13: Haematology

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Section 13 Haematology

Edited by Lindsay Murray

13.1 Anaemia

Introduction

Anaemia is a condition in which the absolute number of red cells in the circulation is abnormally low. The diagnosis is usually made on the basis of the full blood count (FBC). This, together with the blood film, offers qualitative as well as quantitative data on the blood components, and a set of normal values is shown in Table 13.1.1.

Table 13.1.1 Full blood count: normal parameters

Haemoglobin (Hb)  
Males 13.5–18 g/dL
Females 11.5–16.5 g/dL
Red blood cell count  
Males 4500–6500 × 109/L
Females 3900–5600 × 109/L
Haematocrit  
Males 42–54%
Females 37–47%
MCH 27–32 pg
MCHC 32–36 g/dL
MCV 76–98 fL
Reticulocytes 0.2–2%
White blood cells 4–11 × 109/L
Neutrophils 1.8–8 × 109/L
Eosinophils 0–0.6 × 109/L
Basophils 0–0.2 × 109/L
Lymphocytes 1–5 × 109/L
Monocytes 0–0.8 × 109/L
Platelets 150–400 × 109/L

MCH, Hb divided by RBC; MCHC, Hb divided by HCT; MCV, HCT divided by RBC.

Most automated counting machines now give the red cell distribution width (RDW), a measure of degree of variation of cell size.

The average lifespan of a normal red blood cell in the circulation is from 100 to 120 days. Aged red cells are removed by the reticuloendothelial system, but under normal conditions are replaced by the marrow such that a dynamic equilibrium is maintained. Anaemia develops when red cell loss exceeds red cell production. It follows that the anaemic patient is doing at least one of three things: not producing enough red cells, destroying them too quickly or bleeding.

The overriding functional importance of the red cell resides in its ability to transport oxygen, bound to the haemoglobin molecule, from the lungs to the tissues. Functionally, anaemia may be regarded as an impairment in the supply of oxygen to the tissues and the adverse effects of anaemia, from whatever cause, are a consequence of the resultant tissue hypoxia. Anaemia is not a diagnosis: rather, it is a clinical or a laboratory finding that should prompt the search for an underlying cause (Table 13.1.2).

Table 13.1.2 Causes of anaemia

Haemorrhage
Traumatic
Non-traumatic
Acute or chronic
Production defect
Megaloblastic anaemia
Vitamin B12 deficiency
Folate deficiency
Aplastic anaemia
Pure red cell aplasia
Myelodysplastic syndromes
Invasive marrow diseases
Chronic renal failure
Decreased RBC survival (haemolytic anaemia)
Congenital
Spherocytosis
Elliptocytosis
Glucose-6-phosphate-dehydrogenase deficiency
Pyruvate kinase deficiency
Haemoglobinopathies: sickle cell diseases
Acquired autoimmune haemolytic anaemia, warm
Acquired autoimmune haemolytic anaemia, cold
Microangiopathic haemolytic anaemias
RBC mechanical trauma
Infections
Paroxysmal nocturnal haemoglobinuria

RBC, red blood cell.

ANAEMIA SECONDARY TO HAEMORRHAGE

Aetiology

By far the most common cause of severe anaemia encountered in the emergency department (ED) is haemorrhage. Therefore, the assessment of the anaemic patient is often chiefly concerned with the search for a site of blood loss. The most common causes of haemorrhage are outlined in Table 13.1.3. However, the emergency physician must remain alert to the possibility that the patient is not bleeding but manifesting a rarer pathological condition.

Table 13.1.3 Common causes of haemorrhage in the emergency department

Trauma
Blunt trauma to mediastinum
Pulmonary contusions/haemopneumothorax
Intraperitoneal injury
Retroperitoneal injury
Pelvic disruption
Long bone injury
Open wounds: inadequate first aid
Non-trauma
Gastrointestinal haemorrhage
Oesophageal varices
Peptic ulcer
Gastritis/Mallory–Weiss
Colonic/rectal bleeding
Obstetric/gynaecological bleeding
Ruptured ectopic pregnancy
Menorrhagia
Threatened miscarriage
Antepartum haemorrhage
Postpartum haemorrhage
Other
Epistaxis
Postoperative
Secondary to bleeding diathesis

Clinical features

While it may be obvious on history and examination that a patient is bleeding, occasionally the source of blood loss is occult and the extent of loss underestimated.

