16.1 Anaemia
Definition
Anaemia is a common medical condition throughout all ages of childhood. However, the common causes vary with age. Anaemia refers to a reduction in haemoglobin (and hence red cell mass) below that which is considered normal for the patient in question. Normative haemoglobin data differs with age and, in teenage years, sex. Clinicians need to ensure that, when considering a diagnosis of anaemia, correct age-specific and, where applicable, sex-specific reference ranges are used. These reference ranges may vary according to the laboratory analyser in use. Thus each laboratory should report their own specific age-related reference ranges. An example of the age-related variation is shown by the reference ranges in Table 16.1.1. The majority of reference ranges in clinical use reflect 95% confidence intervals, so that 2.5% of individuals who are in fact ‘normal’ would be expected to consistently have haemoglobin levels just below the lower limit of the reported reference range.
Table 16.1.1 Normal haemoglobin values for age
| Age | Haemoglobin (g/L) |
|---|---|
| Birth | 135–200 |
| 1 month | 100–180 |
| 2 months | 90–140 |
| 6 months | 95–135 |
| 1 year | 105–135 |
| 2–6 years | 110–145 |
| 6–12 years | 115–155 |
| > 12 years (female) | 120–160 |
| > 12 years (male) | 130–180 |
Physiology
The prime function of haemoglobin is tissue oxygen delivery. Hence anaemia threatens this critical bodily function. Acutely, severe anaemia can lead to hypoxic tissue injury, and chronic anaemia can lead to growth failure and organ dysfunction as a result of chronic hypoxia or failure of compensatory mechanisms. The physiology of tissue oxygen delivery is critical to understand, as it enables the clinician to understand the concepts of relative anaemia and to determine appropriate treatment of the anaemic patient.
where 1.34 is a constant and represents the amount of oxygen carried by 1 g normal haemoglobin.
The key issues in this basic physiological equation are that:
• the parameters are multiplied, such that small decreases in cardiac output and haemoglobin and haemoglobin saturation lead to an overall large decrease in tissue oxygen delivery. Thus patients with cardiac disease may tolerate less reduction in haemoglobin before developing tissue hypoxia, and hence often have considerable urgency in treating their anaemia. No single haemoglobin (Hb) level can be used as an indication for transfusion therapy as these other factors need to be considered.
• in the presence of anaemia, cardiac output must be increased to maintain tissue oxygen delivery (Hb saturation cannot be increased above 100%). Failure of this compensatory mechanism or limitation of cardiac output by another disease will result in tissue hypoxia. Cardiac output is determined by cardiac stroke volume and heart rate. Therefore, heart rate is an important measure of the stress the anaemia is placing on the patient’s cardiac reserve. All anaemic patients should have their vital signs, especially heart rate and respiratory rate, assessed as part of their initial medical evaluation, and these parameters should be used to monitor progress and response to therapy.
• Hb saturation is normally close to 100% in children without cyanotic congenital heart disease or significant lung pathology. Thus, in otherwise well children with severe anaemia, or children in whom the Hb saturation is measured as 99–100%, inspired oxygen therapy makes little if any contribution to improving tissue oxygenation. Recovery of red cell mass (and hence Hb) is the most effective therapy.
• in children with cyanotic congenital heart disease or pulmonary pathology, the natural compensation for reduced Hb saturation is to increase Hb concentration. Hence, if a child with cyanotic congential heart disease who usually has a relatively increased Hb was to develop a ‘relative anaemia’, they might develop symptoms of anaemia at Hb levels that would be considered normal in most children. Treatment of ‘relative anaemia’, if required, is based on the same principles as treatment of ‘true anaemia’.
Clinical presentations
Children with anaemia most often present with pallor (reflecting the reduced Hb) or signs of reduced exercise tolerance (reflecting inability to increase tissue oxygen delivery to meet the demands of exercise). Reduced exercise tolerance manifests differently according to age. In infants, poor feeding is often described. In older children, shortness of breath on exertion or generalized lethargy are more common. Alternatively, incidental finding of anaemia when full blood examination has been performed for another indication is also very common.
Once the presence of anaemia has been confirmed, thorough history-taking and examination of the patient is required. Patient age and the duration of symptoms is important as a first step in determining the likely aetiology of the anaemia.
In addition, during the history and examination, other key considerations are:
• Is there evidence of cardiac decompensation or other adverse events as a result of the anaemia? This clearly makes appropriate therapy a matter of urgency.
• Are there clues to the aetiology of the anaemia?
• Is there evidence of multilineage cytopenias (neutropenia and thrombocytopenia)?
• Is there evidence of an associated, perhaps causative, disease?
Information that assists in answering these questions is shown in Table 16.1.2.
