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.

Physical examination may reveal necrotizing mucosal lesions, pallor, petechial rashes, lymphadenopathy, bone tenderness, abnormal tonsillar or respiratory findings, spleno- or other organomegaly.2 Careful examination of the skin of the back, the lower limbs and the perineum for evidence of infection is important. The presence of indwelling venous access devices should be noted and insertion sites inspected for evidence of inflammation or infection.

Treatment

Management of the patient with confirmed febrile neutropenia in the ED involves early recognition and treatment of bacterial infection, and institution of supportive care to prevent progression to overwhelming sepsis and shock. Evolving or established haemodynamic instability requires immediate, aggressive resuscitation.

Empiric broad-spectrum antibiotic therapy should be started in the ED after drawing blood for culture in any patient with fever and confirmed significant neutropenia. This strategy has played a pivotal role in reducing mortality rates in febrile neutropenia.3 There is no clear consensus approach to which particular empiric antibiotic regime should be used. Practices vary widely amongst institutions and regions, and are influenced by local patterns of infection, prevalence and risk of inducing resistant organisms, and acquisition costs.4 In general antibiotics should provide good cover for both Gram-positive and Gram-negative organisms. With increased use of indwelling venous access devices for cancer chemotherapy, there has been an increase in the incidence of sepsis due to Gram-positive organisms such as coagulase negative staphylococci, S. aureus and MRSA.5 Although occurring infrequently, bacteraemia due to Pseudomonas aeruginosa is associated with a high morbidity and mortality and therefore should also be covered.6 A reasonable initial regime might include ticarcillin/clavulanate plus either a cephalosporin, such as ceftazidime, or an aminoglycoside, such as gentamicin. The addition of vancomycin might be considered if the patient is in shock, is known to be colonized with MRSA or has clinical evidence of a catheter-related infection in a unit with a high incidence of MRSA. Empiric antifungal therapy is not generally required unless there is persistent fever in high-risk patients beyond 96 h of antibacterial therapy.6

13.3 Thrombocytopenia

Decreased platelet production

Immune-related thrombocytopenia

Non-immune platelet destruction

Clinical features

Thrombocytopenia may be an incidental finding on the FBC or may be diagnosed in the context of abnormal bleeding. There are distinct differences in the patterns of abnormal bleeding associated with disorders of platelet deficiency and disorders of impaired coagulation.

Spontaneous bleeding related to thrombocytopenia typically manifests as cutaneous petechiae and/or purpura, most commonly in dependent areas such as the legs and buttocks.1,3 Other spontaneous manifestations include multiple small retinal haemorrhages, epistaxis, gingival and gastrointestinal bleeding. Bleeding following trauma or surgery in thrombocytopenic patients is often immediate and may respond to local methods of haemostasis. In contradistinction to this the bleeding associated with coagulation disorders is most commonly in the form of large haematomata or haemarthroses that occur spontaneously or develop hours to days following trauma.1

In addition to the haemorrhagic manifestations of platelet insufficiency, patients with thrombocytopenia may present with the clinical features of the underlying causative disorder. Splenic enlargement may be present in cases where thrombocytopenia is due to hypersplenism but is not a feature of immune-related thrombocytopenia.

The level of platelets associated with clinically significant abnormal bleeding is not precisely defined. It varies depending on the platelets’ functional integrity, and with the presence or absence of other risk factors, such as coagulation disorder, trauma, and surgery. There is evidence that platelet counts above 5 × 109/L are sufficient to prevent bleeding when the platelets are functionally normal and there are no other risk factors. Severe haemorrhage is uncommon at platelet counts above 20 × 109/L and in the setting of surgery the risk of abnormal haemorrhage is reduced at counts above 50 × 109/L.4

Treatment

Treatment for specific causes of thrombocytopenia has already been discussed. Bleeding in the face of low platelet count may be responsive to local methods of haemostasis if the remaining platelets are functionally normal and there is no other disorder of coagulation present. Individual case reports provide some support for the use of recombinant Factor VIIa as an enhancer of haemostasis in the treatment of bleeding in the context of severe thrombocytopenia, although evidence from randomized clinical trials is lacking.11 Platelet transfusion may be helpful in cases of severe haemorrhage and is sometimes used prophylactically to prevent bleeding in patients with very low platelet counts.

