Haemolytic Anaemia

Haemolysis leads to haemolytic anemia when bone marrow activity cannot compensate for the increased loss of red blood cells.

Normal red cells have a lifespan of about 120 days. The lifespan may be very short in haemolytic anaemia (e.g. as short as 5 days in sickle cell anaemia). Haemolysis may occur by two mechanisms:¹

• Intravascular: due to complement fixation, trauma, or other extrinsic factors. Examples are prosthetic cardiac valves, glucose-6-phosphate dehydrogenase deficiency, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation and paroxysmal nocturnal haemoglobinuria.
• Extravascular (most common): red cells are removed from the circulation by the mononuclear-phagocytic system either because they are intrinsically defective or because of the presence of bound immunoglobulins to their surfaces.

Genetic

• Red cell membrane abnormalities: hereditary spherocytosis, elliptocytosis
• Haemoglobin abnormalities: sickle cell anaemia, thalassaemia
• Enzyme defects: glucose-6-phosphate dehydrogenase, pyruvate kinase deficiency

Acquired

• Immune:
  • Isoimmune: haemolytic disease of newborn, blood transfusion reaction
• Autoimmune:
  • Warm antibody type: idiopathic, systemic lupus erythematosus, lymphoma, chronic lymphatic leukaemia (CLL), Evans' syndrome (thrombocytopenia associated with a positive direct Coombs test)
  • Cold antibody type: cold haemagglutinin disease, paroxysmal cold haemoglobinuria, mycoplasma pneumonia, lymphoma, infectious mononucleosis or other viral infections
  • Drug related: drug absorbed onto red cell surface, e.g. penicillin, cephalosporins, or immune complex mediated, e.g. sulphonamides, quinidine
• Non-immune: trauma (cardiac haemolysis, microangiopathic anaemia (found in patients with disseminated intravascular coagulation or haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura), infection (malaria, septicaemia), hypersplenism, membrane disorders, paroxysmal nocturnal haemoglobinuria, liver disease.

• Risk factors are variable and depend on the underlying cause.
• Sickle cell disorders: mainly affect Africans and some Arabic peoples.
• Glucose-6-phosphate dehydrogenase deficiency: the A variant is generally found in West Africans and African Americans. The Mediterranean variant occurs in individuals in Southern Europe, the Middle East and in the Indian subcontinent.²
• Autoimmune haemolytic anemia: slightly more common in females than males. Most often presents in middle-aged and older individuals.

Symptoms

• Symptoms are due to both anaemia and the underlying disorder. Patients with minimal or long-standing haemolytic anaemia can be asymptomatic.
• Severe anaemia, especially of sudden onset, may cause tachycardia, dyspnoea, angina and weakness.
• Gallstones may cause abdominal pain. Bilirubin stones can develop in patients with persistent haemolysis.
• Haemoglobinuria can occur in patients with intravascular haemolysis and produces dark urine.
• Medication history:
  • Some medications e.g. penicillin, quinine, quinidine and L-dopa, may cause immune haemolysis.
  • Oxidant drugs, e.g. nalidixic acid, (and also fava beans and infections) can trigger haemolysis in patients with G6PD deficiency.

Signs

• Signs of anaemia: general pallor and pale conjunctivae. Tachycardia, tachypnoea and hypotension if severe.
• Mild jaundice may occur due to haemolysis.
• Splenomegaly: occurs with some causes, e.g. hereditary spherocytosis. May indicate an underlying condition such as chronic lymphocytic leukemia, lymphoma or systemic lupus erythematosus.
• Leg ulcers may occur in some causes of haemolytic anaemia e.g. sickle cell anaemia.
• Right upper abdominal quadrant tenderness may indicate gallbladder disease.
• Bleeding and petechiae indicate thrombocytopenia due to Evans' syndrome or thrombotic thrombocytopenic purpura if neurological signs are also present.
• Signs of underlying disorder e.g. malar rash in patients with SLE