In the context of trauma the history often gives clear pointers to both sites and extent of blood loss. Consideration of the mechanism of injury may allow anticipation of occult pelvic, intraperitoneal or retroperitoneal bleeding. Intracranial bleeding is never an explanation for hypovolaemic shock in an adult. In the context of non-trauma it is essential to obtain an obstetric and gynaecological history in women of childbearing age. The remainder of the formal history may supply information essential in determining the aetiology of anaemia. The past medical history may point to a known haematological abnormality or to a chronic disease process. A drug and allergy history is always relevant. Many drugs cause marrow suppression, haemolytic anaemia and bleeding. The family history points to hereditary disease; the social history may alert the clinician to an unusual occupational exposure in the patient’s past or, more likely, to recreational activities liable to exacerbate an ongoing disease process. The systems review is particularly relevant to the consultation with middle-aged or elderly male patients, who must be asked about symptoms of altered bowel habit and weight loss.

The symptomatology of anaemia proceeds from vague complaints of tiredness, lethargy and impaired performance through to more sharply defined entities such as shortness of breath on exertion, giddiness, restlessness, apprehension, confusion, and collapse. Comorbid conditions may be exacerbated (the dyspnoea of chronic obstructive airway disease) and occult pathologies unmasked (exertional angina in ischaemic heart disease).

Anaemia of insidious onset is generally better tolerated than that of rapid onset because of cardiovascular and other compensatory mechanisms. Acute loss of 40% of the blood volume may result in collapse, whereas in certain developing countries it is not rare for patients with haemoglobin concentrations 10% of normal to be ambulant. Trauma superimposed on an already established anaemia can lead to rapid decompensation.

The cardinal sign of anaemia is pallor. This can be seen in the skin, the lips, the mucous membranes and the conjunctival reflections. Yet not all anaemic patients are pallid, and not all patients with a pale complexion are anaemic. Patients who have suffered an acute haemorrhage may show evidence of hypovolaemia: tachycardia, hypotension, cold peripheries and sluggish capillary refill. The detection of postural hypotension is an important pointer towards occult blood loss. Conversely, patients with anaemia of insidious onset are not hypovolaemic and may manifest high-output cardiac failure as a physiological response to hypoxia.

Other features of the physical examination may provide clues to the aetiology of anaemia. The glossitis, angular stomatitis, koilonychia and oesophageal web of iron-deficiency anaemia are uncommon findings. Bone tenderness, lymphadenopathy, hepatomegaly and splenomegaly may point to an underlying haematological abnormality. The rectal and gynaecological examinations can sometimes be diagnostic.

Treatment

The principles of management of haemorrhage are as follows:

The indications for red cell transfusion are discussed in Chapter 13.5. The faster the onset of the anaemia, the greater the need for urgent replacement. Patients who are tolerating their anaemia may require no more than an appropriate diet with or without the addition of haematinics. Elderly patients with severe bleeding often need red cells urgently. Excessive administration of colloid and/or crystalloid precipitates left ventricular failure, and it can then be difficult to administer red cells.

ANAEMIA SECONDARY TO DECREASED RED CELL PRODUCTION

Megaloblastic anaemia

The finding of a raised MCV is common in the presence or absence of anaemia. Alcohol abuse is a frequent underlying cause, and other causes are listed in Table 13.1.4. MCVs greater than 115 fL are usually due to megaloblastic anaemia, which in turn is usually due to either vitamin B12 or folate deficiency. Vitamin B12 and folate are essential to DNA synthesis in all cells. Deficiencies manifest principally in red cell production because of the sheer number of red cells that are produced. B12 deficiency is usually the result of a malabsorption syndrome, whereas folate deficiency is of dietary origin. Tetrahydrofolate is a co-factor in DNA synthesis and, in turn, the formation of tetrahydrofolate from its methylated precursor is B12-dependent. Unabated cytoplasmic production of RNA in the context of impaired DNA synthesis appears to produce the enlarged nucleus and abundant cytoplasm of the megaloblast. These cells, when released to the periphery, have poor function and poor survival.

