7 Haematological disease
Approach to the patient
Clinical features
• Symptoms are usually non-specific and vary with the speed of onset and severity of the anaemia. If the Hb falls slowly, symptoms are minimal, as there is time for haemodynamic compensation. Severe anaemia (e.g. < 8 g/dL) causes tiredness, light-headedness and dyspnoea; angina and intermittent claudication occur in those with atheromatous disease. If of sudden onset, anaemia with hypovolaemia causes syncope, tachycardia and visual impairment due to anoxia.
Investigations
• Blood count and blood film. The haemoglobin and mean corpuscular volume (MCV) help define the type of anaemia (Fig. 7.1). The red blood cell distribution width (RDW) is the ratio of the width of the red cell divided by the MCV, and is useful in the differential diagnosis of microcytosis but not macrocytosis. In a patient with microcytic anaemia, a raised RDW would favour iron deficiency and a normal RDW favours thalassaemia. The white blood cell count and platelet count can also be useful in the differential diagnosis. The blood film shows the red cell morphology (anisocytosis = variation in size; poikilocytosis = variation in shape). The reticulocyte count reflects marrow red cell activity; a high count would be expected following haemorrhage or haemolysis and during the response to treatment with haematinics. A low reticulocyte count occurs with bone marrow failure and with deficiency of haematinics.
• Additional tests. Other tests may be necessary to confirm the diagnosis, e.g. ferritin, iron studies, serum B12, red cell folate, Hb electrophoresis, glucose-6-phosphate dehydrogenase (G6PD) levels.
• Bone marrow sampling. This is not necessary for simple haematinic deficiencies, but can be useful for assessing iron stores and erythropoiesis. A bone marrow examination is indicated if bone marrow failure (e.g. myelodysplasia, aplastic anaemia, acute leukaemia) or infiltration is suspected from the blood count and blood film.
Microcytic anaemias
Iron deficiency anaemia
Investigations
• Blood count. The red cells are microcytic (MCV < 80 fL) and hypochromic (mean cell haemoglobin (MCH) < 27 pg).
• Iron studies. A low serum ferritin (typical reference range in men 11.6–144 nmol/L (30–300 mcg/L) and women 5.8–96 nmol/L (15–200 mcg/L)) is diagnostic in uncomplicated iron deficiency, but because it is an acute-phase protein, a normal or even high serum ferritin does not exclude the diagnosis. Serum iron is usually low, and total iron binding capacity (TIBC) increased (these markers are less reliable indicators of iron stores). Serum soluble transferrin receptors are also increased.
• Bone marrow examination. This is not indicated unless other tests are unhelpful (e.g. normal/high ferritin in patients with inflammation) or coexisting causes of anaemia are suspected. Staining a bone marrow aspirate with Perls’ reagent will demonstrate absence of iron stores.
• Other investigations. Investigations of the gastrointestinal tract (p. 153) for sources of bleeding or occult malignancy, or a gynaecological referral for menorrhagia may be appropriate, as directed by the history and examination.
Management
• Oral iron. Ferrous sulphate 200 mg 3 times daily (180 mg ferrous iron in total) is best administered on an empty stomach before meals. An increase in Hb of 1 g/dL per week is usual and a rise in the reticulocyte count is seen in 7 days. Absorption is relatively inefficient, but improved by taking iron supplements with a source of ascorbic acid (e.g. fresh orange juice).
• Side-effects are very common and include nausea, abdominal cramping, diarrhoea or constipation; therefore compliance can be a problem. Side-effects may be ameliorated by reducing the frequency or taking the iron with food.
• Ferrous gluconate 300 mg twice daily can be prescribed as an alternative to ferrous sulphate, with fewer side-effects but a slower response (contains less elemental iron, 70 mg/day).
• Parenteral iron. This should only be considered if oral therapy fails because of iron intolerance, in patients with severe malabsorption, or if rapid replenishment of iron stores is required, e.g. in pregnancy. Although replenishment of stores occurs more rapidly than with oral iron, the Hb level increases at the same rate. Iron sucrose (IV) and iron dextran (IV or IM) are the preparations available. The dose depends on iron deficit and body weight (consult product literature).
