Introduction

Anaemia is defined as a reduction in the red blood cell (RBC) volume or haemoglobin concentration below normal values. The normal haemoglobin level is age and sex dependent, and racial differences exist. At birth, the haemoglobin level is 159–191 g L^–1 and this falls to a trough level of 90–114 g L^–1 between 8 and 12 weeks of age before rising again toward normal adult range.

Red blood cell production is regulated by erythropoietin, a hormone produced initially in the foetal liver and, after birth, in the renal peritubular cells. In normal erythropoiesis, erythropoietin stimulates differentiation of marrow stem cells into red blood cells. During this process there is a condensation of the cell’s nuclear material with continual production of the haemoglobin until it comprises 90% of the mass of the RBC. The nucleus is then extruded, leaving the RBC with no synthetic or replication ability, leading to a limited RBC lifespan of 120 days.

Haemoglobin is the major functional constituent of the RBC responsible for the task of carrying oxygen to the tissues, with the RBC acting as the carrier through the cardiovascular system. Haemoglobin is a complex protein consisting of iron-containing haem groups and polypeptide chains, known as globin. The haemoglobin molecule is made up of two pairs of polypeptide chains each coupled with a haem group. Chemical variations in the polypeptide chains lead to different types of haemoglobin being produced. At various stages of life, from the embryo to the adult, there are six different types of haemoglobin normally detectable. The normal adult haemoglobin, HbA, is comprised of two α-polypeptide chains and two β-chains, (α₂β₂). Haemoglobin F, or fetal Hb (HbF), is comprised of two α-chains and two γ-chains, (α₂γ₂) and constitutes 70% of the haemoglobin present at birth, reducing to trace levels by 6–12 months of age. Minor amounts of HbA2 (α₂δ₂) are present at all ages. Pathological variations in the polypeptide chains can produce disease states, known as haemoglobinopathies (see below).

Anaemia is not a single disease, but may occur as a result of a variety of pathological processes. The anaemias of childhood can be usefully divided into two groups: (1) those caused by inadequate production of RBC or haemoglobin; and (2) those due to increased destruction or loss of RBC. Tables 11.2.1 and 11.2.2 outline the major causes of childhood and neonatal anaemias.

Table 11.2.1 Causes of childhood anaemia
Production defect 1. Primary bone marrow failure • Aplastic anaemia (congenital or acquired) • Diamond-Blackfan syndrome • Transient erythroblastopenia of childhood (TEC) 2. Erythropoietin production problem • Chronic renal disease • Hypothyroidism 3. Abnormal cytoplasmic maturation (microcytic anaemias) • Iron deficiency • Sideroblastic anaemia (congenital or acquired) • Lead toxicity • Thalassaemia syndrome 4. Megaloblastic anaemia • Vitamin B₁₂ deficiency • Folate deficiency • Thiamine-responsive megaloblastic anaemia • Orotic aciduria (rare, associated with megaloblastic anaemia) 5. Others • Primary dyserythropoietic anaemias • Erythropoietic protoporphyria • Marrow infiltration, e.g. malignancy or myelofibrosis
Decreased RBC survival 1. Hereditary haemolytic anaemias a. Haemoglobin variants • Thalassaemias • Sickle cell disease b. Abnormal RBC membranes • Hereditary spherocytosis • Hereditary elliptocytosis • Hereditary stomatocytosis c. Abnormal enzymes • Glucose-6-phosphatase dehydrogenase deficiency (G6PD) • Pyruvate kinase deficiency 2. Acquired haemolytic anaemias a. Autoimmune haemolytic anaemia (AIHA) b. Non-immune haemolytic anaemia c. Fragmentation haemolysis • Haemolytic uraemic syndrome (HUS) 3. Haemorrhage
• Traumatic • Non-traumatic – acute or chronic

Table 11.2.2 Causes of anaemia in the neonate
1. Physiological anaemia 2. Abnormal RBC production a. Nutritional deficiency b. Secondary to infection 3. Decreased RBC survival – blood loss a. Overt blood loss • Iatrogenic during delivery • Obstetric accidents b. Occult blood loss • Twin-to-twin transfusion • Fetoplacental haemorrhage • Fetomaternal haemorrhage 4. Decreased RBC survival – haemolysis a. Immune-related: isoimmunisation b. Infection-related c. Hereditary haemoglobin variants, enzyme abnormalities, membrane abnormalities

Overview

The principles of management of anaemia in the emergency department (ED) are:

Resuscitate the patient with circulatory collapse.

Remove or treat the precipitant if known.

Treat the cause if treatment can be initiated in the ED.

Causes of life-threatening anaemia include uncontrolled haemorrhage, acute intravascular haemolysis in glucose-6-phosphatase deficiency (G6PD) or autoimmune haemolytic anaemia (AIHA), sequestration crisis in sickle cell disease (SCD) and acute decompensation in chronic anaemia.