Table 13.1.4 Some causes of a raised mass cell volume

Alcohol
Drugs
Hypothyroidism
Liver disease
Megaloblastic anaemias (B12 and folate deficiency)
Myelodysplasia
Pregnancy
Reticulocytosis

B12 deficiency is an autoimmune disorder in which autoantibodies to gastric parietal cells and the B12 transport factor (intrinsic factor) interfere with B12 absorption in the terminal ileum. Patients have achlorhydria, mucosal atrophy (a painful smooth tongue) and sometimes evidence of other autoimmune disorders, such as vitiligo, thyroid disease and Addison’s disease. This is so-called ‘pernicious anaemia’.

A rare, but important, manifestation of this disease is ‘subacute combined degeneration of the spinal cord’. Demyelination of the posterior and lateral columns of the spinal cord manifests as a peripheral neuropathy and an abnormal gait. The central nervous system abnormalities worsen and become irreversible in the absence of B12 supplementation. Treatment of B12 deficient patients with folate alone may accelerate the onset of this condition.

Undiagnosed untreated pernicious anaemia is not a common finding in the ED, but the laboratory finding of anaemia and megaloblastosis should prompt haematological consultation. The investigative work-up, which includes B12 and red cell folate levels, autoantibodies to parietal cells and intrinsic factor, a marrow aspirate, and Schilling’s test of B12 absorption, may well necessitate hospital admission.

The work-up for folate deficiency is similar to that for B12. Occasionally, patients require investigation for a malabsorption syndrome (tropical sprue, coeliac disease), which includes jejunal biopsy. Folate deficiency is common in pregnancy because of the large folate requirements of the growing fetus. It can be difficult to diagnose because of the maternal physiological expansion of plasma volume and also of red cell mass, but diagnosis and treatment with oral folate supplements are important because of the risk of associated neural tube defects.

Both B12 and folate deficiency are usually manifestations of chronic disease processes. Rarely, an acute megaloblastic anaemia and pancytopenia can develop over the course of days and nitrous oxide therapy has been identified as a principal cause of this condition.

Other causes of decreased red cell production

Bone marrow failure is rarely encountered in emergency medicine practice. The physician must be alert to the unusual, insidious or sinister presentation, and be particularly attuned to the triad of decreased tissue oxygenation, immunocompromise and a bleeding diathesis that may herald a pancytopenia. An FBC may dictate the need for haematological consultation, hospital admission and further investigation.

Among the entities to be considered are the aplastic anaemias, characterized by a pancytopenia secondary to failure of pluripotent myeloid stem cells. Half of cases are idiopathic, but important aetiologies are infections (e.g. non-A, non-B hepatitis), inherited diseases (e.g. Fanconi’s anaemia), irradiation, therapeutic or otherwise, and – most important in the emergency setting – drugs. Drugs that have been implicated in the development of aplastic anaemia include, in addition to antimetabolites and alkylating agents, chloramphenicol, chlorpromazine and streptomycin.

Characteristic of patients with a primary marrow failure is the absence of splenomegaly and the absence of a reticulocyte response. There is a correlation between prognosis and the severity of the pancytopenia. Platelet counts less than 20 × 109/L and neutrophil counts less than 500/mL equate to severe disease. Depending on the severity of the accompanying anaemia, patients may require red cell and sometimes platelet transfusion in the ED, as well as broad-spectrum antibiotic cover. It is imperative to stop all medications that might be causing the marrow failure. Other forms of marrow failure include pure red cell aplasia, where marrow red cell precursors are absent or diminished. This can be a complication of haemolytic states in which a viral insult leads to an aplastic crisis (see haemolytic anaemias).

The myelodysplastic syndromes are a group of disorders primarily affecting the elderly. In these states there is no reduction in marrow cellularity but the mature red cells, granulocytes and platelets generated from an abnormal clone of stem cells are disordered and dysfunctional. There is peripheral pancytopenia. These disorders are classified according to observed cellular morphology (Table 13.1.5). These conditions were once termed ‘preleukaemia’, and one-third of patients progress to acute myeloid leukaemia.

