ACVIM consensus statement on the treatment of immune-mediated hemolytic anemia in dogs

IMHA Treatment Consensus

Timing of treatment

We recommend introducing immunosuppressive interventions after

all diagnostic samples have been collected, provided doing so does

not unduly delay institution of treatment.

STRONG

When should a dog with IMHA get a pRBC transfusion?

We recommend administering packed red blood cells (pRBC) when

dogs with IMHA display clinical features attributable to decreased

tissue oxygen delivery. If pRBC are not available, administration of

whole blood is a reasonable alternative.

Hct <12%

Fresh pRBC, ideally no older than 7-10 days are recommended

Recommend against Bovine Hemoglobin solutions

Do NOT recommend administering FFP empirically

STRONG

What is the initial treatment medication for IMHA recommended?

Prednisone or Prednisolone

Initial PO dosing 2-3 mg/kg/day, or 50-60 mg/m2/day for dogs >25kg

SID or divided BID

Dexamethasone (0.2-0.4 mg/kg/day) administered IV until able to take PO

If the starting dosage of prednisone or prednisolone is >2 mg/kg/day,

we recommend that it be decreased to ≤2 mg/kg/day within the first

1-2 weeks of treatment, provided the dog is responding to treatment,

as demonstrated by a stable or increasing PCV/Hct.

STRONG

When do you add a second immunosuppressive medication?

in any dog from the outset of treatment in an effort to decrease

the dosage of glucocorticoid required.

STRONG

In particular:

• The dog has clinical features at presentation consistent with

severe or immediately life-threatening disease.

• The PCV/Hct does not remain stable, with an absolute decrease

of ≥5% within 24 hours, during the first 7 days of treatment with a glucocorticoid drug as described in #7 above.

• The dog has continued to be dependent on blood transfusions after 7 days of treatment as described in #7 above.

• The dog develops or, based on previous treatment, is expected to develop severe adverse effects related to the use of glucocorticoids at any time during its treatment. This is of particular relevance for dogs >25 kg in body weight.

WEAK

Where a second drug is administered for treatment of IMHA in dogs,

we suggest 1 of the following options (listed in alphabetical order)

1. Azathioprine 2 mg/kg or 50 mg/m2 PO q24

2. Cyclosporine 5 mg/kg PO q12

3. Mycophenolate mofetil 8-12 mg/kg PO q12

4. Leflunomide 2 mg/kg PO q24

WEAK

The benefit of adding a second drug has not yet been established

NO to cyclophosphamide (STRONG)

When do you consider using IVIG?

Administration of IV immunoglobulin (IVIG) at a dosage of 0.5-1

g/kg as a single infusion may be considered as a salvage measure

in dogs not responding to treatment with 2 immunosuppressive

drugs, but we do not recommend it for routine treatment.

STRONG

Should you use 3+ immunosuppressive medications to treat IMHA?

No, should be avoided

Rarely required

No published evidence to show it better controls disease

Use drugs that work at different pathways (i.e. do not use mycophenolate AND azathioprine)

When should you start to decrease the dose of pred?

When the PCV/Hct has remained stable and >30% for 2 weeks

after commencing treatment, with improvement in the majority of

measures of disease activity (including spherocytosis, agglutination,

serum bilirubin concentration, and reticulocyte count), we recommend

decreasing the dosage of prednisone or prednisolone

by 25%

If a second drug has been introduced with the aim of limiting

glucocorticoid-related adverse effects, the dosage of this drug

should not be changed, but a greater reduction in the dose of

prednisone or prednisolone (of 25%-50%) may be possible if the

dog shows an adequate response to treatment.

STRONG

After your first dose reduction, how do you continue to go about dose reduction for pred with IMHA?

Provided the PCV/Hct remains stable and >30%, with improvement

in the majority of measures of disease activity (including

spherocytosis, agglutination, serum bilirubin concentration, and

reticulocyte count), we recommend decreasing the dose of prednisone

or prednisolone by 25% every 3 weeks.

If a second drug has been introduced with the aim of limiting

glucocorticoid-related adverse effects, the dosage of this drug

should not be changed, but a greater reduction in the dose of

prednisone or prednisolone (of 25%-33%), or a shorter interval

between reductions (2 weeks), may be possible if the dog shows

a good response to treatment.

A typical duration of 3-6 months of treatment is expected for

prednisone or prednisolone in the majority of cases, with an

expected duration of 4-8 months for all immunosuppressive

treatment.

STRONG

After stopping pred, what do you do?

Continue to administer the other immunosuppressive drug at

the same dosage for 4-8 weeks, then stop without tapering.

Taper the dosage of the other immunosuppressive drug in the

same way as for the prednisone or prednisolone, as described

in #15 above

weak

What should you always check before dose reduction?

PCV/Hct

Ideally q1-3 weeks

Monitoring for adverse effects of glucocorticoids

• Physical exam

• UA ± UCS q8-12 weeks if patient has clinical urinary signs

• Monitor chemistry (LE) as indicated

• Alopecia, potbelly, PU/PD, panting, lethargy, muscle weakness, calcinosis cutis, pyoderma, demodex, CHF, diabetes, pancreatitis

Monitoring for adverse effects of Azathioprine

CBCs ± chemistry every 2 weeks during the first 2 months; then every 1-2 months

Can also have GI effects

Hepatotoxicity

Myelosuppression

Monitoring for adverse effects of cyclosporine

GI adverse effects

Chemistry q2-3 months (hepatotoxicity)

STRONG

Monitoring for adverse effects of Mycophenolate

GI adverse effects

CBC q2-3 weeks for the first month, then every 2-3 months until treatment discontinued

Ulcerative colitis

Monitoring for adverse effects of leflunomide

CBCs and relevant serum biochemiical values (LE) every 2 weeks for the first 2 months, then q-12 months until treatment discontinued

weak

The most common adverse effects reported with leflunomide administration in dogs are occasional inappetence, lethargy, vomiting, and diarrhea.

