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Editors

Eeva-RiittaSavolainen
SakariKakko

Haemolytic Anaemia

Essentials

  • A reticulocyte count is a first-line investigation in anaemia. It differentiates anaemia caused by excessive consumption (= haemorrhage or haemolysis) from deficiency anaemias (deficiency of iron, folic acid or vitamin B12) and myelogenous anaemias (e.g. malignant haematological diseases).
  • The aetiology of haemolysis must be investigated whenever possible.
  • Anemia that develops rapidly (in days or weeks) is almost always due to either a haemorrhage (more common) or hemolysis (less common).

Epidemiology

  • Haemolytic anaemias are rare in some countries (e.g. the Nordic countries), but rare cases occur, caused by e.g. autoimmune haemolytic anaemia (AIHA http://www.orpha.net/en/disease/detail/98375).
  • In certain geographic regions haemolytic anaemias present a more frequently encountered problem (e.g. sickle cell anaemia Sickle Cell Disease, thalassaemias Thalassaemias), and this must be borne in mind when treating patients originating from such regions.

Background

  • The normal life span of red blood cells is 120 days. In haemolysis, the life span may be shortened down to a few minutes.
  • Haemolysis may be
    • compensated, which is a state in which the increased erythrocyte production is able to compensate for the accelerated consumption, thus averting anaemia.
    • uncompensated, i.e. the patient develops anaemia.
  • The reticulocyte count is raised in both conditions, indicating increased erythrocyte production, provided that the bone marrow is healthy and able to increase erythrocyte production.
  • Signs of haemolysis include, in addition to various degrees of anaemia:
    • enhanced erythropoiesis in the bone marrow sample, resulting in reticulocytosis in the blood
    • an increase in haemoglobin breakdown products
    • in intravascular haemolysis, increased plasma haemoglobin concentration and occasionally haemoglobinuria as well as haemosiderinuria.

Causes of haemolytic anaemia

  • The premature destruction of erythrocytes may be caused by:
    • defects in the erythrocytes themselves (hereditary haemolytic anaemias and paroxysmal nocturnal haemoglobinuria, i.e. PNH).
  • Specific disease forms are listed in table T1.

Causes of haemolysis

Erythrocyte defects
Hereditary cell membrane defects
Hereditary haemoglobin abnormalities
Hereditary enzyme deficiencies
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • Pyruvate kinase deficiency
Paroxysmal nocturnal haemoglobinuria (PNH)
External causes
Immunohaemolysis
  • Autoimmune haemolysis (AIHA)
  • Drug-induced immunohaemolysis
  • Transfusion reaction
  • Mother-child immunisation
Fragmentation haemolysis
  • Prosthetic valves, other prostheses, haemoperfusion
  • March haemoglobinuria
  • Vasculitis
  • Disseminated intravascular coagulation (DIC)
  • Thrombotic thrombocytopenic purpura (TTP)
Other external causes
  • Infections, toxins, burns, hypersplenism

Diagnostic assessment

  • The assessment should aim to
    1. ascertain the presence of haemolysis as the cause of anaemia
    2. uncover the cause and mechanism of the haemolytic condition.
  • The general practitioner can fairly easily exclude the possibility of significant haemolysis.
    • A normal or elevated haptoglobin concentration virtually rules out significant haemolysis.
  • Anaemia and reticulocytosis can be signs of haemorrhage or haemolysis.
  • Co-existing deficiency anaemia is also possible. Consequently, always check transcobalamin II-bound vitamin B12, folate and ferritin levels.
  • Other investigations to be carried out in order to verify haemolysis and its mechanism, as considered necessary
    • Direct Coombs' test
      • Positive in autoimmune haemolytic anaemia (AIHA)
    • Lactate dehydrogenase
      • A very sensitive indicator of haemolysis, but it also increases in many other conditions.
    • Haptoglobin
      • Decreases in haemolysis, but it may also be decreased in liver diseases.
    • Bilirubin
      • The concentration of unconjugated bilirubin, in particular, increases.
    • Urinary haemosiderine
      • indicative of intravascular haemolysis of long duration, and it will remain positive several weeks after the cessation of haemolysis.
    • Blood cell morphology studies and bone marrow examination if indicated.
  • A careful history should be taken regarding current medication, including both regular and temporary drugs.
  • Family history, immigrant populations from regions where thalassaemia and sickle cell disease occur

Treatment

  • Treatment depends on the specific condition and is usually carried out in collaboration with a specialist physician.
  • Patients with severe anaemia that needs blood transfusion (blood haemoglobin < 70 g/l) and patients with symptomatic anaemia should be referred as an emergency case to hospital for treatment.

    References

    • Kavanagh PL, Fasipe TA, Wun T. Sickle Cell Disease: A Review. JAMA 2022;328(1):57-68[PubMed]
    • Kattamis A, Kwiatkowski JL, Aydinok Y. Thalassaemia. Lancet 2022;399(10343):2310-2324[PubMed]
    • Abou-Ismail MY, Kapoor S, Citla Sridhar D, et al. Thrombotic microangiopathies: An illustrated review. Res Pract Thromb Haemost 2022;6(3):e12708[PubMed]
    • Berentsen S, Barcellini W. Autoimmune Hemolytic Anemias. N Engl J Med 2021;385(15):1407-1419[PubMed]
    • Savolainen E-R, Kakko S, Jahnukainen K, Juvonen E. [Haemolytic anaemias]. In: Porkka K, Lassila R, Remes K, Savolainen E-R (eds.). [Diseases of the blood]. Duodecim Publishing Company Ltd 2015
    • Säily M, Armstrong E, Meri S. [Paroxysmal nocturnal haemoglobinuria]. In: Porkka K, Lassila R, Remes K, Savolainen E-R (eds.). [Diseases of the blood]. Duodecim Publishing Company Ltd 2015