Table 13.1.5 Classification of the myelodysplastic syndromes

Refractory anaemia
Refractory anaemia with ringed sideroblasts
Refractory anaemia with excess of blasts
Chronic myelomonocytic leukaemia

Two more causes of failure of erythropoiesis might be mentioned. One is due to invasion of the marrow and disruption of its architecture by extraneous tissue, the commonest cause being metastatic cancer. Finally, but not at all uncommon, is the anaemia of chronic renal failure, where deficient erythropoiesis is attributed to decreased production of erythropoietin. Most patients with chronic renal failure on dialysis treatment tolerate a moderate degree of anaemia, but occasionally require either transfusion or treatment with erythropoietin. Emergency physicians should recognize anaemia as a predictable entity in patients with chronic renal failure, usually not requiring any action.

ANAEMIA SECONDARY TO DECREASED RED CELL SURVIVAL: THE HAEMOLYTIC ANAEMIAS

Patients whose main problem is haemolysis are encountered rarely in the ED. The most fulminant haemolytic emergency one could envisage is that following transfusion of ABO-incompatible blood (discussed in Ch. 13.5), a vanishingly rare event where proper procedures are followed. Haemolysis and haemolytic anaemia are occasionally encountered in decompensating patients with multisystem problems. Rarely, first presentations of unusual haematological conditions occur.

Some of the haemolytic anaemias are hereditary conditions in which the inherited disorder is an abnormality intrinsic to the red cell, its membrane, its metabolic pathways or the structure of the haemoglobin contained in the cells. Such red cells are liable to be dysfunctional, and to have increased fragility and a shortened lifespan. Lysis in the circulation may lead to clinical jaundice as bilirubin is formed from the breakdown of haemoglobin. Lysis in the reticuloendothelial system generally does not cause jaundice but may produce splenomegaly. The anaemia tends to be normochromic normocytic; sometimes a mildly raised MCV is due to an appropriate reticulocyte response from a normally functioning marrow. Serum bilirubin may be raised even in the absence of jaundice. Urinary urobilinogen and faecal stercobilinogen are detectable and serum haptoglobin is depleted. The antiglobulin (Coombs’) test is important in the elucidation of some haemolytic anaemias. In this test, red cells coated in vivo (direct test) or in vitro (indirect test) with IgG antibodies are washed to remove unbound antibodies, then incubated with an antihuman globulin reagent. The resultant agglutination is a positive test.

Any chronic haemolytic process may be complicated by an ‘aplastic crisis’. This is a usually transient marrow suppression brought on by a viral infection which can result in a severe and life-threatening anaemia. Red cell transfusion in these circumstances may be life-saving.

Sickle cell anaemia

Whereas in the thalassaemias there is a deficiency in a given globin chain within the haemoglobin (Hb) molecule, in the haemoglobinopathies a given globin chain is present but structurally abnormal. HbS differs from normal HbA by one amino acid residue: valine replaces glutamic acid at the sixth amino acid from the N-terminus of the β-globin chain. Red cells containing HbS tend to ‘sickle’ at states of low oxygen tension. The deformed sickle-shaped red cell has increased rigidity, which causes it to lodge in the microcirculation and sequester in the reticuloendothelial system – the cause of a haemolytic anaemia.

Sickle cell disease is encountered in Afro-Caribbean people. The higher incidence in tropical areas is attributed to the survival value of the β-S gene against falciparum malaria. Heterozygous individuals have ‘sickle trait’ and are usually asymptomatic. Homozygous (HbSS) individuals manifest the disease in varying degrees. The haemolytic anaemia is usually in the range of 60–100 g/L and can be well tolerated because HbS offloads oxygen to the tissues more efficiently than HbA.