Table 16.1.2 Relevant information required on history and examination for patients with anaemia
| Critical question | Information obtained on history and examination |
|---|---|
| Cardiac decompensation | Exercise tolerance |
| Heart rate and respiratory rate | |
| Signs of congestive heart failure | |
| Altered conscious state, irritability, restlessness | |
| Aetiology | Duration of symptoms (bone marrow failure and haematinic deficiency usually have a longer duration of symptoms) |
| Family history (hereditary spherocytosis, G6PD deficiency, haemoglobinopathies and others are inherited causes of anaemia. Maternal history (e.g. veganism may be associated with B12 deficiency in infants) | |
| Birth and neonatal history (blood loss at birth, birth asphyxia and maternal blood group compatibility are all important in assessing neonatal anaemia. Jaundice at birth may give a clue to an episodic haemolytic disorder in older children) | |
| Presence or absence of jaundice (haemolysis) | |
| Drug exposure: as a cause of haemolysis, or bone marrow suppression | |
| Blood loss: trauma, recent surgery, iatrogenic in neonates, epistaxis, menstrual loss | |
| Dietary history: iron deficiency can be predicted in infants less than 12 months of age fed cow’s milk, or in toddlers who have failed to transfer to solid foods adequately | |
| Multilineage cytopenias | Bruising or bleeding, especially petechiae (thrombocytopenia) |
| Infection, mouth ulceration (neutropenia) | |
| Associated disease | Gastrointestinal symptoms (e.g. coeliac disease, inflammatory bowel disease) |
| Joint or bone pain (e.g. leukaemia, sickle cell disease, arthritis) | |
| Renal disease | |
| Malignancy | |
| Infection: as a primary cause (e.g. malaria), a precipitant of acute deterioration in a more chronic anaemia, or a trigger to acute haemolysis | |
| Neurological disorders, developmental delay/regression, failure to thrive may reflect functional B12 deficiency in infants. Pica may be associated with iron deficiency | |
| Eating disorders in older children | |
| Bleeding disorders |
Initial investigations
Progressive selective investigation, guided by the history, the clinical findings and the result of the blood count, is recommended. The first investigation will be a blood count, which automatically includes red cell indices (full blood examination (FBE) or complete blood count (CBC)), reticulocyte count and examination of the blood film. These initial investigations will usually allow classification of the anaemia. The presence or absence of polychromasia on the blood film, and the reticulocyte count, enable the anaemia to be classified as regenerative or aregenerative. This is a most important initial decision to be made. The red cell indices, in particular the mean corpuscular volume (MCV), and the blood film, enable the anaemia to be classified by red cell size into microcytic, normocytic and macrocytic. Finally, the blood film enables any specific red cell morphology to be determined, and confirms the platelet and leukocyte parameters. At this stage, a probable aetiology is likely and thus the direction of further investigations can be determined.
In the interpretation of these initial tests, there are a number of important considerations. First, sample integrity is vital, and preanalytical variables such as a clotted or inadequately mixed specimen can cause significant erroneous results. If the results do not match the clinical findings, repeat testing should always be considered. Second, MCV also varies with age. MCV is highest in the neonate (98–118 fL), falls to its lowest value between 6 and 24 months of age (79–86 fL, then increases progressively throughout childhood (75–92 fL). A low MCV indicates microcytosis and a high MCV indicates macrocytosis. Reticulocyte counts may be expressed as a percentage of the total red cell count (3–7% in the neonate, thereafter 0–1%), or more usually as an absolute count (normally 20–100 × 109/L). If expressed as a percentage, the reticulocyte count can be misleading, so an absolute count is preferable. An increased reticulocyte count indicates active regeneration of red cells, seen after blood loss, haemolysis or in response to correct haematinic therapy. Blood loss and previous haematinic therapy can usually be excluded on history, so that an increased reticulocyte count is often suggestive of haemolysis. A low reticulocyte response in the presence of anaemia indicates a lack of marrow response, because of a deficiency of the necessary iron or vitamins or inappropriate therapy for the anaemia, or inability to respond, such as marrow aplasia or infiltration.
Examination of the blood film
This is as important as the evaluation of the red cell indices, leukocyte count and platelets. The presence of abnormal red cell size, shape, inclusions, Hb content, and evidence of regeneration will usually suggest the cause of the anaemia and direct the next stage of investigation. The presence of abnormal leukocytes or abnormal platelet numbers may suggest a specific diagnosis such as leukaemia. Examples of a normal blood film and blood films in some conditions associated with anaemia are shown in Figure 16.1.1. Further investigations are suggested by the algorithms in Figures 16.1.2 and 16.1.3.