Platelet transfusion is primarily indicated in patients in whom thrombocytopenia is due to impaired platelet production and who are bleeding or have very low counts. The threshold for prophylactic transfusion in these patients is controversial. It is indicated when the platelet count is below 5 × 109/L, but is probably not indicated above this level unless other risk factors for bleeding are present.4

Platelet transfusion is rarely indicated in immune-related thrombocytopenias as the transfused platelets are rapidly destroyed. Transfusion of platelets may aggravate TTP.4 In DIC, platelet transfusion has not been proven to be effective but may be indicated in bleeding patients. There is little evidence to support the suggestion that blood component therapy aggravates DIC.12 In cases of massive blood transfusion, platelets are not routinely indicated unless there is ongoing bleeding and the platelet count is below 50 × 109/L.4

Raising the platelet count to 20–50 × 109/L is sufficient to prevent serious bleeding. In patients undergoing surgery or other invasive procedures counts up to 60–100 × 109/L may be required. A useful rule of thumb is that in a 70 kg adult, transfusion of one unit of platelets will increase the platelet count by 11 × 109/L.4

At present, platelet preparations for transfusion are stored in liquid at 22 °C. Problems include the continued risk of febrile non-haemolytic reactions, transmission of infectious agents and graft-versus-host disease. Alternatives to conventional liquid storage include frozen storage, cold liquid storage, photochemical treatment and lyophilized platelets. None of these methods is currently widely available. Several platelet substitutes have been developed but remain untested in the clinical setting. Some examples are red cells with surface-bound fibrinogen, fibrinogen-coated albumin microcapsules and liposome-based haemostatic agents.13

References

1 Rodgers GM, Bithell TC. The diagnostic approach to the bleeding disorders. In: Lee GR, Wintrobe MM, Lee GR, et al, editors. Wintrobe’s clinical hematology. 10th edn. Maryland: Lippincott Williams & Wilkins; 1999:1557-1578.

2 George JN. Thrombocytopenia: pseudothrombocytopenia, hypersplenism, and thrombocytopenia associated with massive transfusion. In: Beutler E, Beutler E, Williams WJ, editors. Williams Hematology. 5th edn. New York: McGraw-Hill; 1995:1355-1360.

3 American Society of Hematology. ITP Practice Guideline Panel. Diagnosis and treatment of idiopathic thrombocytopenic purpura. American Family Physician. 1996;54(8):2437-2447. 24512452

4 Mollison PL, Engelfriet CP, Contreras M. Blood transfusions in clinical medicine, 10th edn. Oxford: Blackwell Science, 1997.

5 Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. New England Journal of Medicine. 2007;357(6):580-587.

6 George JN, El-Harake M, Aster RH. Thrombocytopenia due to enhanced platelet destruction by immunological mechanisms. In: Beutler E, et al, editors. Williams hematology. 5th edn. New York: McGraw-Hill; 1995:1315-1354.

7 George JN, El-Harake M. Thrombocytopenia due to enhanced platelet destruction by nonimmunological mechanisms. In: Beutler E, et al, editors. Williams hematology. 5th edn. New York: McGraw-Hill; 1995:1290-1314.

8 Schwartz KA. Gestational thrombocytopenia and immune thrombocytopenias in pregnancy. Hematology and Oncology Clinics of North America. 2000;14(5):1101-1116.

9 Padden MO. HELLP syndrome: recognition and perinatal management. American Family Physician. 1999;60(3):829-836.

10 Ten Cate H. Pathophysiology of disseminated intravascular coagulation in sepsis. Critical Care Medicine. 2000;28(9 suppl):S9-S11.

11 Goodnough LT, Lublin DM, Zhang L, et al. Transfusion medicine service policies for recombinant factor VIIa administration. Transfusion. 2004;44:1325-1331.

12 Levi M, de Jonge E, van der Poll T. Novel approaches to the management of disseminated intravascular coagulation. Critical Care Medicine. 2000;28(9 suppl):S20-S24.

13 Lee DH, Blajchman MA. Novel treatment modalities: new platelet preparations and substitutes. British Journal of Haematology. 2001;114:496-505.

13.4 Haemophilia

Clinical features

Haemophilia A and B are clinically indistinguishable and symptoms vary according to the severity of the inherited disorder. Mild disease may not present till adulthood, whereas moderate to severe disease usually presents in infancy or early childhood.

Bleeding in haemophilia tends to occur spontaneously or following minor trauma and is typically delayed and persistent. This is because although initial platelet ‘plugging’ function is normal, the subsequent coagulation ‘cascade’ response is abnormal. This delay is usually hours, occasionally days. Once bleeding occurs it may persist for days or even weeks. Patients who are severely affected may present with bleeding episodes on a weekly basis.

