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

13.3 Thrombocytopaenia

Non-immune platelet destruction

Thrombotic thrombocytopaenic purpura

Thrombotic thrombocytopaenic purpura (TTP) is considered to be the adult form of the haemolytic uraemic syndrome (HUS). Essentially a thrombotic microangiopathy, the classic pentad of clinical findings is: (1) fever, (2) thrombocytopaenia, (3) microangiopathic haemolytic anaemia, (4) neurological abnormalities and (5) renal involvement.

TTP can occur sporadically as an idiopathic disorder or may be associated with pregnancy, epidemics of verotoxin-producing Escherichia coli and Shigella dysenteriae, malignancy, chemotherapy, marrow transplantation and drug-dependent antibodies. Treatment with plasma exchange has dramatically influenced the outcome of TTP. Mortality has fallen from more than 90% prior to introduction of plasma exchange to less than 20% with this treatment.

Thrombocytopaenia in pregnancy

Gestational thrombocytopaenia develops during an otherwise normal pregnancy and is clinically distinct from autoimmune thrombocytopaenias such as ITP. It is thought to be due to decreased platelet survival consequent to activation of the coagulation system. Thrombocytopaenia is usually mild and there is no corresponding thrombocytopaenia in the infant. The platelet count returns to normal after delivery, although thrombocytopaenia may recur in subsequent pregnancies.

Autoimmune thrombocytopaenias, on the other hand, are often associated with more severe reductions in the platelet count. Antiplatelet antibodies are capable of crossing the placenta and may result in significant thrombocytopaenia in the fetus and newborn. This can lead to complications, such as intracranial haemorrhage, during the delivery. Treatment of the mother with autoimmune thrombocytopaenia is similar in principle to the treatment of non-pregnant cases.

In the context of pregnancy, thrombocytopaenia may also be seen as part of the HELLP (haemolysis, elevated liver enzymes, low platelets) and pre-eclampsia syndromes. The two syndromes are thought to be related. Common to both is a process of microvascular endothelial damage and intravascular platelet activation. This leads to release of thromboxane A and serotonin, which provoke vasospasm, platelet aggregation and further endothelial damage. In both syndromes, the process is terminated by delivery.

Disseminated intravascular coagulation

Thrombocytopaenia is one manifestation of the syndrome of disseminated intravascular coagulation (DIC). DIC is an acquired syndrome of diffuse intravascular coagulation up to the level of fibrin formation, accompanied by secondary fibrinolysis or inhibited fibrinolysis. It occurs in the course of severe systemic diseases or may be provoked by toxins, such as snake venoms.

Thrombocytopaenia due to impaired platelet production

Congenital disorders of impaired platelet production usually present in childhood and will not be discussed.

Of the acquired disorders of impaired platelet production, the most commonly seen in the emergency setting is the incidental finding of reduced platelet count in patients suffering viral illness. Causative viruses include Epstein–Barr virus, rubella and dengue fever. Thrombocytopaenia in these cases is reversible and requires no specific therapy other than monitoring of the platelet count to ensure normalization.

Disorders of bone marrow dysfunction, such as malignant infiltration and bone marrow suppression, cause thrombocytopaenia accompanied by reductions in numbers of other blood components. Examination of the full blood count (FBC) and blood film usually distinguishes these from other causes of isolated thrombocytopaenia. Further investigation is best referred to a haematologist.

Massive blood transfusion and thrombocytopenia

Massive blood transfusion is defined as the transfusion of a volume equivalent to the patient’s normal blood volume within a 24-h period. Thrombocytopaenia results from dilution of the patient’s remaining platelets and, where whole blood is used, decreased survival of platelets in stored blood. It is possibly the most important factor contributing to the haemostatic abnormality seen in massively transfused patients. Platelet transfusion should be reserved for cases where the platelet count falls below 50×10⁹/L.

