13.1 Anaemia

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.

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 pancytopaenia can develop over the course of days and nitrous oxide therapy has been identified as a principal cause of this condition.

Anaemia of chronic disorders

Patients with chronic infective, malignant or connective tissue disorders can develop a mild-to-moderate normochromic normocytic anaemia. Evidence of bleeding or haemolysis is absent and there is no response to haematinic therapy. The pathophysiology of this anaemia is complex and probably involves both decreased red cell production and survival. Possible underlying mechanisms include reticuloendothelial overactivity in chronic inflammation and defects in iron metabolism mediated by a variety of acute-phase reactants and cytokines, such as interleukin-1, tumour necrosis factor and interferon γ, which impair renal erythropoietin production and function.

Anaemia of chronic disorders (ACD) is generally not so severe as to warrant emergency therapy. The importance of ACD in the ED lies in its recognition as a pointer towards an underlying chronic process. Difficulties can arise in distinguishing ACD from iron deficiency and the two conditions may coexist – in rheumatoid arthritis, for example. Iron studies generally elucidate the nature of the anaemia. In iron deficiency, iron and ferritin are low and total iron binding is high, whereas in ACD iron and total iron binding are low and ferritin is normal or high.

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 pancytopaenia. 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 pancytopaenia 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 pancytopaenia. 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 pancytopaenia. 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.

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 Chapter 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 usually a 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.

Hereditary spherocytosis

A deficiency of the red cell wall protein, spectrin, leads to loss of deformability and increased red cell fragility. These cells are destroyed prematurely in the spleen. The condition may present at any age, with anaemia, intermittent jaundice and cholelithiasis. Patients are Coombs’ negative and show normal red cell osmotic fragility. Splenectomy radically improves general health. Hereditary elliptocytosis is a similar disease, with usually a milder course.

Glucose-6-phosphate dehydrogenase deficiency

Glucose-6-phosphate dehydrogenase (G6PD) generates reduced glutathione, which protects the red cell from oxidant stress. G6PD deficiency is an X-linked disorder present in heterozygous males and homozygous females. The disorder is commonly seen in West Africa, southern Europe, the Middle East and Southeast Asia. Oxidant stress leads to severe haemolytic anaemia. Precipitants include fava beans, antimalarial and analgesic drugs and infections. The enzyme deficiency can be demonstrated by direct assay and treatment is supportive.

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 (transient 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.

Haemoglobin S-C disease

Sickle trait or Hb S-C disease occurs in up to 10% in the black population. The clinical presentation resembles that of sickle cell disease but is usually less severe.

Haemoglobin C disease

In HbC, lysine replaces glutamic acid in the sixth position from the N terminus of the β-chain. Red cells containing HbC tend to be abnormally rigid, but the cells do not sickle. Homozygotes manifest a normocytic anaemia but there is no specific treatment and transfusion is seldom required.

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 Southeast 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 chromosomes 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.

Acquired haemolytic anaemias

Many of the acquired haemolytic anaemias are autoimmune in nature, a manifestation of a type II (cytotoxic) hypersensitivity reaction. Here, normal red cells are attacked by aberrant autoantibodies targeting antigens on the red cell membrane. These reactions may occur more readily at 37°C (warm autoimmune haemolytic anaemia, or AIHA), or at 4°C (cold AIHA). Warm AIHA is more common. Red cells are coated with IgG, complement or both. The cells are destroyed in the reticuloendothelial system. Fifty per cent of cases are idiopathic, but other recognized causes include lymphoproliferative disorders, neoplasms, connective tissue disorders, infections and drugs (notably methyldopa and penicillin). Patients have haemolytic anaemia, splenomegaly and a positive Coombs’ test. In the ED setting, it is important to stop any potentially offending drugs and search for the underlying disease. The idiopathic group may respond to steroids, other immunosuppressive or cytotoxic drugs or splenectomy.

In cold AIHA, IgM attaches to the I red cell antigen in the cooler peripheries. Primary cold antibody AIHA is known as cold haemagglutinin disease. Other causes include lymphoproliferative disorders, infections such as mycoplasma, and paroxysmal cold haemoglobinuria. Patients sometimes manifest Reynaud’s disease and other manifestations of circulatory obstruction. Symptoms worsen in winter. Red cell lysis leads to haemoglobinuria.

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.

Haemolytic uraemic syndrome and thrombotic thrombocytopaenic purpura

These are probably manifestations of the same pathological entity, with haemolytic uraemic syndrome occurring in children and thrombotic thrombocytopaenic purpura most commonly in the fourth decade, especially in women. The primary lesion is likely to be in the vascular endothelium. Fibrin and platelet microthrombi are laid down in arterioles and capillaries, possibly as an autoimmune reaction. The clotting system is not activated. Haemolytic anaemia, thrombocytopaenia and acute renal failure are sometimes accompanied by fever and neurological deficits.

In adults, the presentation is usually one of a neurological disturbance (headache, confusion, obtundation, seizures or focal signs). The blood film reveals anaemia, thrombocytopaenia, reticulocytosis and schistocytes. Coombs’ test is negative.

Patients require hospital admission. Adults with this condition may require aggressive therapy with prednisone, antiplatelet therapy, further immunosuppressive therapy and plasma exchange transfusions.

HELLP syndrome

HELLP stands for haemolysis, elevated liver enzymes and a low platelet count and is seen in pregnant women in the context of pre-eclampsia. Treatment is as for pre-eclampsia, early delivery of the baby being of paramount importance.

Disseminated intravascular coagulation

The introduction of procoagulants into the circulation resulting in the overwhelming of anticoagulant control systems may occur as a consequence of a substantial number of pathophysiological insults, obstetric, infective, malignant and traumatic. Disseminated intravascular coagulation has an intimate association with shock, from any cause. The widespread production of thrombin leads to deposition of microthrombi, bleeding secondary to thrombocytopaenia and a consumption coagulopathy, and red cell damage within abnormal vasculature leading to a haemolytic anaemia.

Recognition of this condition prompts intensive care admission and aggressive therapy. Principles of treatment include definitive management of the underlying cause and, from the haematological point of view, replacement therapy that may involve transfusion of red cells, platelets, fresh frozen plasma (FFP) and cryoprecipitate. There may be a role for heparin and other anticoagulant treatments if specific tissue and organ survival is threatened by thrombus.

Paroxysmal noctural haemoglobinuria

This entity is unusual in that an intrinsic red cell defect is seen in the context of an acquired haemolytic anaemia. A somatic stem cell mutation results in a clonal disorder. A family of membrane proteins (CD55, CD59 and C8 binding protein) is deficient and renders cells prone to complement-mediated lysis. Because the same proteins are deficient in white cells and platelets, in addition to being anaemic, patients are prone to infections and haemostatic abnormalities. They may go on to develop aplastic anaemia or leukaemia. Treatment is supportive. Marrow transplant can be curative.

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.

13.2 Neutropaenia