Initial assessment is directed at respiration and circulation. The anaemic patient may be tachypnoeic with tissue hypoxia. The adequacy of ventilation should be ascertained and supplemental oxygen provided. Circulatory compromise in acute haemorrhage and acute haemolysis requires cardiorespiratory monitoring and intravenous access for fluid resuscitation (see Chapter 2.5 on shock). Packed red blood cells are used if haemorrhage or haemolysis is life threatening. If tissue oxygenation is not critically affected, the circulatory volume should be sustained with colloid or crystalloid until group-specific or cross-matched RBCs are available. If the bleeding is controlled, with further bleeding unlikely, the signs mentioned above are stable and the haemoglobin concentration is greater than 70 g L^–1, a cross-match should be performed and the packed RBCs should be held in reserve for 24 hours. Early consultation with a haematologist is important in acute haemolytic anaemia especially if the underlying cause has not been diagnosed.

Anaemia is a clinical finding rather than a disease in its own right and symptoms depend on the timing of its development, the severity and the underlying cause. The presentation is frequently not specific to anaemia. Common presenting features consistent with insidious onset anaemia include:

• lethargy, irritability, sleep or settling difficulty;

• pallor or yellow skin hue;

• loss of appetite ± weight loss ± pica;

• bruising, bleeding or infection.

Patient factors to note are age, ethnicity and the presence of other significant disease. Iron-deficiency anaemia is uncommon in the first 6 months in term infants and sickle cell disease (SCD) is unlikely to present as anaemia under the age of 4 months. Haemolytic uraemic syndrome (HUS) mainly affects those under 4 years of age, whereas thrombotic thrombocytopenic purpura (TTP) affects children from 10 years of age. Iron deficiency is common in adolescent females, whereas G6PD deficiency occurs mainly in males. The association between ethnicity and various types of hereditary anaemia is shown in Table 11.2.3. Family history of anaemia may also suggest hereditary anaemia.

Table 11.2.3 Ethnicity and anaemia
1. Thalassaemia syndromes • α-Thalassaemia – descendants from China, Malaysia, Indonesia and Africa • β-Thalassaemia – descendants from Africa, Middle East, Mediterranean, India, Pakistan, China 2. Sickle cell disease • Descendants from Africa, southern Arabia, Turkey, Greece, central India 3. Hereditary spherocytosis • Descendants from northern Europe 4. G6PD deficiency • Descendants from Africa, China, south-east Asia and the Mediterranean

Dietary history can provide important clues. Iron-deficiency anaemia is likely in prolonged breast-feeding beyond 6 months of age in term infants and sooner in preterm infants if no iron supplementation is provided, if there is excessive dependence on cows’ milk as a food source or if food sources are restricted, e.g. food fads. Ingestion of clay and dirt may cause lead toxicity and iron deficiency. Ingestion of fresh uncooked broad beans is a potent precipitant of haemolysis in G6PD deficiency, along with medications.

Recent infections may precipitate AIHA, non-immune haemolytic anaemia, HUS and TTP. Hyperbilirubinaemia caused by haemolysis leads to jaundice, cholelithiasis, cholecystitis and dark urine. Mechanical destruction of RBCs is caused by vascular malformations, shunts, abnormal native or prosthetic cardiac valves. Septic shock, bleeding disorders, chronic renal disease, severe burns and hypothyroidism may all cause anaemia.

The salient physical findings in the context of anaemia relate to general appearance, cardiovascular status and abdominal examination. Frontal bone expansion and frontal bossing is due to expansion of the medullary spaces and may be seen in severe thalassaemias. Some hereditary anaemias may also have associated physical abnormalities (e.g. Diamond–Blackfan anaemia). Hepatosplenomegaly is a feature of some of the hereditary haemolytic anaemias. Purpuric or petechial rashes are due to coagulation disorders or vasculitis. Dark urine from bilirubinuria is consistent with haemolysis. Haematuria must be confirmed by microscopy to distinguish haemoglobinuria from haematuria.

Anaemia is confirmed by the lowered haemoglobin concentration and decreased RBC count. An age-related reference range must be used. Abnormalities in the other cell lines should be noted. The mean cell volume (MCV) may suggest an underlying cause. The upper limit of normal in adults is 96 fL but MCV in children is less than in adults and average values may be estimated by adding 0.6 fL per year of age to 84 fl. The reticulocyte count is expressed as a percentage of the circulating RBC mass with a normal range of 0.5–1.5%. A low reticulocyte count is found in abnormalities of RBC production and a high reticulocyte count is found in increased destruction or from RBC loss, provided there is no concurrent bone-marrow pathology. Morphological features of RBC may be diagnostic of the underlying cause as shown in Table 11.2.4.

Table 11.2.4 Morphological features of RBCs to assist the diagnosis of anaemia
Schistocytes	Erythrocyte fragmentation syndromes
Sickle cells	Sickle cell disease
Spherocytes	Immune-meditated haemolytic anaemia Hereditary spherocytosis
Blister or bite cells with poikilocytosis	G6P deficiency