The most common manifestations of haemophilia are:

Patients may also present with a complication of therapy. Most haemophiliac patients treated before 1985 have been exposed to pathogenic viruses, of which the most important are hepatitis C, hepatitis B and HIV. Of those who received plasma prior to the mid-1980s, 90% are hepatitis B positive, 85–100% are hepatitis C positive, and 60–90% are HIV positive.

Treatment

Treatment of haemophilia has evolved dramatically in the past 40 years with the discovery in the 1960s that coagulation Factor VIII was concentrated in cryoprecipitate. More recently, highly purified concentrates of Factor VIII and Factor IX have been developed.

Products currently available for the treatment of haemophilia include:

Treatment of acute bleeding episodes primarily involves administration of factor replacement therapy. Complications of bleeding may require specific intervention. Adjunctive therapies include pain relief, rest and immobilization. Specific treatment is influenced by:

Haemophilia patients presenting with suspected bleeds should be triaged as ATS 3 and receive prompt assessment by a senior doctor. For muscle and joint bleeds ‘R.I.C.E.S’ should be initiated on arrival to limit bleeding and reduce pain.

Options for adequate analgesia include:

In the context of pain relief, aspirin (or other platelet-modifying drugs) should be avoided and NSAIDs used with caution. Intramuscular injections should never be administered. In major bleeds there may be a requirement for red cell transfusion. Developing limb compartment syndromes may require surgical decompression and intracranial bleeds may require neurosurgical intervention. In all of these cases, factor replacement must commence as quickly as possible. Management of complex presentations requires a multidisciplinary approach, and early consultation with the relevant state haemophilia centre, especially if the presentation is a major bleed or the patient has inhibitors.

Intravenous cannulation is best performed by a skilled practitioner to help ensure vein preservation. Invasive procedures such as arterial puncture and lumbar puncture must only be performed after clotting factor replacement. Intramuscular injections should be avoided.

Some patients with Factor VIII levels higher than 10% may be successfully treated with 1-amino-8-D-arginine vasopressin (desmopressin, DDAVP). It acts by releasing von Willebrand Factor stored in the lining of the blood vessels. Von Willebrand Factor is a protein that transports Factor VIII in the bloodstream and as such plays an important role in blood clotting. Desmopressin appears to mobilize available Factor VIII stores and may raise Factor VIII activity by a factor of three. If the patient has previously had a documented good response to desmopressin, this can be used as first line therapy for minor bleeding such as haemarthroses.

Desmopressin can be administered intravenously, subcutaneously or by nasal spray. The intravenous dose is 0.3 mcg/kg in 100 mL saline over no less than 45 min. A response should be evident within the first hour. More rapid administration can be associated with blood pressure changes. Side effects, including facial flushing and headache, are usually well tolerated. Tachyphylaxis tends to develop after three or four doses. The antidiuretic properties of desmopressin (which can last up to 24 h after a dose) can produce fluid retention and hyponatraemia (leading to seizures), and the serum sodium levels should be measured before giving further doses. Desmopressin is useful in treating mild and very rarely moderate haemophilia A. It is not of value in severe haemophilia A or with any type of haemophilia B. In serious bleeds or major surgery, desmopressin alone will not control bleeding. In such a case, most patients should also receive Factor VIII concentrate, recombinant Factor VIII replacement and recombinant Factor IX replacement.

Most haemophiliac patients are usually well known to their state haemophilia centres, who often hold specialized treatment protocols for difficult or complex patients. Patients should have their treatment regime cards with them. If not they should be encouraged to do so.

One unit of Factor VIII concentrate provides the amount of Factor VIII activity in 1 mL of normal plasma. Given that a 70-kg adult has a plasma volume of 3500 mL, we can expect that an infusion of 3500 units of Factor VIII will produce 100% Factor VIII activity in a haemophiliac with negligible activity prior to treatment. The half-life of Factor VIII is approximately 12 h. Accordingly, a further dose of 1750 units in 12 hours’ time will again restore 100% activity.

It is not always necessary to provide 100% Factor VIII activity in order to ensure haemostasis: levels of 30–50% may be sufficient in the context of haemarthrosis or dental extraction. Larger infusions should be reserved for life-threatening situations.

Treatment of bleeding

Minor bleed (e.g. spontaneous haemarthrosis or muscle bleed):

Moderate bleed (e.g. epistaxsis, traumatic haemarthrosis, excluding hip):

Major bleed (e.g. intracerebral, hip, neck, throat, psoas muscle):

Many patients can administer Factor VIII concentrate at home ‘on demand’. Indeed, the availability of Factor VIII and the ease of administration have revolutionized the care of haemophiliac patients in the community. However, the following are indications for hospital admission:

Antifibrinolytic agents such as tranexamic acid (cyclokapron) and aminocaproic acid (amicar) have been used as adjunctive therapy in episodes of gastrointestinal and mucosal bleeding, for example following dental extraction. Fibrin tissue adhesives containing fibrinogen, thrombin and Factor XIII have also been successfully placed in tooth sockets and similar surgical sites.

