Immune-mediated hemolytic anemia

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Autoagglutination is visible on the sides of a blood tube, taken from a dog with IMHA.

Immune-mediated hemolytic anemia (IMHA) is a common immune-mediated disease characterized by a type II hypersentivity reaction against erythrocytes. This disease is a common cause of anemia and mortality in dogs[1].

This disease is caused by the binding of antibodies to the surface of red blood cells as a result of recognition of potentially antigenic RBC membrane proteins[2], resulting in their phagocytosis within the spleen.

Two forms of IMHA are observed:

- Anaplasma phagocytophilum[4]
- Bartonella henselae, B. vinsonii subsp berkhoffii
- Borrelia burgdorferi
- Ehrlichia canis
- Erysipelothrix rhusiopathiae[5]
- Leishmania infantum[6]
- Mycoplasma haemocanis[7]
- Rickettsia rickettsii
- paraneoplastic syndrome - e.g. associated with sarcomas[8]
- oxidant agents such as zinc, acetaminophen, onion and garlic

Clinical signs may be initially vague, but lethargy, reduced exercise intolerance, tachycardia and anemia are consistent findings[9]. As the disease progresses, melena, cardiac murmurs, splenomegaly, hepatomegaly, icterus, hemoglobinuria, fever and lymphadenopathy are frequent accompanying signs[10]. Bacteremia is not a feature of this disease[11].

High mortality rates are observed in the first two weeks following presentation, primarily due to the rapidly escalating anemia, a consumptive coagulopathy and consequential disseminated intravascular coagulation.

Preliminary blood tests usually reveal anemia, haematocrits < 15%, leucocytosis, a left shift and reticulocytosis[12]. The anemia of IMHA is usually regenerative, since erythropoeisis is not adversely affected unless the immune response affects hematopoietic cells. Therefore, reticulocytosis, polychromasia, anisocytosis, and nucleated erythrocytes may be present[13].

Approximately 50% to 70% of dogs with IMHA have concurrent thrombocytopenia known as Evans syn­drome[14][15].

Diagnosis is based on presenting clinical signs of anemia, autoagglutination, the presence of spherocytes on blood smears, a positive gel-based direct agglutination test[16] or Coombs’ test, and the elimination of any other underlying cause of anemia.

Dogs with primary IMHA with ≥ 2 Ig isotypes bound to erythrocytes (tested via direct immunofluorescence), are likely to have a more severe degree of anemia, spherocytosis, and autoagglutination[17].

A differential diagnosis would include other causes of anemia such as blood loss, splenic torsion, pyruvate kinase deficiency (Basenji), phosphofructokinase deficiency (English Springer Spaniel, American Cocker Spaniel), hereditary osmotic fragility (Alaskan Malamute, Miniature Schnauzer), hemangiosarcoma and hyperadrenocorticism[18].

The mainstay of treatment involves addressing underlying disease states (especially with secondary IMHA), and use of immunosuppressive drugs to reduced autophagocytosis of erythrocytes.

In severely anemic dogs, oxygen therapy and repeated blood transfusions may also be required.

The drug of choice for IMHA is prednisolone but in non-responsive cases cyclosporine, azathioprine, vincristine, cyclophosphamide, tacrolimus and leflunomide can be used[19].

Prednisolone is given at 2 mg/kg orally every 12 - 24 hours for 1 to 2 weeks, then at a reducing dose over 2 - 4 months[20].

The combination of prednisolone (2 mg/kg) with azathioprine (2 mg/kg daily) and low dose aspirin (0.5 mg/kg daily) or clopidogrel (0.5 - 1.0 mg/kg daily)[21] appear to have the highest survival rates[22].

Splenectomy is indicated in non-responsive patients or adverse medication side-effects[23].

The prognosis with primary IMHA is guarded (25 - 50% mortality rates), despite heightened awareness of the disease and new drug treatment approaches[24].

Mortality increases in association with age[25] and elevated blood levels of cardiac troponin-1 levels[26], AST, ALT, serum bilirubin, lactate[27] and urea concentrations[28].

Long-term complications of IMHA (due presumably to immunosuppression) are relatively common, and include splenic vein thrombosis[29], Citrobacter freundii septicemia[30], gingival overgrowth and periodontitis[31], and dermatopathies due to Toxoplasma gondii[32], Alternaria infectoria[33] and Fusarium sporotrichioides[34] and phaeohyphomycosis[35].

