Immune-mediated hemolytic anemia

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Spherocytes associated with immune-mediated haemolytic anaemia

Immune-mediated haemolytic anaemia (IMHA) is a relatively uncommon adult-onset disease which occurs in all breeds of cats. Anaemia in most cases is characterised by depleted circulating red cells (RBCs) (hematocrit <15%), and a regenerative profile with macrocytic and hypochromic or normochromic RBCs[1].

IMHA is characterized by the immune destruction of RBCs that have been coated with immunoglobulins, complement, or both, resulting in direct destruction or phagocytosis of RBCs and removal from systemic circulation. Antibodies may be directed against normal erythrocytes (primary or idiopathic) or against erythrocytes that have been antigenically-altered through interaction with secondary causes. Immune-mediated haemolytic anaemia more accurately describes a process by which red blood cells are destroyed and has replaced the term autoimmune haemolytic anaemia[3].

Cause

Immune-mediated haemolytic anaemia arises from development of IgG or IgM antibodies directed against the red blood cell membrane. The degree of red blood cell lysis depends on the type and amount of antibody that binds to the red blood cell and the involvement of complement fixation. Most canine cases of IMHA are the result of a combination of IgG and complement binding to the red blood cell. When the red blood cell attaches to an IgG molecule, it is phagocytosed by macrophages possessing multiple receptors for the constant fragment (Fc) portion of the IgG molecule and as these macrophages are found primarily in the spleen, active erythrophagocytosis results in splenomegaly. As immunoglobulin production increases and more molecules are bound to the red blood cell, erythrophagocytosis occurs within the liver, which can result in hepatomegaly.

Once the immunoglobulin is attached, activation of the complement system occurs with binding of complement proteins to the red blood cell. Complement activation can cause immediate intravascular lysis or enhance extravascular lysis and produce spherocytes. CI, a serine protease from the liver, enters the complement cascade and generates a "membrane attack complex" that attaches to the red blood cell membrane. The membrane attack complex then causes "holes to be punched" in the red blood cell membrane, allowing an influx of water and electrolytes, cell swelling, and lysis. The membrane complex can be removed by macrophages within the spleen (partial erythrophagocytosis), producing spherocytes.

IgG possesses only two antigen-binding sites (monomeric) and usually cannot directly agglutinate red blood cells unless a large amount of antibody is present. On the other hand, IgM is a large pentameric molecule that can directly agglutinate red blood cells. IgM may also detach after complement activation and bind to other red blood cells. The red blood cell-IgM complex may bind complement and be phagocytised by macrophages that possess the Fc receptor. This most commonly occurs in the liver with about 20% of receptors in the spleen.

Causative factors that can be associated with sIMHA in the cat include:

Clinical signs

Feline IMHA has been predominantly reported in younger male animals. Clinical examination may show pale mucous membranes, icterus (rarely), hepatosplenomegaly with abdominal discomfort, tachypnoea, water-hammer pulse, and a soft systolic heart murmur. Patients with IMHA commonly present with a regenerative anaemia, although there may be a delay of 2-5 days before a regenerative response is apparent in the peripheral blood. Immune mediated haemolytic anaemia may also be non-regenerative if antibodies or complement is directed against erythrocyte precursors within the bone marrow[13].

IMHA is often associated with a strongly regenerative bone marrow erythroid response, however, a high percentage of cats do not have reticulocytosis at the time of diagnosis[14].

Diagnosis

A regenerative anaemia is often seen (PCV <10% is common)[15]. Leucocytosis is rare, and 30-40% of cats have concurrent thrombocytopenia, caused by consumption (DIC), sequestration in the spleen or immune-mediated destruction[16]. Hyperglobulinaemia and elevated ALT are commonly seen.

The presence of IMHA is confirmed of demonstration of in-saline agglutination (macroscopic and microscopic evaluation), Coomb's test, or flow cytometry. These tests will, however, not differentiated primary from secondary IMHA[17]. A detailed history remains the cornerstone for an accurate diagnosis. The patient may have been recently vaccinated, traveled to tick/parasite-infested regions, or given antibiotics.

Severe regenerative anaemia, haemoglobinaemia, and spherocytosis are hallmarks of IMHA, but their presence depends on how acutely the haemolytic crisis occurred. The release of reticulocytes into the blood stream does not occur until several days after the acute haemolytic episode. An absolute reticulocyte count and a corrected reticulocyte percentage are essential for the assessment of red blood cell regeneration. Patients with IMHA may typically exhibit a mild to marked leukocytosis and often have a left shift with toxic changes in the neutrophils. Although thrombocytopenia is a common finding, only a small percentage (<20%) may show signs, such as petechiae, ecchymosis, epistaxis, and melaena.