A patient with sickle cell disease may occasionally develop a rapidly worsening anaemia. This may be due to:

In any of these circumstances transfusion may be life-saving. However, these events are unusual and more commonly encountered is the vaso-occlusive crisis. A stressor – for example infection, dehydration, or cold – causes sickle cells to lodge in the microcirculation. Bone marrow infarction is one well-recognized complication of the phenomenon, but virtually any body system can be affected. Common presenting complaints include acute spinal pain, abdominal pain (the mesenteric occlusion of ‘girdle sequestration’), chest pain (pulmonary vascular occlusion), joint pain, fever (secondary to tissue necrosis), neurological involvement (translent ischaemic attacks, strokes, seizures, obtundation, coma), respiratory embarrassment and hypoxia, priapism, ‘hand-foot syndrome’ (dactylitis of infancy), haematuria (nephrotic syndrome, papillary necrosis), skin ulcers of the lower limbs, retinopathies, glaucoma and gallstones.

Most patients presenting with a vaso-occlusive crisis know they have the disease but otherwise the differential diagnosis is difficult. Sickle cells may be seen on the blood film, and can also be induced by deoxygenating the sample. Hb electrophoresis can establish the type of Hb present. Other investigations are dictated by the presentation, and may include blood cultures, urinalysis and culture, chest X-ray, arterial blood gases and electrocardiograph.

Pain relief should commence early. A morphine infusion may be required for patients with severe ongoing pain. Other supportive measures are dictated by the presentation. Intravenous fluids are particularly important for patients with renal involvement. Aim to establish a urine output in excess of 100 mL/h in adults. Antibiotic cover may be required in the case of febrile patients with lung involvement. It may be impossible to differentiate between pulmonary vaso-occlusion and pneumonia. Many patients with sickle cell disease are effectively splenectomized owing to chronic splenic sequestration with infarction, and are prone to infection from encapsulated bacteria. The choice of antibiotic depends on the clinical presentation. Indications for exchange transfusion are shown in Table 13.1.6. The efficacy of exchange transfusion in painful crises remains unproven.

Table 13.1.6 Indications for exchange transfusion in sickle cell crisis

Neurological presentations: TIAs, stroke, seizures
Lung involvement (PaO2 < 65 mmHg with FiO2 60%)
Sequestration syndromes
Priapism

TIA, transient ischaemic attack

Thalassaemias

There is a high incidence of β-thalassaemia trait among people of Mediterranean origin, although in fact the region of high frequency extends in a broad band east to South East Asia.

Thalassaemias are disorders of haemoglobin synthesis. In the haemoglobin molecule, four haem molecules are attached to four long polypeptide globin chains. Four globin chain types (each with their own minor variations in amino acid order) are designated α, β, γ and δ. Haemoglobin A comprises two α and two β chains; 97% of adult haemoglobin is HbA. In thalassaemia there is diminished or absent production of either the α chain (α-thalassaemia) or the β chain (β-thalassaemia). Most patients are heterozygous and have a mild asymptomatic anaemia, although the red cells are small. In fact, the finding of a marked microcytosis in conjunction with a mild anaemia suggests the diagnosis.

There are four genes on paired chromosome 16 coding for α-globin and two genes on paired chromosomes 11 coding for β-globin. α-Thalassaemias are associated with patterns of gene deletion as follows: (-/-) is Hb-Barts hydrops syndrome, incompatible with life, and (-α/-) is HbH disease.

Patients who are heterozygous for β-thalassaemia have β-thalassaemia minor or thalassaemia trait. They are usually symptomless. Homozygous patients have β major.

Diagnosis of the major clinical syndromes is usually possible through consideration of the presenting features in conjunction with an FBC, blood film and Hb electrophoresis.

HbH disease patients present with moderate haemolytic anaemia and splenomegaly. The HbH molecule is detectable on electrophoresis and comprises unstable β tetramers. α Trait occurs with deletion of one or two genes. Hb, MCV and mean corpuscular haemoglobin(MCH) are low, but the patient is often asymptomatic.

β major becomes apparent in the first 6 months of life with the decline of fetal Hb. There is a severe haemolytic anaemia, ineffective erythropoiesis, hepatosplenomegaly and failure to thrive. With improved care many of these patients survive to adulthood, and may possibly present to the ED, where transfusion could be life-saving. Patients with β trait may be encountered in the ED relatively frequently. They are generally asymptomatic, with a mild hypochromic microcytic anaemia. It is important not to work these patients up continually for iron deficiency, and not to subject them to inappropriate haematinic therapy.