Hypersplenism

Hypersplenism refers to the thrombocytopaenia due to pooling in patients with splenic enlargement. It is the primary cause of thrombocytopaenia in hepatic cirrhosis, portal venous hypertension and congestive splenomegaly. In these cases, thrombocytopaenia is rarely severe and not usually of clinical importance.

Transient thrombocytopaenia has been described in patients suffering severe hypothermia and is due to splenic sequestration. Platelet counts usually return to normal within days of rewarming.

Clinical features

Thrombocytopaenia 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 thrombocytopaenia typically manifests as cutaneous petechiae and/or purpura, most commonly in dependent areas, such as the legs and buttocks. Other spontaneous manifestations include multiple small retinal haemorrhages, epistaxis, gingival and gastrointestinal bleeding. Bleeding following trauma or surgery in thrombocytopaenic 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 haematomas or haemarthroses that occur spontaneously or develop hours to days following trauma.

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

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.

Clinical investigation

The FBC and examination of the blood film are diagnostic of thrombocytopaenia. The pattern of deficiency should be considered. Isolated thrombocytopaenia refers to a low platelet count in the presence of an otherwise normal FBC and blood film. In these cases, FBC combined with a careful clinical history and examination is often sufficient to lead to a final diagnosis. Coexistent anaemia and/or leucopaenia suggest bone marrow dysfunction as the primary aetiological process.

Other useful investigations may include coagulation studies and D-dimer (DIC, pre-eclampsia), electrolytes, urea and creatinine (TTP), liver function tests (HELLP, and liver disease) and thyroid function tests (autoimmune thyroid disorders). Platelet antibody titres are indicated in the work-up of pregnancy- related thrombocytopaenia and bone marrow aspirate may be indicated in investigation of thrombocytopaenia due to bone marrow dysfunction, but neither of these tests is useful in the emergency department setting.

Treatment

Treatment for specific causes of thrombocytopaenia 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 Vlla as an enhancer of haemostasis in the treatment of bleeding in the context of severe thrombocytopaenia, although evidence from randomized clinical trials is lacking. 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 thrombocytopaenia 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.

Platelet transfusion is rarely indicated in immune-related thrombocytopaenias as the transfused platelets are rapidly destroyed. Transfusion of platelets may aggravate TTP. 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. 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.

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.

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.

Disposition

Disposition will depend on the presence and extent of abnormal bleeding, the degree of thrombocytopaenia and the underlying aetiology. In general, patients who present with abnormal bleeding and a low platelet count should be admitted for further evaluation and treatment. In the absence of bleeding, patients who have isolated thrombocytopaenia with counts above 20×10⁹/L may be investigated on an outpatient basis.

13.4 Haemophilia

Disposition

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:

Useful contacts

Websites

Contact numbers for advice/referrals

ACT

NSW

NT

QLD

SA

TAS

VIC

WA

13.5 Blood and blood products

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 should be mandated 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 administrative errors. Any systematic change in documentation protocols, for example, the adoption of an electronic record, needs to be accompanied by obsessive risk management strategies.

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 on clinical urgency. 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 may precipitate cardiac failure in the elderly. Hypothermia may be a problem if a blood warmer is not used.

Adverse reactions to transfusion

The principal adverse reactions to blood transfusion are listed in Table 13.5.4. Serious adverse reactions are relatively rare (Table 13.5.5), although some are more likely to occur when blood is administered urgently.

Immunological transfusion reactions

Immunological transfusion reactions may be immediate or delayed in onset.

Immediate

Febrile non-haemolytic reactions

The most common transfusion reaction is a febrile, non-haemolytic transfusion reaction (FNHTR), which is defined as an increase in temperature of 1°C or more over baseline during a transfusion. It manifests as fever and occasionally shortness of breath 1–6 h after transfusion. FNHTRs are benign, but their presentation is very similar to acute haemolytic transfusion reaction and infection, which have a higher rate of mortality and morbidity, mandating early clinical review to exclude more serious complications.

