Immune-mediated hemolytic anemia (IMHA) is far from a simple disease with a straightforward treatment plan. Difficult to treat and confusing to manage over time, this disease has many clinicians referring patients to internists for both short- and long-term management. The difficulties may be due largely to the fact that each patient is so different in how they present, how the disease progresses, how they respond to treatment and how they fare over the long term:
- How they present: A patient with IMHA may present clinically normal with abnormal routine lab work, or may come in nearly dead.
- How they progress: A dog with questionable bloodwork can crash in a hemolytic crisis within 24 hours after a normal physical exam.
- How they respond to treatment: The protocol that keeps one dog alive can appear to be useless for another patient, or a protocol that worked initially can appear ineffective after a relapse.
- How they do long term: One dog never relapses, the next never seems to stop relapsing or ever get out of its initial crisis.
At a recent Fetch dvm360 conference, Elisa Mazzaferro, MS, DVM, PhD, DACVECC, a criticalist at Cornell University Veterinary Specialists and adjunct associate clinical professor at Cornell University College of Veterinary Medicine, shared her approach to IMHA cases. A previous article discussed Dr. Mazzaferro’s insight on the causes and diagnosis of IMHA.1 Here she sheds light on short- and long-term treatment, as well as patient monitoring.
Emergency and short-term therapy
Initial treatment for IMHA depends on the severity of the clinical presentation, the clinician’s preference and the owner’s cost limitations. Any moderately affected patient is better off being hospitalized than being monitored at home, but this is not always something you can convince owners to do.
First, Dr. Mazzaferro said, identify and remove any inciting cause, if possible. These may include ticks, pennies or other metals (e.g., zinc intoxication); note that zinc-containing ointments such as sunblock and Desitin can also be culprits.
Glucocorticoids and other immunosuppressive agents
“Steroids, steroids, and more steroids”—this is the one and only proven treatment, and sometimes it is the only immunosuppressive treatment chosen, Dr. Mazzaferro said, adding that “you cannot skip steroids, but you will need to wean them sooner or later and you may need to add a second drug.” The current recommended dose for prednisone (or prednisolone) is 1 to 2 mg/kg/day, divided (it is no longer 2-4 mg/kg/day). With vomiting animals, you can start with injections of dexamethasone sodium phosphate at about 0.1 to 0.2 mg/kg IV every 12 hours, which is roughly equivalent to the prednisone dose.
If there is proof of autoagglutination, or in severe cases that require multiple transfusions, Dr. Mazzaferro will start a second immunosuppressive drug and thromboprophylactic therapy right away, but when to do this is not clear from the literature (see Is combination therapy effective?). None of the drugs below have proven efficacy by themselves in patients with IMHA2:
- Cyclosporine suppresses T cells and inflammatory cytokines and has a rapid onset; the dose is 5 to 10 mg/kg PO every 12 hours. Side effects include infections, gingival hyperplasia and, occasionally, renal or liver toxicity.
- Azathioprine suppresses T-cell function, and takes one to two weeks to start working; the dose is 2 mg/kg/day PO for five to seven days and then every other day. It can cause vomiting, diarrhea, pancreatitis and myelosuppression.
- Mycophenolate inhibits T and B cells, and inhibits B-cell antibodies; the dose is 10 mg/kg/day PO or IV. This drug has variable bioavailability, and can cause lethargy, vomiting, diarrhea, lymphopenia and pyoderma.
- Leflunomide, a newer agent, blocks both T and B cells; the dose is 2 to 4 mg/kg/day PO. Side effects include vomiting, diarrhea and bone marrow suppression. (Leflunomide is not used commonly — consult with your local internist.)
Is combination therapy effective?
Dr. Mazzaferro noted that “at this time, there are no studies to support combination therapy of other immunosuppressive agents with glucocorticoids versus administration of glucocorticoids alone.” According to the American College of Veterinary Internal Medicine guidelines2 for treating IMHA, a second drug may be added if the patient is very severely affected on presenta-tion, packed cell volume does not stabilize within seven days, the dog continues to be transfusion dependent over seven days or the patient is having severe adverse effects from steroids. The choice of which drug to add may be based on several factors:
- How quickly you want the second drug to start working (i.e., how quickly you want to start weaning prednisone or how quickly you want the immune system suppressed — maybe faster with a severely affected cocker spaniel, for example)
- What is available
- Cost
- What the internist you consult with recommends
Transfusions
If your patient is symptomatic for anemia (weak, pale, elevated respiratory rate or heart rate), or the packed cell volume (PCV) is 13% or lower, immediate transfusion is required. This will likely need to be done at a 24-hour care facility using the freshest packed red blood cells (RBCs) available.
