IMHA: diagnosis and therapy (Proceedings)

Immune-Mediated Hemolytic Anemia

Etiology and pathophysiology:

The cause of IMHA has been discussed at length. Genetics are involved as there are breed predispositions such as the Cocker Spaniel. In addition gender may also play a role. The reason why a predisposition exists are to date unclear, though they may have something to do with red blood cell antigens or the way the immune system works. Various triggers are also thought to play a role. Vaccination has also been incriminated. In one paper 25% of dogs had been vaccinated within the last month before presentation. In several other papers an association has not been seen. Certainly in my research such a link could not be made. Drug administration and infections may also play a role. The majority of cases are idiopathic.

Once the process has been initiated, red cells are tagged for destruction by the binding of immunoglobulins or complement. Depending upon how tagged, the RBCs will be destroyed either intravascularly or extravascularly. The sites of red cell removal include liver, spleen and bone marrow. The autoantibodies can be directed at very early RBCs such as reticulocytes causing an anemia that appears non-regenerative as the precursors are removed first.

Diagnosis:

Diagnosis with IMHA can proceed along the name of the disease. All components of the name, that is "immune-mediated" "hemolytic" and "anemia" need to be satisfied for a definitive diagnosis. Anemia is usually the easiest part to determine. At times one or the other areas will be present without being able to satisfy the others. This is the case when a positive Coombs test is present in an animal without anemia. This does not diagnose IMHA, in fact it may be a marker for neoplasia.

There are a variety of ways to determine that an anemia is immune-mediated. One way is a positive Coombs test, unfortunately both false positive and false negative results occur. The Coombs test identifies bound immunoglobulins or complement on the RBCs. Some types of antibodies will be picked up better than others and at times processing of the RBCs wash the antibodies off. Overall it still is a very good test. The presence of autoagglutination is definitive for IMHA. It must be differentiated from Rouleaux formation by diluting 1 drop of blood with several drops of saline. If gross agglutination is not seen, look at the slide under a microscope for aggregates of clumped RBCs. The presence of a large number of spherocytes is also a strong indicator of IMHA (pieces of the RBC membrane have been removed, leaving more hemoglobin behind in a smaller RBC).

Hemolysis must also be present to confirm IMHA. Spherocytes are a sign of both immune-mediated destruction as well as hemolysis. Icterus is if present can indicate hemolysis, though the degree of jaundice will depend upon the rapidity of hemolysis as well as possible damage to the liver (hypoxia through anemia, thrombi). Hemoglobinuria is also a strong indicator of hemolysis if urinary tract disease has been ruled out. Hemolysis determined on a blood draw is however very easy to induce, even in normal animals so it has be interpreted carefully.

It is important to remember that all the various areas must be present to have a definitive diagnosis of IMHA. Hemolysis can occur through mechanisms that are not immune mediated. Anemia can be caused by many problems. Unfortunately in some cases all the pieces of the puzzle will not fit together and the diagnosis will merely be presumptive. A definitive diagnosis does allow a very aggressive treatment approach. If not definitive, frequent reassessment is indicated to make sure another disease process has not been overlooked.

Clinical findings:

Clinical signs will depend predominantly on how anemic the animal is and how rapidly it got to the reduced PCV. If given time, animals can adapt to relatively severe anemias, on the other hand rapid progression usually makes the animal more symptomatic. Because a large part of the body is being attacked a very vigorous immune response is occurring with the liberation of many cytokines and inflammatory mediators. These cause many of the severe systemic signs seen with IMHA such as dever, lethargy, and anorexia.In most cases the mucous membranes will be pale and jaundiced. Often liver and splenic enlargement is palpated in these patients. Concurrent ITP (IMHA and ITP together are called Evan's Syndrome) can also contribute clinical signs such as petechia, melena and hematuria. Discoloration of the urine is common either through blood, hemoglobin or bilirubin.