Tranexamic acid and aminocaproic acid are useful in treating both haemophilia A and B. These drugs help to hold a clot in place once it has formed. They act by stopping the activity of plasmin, which dissolves blood clots. They do not help to actually form a clot which means they cannot be used instead of desmopressin or Factor VIII or IX concentrate, but can be used to hold a clot in place on mucous membranes, including in the oral cavity, nasal cavity, intestinal and uterine walls. Tranexamc acid and aminocaproic acid are associated with minor side effects including nausea, lethargy, vertigo, diarrhoea and abdominal pain.

Antibodies to factor VIII

Some patients develop antibodies to Factor VIII, known as ‘inhibitors’. Treatment has to be modified according to the titre of inhibitor present (measured by the Bethesda Inhibitor Assay). Patients are classified as ‘high responders’ if their baseline inhibitor titre exceeds 10 Bethesda Units (BU) or if the titre rises above 10 BU on exposure to Factor VIII. Different management strategies are employed according to the severity of the bleed. These include increasing the dose of Factor VIII or alternative therapies such as activated prothrombin complex, porcine Factor VIII or recombinant Factor VIIa.

Most patients who develop inhibitors do so early in life and are known to have severe hereditary haemophilia, but inhibitors can also arise in previously normal individuals to produce an acquired haemophilia. The incidence of this phenomenon is from 0.2 to 1/1 000 000/year. Patients tend to be elderly and some have autoimmune disease, but there is also an association with pregnancy as well as with some drugs, notably penicillin. Patients haemorrhage into muscle and soft tissues, and may present with haematemesis, or with unusual postoperative bleeding. In the laboratory the patient’s blood shows a prolonged APPT that is not corrected by ‘mixing’, that is, by the addition of normal plasma. Factor VIII levels are low. Management is directed towards control of the bleeding episode, replacement therapy and the prevention of further reactions using a variety of immunosuppressive remedies.

von Willebrand disease

Factor VIII has an intimate association with von Willebrand factor (vWF). This is an adhesive glycoprotein secreted by endothelium and megakaryocytes, which is required for the normal instigation of platelet plug formation and for stabilization and transport of Factor VIII within the circulation. Thus von Willebrand disease (vWD) is a result of dysfunction, reduction, or a complete lack of the vWF and is often associated with low Factor VIII activity. It is the most common inherited bleeding disorder, affecting 0.1–1% of the population, and affects males and females equally.

Three types of von Willebrand disease are recognized:

Common symptoms of vWD are:

Useful contacts

Contact numbers for advice/referrals

13.5 Blood and blood products

Introduction

Blood is a living tissue composed of blood cells suspended in plasma; it transports nutrients and oxygen, and facilitates temperature control. An average 70-kg male has a blood volume of about 5 L. The cellular elements comprise red blood cells, white blood cells and platelets, and make up about 45% of the volume of whole blood. Plasma, which is 92% water, makes up the remaining 55%.

Early attempts at blood transfusion were thwarted by adverse reactions. In 1900 Karl Landsteiner demonstrated the ABO blood group system and explained many of the observed severe incompatibility reactions (Table 13.5.1). He won the Nobel prize for medicine in 1930 and went on to discover the Rhesus factor in 1940. The next major advance in transfusion medicine occurred with the development of long-term anticoagulants such as sodium citrate, which allowed extended preservation of blood. Development of refrigeration procedures allowed storage of anticoagulated blood. The addition of a citrate-glucose solution extended the viability of collected blood to several days. The ability to preserve blood for longer than a few hours paved the way for the establishment of the first blood bank in a Leningrad hospital in 1932.

Table 13.5.1 The ABO group system

ABO blood group Antigens on red cells Antibody in serum
O None Anti-A, Anti-B
A A Anti-B
B B Anti-A
AB A, B None

Transfusion of blood and blood products is now routine and vital to the practice of emergency medicine. As with any prescribed treatment, these products are associated with potential hazards as well as advantages. The hazards are more likely to be encountered with blood products used during emergencies. The blood products available in most Australian emergency departments (EDs) are packed red blood cells, platelets, fresh frozen plasma (FFP), cryoprecipitate, activated Factor VII, prothrombin complex concentrates and other factor concentrates.