Increased LE reported

What do you do if an immunosuppressive drug is causing myelosuppression?

Discontinue the drug

STRONG

What do you do for asymptomatic neutropenic patients?

Neuts 1k-3k: antibiotics not be administered unless other independent

risk factors for infection are present.

When the neutrophil count is <1000 cells/μL, prophylactic antibiotics are indicated.

We recommend close observation for any change in vital signs,

demeanor, or development of new gastrointestinal signs, which

could signal the onset of sepsis.

STRONG

How would you manage sympatomatic neutropenic patients?

• Identify source of infection

• Institute parenteral 4-quadrant coverage with antibiotics

• IV fluids

• Hemodynamic monitoring

• Recombinant gCSF could be considered if patient given inadvertent overdose, or if profound neutropenia persists >1 week

STRONG

If available, consider appropriate therapeutic drug monitoring in cases with actual or anticipated problems, including:

• Poor response to treatment

• Possible interaction between drugs

• Emerging secondary infection

Available for cyclosporine and leflunomide

How do you confirm IMHA relapse?

Using the same standard criteria for initial diagnosis of IMHA

STRONG

The results of some tests may be affected by previous administration of immunosuppressive drugs

Make sure there’s no other cause for Anemia, such as a GI bleed

Also assess for trigger that could derange immune homeostasis, such as emerging infection

Immune homeostasis can be affected by?

• Drugs

• Vaccines

• Onset of inflammatory disease

• Emerging infections (particularly vector-borne)

• Neoplasia

If a relapse of IMHA occurs before any attempted dose reduction, what do you do?

Add a second immunosuppressive drug

If already on a 2nd drug, perform TDM

Weak

If a relapse of IMHA occurs during tapering drugs, what do you do?

Increase dose of immunosuppressive, back to initial induction protocol

Or if mild - back to the last dose that worked

weak

then taper more slowly….

If recurrent relapses keep occurring, what do you do?

Consider lifelong immunosuppressive treatment, aiming to maintain remission using the lowest possible dosage

weak

When do you consider splenectomy?

In dogs requiring continued immunosuppressive treatment, suffering repeated relapses

provided that vector-borne diseases have been eliminated (may be latent)

weak

How do you handle a temporal association with estrus cycle and relapse in an intact female?

Spayed once they have been weaned off, or onto the lowest effective dose of, immunosuppressife drugs

Similarly for association between pregnancy and relapse - do not breed again

Are other treatments such as therapeutic plasmapheresis, liposomal chondrate, hyperbaric oxygen therapy, and melatonin recommended?

Further investigation is needed

weak

When is thromboprophylaxis recommended for dogs with IMHA? When is it contraindicated?

All patients

We suggest that thromboprophylaxis be initiated at the time of

diagnosis and continued until the patient is in remission and no

longer receiving prednisone or prednisolone

Except those with platelets <30,000

STRONG

The pathophysiology of thrombosis in IMHA is

complex, involving endothelial activation, intravascular tissue

factor expression, procoagulant microparticle generation, platelet

activation, and an imbalance of pro- and anticoagulant factors

Which thromboprophylaxis drugs are recommended for dogs with IMHA?

#1 choice: Unfractionated heparin with individual dose adjustment ± antiplatelet drug

OR

#2 LMW Heparins + Direct oral Xa inhibitor

If not available, or feasible, or used in combination:

#3 Antiplatelet drug (Clopidogrel) ± aspirin

Based on the pathophysiology of venous thromboembolism commonly

encountered in dogs with IMHA, we suggest that a regimen

incorporating anticoagulants may be preferred for?

Thromboprophylaxis,

particularly during the first 2 weeks after diagnosis. The available

anticoagulants may be used alone or combined with antiplatelet

drugs. If treatment with an anticoagulant, and its associated

monitoring, is not available or feasible, we suggest administration

of antiplatelet drugs in preference to no antithrombotic

drug.

Are there strong recommendations for dosing anticoagulants for patients with IMHA?

Insufficient evidence is available to make strong recommendations on

the choice of anticoagulant in IMHA (Table 5 and Figure 8). The strongest

evidence supports the use of individually dose-adjusted UFH.26

Other anticoagulants including enoxaparin and rivaroxaban appear to

be safe and may be efficacious,27,55 but RCTs are lacking

How is clopidogrel dosed? Recommendation?

1.1-4 mg/kg PO q24, can do a loading dose (double, or up to 10 mg/kg) to reach therapeutic plasma levels more quickly

Clopidogrel may be efficacious for arterial thromboprophylaxis in

dogs.171–175 However, insufficient evidence is available to judge the

efficacy of clopidogrel for prevention of venous thrombosis in dogs

When are gastroprotectants recommended for dogs with IMHA?

Ongoing evidence of GI ulceration (i.e. melena)

Known or potential risk factors for ulcers or GI bleed

weak

PPI**** ; discontinue once risk factors abate

When is it recommended to give empirical antibiotics?

In dogs considered high risk for infection given geographic location, lifestyle, and travel or import history —- while awaiting results of testing.

STRONG

CBC monitoring in remission

for 4 weeks

weak