References

  1. McAlees TJ (2010) Immune-mediated haemolytic anaemia in 110 dogs in Victoria, Australia. Aust Vet J 88(1-2):25-28
  2. Tan E et al (2012) Potentially antigenic RBC membrane proteins in dogs with primary immune-mediated hemolytic anemia. Vet Clin Pathol 41(1):45-55
  3. Giger U (2000) Regenerative anemias caused by blood loss or hemolysis. Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat, 5th ed. Philadelphia, W. B. Saunders Co., pp:1784-1804
  4. Mazepa AW et al (2010) Clinical presentation of 26 anaplasma phagocytophilum-seropositive dogs residing in an endemic area. J Am Anim Hosp Assoc 46(6):405-412
  5. Foster JD et al (2012) A case of apparent canine erysipeloid associated with Erysipelothrix rhusiopathiae bacteraemia. Vet Dermatol 23(6):528
  6. Karagianni AE et al (2012) Perinuclear antineutrophil cytoplasmic autoantibodies in dogs infected with various vector-borne pathogens and in dogs with immune-mediated hemolytic anemia. Am J Vet Res 73(9):1403-1409
  7. Warman SM et al (2010) Haemoplasma infection is not a common cause of canine immune-mediated haemolytic anaemia in the UK. J Small Anim Pract 51(10):534-539
  8. Mellanby RJ et al (2004) Immune-mediated haemolytic anaemia associated with a sarcoma in a flat-coated retriever. J Small Anim Pract 45(1):21-24
  9. Reimer ME, Troy GC, Warnick LD (1999) Immune-mediated hemolytic anemia: 70 Cases 1988-1996). J Am Anim Hosp Assoc 35:384-390
  10. Reimer ME et al (1999) Immune-mediated hemolytic anemia: 70 cases (1988-1996). JAAHA 35(5):384-390
  11. Miller SA et al (2004) Case-control study of blood type, breed, sex, and bacteremia in dogs with immune-mediated hemolytic anemia. J Am Vet Med Assoc 224(2):232-235
  12. Piek CJ (2011) Canine idiopathic immune-mediated haemolytic anaemia: a review with recommendations for future research. Vet Q 31(3):129-141
  13. Klag A, Giger U, Shofer F (1993) Idiopathic immune-mediated hemolytic anemia in dogs: 42 cases (1986-1990). J Am Vet Med Assoc 202:783-787
  14. Klag A et al (1993) Idiopathic immune-mediated hemolytic anemia in dogs: 42 cases (1986-1990). JAVMA 202(5):783-788
  15. Carr AP et al (2002) Prognostic factors for mortality and thromboembolism in canine immune-mediated hemolytic anemia: A retrospective study of 72 cases. J Vet Intern Med 16(5):504-509
  16. Piek CJ et al (2012) Good agreement of conventional and gel-based direct agglutination test in immune-mediated haemolytic anaemia. Acta Vet Scand 54:10
  17. Harkin KR et al (2012) Erythrocyte-bound immunoglobulin isotypes in dogs with immune-mediated hemolytic anemia: 54 cases (2001-2010). J Am Vet Med Assoc 241(2):227-232
  18. Miller AG et al (2012) Antiphospholipid antibodies in dogs with immune mediated hemolytic anemia, spontaneous thrombosis, and hyperadrenocorticism. J Vet Intern Med 26(3):614-623
  19. Whitley NT & Day MJ (2011) Immunomodulatory drugs and their application to the management of canine immune-mediated disease. J Small Anim Pract 52(2):70-85
  20. McCullough S (2003) Immune-mediated hemolytic anemia: Understanding the nemesis. Vet Clin Small Anim 33:1295-1315
  21. Mellett AM et al (2011) A prospective study of clopidogrel therapy in dogs with primary immune-mediated hemolytic anemia. J Vet Intern Med 25(1):71-75
  22. Weinkle TK et al (2005) Evaluation of prognostic factors, survival rates, and treatment protocols for immune-mediated hemolytic anemia in dogs: 151 cases (1993-2002). JAVMA 226(11):1869-1880
  23. Feldman B et al (1985) Splenectomy as adjunctive therapy for immune-mediated thrombocytopenia and hemolytic anemia in the dog. JAVMA 187(6):617-619
  24. Bennett D et al (1981) Primary autoimmune hemolytic anemia in the dog. Vet Rec 109(8):150-153
  25. Orcutt ES et al (2010) Immune-mediated hemolytic anemia and severe thrombocytopenia in dogs: 12 cases (2001-2008). J Vet Emerg Crit Care (San Antonio) 20(3):338-345
  26. Gow DJ et al (2011) Serum cardiac troponin I in dogs with primary immune-mediated haemolytic anaemia. J Small Anim Pract 52(5):259-264
  27. Holahan ML et al (2010) The association of blood lactate concentration with outcome in dogs with idiopathic immune-mediated hemolytic anemia: 173 cases (2003-2006). J Vet Emerg Crit Care (San Antonio) 20(4):413-420
  28. Swann JW & Skelly BJ (2011) Evaluation of immunosuppressive regimens for immune-mediated haemolytic anaemia: a retrospective study of 42 dogs. J Small Anim Pract 52(7):353-358
  29. Laurenson MP et al (2010) Concurrent diseases and conditions in dogs with splenic vein thrombosis. J Vet Intern Med 24(6):1298-1304
  30. Galarneau JR et al (2003) Citrobacter freundii septicemia in two dogs. J Vet Diagn Invest 15(3):297-299
  31. Namikawa K et al (2012) Gingival overgrowth in a dog that received long-term cyclosporine for immune-mediated hemolytic anemia. Can Vet J 53(1):67-70
  32. Webb JA et al (2005) Cutaneous manifestations of disseminated toxoplasmosis in an immunosuppressed dog. J Am Anim Hosp Assoc 41(3):198-202
  33. Dedola C et al (2010) Cutaneous Alternaria infectoria infection in a dog in association with therapeutic immunosuppression for the management of immune-mediated haemolytic anaemia. Vet Dermatol 21(6):626-634
  34. Kano R et al (2011) Chronic ulcerative dermatitis caused by Fusarium sporotrichioides. Med Mycol 49(3):303-305
  35. Swift IM et al (2006) Successful treatment of disseminated cutaneous phaeohyphomycosis in a dog. Aust Vet J 84(12):431-435