In the Australian urban hospital setting, 50% of packed red cells are used for the treatment of anaemia, 22% pre- or perioperatively and 13% for abnormal, excessive or continued bleeding.1 Medical oncology uses 78% of all platelets.2 Forty-one per cent of all FFP is used to correct coagulopathy associated with surgery, 27% to correct coagulopathy in bleeding, 16% to reverse haemostatic disorders in patients having massive blood transfusion, 11.5% for reversal of warfarin effect and the remaining 4.5% for a number of miscellaneous conditions, including liver disease and disseminated intravascular coagulation (DIC).

In the ED setting, blood products are most often administered to patients with acute rather than chronic blood loss. In most EDs, trauma patients are the major consumers of blood products and in this setting they need to be provided rapidly and infused often in large quantities. However, as short stay units are developed, non-time critical transfusions of blood products for other medical indications are increasingly the responsibility of ED staff.

Packed red blood cells

Packed red blood cells are produced from whole blood collections by removing most of the plasma by centrifugation and then resuspending the red cells in citrate-based anticoagulant-preservative solution to prolong storage time. Each unit of packed cells contains approximately 200 mL of red cells. Transfusion of one unit can be expected to raise the haematocrit by 3% and the haemoglobin by 10 g/L provided there is no ongoing blood loss.

Packed red cells are the blood product most commonly prescribed in the ED, the usual indication being the replacement of acute blood loss.3 Transfusion of packed red cells is indicated where the patient’s oxygen-carrying capacity is so impaired that control of bleeding alone, if indeed it can be readily achieved, is regarded as insufficient to take the patient out of danger. Occasionally it may be necessary to transfuse a patient with a primary haematological condition, a failure of erythropoiesis or a haemolytic process. The indication for transfusion is the same as for haemorrhage: a severe reduction in oxygen-carrying capacity. Complex multisystem failure, such as DIC or septic shock, may result in simultaneous blood loss, circulatory collapse, haemolysis and a coagulopathy. Transfusion therapy may be life saving in this context (Table 13.5.2).

Table 13.5.2 Potential indications for red cell transfusion

Haemorrhage
Dilutional anaemia following severe burns
Iron-deficiency anaemia
Megaloblastic anaemia
Anaemia of chronic disorders
Chronic renal failure
Failure of erythropoiesis
Sickle cell disease
Septic shock
Disseminated intravascular coagulopathy

Fluid administration is the cornerstone of management during initial trauma reception and resuscitation, as hypovolaemia is one of the leading causes of death in trauma. Fluid resuscitation must be rapid and appropriate, and should be reassessed and adjusted at regular intervals. This has led to a significant decrease in morbidity and mortality from major trauma.4

The American College of Surgeons estimates fluid and blood loss by using six physiological parameters to grade patients into classes I–IV (Table 13.5.3). This allows more accurate characterization of a patient’s immediate haemodynamic status than do laboratory parameters such as haemoglobin and haematocrit. It is recommended that patients in groups III and IV receive blood.

Transfusion is not indicated when alternative haematinic therapy is deemed safe and appropriate. A moderately anaemic patient who is asymptomatic and not bleeding, with some reserve oxygen-carrying capacity, does not require blood transfusion. A haemoglobin of 7 g/dL is sometimes taken as the failsafe point in the decision whether to transfuse, although of course the patient’s unique circumstances need to be taken into account: treat the patient, not the number. The National Health and Medical Research Council together with the Australasian Society of Blood Transfusion have published transfusion guidelines for red blood cells and other products (Table 13.5.4).