Fig. 16.1.1 Blood films. (A) Normal. (B) Macrocytosis – note hypersegmented polymorph. (C) Spherocytes in hereditary spherocytosis. (D) Autoimmune haemolytic anaemia showing red cell agglutination. (E) Sickle cell disease. (F) Thalassaemia major showing hypochromic microcytes and macrocytes, with nucleated red cells.
Fig. 16.1.2 Further investigation and initial management of regenerative anaemia. DAT, direct antiglobulin test; DIC, disseminated intravascular coagulopathy; E5M, eosin-5-maleimide; FBE, full blood examination; G6PD, glucose-6-phosphate dehydrogenase; Hb, haemoglobin; HPLC, high-performance liquid chromatography; HUS, haemolytic–uraemic syndrome; Ig, immunoglobulin; TTP, thrombotic thrombocytopenic purpura.
Fig. 16.1.3 Further investigation of aregenerative anaemia. DBS, Diamond–Blackfan syndrome; DEB, diepoxybutane; HPLC, high-performance liquid chromatography; MMA, methylmalonic acid; TCII, transcobalamin II; TEC, transient erythroblastopenia of childhood.
Practical pointsDetermining the urgency of investigation of anaemia
• Mild anaemia (Hb > 8 g/L) may still require urgent investigation and management, depending on the cause. Hence, until the cause of anaemia has been determined in a broad sense, discharge from emergency department/hospital should not be considered.
• Acute regenerative anaemia (blood loss or haemolysis) has the capacity rapidly to develop severe anaemia. Blood loss is usually obvious, so haemolysis must be excluded or the rate of haemolysis (multiple Hb levels over a number of hours) understood before a patient can safely leave hospital. Thus, a FBE, reticulocyte count, blood film examination and serum bilirubin are almost always indicated in initial investigations.
• Megaloblastic anaemia in infancy, irrespective of the level of anaemia, requires urgent investigation because of the potential for rapid neurological deterioration. Hence the MCV is a crucial piece of information in the initial FBE, as is the blood film examination. A history of failure to thrive and neurological impairment in infancy should lead to consideration of megaloblastosis, as anaemia is often not the presenting symptom. A FBE with careful consideration of the red cell parameters is always warranted in this circumstance.
• Anaemia as part of a multilineage failure may have a degree of urgency because of the potential for febrile neutropenia or thrombocytopenic haemorrhage.
Specific disease entities
Disorders of stem cell proliferation
Pluripotential stem cell failure (aplastic anaemia)
Normal marrow function is dependent on stem cell renewal and maturation of all cell lines. Failure of stem cell proliferation and differentiation results in aplastic anaemia. Both genetically determined and acquired forms occur (Table 16.1.3).
Fanconi anaemia
Fanconi anaemia, the commonest of the genetic forms of aplastic anaemia, is recessively inherited and is characterized by a variable phenotype, progressive marrow failure and an increased risk of malignancy. There appear to be multiple gene defects in this condition, which explains the diversity of clinical manifestations.
Approximately 75% of children have congenital abnormalities, with a wide range of defects. The commonest are café-au-lait spots, short stature, microcephaly and skeletal anomalies, with thumb and radial hypoplasia or aplasia being most characteristic. Renal anomalies, stenosis of auditory canals, micro-ophthalmia, hypogenitalism and a variety of anomalies of the gastrointestinal tract may also occur. The child shown in Figure 16.1.4 has many features of this disorder.
Fig. 16.1.4 Child with Fanconi anaemia. Note short stature, absent right radius and thumb, micro-ophthalmia and the presence of a hearing aid.
The diagnosis may be suspected at birth if there are congenital abnormalities. Haematological abnormalities are rare at birth. Pancytopenia develops gradually, usually by the age of 10 years. Onset is earlier in boys than girls. Macrocytosis is followed by thrombocytopenia, neutropenia, then anaemia. Bone marrow aspirate and trephine show hypoplasia or aplasia.
In contrast, infants with the thrombocytopenia–absent radius (TAR) syndrome are severely thrombocytopenic at birth and have radial anomalies without thumb abnormalities.
The diagnosis of Fanconi anaemia is established by special chromosome studies of lymphocytes. Chromosomes from patients with Fanconi anaemia show markedly increased spontaneous and alkylating agent (cells incubated with mitomycin C or diepoxybutane) induced chromosomal breaks, gaps, rearrangements, exchanges and endoreduplication. Antenatal diagnosis is possible.
Androgen therapy may produce long remissions of the anaemia but has little effect on thrombocytopenia and neutropenia. Its use is associated with masculinization and is therefore undesirable in young children, particularly girls. Granulocyte–macrophage colony-stimulating factor has been used with some success. Bone marrow transplantation offers the only possibility of cure of the aplasia. Supportive care with transfusions and antibiotics is required for patients without a marrow donor, but death from infection, bleeding or the development of leukaemia usually occurs within a decade of diagnosis.