Acute haemolytic reactions

Acute haemolytic transfusion reactions (ATHRs) result from the rapid destruction of donor red cells by preformed recipient antibodies and are a medical emergency. They are usually due to ABO incompatibility and most often the result of clerical or procedural errors. ABO and Rhesus compatibility between donors and recipients is presented in Table 13.5.6. Some acquired alloantibodies, such as anti-Rh or anti-Jka, are occasionally implicated, but AHTRs more typically occur when a group O recipient is transfused with non-group O red cells. This may lead to DIC, shock and acute tubular necrosis precipitating acute renal failure. These reactions usually manifest with fever and rigors, lumbar pain, crushing chest pain, tachycardia, hypotension and haemoglobinaemia with subsequent haemoglobinuria. The symptoms usually develop within the first 30 min of transfusion.

Anaphylactoid transfusion reactions

Anaphylactoid reactions usually begin within 1–45 min of the start of transfusion of blood products but less severe reactions can be delayed up to 2–3 h. Generally, a shorter time between commencement of the transfusion and onset of symptoms is associated with a more severe reaction. These reactions are manifested by rapid onset of shock, hypotension, angio-oedema and respiratory distress. They are almost always due to the presence of class-specific IgG, anti-IgA antibodies in patients who are IgA deficient. Selective IgA deficiency is not uncommon, occurring in about 1 in 300–500 people. The incidence of anaphylactic transfusion reactions can be reduced by the use of washed products (e.g. washed red cells) and by premedicating the patient with antipyretics and antihistamines.

Treatment of an anaphylactoid transfusion reaction consists of immediate cessation of transfusion and standard treatment of anaphylaxis including, oxygen fluids and adrenaline (see Chapter 28.7).

Transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is a syndrome characterized by acute respiratory distress following transfusion. All plasma-containing blood products have been implicated including rare reports involving IVIG and cryoprecipitate. It is a rare complication of allogeneic blood transfusion but the incidence has not been well established due to difficulty in defining the syndrome and variable reporting mechanisms worldwide. Symptoms of TRALI typically develop during, or within 6 hours of a transfusion. Patients present with the rapid onset of dyspnoea and tachypnoea. There may be associated fever, cyanosis and hypotension. Clinical exam reveals respiratory distress and pulmonary crackles may be present with no signs of congestive heart failure or volume overload. Chest X-ray (CXR) shows evidence of bilateral pulmonary oedema unassociated with heart failure (non-cardiogenic pulmonary oedema), with bilateral patchy infiltrates, which may rapidly progress to complete ‘white out’ indistinguishable from acute respiratory distress syndrome. The central venous pressure is normal, which helps distinguish the condition from transfusion-associated circulatory overload. Treatment is supportive. There is no role for diuretics or corticosteroids The blood bank needs to be notified as reporting of TRALI allows better understanding of the true incidence of this reaction, in addition to its clinical course and associated mortality

Delayed

Delayed haemolytic transfusion reaction

These reactions occur in patients who have developed antibodies from previous transfusions or pregnancy but, at the time of pretransfusion testing, the antibody in question is too weak to be detected by standard procedures. Subsequent transfusion with red cells having the corresponding antigen results in an anamnestic antibody response and haemolysis of transfused red cells. These delayed reactions are seen generally within 2–10 days after transfusion. Haemolysis is usually extravascular, gradual and less severe than with acute reactions, but rapid haemolysis can occur. A falling haematocrit, slight fever, mild increase in serum unconjugated bilirubin and spherocytosis on the blood smear may be noted.

Treatment of a delayed haemolytic transfusion reaction is usually not required unless anaemia is severe enough to require treatment. However, future transfusions containing the implicated red cell antigen need to be avoided. Alternatives to transfusion should be explored whenever possible.

