Immune-mediated haemolytic anaemia (IMHA)

Immune-mediated haemolytic anaemia (IMHA) is a clinical syndrome that involves the uncontrolled production of autoantibodies against red blood cells. It can occur intravascularly, as a complement-mediated process, or extravascularly (more frequently), in which it is mediated by the mononuclear phagocytic system of the spleen, liver and bone marrow. The result, in both cases, is anaemia.

The aetiology may be primary or secondary:

• Primary:
  Caused by antibodies directed against erythrocyte membrane antigens. In 30% of cases, it may be associated with other autoimmune diseases such as systemic lupus erythematosus or autoimmune thrombocytopaenia.
• Secondary:
  Caused by other underlying pathologies that leads to the appearance of new erythrocyte membrane antigens (Table 1). The antigens of some infectious agents may be similar to erythrocyte membrane antigens; in this case, the antibodies directed against these agents will also be directed against the erythrocyte membrane.

IMHA can be classified in three ways:

• By the immunoglobulins involved: in dogs the most frequent are IgG, followed by IgM, and very rarely IgA, while in cats the most frequent are IgM.
• By the haemolytic process: intravascular or extravascular.
• By the thermosensitivity of the induced antibodies:
  • Warm antibodies become active at body temperature.
  • Cold antibodies become active at temperature under 34ºC.

In dogs, IMHA is more common in females (70%) than males, and in adults around 6 years old. Breeds such as Cocker Spaniels, Bichon Frisés, Miniature Pinschers, Miniature Schnauzers, English Springer Spaniels, Wirehaired Collies and Finnish Spitzs have a genetic predisposition to the disease.

Clinical Signs

• Anorexia
• Pallor
• Jaundice
• Vomiting
• Diarrhoea
• Syncope
• Weakness
• Fever
• Tachycardia
• Tachypnoea
• Splenomegaly
• Hepatomegaly
• Abdominal pain

The complications most frequently associated with IMHA are disseminated intravascular coagulation (DIC) and pulmonary thromboembolism, both with their associated symptoms.

The signs will depend on the speed of progression of the disease, its severity, and the mechanism of red blood cell destruction. The most common form is chronic and insidious, and is caused by warm antibodies. If the antibodies involved are cold agglutinins, the animal will present inflammation, erythema, cyanosis, ulceration and necrosis of the extremities (ears, tail, nose, tips of the paws), which will worsen in winter.

If the disease is associated with thrombocytopaenia, petechiae and ecchymoses will also be found.

Interpretation of laboratory tests

General Tests

• Complete blood count:
  • Moderate to severe usually regenerative anaemia. However, no regeneration may be observed (up to 30%) if the disease involves the erythroid precursors in the bone marrow, less than 5 days have passed since onset, or a concomitant disease is present. MCH is decreased, MCV may be elevated due to agglutination, haemolysis, or reticulocytosis, and MCHC values are normal.
    Leucocytosis due to neutrophil left shift, and monocytosis, which may be a sign of tissue damage (necrosis, thromboembolisms) or may be caused by stimulation of the bone marrow and inflammatory response.
  • Mild to severe thrombocytopaenia (60% of cases), especially when associated with the presence of anti-erythrocyte and anti-platelet autoantibodies (Evans syndrome), DIC, and splenic sequestration.
• Blood biochemistry:
  • Increased TBIL and alkaline phosphatase (associated with a worse prognosis and shorter survival).
  • Increased alanine aminotransferase (ALT) in 50% of cases.
  • Normal or elevated plasma proteins; low plasma proteins are more suggestive of blood loss than haemolytic anaemia.
• Clotting tests: The greater the degree of haemolysis, the more abnormal the test.
  • Increased prothrombin time (PT) and activated partial thromboplastin time (aPTT).
  • Abnormal fibrinogen levels.
• Urine test:
  • Haemoglobinuria
  • Bilirubinuria

Specific tests

• Peripheral blood smear:
  • Spherocytes but no schistocytes (>2%). However, this is also true of other autoimmune imbalances (Zn poisoning), albeit to a lesser extent (1%). They are difficult to identify in cats due to the lack of central pallor in their normal red blood cells.
  • Anisocytosis
  • Polychromatophilic erythrocytes
  • Erythrophagocytosis
• Slide agglutination: Blood clumping is a sign of an immune-mediated disease, but its absence does not rule it out (it appears in 78%). Clumping must be distinguished from red blood cell stacking (Rouleaux phenomenon). Clumping can also be observed macroscopically in the EDTA tube.
• Osmotic fragility test in saline solution: Spherocytes become lysed in a mildly hypotonic saline solution that would not be able to lyse normal red blood cells.
• Bone marrow cytology: Erythrophagocytosis, hyperplasia or aplasia of the red blood cell series. The test is indicated if there is no regeneration 5-7 days after disease onset.
• Coomb's test: This test detects the presence of anti-erythrocyte antibodies on the surface of the erythrocytes, but it is not pathognomonic of an autoimmune process (it may be due to infectious or parasitic diseases). It is positive in 70% of cases of IMHA, but a negative result does not rule out immune-mediated anaemia. A negative result together with spherocytosis, polychromasia, autoagglutination and a compatible clinical picture is highly indicative of immune-mediated haemolytic anaemia.

Response to treatment is assessed by increased Hct, decreased haemolysis, agglutination, spherocytosis, and clinical improvement.

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