Microangiopathic haemolytic anaemia

In this important group of conditions intravascular haemolysis occurs in conjunction with a disorder of microcirculation. Important causes are shown in Table 13.1.7.

Table 13.1.7 Causes of microangiopathic haemolytic anaemia

Disseminated intravascular coagulation
Haemolytic uraemic syndrome
HELLP
Malignancy
Malignant hypertension
Snake envenoming
Thrombotic thrombocytopenic purpura
Vasculitis

Other causes of haemolysis

Haemolysis may be due to mechanical trauma, as in ‘March haemoglobinuria’. Artificial heart valves can potentially traumatize red cells. Historically, ball-and-cage type valves have been most prone to cause haemolysis, whereas disc valves are more thrombogenic. Improvements in design have made cardiac haemolytic anaemia very rare. Haemolysis is sometimes seen in association with a number of infectious diseases, notably malaria. Other infections that have been implicated are listed in Table 13.1.8. Certain drugs and toxins are associated with haemolytic anaemia (Table 13.1.9). The haemolytic anaemia that is commonly seen in patients with severe burns is attributed to direct damage to the red cells by heat.

Table 13.1.8 Infections associated with haemolysis

Babesiosis
Bartonella
Clostridia
Cytomegalovirus
Coxsackie virus
Epstein-Barr virus
Haemophilus
Herpes simplex
HIV
Malaria, especially Plasmodium falciparum (Blackwater fever)
Measles
Mycoplasma
Varicella

Table 13.1.9 Drugs and toxins associated with haemolysis

Antimalarials
Arsine (arsenic hydride)
Bites: bees, wasps, spiders, snakes
Copper toxicity
Dapsone
Lead (plumbism)
Local anaesthetics: lidocaine, benzocaine
Nitrates, nitrites
Sulfonamides

Further reading

Bain BJ. Morphology in the diagnosis of red cell disorders. Hematology. 2005;10S(1):178-181.

Bayless PA. Selected red cell disorders. Emergency Medicine Clinics of North America. 1993;11(2):481-493.

Bojanowski C. Use of protocols for ED patients with sickle cell anaemia. Journal of Emergency Nursing. 1989;15:83-87.

Brookoff D, Polomano R. Treating sickle cell pain like cancer pain. Annals of Internal Medicine. 1992;116(5):364-368.

Carbrow MB, Wilkins JC. Haematologic emergencies. Management of transfusion reactions and crises in sickle cell disease. Postgraduate Medicine. 1993;93(5):183-190.

Erslev A. Erythropoietin. New England Journal of Medicine. 1991;316:101.

Evans TC, Jehle D. The red blood cell distribution width. Journal of Emergency Medicine. 1991;9(suppl 1):71-74.

Friedman EW, Webber AB, Osborn HH, et al. Oral analgesia for treatment of painful crisis in sickle cell anaemia. Annals of Emergency Medicine. 1986;15:787-791.

Gaillard HM, Hamilton GC. Hemoglobin/hematocrit and other erythrocyte parameters. Emergency Medicine Clinics of North America. 1986;4(1):15-40.

Gregory SA, McKenna R, Sassetti RJ, et al. Hematologic emergencies. Medical Clinics of North America. 1986;70(5):1129-1149.

Losek JD, Hellmich TR, Hoffman GM. Diagnostic value of anemia, red blood cell morphology, and reticulocyte count for sickle cell disease. Annals of Emergency Medicine. 1992;21(8):915-918.

Pollack CV. Emergencies in sickle cell disease. Emergency Medicine Clinics of North America. 1993;11(2):365-378.

Powers RD. Management protocol for sickle-cell disease patients with acute pain: impact of emergency department and narcotic use. American Journal of Emergency Medicine. 1986;4(3):267-268.

Thomas C, Thomas L. Anemia of chronic disease: pathophysiology and laboratory diagnosis. Laboratory Hematology. 2005;11(1):14-23.

13.2 Neutropenia

Pathophysiology and aetiology

Polymorphonuclear neutrophils are formed in marrow from the myelogenous cell series. Pluripotent haematopoietic stem cells are committed to a particular cell lineage through the formation of colony-forming units, which further differentiate to form given white cell precursors. The mature neutrophil has a multilobed nucleus and granules in the cytoplasm. The cells are termed ‘neutrophilic’ because of the lilac colour of the granules caused by the uptake of both acidic and basic dyes.