Therapy:

Many things have been tried to treat IMHA, whether they work or not has been definitively determined. Most of the preferences listed are individual opinions, though there has been interest in generating data in this regard recently. Though many things have changed in veterinary medicine, the cornerstone of IMHA therapy still are corticosteroids. These usually are given at immune-suppressive dosages (2mg/kg of prednisone BID or equivalent dosages of other glucocorticoids). This dose is then very gradually tapered over months. The corticosteroids cause side-effects frequently, fortunately they are rarely life threatening.

Many other immune suppressives have been used. Unfortunately there is no hard clinical evidence to guide the clinician in the choice of therapy to use. Cyclophosphamide (200 mg/m2 given once i.v. or p.o.) has been a drug commonly used in severe cases of IMHA. Concern has been raised whether this medication may actually have a negative effect. Overall I have not been impressed by its efficacy and generally no longer use this medication in IMHA. Certainly bone marrow suppression can occur which would tend to interfere with a proper and vigorous regenerative response. Azathioprine has also been used, I routinely start this medication concurrently to the corticosteroids. This will allow me to taper the corticosteroids more rapidly, improving the owners perception of the quality of life. It is thought that this drug takes 3 to 4 weeks before becoming effective, though this has been questioned as well. It is unlikely that it works very rapidly however. Danazol (5 mg/kg BID) has also been used, though recent work does raise the question whether it has any benefit and the costs are quite high. Certainly it also is not a fast acting agent. Cyclosporine has relatively immediate effects. In a small study it did show some efficacy, and I have the impression it is a useful therapy to help to get a more rapid response to therapy. It is relatively expensive, though this disease generally is rarely cheap to treat. We compared a group of dogs receiving prednisone and azathioprine to a group getting these two drugs as well as cyclosporine. Outcomes were essentially similar. There was wide variation in the blood levels achieved so that therapeutic monitoring of cyclosporine therapy is recommended. Another treatment modality is the infusion of human intravenous IgG which was the most expensive. Though a promising treatment it can be difficult to impossible to get the medication. We have seen adverse effects in one dog that became extremely pruritic. Though the medication worked fast, in a small study mortality remained unchanged, apparently because the animals still thrombosed.

Besides immune suppression, supportive care is vital in these patients. Fluid therapy is almost always indicated. This may help to prevent sludging (promotes thrombosis) as well as helping the kidneys deal with hemoglobin (can cause acute renal damage). Some people are worried about further diluting the PCV, but it is important to remember that fluids do not decrease the overall body's red blood cell mass. Fluid therapy counters the decrease in PCV from dilution by increasing perfusion. If the PCV is low enough (usually a clinical judgement, certainly most cases in the single digits qualify) a transfusion is indicated. In fact we may be letting the PCV drop too low in these patients. The presence of hepatic necrosis in these cases is not rare and probably relates to hypoxia. This may play a central role in promoting clotting. As such we probably should be aiming for higher PCVs than we previously have, although there is no objective data to support this contention. This can be blood or blood substitutes (whereby substitutes have only a 24 to 48 hour half life). With blood transfusions it is likely that the transfused blood will be destroyed as rapidly as the patient's own blood. There was some concern raised that transfusions may worsen prognosis (adding fuel to a fire), but this has not been backed up by most recent studies. It is likely that this initial finding was because those dogs more seriously affected needed more blood and had a worse outcome because of the more severe disease they had rather than because of the transfusions per se. Heparin has been given (50-75 units/kg s.q. TID) to possibly reduce thrombotic problems, though to date information is not available if this truly is efficacious. The main concern is that we focus on immune suppression, however most cases die within the first week of presentation, where immune suppression is not yet likely to have occurred. We need focus more on preventing thrombi and providing optimal supportive care rather than playing with newer and more potent immune suppressives. A recent study has suggested that low dose aspirin (0.5 mg/kg/day) may be helpful as well.

Recent work has suggested that some novel therapies might be of benefit. These therapies specifically target macrophages. Work in mice and very limited work in dogs suggests that liposomal encapsulated clodronate may be a promising new avenue to consider in these dogs.

References

Available upon request from the author.