Aetiology

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. Co-morbid 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.

Clinical investigations

The full blood count often reveals an anaemia that has not been clinically suspected and that must be interpreted in the light of the history and examination. If the anaemia is mild it may be a chance finding with little relevance to the patient’s presenting complaint, but such a finding should never be ignored. At the very least a follow-up blood count should be arranged.

Red cell morphology, particularly the mean corpuscular volume (MCV), can help elucidate the cause of anaemia. The finding of a pancytopaenia suggests a problem in haematopoiesis, rather than haemolysis or blood loss. In women of childbearing age, assay of blood or urine β-HCG is important.

Treatment

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).

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.

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.

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

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