Note that cross-matching can be difficult for dogs that are already macroagglutinating, but the RapidVet-H cross-match kit (DMS Laboratories) is not supposed to be affected by this. If the dog has never had a transfusion, it can be done without cross-matching. If the patient is four days or more out from a recent transfusion, you must cross-match as they may have started making antibodies against foreign RBCs already.
Other medical therapies
Several other medications can also be used to treat IMHA. Crystalloids (ideally, intravenous fluids) can help flush out bilirubin, which can be nephrotoxic.
An estimated 50% to 80% of dogs with IMHA develop life-threatening thromboem-bolic complications. Steroids are pro-coagulable, and the systemic inflammation from hemolysis can trigger clots, consumption of clotting factors and other clotting dyscra-sias. To prevent these compli-cations, patients should be started on one of the following anticoagulant drugs:
- Aspirin: 0.5-1 mg/kg/day PO (can be compounded for small dogs) Dr. Mazzaferro noted that this dose is largely ineffective as an antiplatelet drug in dogs, but this is the "recommended" dose.
- Clopidogrel: 10 mg/kg/day PO loading dose on day 1, then 2 mg/kg/day PO
- Rivaroxaban: 0.8 mg/kg/day PO
- Unfractionated heparin: may be useful only if dose adjustments are based on an individual patient's daily anti–factor Xa activity measurements, so it is not widely used or recommended at this time
- Fractionated heparin (enoxaparin): 0.8 mg/kg SC every six to eight hours, with dose adjustments based on anti–factor Xa activity
Gastrointestinal protectants, such as proton pump inhibitors, histamine blockers, anti-emetics and/or sucralfate, may also be considered for these patients.
Dr Mazzaferro prefers to start doxycycline empirically at 5 to 10 mg/kg every 12 to 24 hours in all patients with IMHA. She will stop if there are signs of gastrointestinal upset and restart it later if indicated by the infectious disease panel. Doxycycline can be discontinued if an infectious cause is no longer suspected.
Monitoring and long-term therapy
These are tailored to the indi-vidual patient and also guided by clinician preference. Monitoring and long-term treatment can get complicated, but here are some basic guidelines.
Once the patient is out of the hospital, recheck the PCV/total protein every seven to 14 days initially, then every two to four weeks, and do blood smears and a full complete blood cell count (CBC) as often as owners will allow. Each CBC should have an add-on review by a pathologist.
Taper the prednisone when (1) PCV has risen to a normal level, (2) there are no longer any reticulocytes or evidence of regeneration, and (3) all of the spherocytes and abnormal RBCs (including nucleated RBCs) are gone from the comprehensive CBC with a pathol-ogist’s review. (You can roughly monitor in-house with cytology if you are skilled, Dr. Mazzafero said, but send blood to the lab for confirmation that everything has normalized.)
Do not taper too hastily. Decrease prednisone by 25% and then recheck every three to four weeks. If the pathologist’s review reveals ongoing evidence of IMHA (spherocytes, reticulocytes, anemia, abnormal blood cells or recurrence of anemia), increase the prednisone dose. If CBCs remain normal with no evidence of reticulocytosis or spherocytosis, lower the dose by another 25% of the original dose every four to six weeks.
Wean steroids in total over three to six months, and be aware that relapse can occur at any time. In the face of an altered immune system, regularly check for urinary tract and skin infections, and treat these based on culture and sensitivity results.
Stop the anticoagulant therapy when prednisone is stopped.
If using adjunctive cyclosporine, start to decrease it in the same way as the prednisone, at about 20 weeks out, and check lab work monthly.
Summary
Due to patient variability, there will be many exceptions to these guidelines. More often than not, Dr. Mazzaferro says, you will seek a consultation with or refer to an internal medicine specialist— and you should. With a complicated disease, however, having some simplification allows us to manage a good portion of the care, helps us catch relapses and diagnose the disease on initial presentation, and allows us do our part in co-managing these cases. Maybe we can save more of them.
Dr. Johnson practices emergency medicine at Berkeley Dog and Cat Hospital in Berkeley, California, and general practice at Cameron Veterinary Hospital in Sunnyvale, California. Her nonveterinary loves are writing, dressage with her Iberian warmblood mare Synergy; watercolor painting on yupo; vinyasa yoga; and running with her dog Tyson. Try as she might, her curly-coated Scottish Fold, Hootie, refuses to go jogging with her.
References
- Johnson C. Possible IMHA dog—now what? Vetted. 2020;117(7):10-12.
- 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. doi:10.1111/jvim.15463