• Anaphylaxis. N.B. Anaphylaxis (See Ch 20, p. 706) may occur with parenteral iron, so a small test dose should be given 1 hour before infusion. Facilities for cardiopulmonary resuscitation, including adrenaline (epinephrine), must be available.
The thalassaemias
α-Thalassaemia
α-Thalassaemia is caused by deletions or mutations in one or more of the four α-globin genes (two genes on each copy of chromosome 16), leading to an excess of β-globin chains. Deletion of one gene results in silent α-thalassaemia, which is of no clinical significance and the blood picture is usually normal. Deletion of two genes results in α-thalassaemia trait (microcytosis with or without mild anaemia but with normal serum iron and ferritin). Haemoglobin H (HbH) disease is caused by a deletion of three α-globin genes, and is characterized by a moderate haemolytic anaemia (Hb 7–10 g/dL) and splenomegaly. Regular transfusion is rarely required, but increased haemolysis may occur with oxidant drugs, as in G6PD deficiency (p. 216), and folic acid should be administered throughout pregnancy. If all four α-globin genes are deleted (Hb Barts), there is a complete absence of normal Hb production, which is incompatible with life outside the uterus (hydrops fetalis).
• Diagnosis is by α–globin gene analysis if required (e.g. pre-pregnancy genetic counselling), as Hb analysis by high-performance liquid chromatography (HPLC) or electrophoresis is normal.
β-Thalassaemia
• Thalassaemia minor (trait). This is the asymptomatic heterozygous carrier state, associated with a mild hypochromic microcytic anaemia with a low MCV and MCH; it may be confused with iron deficiency but the RDW is normal. Iron stores are normal and iron should not be given.
• Thalassaemia intermedia. Thalassaemia intermedia is associated with moderate anaemia (Hb 7–10 g/dL) but patients are rarely transfusion-dependent. They may have splenomegaly, bone deformities and leg ulcers.
• Thalassaemia major. In thalassaemia major, both β-globin genes are severely dysfunctional, with extramedullary haematopoiesis leading to hepatosplenomegaly and bone expansion; the latter produces the classical thalassaemia facies. Disease presents in early infancy and results in severe transfusion-dependent anaemia.
• Management of thalassaemia major
• Red cell transfusion is required every 2–4 weeks in order to suppress ineffective erythropoiesis and encourage normal growth and development throughout childhood. A ‘trigger’ Hb concentration of around 9.5 g/dL is adequate, and lowers the rate of transfusional iron overload (transfusion haemosiderosis) associated with older ‘hypertransfusion’ regimens.
• Iron chelation therapy is essential in order to reduce damage to endocrine glands, liver, pancreas and myocardium caused by transfusion haemosiderosis.
a) Desferrioxamine 20–50 mg/kg is administered by SC infusion over 8–12 hours on 3–7 nights per week, to chelate excess iron for excretion in the urine and faeces. Compliance is often a problem, especially in younger patients, so alternatively up to 2 g desferrioxamine can be administered intravenously alongside each unit of blood transfused (through a different IV line but using the same cannula). Local reactions occur and can be ameliorated by 2 mg of hydrocortisone added to the infusion bag. Ascorbic acid 200 mg daily increases the urinary excretion of iron in response to desferrioxamine, but should not be taken with food as it also increases iron absorption. Complications of long-term desferrioxamine therapy include cataracts, retinal damage, nerve deafness and infections, e.g. with Yersinia enterocolitica. The efficacy of iron chelation therapy should be periodically assessed by measurement of serum ferritin and hepatic iron stores. Visual acuity and hearing checks must be performed before long-term treatment and at 3-month intervals. Warn patients that desferrioxamine can turn their urine brown.
b) Deferasirox (10–30 mg/kg daily) and deferiprone (25 mg/kg 3 times daily) are oral iron-chelating agents for use in patients with thalassaemia major who are unable to tolerate desferrioxamine. These oral agents are well tolerated, if taken dissolved in water or juice. They should be avoided in pregnancy; deferiprone is contraindicated, as it is teratogenic, and women of childbearing age should be advised to use appropriate contraception. There have also been reports of drug-induced neutropenia and hepatic damage with deferiprone, so it is not recommended as first-line therapy.
• Long-term folic acid supplementation is needed, as with all chronic haemolytic conditions (5 mg orally per day).
