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Hemolytic anemias are typically regenerative and result from lysis of RBC in either the intra- or extravascular space. Intravascular hemolysis results in hemoglobinemia and hemoglobinuria, whereas extravascular hemolysis does not. Both types of hemolysis can result in icterus. In dogs, the most common cause of hemolytic anemia is immune mediated (60–75%), although toxins, RBC trauma, infections, and RBC membrane defects can also cause hemolysis.
Immune-Mediated Hemolytic Anemia
Immune-mediated hemolytic anemia (IMHA, see Immunologic Diseases: Immune-Mediated Hemolytic Anemia (IMHA) and Thrombocytopenia) can be primary or secondary to neoplasia, infection, drugs, or vaccinations. In IMHA, the body no longer recognizes RBC as self and develops antibodies to circulating RBC, leading to RBC destruction by macrophages and complement. In some cases, antibodies are directed against RBC precursors in the marrow, resulting in pure red cell aplasia and a nonregenerative anemia. Animals with IMHA are usually icteric, sometimes febrile, and may have splenomegaly. Hematologic hallmarks of IMHA are spherocytosis, autoagglutination, and a positive Coombs' test.
A newer methodology for evaluating dogs for anti-RBC antibodies is flow cytometry. Flow cytometry allows for detection and quantitation of red cell surface-bound IgG and IgM. Flow cytometry was found to be 88–100% specific for diagnosing dogs with anti-RBC antibodies. One report suggests using flow cytometry to assess response to treatment for dogs, because there is a decrease in surface anti-RBC antibodies before a reticulocytosis or increase in red cell count.
Animals with IMHA can show mild, indolent signs or be in an acute crisis. It is important to tailor treatment to the animal's signs. Any underlying infections must be treated 1ndicated by the severity of signs. Bovine hemoglobin solutions (Oxyglobin®) may be given if compatible blood is not available. The goal of therapy is to stop the destruction of RBC by treating with immunosuppressive drugs. Prednisone or prednisolone at a dosage of 2 mg/kg, along with azathioprine at 2 mg/kg/day (azathioprine is contraindicated in cats), is considered first-line treatment. In a recent study, low-dose aspirin at 0.5 mg/kg, sid improved survival times in dogs treated with azathioprine and prednisone.
In the acute hemolytic crisis, drugs such as cyclosporine (10 mg/kg, sid initially) or human intravenous immunoglobin (IVIG, 0.5–1.5 g/kg as a single dose) may also have benefit. Human IVIG should be diluted in sterile saline and given slowly over 6 hr. During the infusion, dogs should be watched for allergic reactions. Human IVIG is used only once due to the concern over allergic reactions with multiple dosing. The compound is very osmotic and should be used with caution in dogs with cardiac disease. It is not considered first-line therapy for IMHA at this time. Longterm follow-up has not yet been reported.
Pulmonary thromboembolism is a risk in dogs with IMHA. The underlying cause is unknown, but the risk may be reduced by supportive care with fluids and transfusions. Fluids are important to maintain renal perfusion and to protect the kidneys from the high concentrations of circulating bilirubin. If thromboemboli are suspected or the risk of forming thromboemboli is high, heparin (100–200 IU/kg, SC, qid) can be used. If the prothrombin time and activated partial thromboplastin time are elevated or if signs of disseminated intravascular coagulation are present, fresh frozen plasma should be given at a rate of 10 mL/kg bid until clinical signs or coagulation parameters improve.
Mortality rates for IMHA range from 20–75%, depending on the severity of initial clinical signs. Negative prognostic indicators include a rapid drop in PCV, high bilirubin concentration, moderate to marked leukocytosis (28,000 to >40,000 cells/μL), elevated BUN, petechiae, intravascular hemolysis, autoagglutination, and thromboembolic complications. Moderate to marked leukocytosis has been reported to be associated with tissue necrosis, most likely secondary to tissue hypoxia or thromboembolic disease. Referral to tertiary care facilities may improve survival.