Serum biochemistry will often reflect hypoxic changes such as azotaemia (prerenal or renal) and increased proteins, liver enzymes, and total bilirubin. Coagulation profiles serve as an early indicator of disseminated intravascular coagulopathy (DIC) and thromboembolism, both of which occur in primary and secondary IMHA patients.

A complete evaluation of the IMHA patient should include thoracic and abdominal radiographs and abdominal ultrasound. Evaluation of the bone marrow may be also needed, especially if the patient's anaemia is non-regenerative, a destruction process directed at red cell precursors is suspected, or another cytopaenia is present. Bone marrow aspirates may be helpful in diagnosing red blood cell aplasia or hypoplasia, neoplastic infiltration, or immune destruction of erythrocyte precursors.

Treatment

In secondary IMHA both the primary disease and the red blood cell destruction needs to be aggressively treated with blood transfusion, broad-spectrum antimicrobial drugs, and immunosuppressive therapy.

Immunosuppressive drugs that can be used include corticosteroids, azathioprine, cyclophosphamide, cyclosporine, danazol, intravenous immunoglobulins, mycophenolate, and leflunonamide. The goal of therapy is the initial stabilisation of the haematocrit, followed by the normalisation of the haematocrit over a period of time[18].

Supportive care with patients with IMHA includes anticoagulant therapy, gastric protectants and fluid therapy. Prognosis varies depending on cause(s).

References

  1. Kohn, B (2010) Immune-mediated hemolytic anemia. In August, JR (Ed): Consultations in feline internal medicine. Vol 6. Elsevier Saunders, Philadelphia. pp:617
  2. Day, MJ (1999) Antigen specificity in canine autoimmune haemolytic anaemia. Vet Immunol Immunopathol 69:215
  3. Lobetti, R (2004) Secondary Immune Mediated Haemolytic Anaemia in the Dog. WSAVA 29th Congress, Greece
  4. Maede, Y & Hata, R (1975) Studies of feline haemobartonellosis. II. The mechanism of aneamia produced by infection with haemobartobnella felis. Jap J Vet Sci 37:49
  5. Scott, DW et al (1973) Autoimmune hemolytic anaemia in the cat. J Am Anim Hosp Assoc 9:530
  6. Gunn-Moore, DA et al (1999) Immune-mediated haemolytic anaemia in two sibling cats associated with multicentric lymphoblastic infiltration. JFMS 1:209
  7. Kohn, B et al (2006) Primary immune-mediated haemolytic anaemia in 19 cats: diagnosis, therapy, and outcome (1998-2004). J Vet Intern Med 20:159
  8. Duval, D & Giger, U (1996) Vaccine-associated immune-mediated haemolytic anaemia in the dog. J Vet Intern Med 10:290
  9. Penhale, WJ et al (1990) A review of cases submitted to Murdoch University for immunodiagnostic testing: 1978-1989. Aust Vet J 67:148
  10. Faircloth, JC & Montgomery JK (1981) Systemic lupus erythematosus in a cat presenting with autoimmune haemolytic anaemia. Fel Pract 11:22
  11. Lusson, D, Billiemaz, B & Chabanne, JL (1999) Circulating lupus anticoagulant and probable systemic lupus erythematosus in a cat. JFMS 3:193
  12. Griot-Wenk, ME & Giger, U (1995) Feline transfusion medicine. Blood types and their clinical importance. Vet Clin North Am Small Anim Pract 25:1305
  13. Husbands, BD, Smith, SA & Weiss, DJ (2002) Idiopathic immune-mediated haemolytic anaemia (IMHA) in 25 cats. Proceedings of the 20th ACVIM Forum, Dallas
  14. Kohn, B, Linden, T & Leibold, W (2006) Platelet-bound antibodies detected by a flow cytometric assay in cats with thrombocytopenia. JFMS 8:254
  15. Stokol, T & Blue, JT (1999) Pure red cell aplasia in cats: 9 cases (1989-1997). J Am Vet Med Assoc 214:75
  16. Weiss, DJ (2008) Bone marrow pathology in dogs and cats with non-regenerative immune-mediated haemolytic anaemia and pure red cell aplasia. J Comp Pathol 138:46
  17. Piek, CJ et al (2003) Idiopathic immune-mediated haemolytic anaemia (IMHA) in cats: differentiation from secondary IMHA and outcome of treatment. Proceedings of the 13th ECVIM-CA Forum, Uppsala. pp:162
  18. Gibson, GR et al (2002) Use of haemoglobin based oxygen carrying solutions in cats: 72 cases (1998-2000). J Am Vet Med Assoc 221:96