The neutrophils leave the marrow and enter the circulation, where they have a lifespan of only 6–10 h before entering the tissues. Here they migrate by chemotaxis to sites of infection and injury, and then phagocytose and destroy foreign material. In health, about half of the available mature neutrophils are in the circulation. ‘Marginal’ cells are adherent to vascular endothelium or in the tissues and are not measured by the full blood count. Some individuals have fixed increased marginal neutrophil pools and decreased circulating pools; they are said to have benign idiopathic neutropenia.

For a previously normal individual to become neutropenic there must be decreased production of neutrophils in the marrow, decreased survival of mature neutrophils or a redistribution of neutrophils from the circulating pool. The important causes are shown in Table 13.2.1.

Table 13.2.1 Important causes of neutropenia

Decreased production
Aplastic anaemia
Leukaemias
Lymphomas
Metastatic cancer
Drug-induced agranulocytosis
Megaloblastic anaemias

CD8 and large granular lymphocytosis Myelodysplastic syndromes Decreased survival Idiopathic immune related Systemic lupus erythematosis Felty syndrome Drugs Redistribution Sequestration (hypersplenism) Increased utilization (overwhelming sepsis) Viraemia

It is a defect in neutrophil production that is most likely to prove life threatening. Consumption of neutrophils in the periphery, as occurs early in infectious processes, is likely to be rapidly compensated for by a functioning marrow. Fortunately, most of the primary diseases of haematopoiesis are rare, and in practice many of the acquired neutropenias are drug induced. Processes interfering with haematopoiesis, often involving autoimmune mechanisms, may affect neutrophils both in the marrow and in the periphery. Some drugs cause neutropenia universally but many more reactions are idiosyncratic, be they dose-related or independent of dose. Some commonly implicated drugs are listed in Table 13.2.2. Cancer chemotherapy drugs are now recognized as the commonest cause of neutropenia.

Table 13.2.2 Drugs commonly associated with neutropenia

Antibiotics: chloramphenicol, sulfonamides, isoniazid, rifampicin, β-lactams, carbenicillin
Antidysrhythmic agents: quinidine, procainamide
Antiepileptics: phenytoin, carbamazepine
Antihypertensives: thiazides, ethacrynic acid, captopril, methyldopa, hydralazine
Antithyroid agents
Chemotherapeutic agents: especially methotrexate, cytosine arabinoside, 5-azacytidine, azothioprine, doxorubicin, daunorubicin, hydroxyurea, alkylating agents
Connective tissue disorder agents: phenylbutazone, penicillamine, gold
H2-receptor antagonists
Phenothiazines, especially chlorpromazine
Miscellaneous: imipramine, allopurinol, clozapine, ticlopidine, tolbutamide

Clinical features

Neutropenia is frequently anticipated based on the clinical presentation, such as fever developing in the context of cancer chemotherapy, by far the most common scenario in which severe neutropenia is seen in the ED. Alternatively, it may be identified in the course of investigation for a likely infective illness, or it might be an incidental finding during investigation for an unrelated condition.

Chronic neutropenia may be asymptomatic unless secondary or recurrent infections develop. Acute severe neutropenia may present with fever, sore throat, and mucosal ulceration or inflammation.2 Symptoms or signs of an associated disease process may also be present, such as pallor from anaemia, or bleeding from thrombocytopenia, as might occur in conditions causing pancytopenia.

The history of the mode of onset and duration of the illness is important. Systems enquiry may reveal cough, headache and photophobia, a diarrhoeal illness, or urinary symptoms. The past history may reveal a known haematological illness or previous evidence of immunosuppression, such as frequent and recurrent infections. A detailed drug history is vital. Most neutropenic drug reactions occur within the first 3 months of taking a drug.

In the ED, vital signs, including pulse, blood pressure, temperature, respiratory rate and pulse oximetry, should be performed at initial assessment and monitored regularly until disposition. Attention should be paid to identifying early signs of severe sepsis and the progression to septic shock.

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