Table 13.5.4 Guidelines for transfusion of blood components

Indications Considerations
Red blood cells
Hb
<70 g/L Lower thresholds may be acceptable in patients without symptoms and/or where specific therapy is available
70–100 g/L Likely to be appropriate during surgery associated with major blood loss or if there are signs or symptoms of impaired oxygen transport
>80 g/L May be appropriate to control anaemia-related symptoms in a patient on a chronic transfusion regimen or during marrow suppressive therapy
>100 g/L Not likely to be appropriate unless there are specific indications
Platelets
Bone marrow failure At a platelet count of <10 × 109/L in the absence of risk factors and <20 × 109 in the presence of risk factors (e.g. fever, antibiotics, evidence of systemic haemostatic failure)
Surgery/invasive procedure To maintain platelet count at >50 × 109/L. For surgical procedures with high risk of bleeding (e.g. ocular or neurosurgery) it may be appropriate to maintain at 100 × 109/L
Platelet function disorders May be appropriate in inherited or acquired disorders, depending on clinical features and setting. In this situation, platelet count is not a reliable indicator
Bleeding May be appropriate in any patient in whom thrombocytopenia is considered a major contributory factor
Massive haemorrhage/transfusion Use should be confined to patients with thrombocytopenia and/or functional abnormalities who have significant bleeding from this cause. May be appropriate when the platelet count is <50 × 109/L (<100 × 109/L in the presence of diffuse microvascular bleeding)
Fresh frozen plasma
Single factor deficiencies Use specific factors if available
Warfarin effect In the presence of life-threatening bleeding. Use in addition to vitamin-K-dependent concentrates
Acute DIC Indicated where there is bleeding and abnormal coagulation. Not indicated for chronic DIC
TTP Accepted treatment
Coagulation inhibitor deficiencies May be appropriate in patients undergoing high-risk procedures. Use specific factors if available
Following massive transfusion or cardiac bypass May be appropriate in the presence of bleeding and abnormal coagulation
Liver disease May be appropriate in the presence of bleeding and abnormal coagulation
Cryoprecipitate
Fibrinogen deficiency May be appropriate where there is clinical bleeding, an invasive procedure, trauma or DIC

TTP, idiopathic thrombocytopenia purpura ;DIC, disseminated intravascular coagulation.

Adapted from the National Health and Medical Research Council and Australasian Society Clinical Practice Guidelines on appropriate use of blood components http://www.nhmrc.gov.au/publications/synopses/-files/cp82.pdf

Prior to transfusion, except in an extreme emergency, the patient’s informed consent should be sought, obtained and documented. Rarely, patients may be encountered who refuse transfusion, either on religious grounds or for fear of adverse reactions, particularly with respect to the transfer of viral agents. This can pose problems if the patient appears incompetent to give or withhold informed consent. The situation of an exsanguinating minor whose parents refuse permission to transfuse is particularly difficult. Court orders can be obtained to treat minors without parental consent, and in such an extreme situation many doctors would feel justified in applying to obtain one, even retrospectively.

Effect of storage on red blood cells

Although it makes intuitive sense that blood loss should be replaced by blood products, there is evidence that the immediate observed benefit is from volume replacement rather than improved oxygen carriage.5,6 Red blood cells may not be fully functional until 2–6 h after transfusion because storage affects the oxygen-carrying capacity of blood. This is probably due to decreased intracellular 2,3-diphosphoglycerate (2,3-DPG), loss of red cell viability, decreased red cell deformability, relative acidosis and potassium leakage.7

Storage reduces 2,3-DPG levels, leading to a leftward shift of the oxyhaemoglobin dissociation curve and increased affinity of oxygen binding. The transfused red cell does regenerate 2,3-DPG to normal levels but this can take 6–24 h post transfusion. With increasing age of stored red cells, levels of 2,3-DPG progressively fall such that by 5–6 weeks the level is 10% of normal. It is still uncertain whether this abnormality is physiologically important, even in critically ill patients.8

When red cells are transfused, some of the cells are removed from the circulation within a few hours, with the rest surviving normally; as the storage time increases to 42 days, more cells are removed immediately after transfusion. This loss of viability is highly dependent upon the anticoagulant-preservative solution used.9

Potassium gradually leaks out of stored red cells and this raises the plasma potassium by approximately 1 meq/L per day.10

Choice of red cell product

The choice of red cell product is determined by time and safety considerations. O-negative red cells, the universal donor group, are readily available in most major hospitals. Supplies of O-negative blood are limited and the product should be used with care. It is preferable that blood be collected prior to infusion of such cells so as to characterize the recipient’s blood group serology. Premenopausal female patients should be given group O Rhesus negative, Kell negative blood in an emergency situation in order to avoid sensitization and possibility of haemolytic disease of newborn in subsequent pregnancies. Male patients, however, can be transfused either Rhesus positive or negative blood. The incidence of adverse reaction using this type of blood is approximately 3%. O-negative may be given immediately on arrival where the patient has not responded to adequate crystalloid given during transport, or the patients are in class III or IV shock.11 By contrast, the provision of group-specific blood requires matching a blood sample to the major (ABO) and Rhesus D compatibility groups only. Group-specific blood can be available for transfusion within 35 min depending on the logistic support and staffing levels within the haematology laboratory. It has an incidence of adverse reaction similar to O-negative blood. As O-negative blood is usually in short supply it is preferable where possible to infuse group-specific blood. A more comprehensive cross match where there are no atypical antibodies identified in the initial screening can take 30 min or more and the incidence of adverse transfusion reaction is reduced to 0.01%. Due to the time required for sample collection and cross matching, it is generally not possible to provide fully cross-matched blood within the first 30 min of trauma reception.

