possible if autoagglutination major cause of death. Therefore, during the initial
interferes with the test method. Fortunately, for dogs, a treatment of IMHA, thromboprophylactic therapy is

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recommended.16 For first-line therapy, anticoagulant References

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the diagnosis of immune-mediated hemolytic anemia in dogs and cats.
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11. Overmann JA, Sharkey LC, Weiss DJ, Borjesson DL. Performance of 2
treatment is fair; relapse rates are up to about 20%.21 microtiter canine Coombs’ tests. Vet Clin Pathol 2007;36(2):179-183.
For most dogs, treatment can be discontinued within 12. Paes G, Paepe D, Meyer E, et al. The use of the rapid osmotic fragility
test as an additional test to diagnose canine immune-mediated
6 to 12 months of presentation, although some require haemolytic anaemia. Acta Vet Scand 2013;55(1):74.
lifelong immunosuppressive therapy. Most cats with 13. Stokol T, Blue JT, French TW. Idiopathic pure red cell aplasia and
IMHA respond well to standard therapy. In recovered nonregenerative immune-mediated anemia in dogs: 43 cases (1988-
1999). JAVMA 2000; 216:1429–1436.
IMHA patients, no strong evidence indicates that 14. Lucidi CD, de Rezende CL, Jutkowitz LA, Scott MA. Histologic and
routine preventive modalities (e.g., vaccination, cytologic bone marrow findings in dogs with suspected precursor-
targeted immune-mediated anemia and associated phagocytosis of
heartworm prevention, or flea and tick control) will erythroid precursors. Vet Clin Pathol 2017 Sep;46(3):401-415.
precipitate disease relapses. 15. Swann JW, Szladovits B, Threlfall AJ, et al. Randomised controlled trial
of fractionated and unfractionated prednisolone regimens for dogs
with immune-mediated haemolytic anaemia. Vet Rec 2019;184(25):771.
16. Swann JW, Garden OA, Fellman CL, et al. ACVIM consensus statement
on the treatment of immune-mediated hemolytic anemia in dogs.
J Vet Intern Med 2019;33(3):1141-1172.
17. Wallisch K, Trepanier LA. Incidence, timing, and risk factors of
Andrew Mackin azathioprine hepatotoxicosis in dogs. J Vet Intern Med
Dr. Mackin is a professor and head of the department 2015;29(2):513-518.
of Clinical Sciences at Mississippi State University. After 18. Gregory CR, Kyles AE, Bernsteen L, Mehl M. Results of clinical renal
graduating from Murdoch University, Australia, in 1983, transplantation in 15 dogs using triple drug immunosuppressive
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at the Ontario Veterinary College in Canada. In 1993, 2014;28(6):1830-1837.
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Immune-Mediated Hemolytic Anemia

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1. Immune-mediated hemolytic anemia (IMHA) is a 6. Which red blood count abnormality strongly
good example of which type of immune-mediated supports a diagnosis of IMHA in dogs?
reaction? a. Heinz bodies
a. Type I (allergic) b. Eccentrocytes
b. Type II (cytotoxic) c. Schistocytes
c. Type III (immune complex) d. Spherocytes
d. Type IV (delayed)
7. Which of the following immunosuppressive agents
2. Which of the following clinical features does not has no known marrow suppressive effects?
strongly suggest the presence of intravascular a. Azathioprine
hemolysis? b. Mycophenolate mofetil
a. Hemoglobinemia c. Leflunomide
b. Hemoglobinuria d. Cyclosporine
c. Jaundice
d. Ghost cells 8. Which of the following immunosuppressive agents
is considered to be highly dangerous in cats?
3. Which organ is most likely to be damaged by the a. Prednisolone
presence of intravascular hemolysis? b. Cyclosporine
a. Brain c. Mycophenolate mofetil
b. Heart d. Azathioprine
c. Liver
d. Kidney 9. Which is the preferred blood product for
transfusing dogs with IMHA?
4. Which of the following infectious diseases has a. Fresh frozen plasma
been strongly associated with secondary IMHA b. Packed red blood cells that are fresh or have
in dogs? been stored for fewer than 10 days
a. Brucellosis c. Whole blood that is fresh or has been stored for
b. Leptospirosis fewer than 10 days
c. Babesiosis d. Whole blood that has been stored for more than
d. Bartonellosis 10 days

5. Evans syndrome should be suspected in IMHA 10. Which of the following anticoagulants used to
patients that have what abnormality on routine prevent pulmonary thromboembolism can be
complete blood count evaluation? given orally?
a. Marked thrombocytopenia a. Unfractionated heparin
b. Marked neutrophilia b. Dalteparin
c. Pancytopenia c. Enoxaparin
d. Schistocytosis d. Rivaroxaban

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