Non-specific findings

• Full blood count:
  • Platelet count: normal in most haemolytic anemias. Thrombocytopenia can occur in SLE, CLL, and microangiopathic haemolytic anemia (defective prosthetic cardiac valves, thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome and disseminated intravascular coagulation).
  • A low MCV and mean corpuscular hemoglobin (MCH): consistent with a microcytic hypochromic anaemia, which may occur in chronic intravascular haemolysis, e.g. paroxysmal nocturnal haemoglobinuria.
  • High MCH and mean corpuscular haemoglobin concentration (MCHC): suggest spherocytosis.
• Coombs test: The direct Coombs test is used clinically when immune-mediated haemolytic anaemia (antibody-mediated destruction of RBCs) is suspected.
• Cold agglutinins: a high titre of anti-I antibody may be found in mycoplasma infections and a high titre of anti-i antibody may be found in haemolysis associated with infectious mononucleosis. An anti-P cold agglutinin may be seen in paroxysmal cold haemoglobinuria.
• Ultrasound to estimate spleen size: physical examination is not reliable.
• Chest x-ray and ECG may be needed to assess cardiopulmonary status.

Assess presence of haemolysis

• Red cell destruction:
  • Reduced haemoglobin
  • Spherocytes, fragmented red cells, nucleated red cells or other abnormal red cells
  • Increased serum unconjugated bilirubin, increased LDH and reduced or absent haptoglobin
  • Increased urinary urobilinogen, haemosiderinuria
• Increased red cell production:
  • Increased reticulocytosis: may also be due to blood loss or a bone marrow response to iron, vitamin B₁₂ or folate deficiencies
  • Increased red cell MCV (due to reticulocytosis; but many other causes, e.g. B₁₂ and folate deficiency

Determine if the haemolysis is intravascular

• Increased plasma haemoglobin
• Methaemoglobinaemia
• Haemoglobinuria

Identify the cause

• Genetic:
  • Red cell morphology: spherocytes (suggest congenital spherocytosis or autoimmune haemolytic anaemia), elliptocytes, schistocytes (fragmented red cells suggesting thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome or mechanical damage)
  • Screen for sickle cell: sickling under reduced conditions
  • Haemoglobin electrophoresis
  • Red cell enzyme assays
• Acquired:
  • Antibodies: IgG warm antibodies in autoimmune haemolytic anaemia react at 37 degrees centigrade whereas IgM cold antibodies react at lower temperatures, i.e. 20 degrees or below.³ The direct antiglobulin test is usually but not always positive in autoimmune haemolytic anaemia.
  • Red cell morphology: e.g. haemolytic uraemic syndrome, thrombotic thrombocytopaenic purpura

General measures

Administer folic acid because active haemolysis may cause folate deficiency.
Discontinue medications that may have precipitated or aggravated haemolysis.

Transfusion therapy

Avoid transfusions unless absolutely necessary, but they may be essential.
In autoimmune haemolytic anaemia, type matching and cross matching may be difficult. Use the least incompatible blood if transfusions are indicated. The risk of acute haemolysis of transfused blood is high, but the degree is dependent on the rate of infusion.

Iron therapy

This is indicated for patients with severe intravascular haemolysis in which persistent haemoglobinuria has caused substantial iron loss. Iron stores increase in haemolysis and so iron administration is generally contraindicated in haemolytic disorders, particularly those that require chronic transfusion support.

Autoimmune haemolytic anaemia therapy

Corticosteroids are indicated for the warm type. Other immunosuppressive drugs, e.g. azathioprine, may be required. Management of the cold type includes keeping extremities warm; steroids and splenectomy are less successful and transfusions should be avoided if possible.

Splenectomy

This may be the first choice of treatment in some types of haemolytic anaemia such as hereditary spherocytosis. In other cases it is recommended when other measures, such as in autoimmune haemolytic anaemia, have failed.
Splenectomy is usually not recommended in haemolytic disorders such as cold agglutinin haemolytic anaemia.

• Anaemia: high output cardiac failure
• Jaundice: increased unconjugated bilirubin
• In patients with intravascular haemolysis, iron deficiency due to chronic haemoglobinuria can exacerbate anaemia and weakness