Precautions when cross-matching and transfusing blood

Although most patients do not require transfusion in the ED, it is often appropriate to ‘group and hold’ or cross-match the patient while in the department. Many hospitals have written protocols detailing the anticipated requirements for a given surgical procedure. Documentation should be meticulous. It is preferable that the person drawing the blood for cross-matching should also fill in and sign the laboratory request form. Most severe incompatibility reactions to blood transfusion result not from exposure to unusual antigens but from an administrative error. Any systematic change in documentation protocols, for example the adoption of an electronic record, needs to be accompanied by an obsessive risk management strategy.

The checking of the compatibility details of blood to be transfused must be meticulous. Blood products should not be left lying around workbenches. Universal precautions must be observed by staff setting up transfusions. Rapid or large transfusions should be via a blood warmer. Blood is transfused intravenously through sterile giving sets containing 170 μm filters. Alternative routes (arterial, intraperitoneal or intraosseous) are only used in exceptional circumstances. Lines for transfusion should be dedicated lines; drugs and other additives should be administered at separate sites. Normal saline is compatible with all blood components.

Pulse, blood pressure and temperature are measured at regular intervals, and particular attention is paid to the patient during the first 25 min of the transfusion. The transfusion is started slowly. The rate at which it continues depends upon the clinical urgency. The usual regime is 500 mL over 1–2 h. As a general rule, the faster the anaemia has developed the more rapidly it needs to be corrected. Rapid infusion techniques may be indicated in patients who appear to be exsanguinating, but over-rapid infusion can precipitate cardiac failure in the elderly. Hypothermia may be a problem if a blood warmer is not used.

HIV, human immunodeficiency virus; HTLV, human T-cell lymphotropic virus.

Table 13.5.6 Incidence of adverse transfusion reactions (per unit packed red cells transfused)

Adverse transfusion reaction Incidence Mortality
Bacterial sepsis 1 in 40 000–500 000 1 in 4–8 million
Acute haemolytic reaction 1 in 12 000–38 000 1 in 600 000–1.5 million
Delayed haemolytic reaction 1 in 1000–12 000 1 in 2.5 million
Anaphylaxis 1 in 20 000–50 000  
Transfusion-related acute lung injury 1 in 5000–100 000 1 in 5 million
Fluid overload 1 in 100–700  
Transfusion-associated graft versus host disease Rare 90% fatality

Adapted from Australian Red Cross website: http://www.transfusion.com.au/TRANSFUSIONPOCKETGUIDES/Pocket_RiskConsent.asp (accessed 25th February 2008).

Immunological transfusion reactions

Immunological transfusion reactions may be immediate or delayed in onset.

Immediate

Delayed

Transmission of infection

In Australia, blood is tested for ABO and Rh (D) blood groups, red cell antibodies, and the following infections:

In terms of viral safety Australia has one of the safest blood supplies in the world (Table 13.5.7).

Table 13.5.7 Risks of transfusion transmitted infection (per unit tested blood transfused)

Infection Residual risk
CMV 1 in 127 000
Hepatitis B Approximately 1 in 660 000
Syphilis Considerably less than 1 in a million
Hepatitis C <1 in 10 million
HIV <1 in 10 million
HTLV I and II <1 in 10 million
Variant CJD Possible and cannot be excluded

CMV, cytomegalovirus; HIV, human immunodeficiency virus; HTLV, human T-cell lymphotropic virus; CJD, Creutzfeldt–Jakob disease.

Adapted from Australian Red Cross website: http://www.transfusion.com.au/TRANSFUSIONPOCKETGUIDES/Pocket_RiskConsent.asp (accessed 25th February 2008).

Management of transfusion reactions

The first action to be taken in the management of any suspected transfusion reaction is to stop the transfusion immediately and assess the patient. The bag containing the transfused cells, along with all attached labels, should not be discarded so as to allow repeat typing and cross-matching of this unit by the blood bank. Management then proceeds as follows:

The laboratory which tested and issued the blood should be alerted immediately, and a search for any clerical error instituted. Every hospital has a protocol for evaluating transfusion reactions, which should be rigorously followed. The haematology unit should notify the local blood bank, who have a haematologist on-call at all times and are responsible for the recall of any other implicated components from the same donor in the case of suspected infection or transfusion-related acute lung injury. If there is any suggestion (e.g. clerical mistake, hypotension, pink plasma or urine) that an AHTR is possible, oxygen should be applied to the patient and fluid resuscitation with saline to maintain a urine output of 2–3 mL/kg/h, in an attempt to prevent acute oliguric renal failure. A vasopressor such as adrenaline may be required. If massive intravascular haemolysis has already occurred, hyperkalemia is likely and cardiac monitoring and acute haemodialysis may be required.