Alloimmune Hemolysis
Neonatal isoerythrolysis (NI) is an immune-mediated hemolytic disease seen in newborn horses, mules, cattle, pigs, cats, and rarely, in dogs. NI is caused by ingestion of maternal colostrum containing antibodies to one of the neonate's blood group antigens. The maternal antibodies develop to specific foreign blood group antigens during previous pregnancies, unmatched transfusions, and from Babesia and Anaplasma vaccinations in cattle. Cats are unique in that blood type B cats have naturally occurring anti-A antibodies without prior exposure, and their kittens that are type A develop hemolysis after nursing. In horses, the antigens usually involved are A, C, and Q; NI is most commonly seen in Thoroughbreds and mules. Neonates with NI are normal at birth but develop severe hemolytic anemia within 2–3 days and become weak and icteric. Diagnosis is confirmed by screening maternal serum, plasma, or colostrum against the paternal or neonatal RBC. Treatment consists of stopping any colostrum while giving supportive care with transfusions. If necessary, neonates can be transfused with triple-washed maternal RBC. NI can be avoided by withholding maternal colostrum and giving colostrum from a maternal source free of the antibodies. The newborn's RBC can be mixed with maternal serum to look for agglutination before the newborn is allowed to receive maternal colostrum.
Microangiopathic Hemolysis
Micro-angiopathic hemolysis is caused by RBC damage secondary to turbulent flow through abnormal vessels. It can be seen in dogs secondary to severe heartworm infection, vascular tumors (hemangiosarcoma), splenic torsions, and disseminated intravascular coagulation; hemolytic uremic syndrome in calves, equine infectious anemia, African swine fever, and chronic classical swine fever are causes in other species. Schistocytes are common in blood smears from these patients. Treatment involves correction of the underlying disease process.
Metabolic Causes of Hemolysis
Hypophosphatemia (see Disorders of Phosphorus Metabolism: Hypophosphatemia) causes postparturient hemoglobinuria and hemolysis in cattle, sheep, and goats. It can occur 2–6 wk after parturition. Hypophosphatemia with secondary hemolysis is seen in dogs and cats secondary to diabetes mellitus, hepatic lipidosis, and refeeding syndrome. Treatment with either oral or IV phosphorus is indicated, depending on the degree of hypophosphatemia. Cattle that drink too much water (water intoxication) are at risk of developing hemolysis secondary to hypotonic plasma. This is seen in calves 2–10 mo old and causes respiratory distress and hemoglobinuria. Clinical signs can progress to convulsions and coma. A calf with hemolytic anemia, hyponatremia and hypochloremia, decreased serum osmolality, and low urine specific gravity would support the diagnosis of water intoxication. Treatment consists of hypertonic fluids (2.5% saline) and diuretics (eg, mannitol).
Toxins
Toxins and drugs can cause anemia by many mechanisms. Those implicated most frequently in animals and their pathogenic mechanisms are listed (see Anemia: Toxic Causes of Anemia ).
Infections
Many infectious agents—bacterial, viral, rickettsial, and protozoal—can cause anemia, by direct damage to RBC, leading to hemolysis, or by direct effects on precursors in the bone marrow (see Anemia: Infectious Causes of Anemia).
Heritable Diseases
Several heritable RBC disorders cause anemia. Pyruvate kinase deficiencies are seen in Basenjis, Beagles, West Highland White Terriers, Cairn Terriers, and other breeds, as well as Abyssinian and Somali cats. Phosphofructokinase deficiency occurs in English Springer Spaniels. Deficiencies in these enzymes lead to shortened RBC life span and a regenerative anemia. In dogs with phosphofructokinase deficiency, the hemolytic crises are set off by alkalosis secondary to excessive excitement or exercise. If such situations are minimized, these dogs may have a normal life expectancy. There is no treatment for pyruvate kinase deficiency, and affected dogs will have a shortened life span due to myelofibrosis and osteosclerosis of the bone marrow. Affected cats will have chronic intermittent hemolytic anemia, which is sometimes helped by splenectomy and steroids. Unlike dogs, cats have not been reported to develop osteosclerosis. A hereditary hemoglobinopathy, porphyria (see Congenital Erythropoietic Porphyria), leads to build up of porphyrins in the body and has been described in cattle, cats, and pigs. It is most prevalent in Holstein cattle and can lead to a hemolytic crisis. Affected calves fail to thrive and are photosensitive. Diagnosis is made by finding increased levels of porphyrins in bone marrow, urine, or plasma. Teeth of affected animals fluoresce under ultraviolet light.
Last full review/revision July 2011 by Sarah E. Kraiza, DVM, DACVIM (Oncology)
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