Red cell alloimmunization

When antibodies are formed against foreign antigens from one’s own species, the process is termed alloimmunization and the antibodies are called alloantibodies (as opposed to forming autoantibodies to one’s own antigens or forming xenoantibodies to antigens from a foreign species). Transfused (non-leucocyte depleted) red cells and platelets contain leucocytes to which antibodies can be made. This may cause patients to become resistant to subsequent platelet transfusions. Approximately 50% of patients undergoing multiple blood transfusions become alloimmunized and are refractory to further platelet transfusions. Refractory patients require platelets matched to their specific platelet/human leucocyte antigen (HLA) type. Patients receiving leucocyte reduced blood products are at a much lower risk for refractoriness to platelet transfusion than are recipients of non-leucocyte reduced blood products. Although debate exists about its merits, for selected high-risk patients with transfusion-dependent diseases (e.g. sickle cell anaemia, thalassaemia, etc.), some transfusion services phenotype patients and provide phenotypically matched donor RBC, even to those patients without alloantibodies (i.e. to prevent the formation of antibodies). There is general agreement that this is useful for Rhesus and Kell blood group antigens in these groups of patients, but debate exists about its merits for more extensive phenotyping.

Transfusion-associated graft-versus-host disease (TA-GVHD)

Transfusion-associated graft-versus-host disease results from transfusion of viable T lymphocytes which proliferate and damage the recipient’s tissue, particularly skin, gastrointestinal tract, liver, spleen and bone marrow. This is a rare and almost always fatal complication of transfusion. Clinical manifestations typically develop 10–14 days following transfusion and consist of fever, erythematous skin rash, pancytopaenia, diarrhoea and abnormal liver function. High-risk patients for this complication include bone marrow transplant recipients, patients receiving granulocyte transfusions, transfusions from a biologically related donor (directed donation), the fetus (intrauterine transfusion), exchange transfusion, patients with Hodgkin lymphoma and patients with congenital cellular immune deficiency.

The investigation begins with the confirmation of the presence of GVHD. This is a pathological diagnosis requiring a skin or intestinal biopsy. Currently, the only method of preventing TA-GVHD is to gamma irradiate cellular components at risk of causing TA-GVHD or destined for at-risk recipients. Current techniques to leucoreduce cellular blood components are not adequate to prevent TA-GVHD

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).

Hypothermia

Red blood cells are stored at 4°C. Rapid infusion of large volumes of stored blood can contribute to hypothermia. Blood warmers should be used during massive blood transfusion. In addition, other intravenous fluids should be warmed and other measures instituted to maintain patient body temperature (see Chapter 28.2).

Dilutional coagulopathies

Clinically significant depletion of coagulation proteins and platelets is a complication of massive transfusion, secondary to dilution and the consumptive coagulopathy of trauma. Stored red cells are deficient in platelets and clotting factors and transfusion of large amounts can complicate bleeding when not accompanied by assessment and correction of coagulation disturbances. Coagulation parameters including the prothrobin time (PT), activated partial thromboplastin time (APTT), platelet count and fibrinogen level should be monitored and corrected if deficiencies occur in the presence of abnormal bleeding. In actively bleeding patients, however, these parameters may not provide an accurate estimate of clot strength and results are often delayed by 30–60 minutes. Thromboelastography has the advantage of providing real-time assessment of clot strength and should be utilized where available.

Volume overload

This complication occurs when excessive volume of fluid is administered. Pulmonary oedema is a particular risk in the elderly, in infants and in patients with chronic severe anaemia where the red cell mass is decreased but the blood volume is normal. Abdominal compartment syndrome may result in bowel ischaemia and should be watched for.

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, hyperkalaemia 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 leucocyte reduction, irradiation, plasma depletion and the use of platelet additive solutions.

Platelets are transfused to prevent or treat haemorrhage in patients with thrombocytopaenia or defects in platelet function. Specific indications for platelet transfusion are shown in Table 13.5.3. Use of platelets is not generally considered appropriate in the treatment of immune-mediated platelet destruction, thrombotic thrombocytopaenic purpura, haemolytic uraemic syndrome or drug-induced or cardiac bypass thrombocytopaenia without haemorrhage.

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 to 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 4 units, which is equivalent to 1 unit of apheresis platelets or 1 unit of pooled platelets.