Platelets

Platelets are one of the main cellular components of blood and are central to haemostasis. Platelet products commonly available for transfusion are obtained by apheresis from a single donor or from donated blood using buff-coat or platelet-rich plasma techniques. Modifications to reduce the risk of viral transmission and prevent graft-versus-host disease include leukocyte reduction, irradiation, plasma depletion and the use of platelet additive solutions.

Platelets are transfused to prevent or treat haemorrhage in patients with thrombocytopenia or defects in platelet function. Specific indications for platelet transfusion are shown in Table 13.5.4. Use of platelets is not generally considered appropriate in the treatment of immune-mediated platelet destruction, thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome or drug-induced or cardiac bypass thrombocytopenia without haemorrhage.3

In general, one platelet unit will raise the platelet count about 5–10 × 109/L in an average adult. Depending on the method of manufacture the volume of each unit of platelets varies from 100–160 mL, with a storage life of about 5 days at 20–24 °C.

Compatibility testing is not necessary in routine platelet transfusion, although platelet components should preferably be ABO and Rh type compatible with the recipient. ABO-incompatible platelets may be used if ABO compatible platelets are not available. The usual dose in an adult patient is four units, which is equivalent to one unit of apheresis platelets or one unit of pooled platelets.

Massive transfusion

In the 1970s, massive transfusion was defined as more than 10 units of blood over a 24-h period. This is equivalent to approximately one patient blood volume in a person of average weight person.14 Recent reviews in the literature have expanded this definition, with some reports using up to 50 units of blood in 24 or 48 h.15

There is wide institutional variation in massive or emergency transfusion protocols. Many recommend a ratio of red cells to clotting factors. One institution advocates for every 10 units of red blood cells one should consider transfusing 6 units of FFP, 5 units of platelets and 5 units of cryoprecipitate, and if the fibrinogen level is less than 1.0 g/L, then 10 units of cryoprecipitate. If laboratory parameters are available then one should consider treatment when platelets <100 × 109/L, international normalized ratio (INR) >1.5, fibrinogen <1.0 g/L or when there is ongoing and uncontrollable ooze from damaged tissue. This should always be in close consultation with the transfusionist/haematologist as each individual shocked trauma patient should be assessed and transfusion decisions made on physiological and haematological parameters, as well as availability and access to appropriate transfusion products available at the time. As products such as FFP and cryoprecipitate require up to 25 min preparation time, and if one is anticipating a major transfusion situation (i.e. greater than 10 units of red cells) then the laboratory should be notified of the potential need for cryoprecipitate and FFP, and the provision of pre-thawed AB plasma, O-negative cells.

References

1 Rubin GL, Schofield WN, Dean MG, et al. Appropriateness of red blood cell transfusions in major urban hospitals and effectiveness of an intervention. Medical Journal of Australia. 2001;175:354-358.

2 Metz J, McGrath KM, Copperchini ML, et al. Appropriateness of transfusions of red cells, platelets and fresh frozen plasma. An audit in a tertiary care teaching hospital. Medical Journal of Australia. 1995;162:572-577.

3 Practice Guidelines on the Use of Blood Components. National Health and Medical Research Council and Australasian Society of Blood Transfusion Clinical, 2001 http://www.nhmrc.gov.au/publications/synopses/_files/cp78.pdf (accessed 4 August 2008).

4 Champion H, Bellamy RF, Roberts CP, et al. A profile of combat injury. Journal of Trauma. 54(suppl), 2003. s31-s19

5 Dabrowski GP, Steinberg SM, Ferrara JJ, et al. A critical assessment of endpoints of shock resuscitation. Surgical Clinics of North America. 2000;80:825-844.

6 Revell M, Greaves I, Porter K. Endpoints for fluid resuscitation in hemorrhagic shock. Journal of Trauma. 2003;54(suppl):s63-s67.

7 McKinley BA, Valdivia A, Moore FA. Goal orientated shock resuscitation for major torso trauma. Current Opinions in Critical Care. 2003;9:292-299.

8 Walsh TS, McArdle F, McLellan SA, et al. Does the storage time of transfused red blood cells influence regional or global indexes of tissue oxygenation in anaemic critically ill patients? Critical Care Medicine. 2004;32:364-371.

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