Clinical exampleJohn, aged 5 years, presented with pallor and bruising of several months duration. He had a past history of tracheo-oesophageal fistula and had always been small, with his height and weight on the third centile for age. His teacher had expressed concern about his hearing. On examination he was pale and had multiple bruises and several café-au-lait spots. He had a convergent squint and his external auditory canals were narrow. There was no hepatosplenomegaly or lymphadenopathy. A blood test showed a macrocytic anaemia with a Hb level of 80 g/L and a white cell count of 1.4 × 109/L with neutrophils 0.7 × 109/L. The platelet count was 25 × 109/L. A bone marrow aspirate showed hypocellular fragments, and trephine biopsy confirmed marrow aplasia. Cytogenetic studies on peripheral blood lymphocytes confirmed that John had Fanconi anaemia by showing an increased rate of spontaneous and mitomycin C-induced chromosome breaks. His sister was found to be HLA-identical with normal cytogenetic studies, and plans were made for elective bone marrow transplantation within the next few months.
Acquired aplastic anaemia
A number of agents may cause marrow failure, either in a dose-dependent fashion (irradiation and cytotoxic drugs) or in an idiosyncratic fashion. Some viral infections are associated with marrow suppression. No cause is identified in about 50% of children with marrow failure. Fanconi anaemia must be excluded by cytogenetic studies, as not all affected individuals have congenital abnormalities.
• drugs: chloramphenicol, anticonvulsants, non-steroidal anti-inflammatory agents and cytotoxic drugs
• chemicals: benzene, organic solvents, insecticides
• viral hepatitis: usually non-A, non-B, non-C hepatitis, less commonly Epstein–Barr virus, cytomegalovirus, parvovirus or human immunodeficiency virus (HIV)
• preleukaemic: acute lymphoblastic leukaemia occasionally has a transient period of aplasia before the onset of the disease
Presentation is with the gradual onset of pallor, lethargy and bruising. There may be a history of recent infection. Physical examination reveals little other than pallor, bruising, petechiae and oral mucosal bleeding. Importantly there is no enlargement of liver, spleen or lymph nodes, but there may be fever and focal infection associated with the neutropenia.
The blood shows a pancytopenia with a normocytic anaemia without regeneration. Bone marrow aspirate and trephine biopsies reveal absent or decreased haemopoiesis.
Initial management depends on the severity and clinical manifestations of the aplasia. Potentially causative agents must be removed. Infections are treated vigorously. Supportive red cell and platelet transfusions are given as required. The general principles of transfusion therapy in aplastic anaemia are to avoid HLA sensitization by using leukocyte-depleted cellular products, and to minimize alloimmunization by minimizing donor exposure through the appropriate selection of blood products. Early referral to a tertiary centre is vital. Although a small number of children will recover within a few weeks, bone marrow transplantation from an HLA-compatible sibling is generally regarded as the treatment of choice for severe aplastic anaemia, particularly in those aged under 5 years. Only 30% of children will have a matched sibling donor. For the remainder, antithymocyte globulin, together with granulocyte colony-stimulating factor and cyclosporine, produces improvement or complete recovery in about two-thirds of children. Onset of response may not occur for 2–3 months after initiation of therapy, and supportive care during this time is vital. For those failing to respond, unrelated donor transplantation is an option and a donor search should be initiated early.
Red cell aplasia (erythroid stem cell failure)
Isolated aplasia of red cells results in a normocytic normochromic anaemia without reticulocytosis. The platelets and white blood cells are normal. Congenital and acquired forms occur.
Congenital red cell aplasia (Diamond–Blackfan syndrome)
This disorder is almost certainly heterogeneous, with sporadic, dominant and recessive forms occurring. Faulty ribosome biogenesis, resulting in pro-apoptotic erythropoiesis leading to erythroid failure, is hypothesized to be the underlying defect.
Normocytic anaemia may be present at birth and usually is evident by 2–3 months of age. However, diagnosis beyond 1 year of age is reported. Early treatment with steroids results in a reticulocytosis and an increase in Hb levels in about two-thirds of patients. In steroid responders, long-term low-dose steroids are recommended before total weaning is attempted. Some steroid-responsive patients are successfully weaned off steroids, but many remain steroid-dependent. Those failing to respond to steroids or requiring large doses will need regular blood transfusion and chelation therapy. Bone marrow transplantation has corrected the condition in steroid-resistant patients.
Acquired red cell aplasia
Pure red cell aplasia (PRCA) is primarily a disease of adults but cases have been documented in teenagers. A large number of disorders, including thymoma, malignancy, autoimmune disease, viral infection and drug administration, have been implicated. Therapy is directed primarily toward the cause but may include immunosuppression, plasmaphaeresis, thymectomy and splenectomy.
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