• Splenectomy is indicated in patients over the age of 6 years if transfusion requirements are increasing (there is an unacceptably high risk of sepsis associated with splenectomy in the under-6 age group). The spleen is the primary site of extravascular haemolysis. For post-splenectomy care, see Box 7.1.
• Stem-cell transplantation (SCT) is an option for young patients with an HLA-matched sibling donor, but the mortality increases significantly with age due to iron overload and hepatic dysfunction, and increasing alloimmunization by multiple transfusions (increasing the risk of graft rejection).
Anaemia of chronic disease
A normochromic normocytic anaemia commonly occurs in association with chronic inflammatory and infective conditions (e.g. rheumatoid arthritis, malignancy, TB). The exact pathogenesis is complicated and contributing factors include a cytokine-mediated failure of iron utilization during erythropoiesis and high levels of hepcidin, which destroy ferroportin, limiting iron absorption in the intestinal cell. Red cell survival is decreased and there is an inappropriately low erythropoietin response for the level of anaemia. The MCV can be normal, or low in longstanding disease (resembling iron deficiency). The serum ferritin is usually normal or raised because of the inflammatory process. Iron is present in the bone marrow but not in developing erythroblasts.
Treatment
Address the underlying disorder, e.g. treat infection with antibiotics. Red cell transfusions may be necessary for symptomatic anaemia. Patients do not respond to oral iron, but coexisting iron deficiency should be identified and treated with parenteral iron (p. 202). Recombinant erythropoietin therapy at relatively high doses, e.g. 150–300 U/kg SC three times per week, is used, e.g. in rheumatoid arthritis, or intravenously in chronic kidney disease. Pegylated (PEG) erythropoietin is an alternative, administered once every 2 weeks.
Macrocytic anaemias
Megaloblastic anaemia
Impaired DNA synthesis results in morphological abnormalities of blood cell precursors, characterized by delayed nuclear maturation (nuclear-cytoplasmic asynchrony). All haematopoietic cell lines (and other rapidly dividing cells) are affected, and in severe cases there may be pancytopenia (i.e. anaemia, leucopenia and thrombocytopenia). Causes are predominantly those leading to B12 and folate deficiencies, although drugs (azathioprine, hydroxycarbamide, zidovudine), myelodysplasia and rare enzyme deficiencies affecting DNA synthesis (e.g. orotic aciduria) can also cause macrocytosis and anaemia.
• Folic acid deficiency develops over a few months, whereas B12 deficiency takes years to develop as B12 is stored in the liver. Folate deficiency is due to poor intake (elderly, excess alcohol use); increased utilization (pregnancy, haemolytic anaemia); malabsorption (e.g. coeliac disease); and drug therapy (anticonvulsants, trimethoprim, oral contraceptives, methotrexate, sulfasalazine, pyrimethamine), which can interfere with folate metabolism.
• Vitamin B12 deficiency can be caused by failure of intrinsic factor production in the stomach (pernicious anaemia, post-gastrectomy); malabsorption (pancreatic insufficiency, bacterial overgrowth); ileal lesions leading to B12 malabsorption (ileitis, e.g. inflammatory bowel disease); terminal ileal resection; and fish tapeworm (e.g. Diphyllobothrium latum). Vegans do not consume animal products and can become B12-deficient, but will respond to oral B12 supplementation.
Investigations
• Blood count. This shows a macrocytic anaemia with anisocytosis, poikilocytosis and hypersegmented neutrophils (Fig. 7.3). Leucopenia and thrombocytopenia occur.
• Serum B12 and red cell folate. Samples must be taken before commencement of treatment. Red cell folate is a more accurate assessment of body stores than serum folate (which reflects recent intake).
• Other investigations
• Serum intrinsic factor auto-antibodies are specific for pernicious anaemia but found in only 50% of cases. Parietal cell antibodies are less specific but are present in 90%. Serum methylmalonic acid (MMA) and homocysteine (HC) are raised in B12 deficiency. HC alone is raised in folate deficiency. Bone marrow biopsy is occasionally indicated to differentiate from myelodysplasia or malignancy, e.g. chronic myeloid leukaemia (CML).