Fresh frozen plasma

FFP is prepared from anticoagulated blood by separating the plasma from the blood cells through centrifugation of whole blood or apheresis. It is stored frozen until used. It contains all coagulation factors including small amounts of Factor V and approximately 200 units of Factor VIII. Fresh frozen plasma can be stored at below−25 °C for up to 12 months. Indications for use of FFP are shown in Table 13.5.3.

The appropriate dose depends on the clinical indication, patient size and results of laboratory tests. A general guide is 10–15 mL/kg per dose but, in some situations, dosages greater than this may be required (e.g. dilutional coagulopathy in the context of massive transfusion). On average 1 mL of FFP/kg patient weight will raise most coagulation factors by 1%, therefore a dose of 10–15 mL/kg would be expected to increase levels by 10–15%. Compatibility testing is not required, however, ABO compatible plasma should be used wherever possible. Group AB plasma can be used for all patients in an emergency.

Cryoprecipitate

Cryoprecipitate is prepared by thawing FFP to between 1 and 6°C and recovering the precipitable protein fraction. It contains most of the Factor VIII, fibrinogen, Factor XIII, von Willebrand factor and fibronectin from the FFP. It may be stored for up to 12 months at−25°C or below. Once thawed it must be used immediately or stored at 2–6°C for up to 24 h. Cryoprecipitate is indicated in fibrinogen deficiency with clinical bleeding or prior to an invasive procedure and in DIC. Cryoprecipitate is transfused to keep fibrinogen levels above 1.0 g/L in the acutely bleeding patient. Compatibility tests before transfusion are not necessary. It is preferable to use an ABO group compatible with the recipient’s red cells, however, ABO incompatible can be used with caution. Up to 4 units/10 kg body weight may be required to raise the fibrinogen concentration by approximately 0.5 g/L in the absence of continued haemorrhage.

The use of cryoprecipitate is not generally considered appropriate in the treatment of haemophilia, von Willebrand’s disease or deficiencies of Factor XIII or fibronectin, unless alternative therapies are unavailable.

Refusal of blood and blood product transfusion

Patients with certain religious beliefs may refuse blood and blood product transfusion, e.g. Jehovah’s witnesses. Healthy volunteers can tolerate Hb levels of 50 g/L without evidence of end-organ hypoxia. However, it is estimated that the median Hb concentration associated with mortality is about 25 g/L. The patient’s wishes must be rigorously protected and blood products avoided. Several strategies may be used to manage the anaemia. Sedation should be instituted to minimize metabolic demand. A ventilation cycle of 2 hours of 90% FiO₂, followed by 2 hours of 90% SpO₂ and then 20 hours of 95% SpO₂ may be employed to maximize oxygen delivery while minimizing shunt from absorption atelectasis and to promote erythropoiesis. Recombinant erythropoietin (36 000 units daily), folic acid (5 mg daily), vitamin B12 (1 mg daily) and iron infusions are options to maximize haematopoiesis. In female patients, where applicable, menses should be inhibited with progesterone. Blood testing should be rationalized and performed using paediatric-sized samples.

A few case studies on the use of synthetic haemoglobin have been published. HBOC-201 is the commonest product used and is a modified lactated Ringer’s solution containing 130 g/L of polymerized Hb of bovine origin. It is compatible with all blood types, stable for 3 years when stored at 2–30°C and stable for 2 years when stored at 40°C. When fully saturated, HBOC-201 has the same oxygen-carrying capacity as whole blood with the same Hb concentration. The partial pressure of oxygen at which HBOC-201 is 50% saturated (40 mmHg) is higher than that for cellular Hb (27 mmHg), which facilitates oxygen delivery to tissues. The half-life of HBOC-201 is approximately 20 hours. Polymerization of the Hb reduces its glomerular diffusion and nephrotoxicity. The use of synthetic haemoglobin remains experimental at this stage and outcomes of further trials currently underway aim to determine the efficacy and safety profile of such products.