• Gastrointestinal investigations to exclude coeliac disease (p. 154), and imaging studies for inflammatory bowel disease (p. 157). Endoscopy is performed if there are gastric symptoms. The Schilling test to investigate B12 absorption is no longer routinely available.
Treatment
• Vitamin B12 deficiency. IM hydroxocobalamin 1 mg every 3–4 days is administered to a total dose of 5–6 mg. Thereafter, maintenance treatment with 1 mg IM every 3 months is usually necessary for life. A clinical improvement may be seen within 48 hours, and a peak reticulocytosis at 5–7 days. Hypokalaemia and iron deficiency can occur with the commencement of treatment and serum potassium should be checked. Oral vitamin B12 is absorbed by passive diffusion (1–2%) in the absence of intrinsic factor, so a 2 mg daily dose may be sufficient maintenance therapy for selected compliant patients.
• Folate deficiency. Oral folic acid 5 mg daily for at least 4 months is necessary to replenish stores in patients with folic acid deficiency. In pregnancy, all women are advised to take 400 mcg folic acid daily from at least 3 months prior to conception until the end of the first trimester, except where overt folic acid deficiency has been demonstrated (full-dose treatment required). N.B. Unless the serum B12 level is known to be normal, patients with megaloblastic anaemia should never receive folic acid replacement alone (risk of precipitating subacute combined degeneration of the spinal cord).
Aplastic anaemia
Treatment
• Supportive care. This is the mainstay of therapy whilst awaiting bone marrow recovery (including stringent measures to prevent infection). Rapid treatment of infection with broad-spectrum parenteral antibiotics is essential, as for neutropenic patients (p. 261). Red cell transfusion and platelets should be kept to a minimum (p. 231, platelet transfusion thresholds) if SCT is being considered, as alloimmunization by donor blood products increases the risk of graft rejection.
• SCT. This is the treatment of choice for young patients with severe disease (characterized by the presence of two or more of the following: neutrophils < 0.5 × 109/L, platelets < 20 × 109/L, reticulocytes < 40 × 109/L) and an HLA-identical sibling donor. For eligible patients (< 40 years of age), the search for a donor should begin as soon as the diagnosis has been made. Long-term survival and recovery of blood count to normal occurs in 75–90% of patients who have a sibling donor. Results with SCT from an unrelated donor are less favourable (5-year survival of 30%) due to a high incidence of graft versus host disease (GVHD), viral infection (e.g. cytomegalovirus reactivation) and graft rejection. Therefore, unrelated donor-SCT is often reserved for patients who do not respond to immunosuppressive therapy.
• Immunosuppressive therapy. A combination of antithymocyte globulin (ATG) and ciclosporin produces a response in 60–80% of patients, although there is a high relapse rate and risk of development of other clonal haematopoietic disorders. With treatment the 5-year survival is ~75%. Rabbit ATG (3.75 mg/kg/day for 5 days) is administered as an IV infusion into a central vein over 12–18 hours. Horse ATG was first-line therapy until recently but is no longer available. Profound immunosuppression and anaphylaxis can occur (a test dose is recommended before starting therapy). Corticosteroids have little activity in aplastic anaemia, but prednisolone is used to prevent serum sickness in patients receiving ATG (methylprednisolone 2 mg/kg/day given IV as a 30-min infusion before each ATG infusion, then oral prednisolone 1 mg/kg/day for 9 days from day 6 of therapy, tailed off over 5 days). Ciclosporin 5 mg/kg/day in a divided dose is commenced on the first day of ATG therapy (to maintain a trough blood level of 150–250 mcg/L for adults, 100–150 mcg/L for children). The dose of ciclosporin may need to be reduced if itraconazole is used for antifungal prophylaxis. Immunosuppressive therapy for aplastic anaemia should only be given under specialist supervision, and is contraindicated in the presence of active infection or uncontrolled bleeding.
• Androgenic steroids. Oxymetholone (1–5 mg/kg/day for 3–6 months) is sometimes effective in patients not responding to immunosuppression. Side-effects include hepatotoxicity and virilization.
Myelodysplastic syndromes
Investigations
• Bone marrow histology is often hypercellular, despite cytopenias in the peripheral blood, but with gross morphological abnormalities. Ringed sideroblasts may be present (abnormal iron distribution in developing erythroblasts on Perls’ stain). A high proportion of blast cells (> 5%) is associated with a poor prognosis. Bone marrow chromosomal analysis (cytogenetics) may show clonal abnormalities, which confirm the diagnosis and provide valuable prognostic information.
Treatment
• Red-cell transfusions as required are used to treat symptomatic anaemia. Iron chelation with SC desferrioxamine or oral therapy (p. 204) should be considered once 25 U red cells (~5 g iron) have been transfused. Vitamin C 100–200 mg/day orally can be added after 1 month of therapy. Neutropenic sepsis requires urgent broad-spectrum IV antibiotics (p. 261). For thrombocytopenia, platelet transfusions are given to maintain a platelet count > 10 × 109/L, or higher in patients with active bleeding.
• Erythropoietin (EPO) ± granulocyte-colony stimulating factor (G-CSF) may reduce or eliminate the need for red cell transfusion in some patients with MDS. Low-dose G-CSF may be appropriate in patients with severe chronic neutropenia, to maintain a neutrophil count of > 1 × 109/L (dose depends on product — refer to product literature).
• Immunosuppression with antilymphocyte globulin (ALG) as for aplastic anaemia can produce a sustained neutrophil and platelet response in hypoplastic MDS.
• 5-azacytidine 75 mg/m2 SC for 7 days of a 28-day cycle, for 4–6 cycles, is an epigenetic therapy (hypomethylating agent) currently under scrutiny in clinical trials. Overall response rates of up to 47% have been seen in some subtypes of MDS, with a tendency towards increased overall survival.
• Lenalidomide (a thalidomide analogue) 10 mg daily for 21 days of a 28-day cycle is useful in the 5q- syndrome. N.B. Contraindicated in pregnancy; appropriate contraception must be advised. Neutropenia, thrombocytopenia and thromboembolism are all complications.
• Intensive chemotherapy regimes, as for AML (p. 284), are sometimes used for younger patients with high-risk MDS and good performance status. However, unless followed by an SCT procedure, there is little or no benefit in terms of overall survival for most patients.
• SCT offers the best chance of long-term remission in patients < 50 years with intermediate- or high-risk MDS, especially if an HLA-identical sibling donor is available. Matched unrelated donor SCT is associated with a high transplant-related mortality and is usually reserved for otherwise healthy intermediate-/high-risk patients under the age of 40, but the age limit is increasing with the introduction of reduced-intensity conditioning (RIC) protocols (p. 264).
Haemolytic anaemias
• Extravascular haemolysis occurs when red cells are phagocytosed and destroyed by macrophages in the reticuloendothelial system (mainly spleen and liver). A proportion of red cells are not completely destroyed and are released back into the circulation as spherocytes.
• Intravascular haemolysis occurs when red cells are lysed and release free Hb directly into the circulation. Most of the free Hb binds to plasma haptoglobins or is excreted in the urine, but some is deposited inside renal tubular cells as haemosiderin. This leads to raised levels of plasma haemoglobin, haemosiderinuria, very low or absent haptoglobulins and the formation of methaemalbumin (positive Schumm’s test). Clinical features include fever and backache; renal failure can occur, depending on the aetiology.
Inherited haemolytic anaemias
Hereditary spherocytosis
Hereditary spherocytosis (HS) is the commonest inherited cause of chronic haemolytic anaemia in Northern Europeans (1 in 5000 births). Inheritance is usually autosomal dominant but 25% of cases are due to spontaneous mutations. The red cells are poorly deformable due to abnormalities in the red cell cytoskeleton, so they become trapped in splenic sinusoids where they are destroyed. HS can present at any age (neonatal jaundice is common) and the clinical features are highly variable. Many patients are asymptomatic but features of chronic compensated haemolysis may be present, e.g. pigment gallstones, mild jaundice and splenomegaly. Aplastic crises sometimes occur after viral infections, e.g. erythrovirus B19. Investigations show anaemia and spherocytes on blood film, with evidence of haemolysis (see above).
• Treatment
• Splenectomy removes the major site of red cell destruction and corrects the anaemia in patients with moderate to severe disease, but should be avoided until after 6 years of age because of the increased risk of overwhelming infection (Box 7.1, p. 205). Mildly affected patients may only require supportive treatment, but splenectomy is usually necessary in patients with hyperbilirubinaemia or symptomatic cholelithiasis.
• Oral folic acid 5 mg daily is recommended for adults with moderate and severe HS to correct losses incurred by increased bone marrow turnover.
Sickle cell anaemia (HbSS)
Investigations
(See also demonstration of haemolysis, Fig. 7.4).
• Blood count and blood film (Fig. 7.5). Anaemia (Hb 6–8 g/dL) with normal MCV and MCH (unless coexisting thalassaemia), sickle cells, target cells and polychromasia (due to reticulocytosis). Adult patients will also have features of hyposplenism (basophilic stippling, Howell–Jolly bodies, Pappenheimer bodies).
• Sickle solubility test. Positive in the presence of HbS, but does not distinguish between sickle cell trait and sickle cell disease. Rapid screening solubility tests are available.
• Hb electrophoresis. Required for confirmation of the diagnosis, and in homozygous sickle cell anaemia shows 80–95% HbS, with 2–20% fetal Hb (HbF). Normal Hb (HbA) is absent. Parents of an affected child will have features of sickle cell trait.
Clinical syndromes and management
• General management. Patients should be advised to seek urgent treatment for infections, and to minimize other factors that may precipitate a crisis where possible, such as dehydration, hypoxia and acidosis (e.g. from vigorous physical exercise) or exposure to cold temperatures. Multiple splenic infarctions over time result in autosplenectomy; therefore all patients should receive appropriate antibiotic prophylaxis and vaccination (Box 7.1, p. 205).
• Preventive therapy includes hydroxycarbamide (hydroxyurea), which reduces the frequency of painful crises and acute chest syndrome, and the need for blood transfusions (and iron chelation, p. 204) in adults with sickle cell disease. It increases the concentration of fetal Hb (HbF), which protects against sickling. The usual dose is 20–30 mg/kg/day orally. Long-term safety data suggest that there is a low incidence of secondary malignancy with prolonged use. Hydroxycarbamide is contraindicated during pregnancy and breast feeding, and should be avoided in both female and male patients who are trying to conceive. In an acute crisis, hydroxycarbamide must be stopped if platelets are < 100 × 109/L, neutrophils < 1 × 109/L or reticulocytes < 100 × 109/L.
• Anaemia. Chronic haemolysis results in a steady state Hb of 6–8 g/dL, but symptoms of anaemia are mild because HbS releases oxygen to tissues more readily than normal Hb. Increased haemolysis can occur with certain drugs, acute infection and associated G6PD deficiency. Anaemia can also result from folate deficiency. A sudden drop in Hb is suggestive of aplastic or sequestration crisis (see below). Transfusion is not indicated for steady state anaemia, but if it is necessary a full antibody screen should be performed, and blood should be fully matched for Rh (C, D and E) and Kell antigens to reduce the risk of alloimmunization.
• Vaso-occlusive crises. Episodes of acute severe pain and fever due to bone marrow infarction and inflammation can present with variable frequency in patients with sickle cell disease. Dactylitis (painful swollen hands and feet) is common in young children, whereas severe pain in long bones, vertebrae, ribs and pelvis occurs in older children and adults.
• Analgesia
– Antiemetics, e.g. cyclizine 50 mg 3 times daily should always be given with these analgesics. Inhaled nitrous oxide/oxygen (50/50) is sometimes useful for initial pain control but should not be used for more than 60 mins at a time. Pethidine should not routinely be prescribed because the duration of the analgesic effect is much shorter than with morphine and there are concerns over safety (CNS and renal toxicity). With opioid analgesia, pain, respiratory rate and level of sedation should be monitored every 30 mins until the pain is controlled and every 2 hours thereafter. The dose should be reduced gradually (every 2–3 days) and replaced with oral analgesia as necessary. Regular laxatives should always be prescribed with opioids.
– Adjunctive oral analgesics, e.g. codeine, paracetamol or NSAIDs, are effective and can be used alone for less severe pain, which is often managed in the community.
• Supportive therapy. This includes IV fluids and bed rest. If infection is suspected, empirical antibiotic therapy (e.g. a cephalosporin) should be started pending the results of blood, urine and sputum cultures. There is an increased risk of venous thromboembolic disease in patients with sickle cell disease, so prophylaxis with a low-molecular-weight heparin (LMWH, p. 243) should be given during an acute crisis. Blood transfusion is not indicated in uncomplicated crises.
• Acute chest syndrome (Box 7.2)
• This is a major cause of sudden death among patients with sickle cell disease. Chest pain, dyspnoea, fever, hypoxia and evidence of consolidation on physical and radiological examination are highly suggestive of chest crisis.
• Precipitating causes include infection (e.g. Streptococcus pneumoniae, Mycoplasma, Chlamydia), pulmonary infarction and fat embolization from necrotic bone marrow.
Box 7.2
(Adapted from Rees DC et al. 2003.)
Management of acute painful crisis in opioid-naïve adults with sickle cell disease. Higher doses may be required for patients who have previously received opioids.
• Management of acute chest crises
• High-flow supplemental oxygen, analgesia and antibiotics — a broad-spectrum cephalosporin such as cefotaxime 1 g 12-hourly, and a macrolide such as clarithromycin 500 mg twice daily — should be commenced without delay.
• Continuous positive airway pressure (CPAP) ventilation may be beneficial, but transfer to ICU for ventilation should be arranged if the PO2 on air cannot be maintained above 8 κP (approx < 60 mmHg) with FiO2 > 0.6.
• Sequestration crisis. Vaso-occlusion and pooling of red cells within splenic sinusoids and liver can lead to sudden severe anaemia, hypovolaemia and death. It is commonest in children before autosplenectomy occurs, but may present in adults with composite heterozygous conditions (e.g. HbSC disease) where the spleen is still functional. Emergency blood transfusion and haemodynamic support are required, and splenectomy may be needed for recurrent episodes.
• Aplastic crisis. Viral infections (usually erythrovirus B19) can trigger a sudden decrease in marrow production of blood cells. Bone marrow function usually recovers spontaneously within 1–2 weeks, but transfusional support is required in the interim.
• Cerebral vascular event (stroke). This is a relatively common occurrence in children under the age of 10 years and adults over 30. Yearly Doppler ultrasound is performed to look for significant arterial stenosis. Emergency exchange transfusion is indicated for acute stroke and the patient should be regularly transfused to maintain an HbS concentration of < 30% for at least 3 years; this reduces the incidence of recurrence. One-third of strokes are due to haemorrhage and this has a high mortality.
• Priapism. A persistent and painful penile erection due to vaso-occlusion occurs in over half of male patients at some time, and can lead to erectile dysfunction if left untreated for > 24 hours. Urgent referral to a urologist is necessary, and treatment options include exchange transfusion and surgical decompression.
• Infections. Hyposplenism and vaso-occlusion predispose patients to infection with organisms such as Salmonella, Staphylococcus aureus and Strep. pneumoniae. Osteomyelitis, pyelonephritis and pneumonia are common and should be treated with appropriate antibiotics.
• Preparation for surgery. Repeated transfusions over several weeks to reduce the proportion of circulating HbS to < 20% should prevent sickling for elective procedures. Exchange transfusion may be necessary before emergency surgery.
• Pregnancy. Painful episodes, infection and severe anaemia in the mother are more common, particularly in the third trimester, and are managed as for non-pregnant patients. Regular transfusion to reduce the proportion of circulating HbS to < 20% is occasionally necessary. Pre-eclampsia, spontaneous abortion and intrauterine growth retardation also occur more frequently in patients with sickle cell disease, but prophylactic transfusion does not improve fetal outcome.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Clinical and laboratory features
Rapid intravascular haemolysis with symptomatic anaemia, jaundice and haemoglobinuria occurs 1–3 days after ingestion of certain drugs (Box 7.3). Infection can also precipitate haemolysis but the anaemia is usually mild. Favism (severe haemolysis after ingestion of fava beans) occurs with the Mediterranean variant and can be rapidly fatal. Chronic non-spherocytic haemolytic anaemia (in the absence of a precipitating cause) and neonatal jaundice are also seen in some types of G6PD deficiency.
• The blood count and blood film are only abnormal during an acute episode, when ‘bite’ cells and Heinz bodies (on methyl violet staining) may be seen.
• Measurement of G6PD levels (during the steady state between attacks) and DNA analysis will confirm the diagnosis.
