6 Haematology and Oncology
Microcytic and macrocytic anaemia
Assessment
The impact of anaemia on an individual is variable and will depend on:
Symptoms are non-specific and clinical signs easily overlooked:
Investigations
The classification of anaemia (Fig. 6.1) is based on the mean red cell volume (MCV; NR 76–96 fL).
What is the reason for her anaemia and is it relevant to her presentation?
• Very low MCV with only moderate anaemia
• Minimal variation in red cell size (anisocytosis) and shape (poikilocytosis).
• The serum ferritin (30 µg/L) was normal, indicating normal tissue stores of iron (Note: ferritin can be high because it is an acute-phase protein that rises whenever the ESR or CRP is elevated).
The anaemia of chronic disorder, a form of functional iron deficiency, is also unlikely without an obvious underlying illness and a normal ESR.
Remember
• Ferritin is an acute-phase protein. Iron deficiency can therefore be difficult to diagnose in the presence of inflammatory disease and tissue iron stores might need to be examined directly by bone marrow aspiration
• Serum transferrin receptor assay does differentiate between these conditions (see p. 142).
β-thalassaemia trait is confirmed by measuring HBA2, which is normally < 3.4% of total haemoglobin.
Iron deficiency anaemia
Iron deficiency anaemia (Fig. 6.2 and see p. 142) responds to treatment with oral iron supplements – ferrous sulphate 200 mg × 3 daily (or all in one dose) for 6 months – it is essential to give a full course of treatment. Lower the dose if GI symptoms occur. Parenteral therapy is required only rarely. The cause of iron deficiency is almost always blood loss and the cause must be determined.
Provan D. Mechanisms and management of iron deficiency anaemia. British Journal of Haematology. 1999;105(Suppl 1):19–26.
Case history (2)
An 81-year-old woman presents to the A&E department with recent onset congestive cardiac failure.
Make a precise diagnosis by measuring serum vitamin B12, serum and red cell folate:
• In vitamin B12 deficiency the serum vitamin B12 concentration is always reduced; in folate deficiency the red cell folate concentration is always reduced.
• Severe vitamin B12 deficiency can be associated with a low red cell folate and a normal or high serum folate. Vitamin B12 is required to polyglutamate folate, without which folic acid cannot be retained within cells.
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Causes
• Folate deficiency? Nutritional deficiency is almost always a factor in any cause of folate deficiency, whether this is due to increased requirements (e.g. myelofibrosis, haemolysis) or to excess alcohol use. In malabsorption, e.g. coeliac disease, there is also poor dietary intake of folate.
• B12 deficiency? Most cases of vitamin B12 deficiency are due to malabsorption, either gastric (because of intrinsic factor deficiency) or intestinal (due to small bowel disease). Pernicious anaemia (antibodies against intrinsic factor) is the most common cause.
Additional investigations
• Intrinsic factor antibody assay (positive in 50% of patients with pernicious anaemia).
• Anti-tissue transglutaminase antibodies and/or jejunal biopsy (to exclude coeliac disease).
• Barium meal and follow-through (to exclude small bowel disease, e.g. Crohn’s disease); in a woman of this age only after the other causes have been excluded.
Many patients with moderate vitamin B12 or folate deficiency have a normal haemoglobin with a raised MCV. Vitamin assays should be performed if the clinical picture is suggestive of a deficiency picture.
• Gastrointestinal disease or surgery including glossitis, malabsorption or diarrhoea
• Neurological disease, including visual loss, a peripheral neuropathy or evidence of demyelination
• Psychiatric disorders including dementia, confusion or depression
• Malabsorption or restricted diets, including vegans and those with anorexia nervosa
• Autoimmune endocrine disease
Management
Remember
Never give folate alone because, although it might partially correct the blood abnormalities associated with vitamin B12 deficiency, it will also cause the B12 level to drop even further and might precipitate severe neuropathy.
• Hypokalaemia, which can occasionally develop 1–2 days post therapy
• Reticulocyte count, which starts to increase 2–3 days after treatment and reaches a peak on days 5–7
• The haemoglobin concentration, which often falls further before starting to rise
• Stay calm! Avoid blood transfusion. Failure of the reticulocyte count and haemoglobin to rise in the predicted manner might be due to:
Anaemia due to folic acid deficiency
These patients need 6 months’ treatment with folic acid 5 mg daily after the cause (e.g. coeliac disease, see p. 51) has been defined and treated. Folic acid is, however, ineffective in the treatment of methotrexate toxicity, when folinic acid 15 mg IV daily is given.
Haemolytic anaemia
Haemolytic anaemias are caused by increased destruction of red cells in two sites, intravascular or extravascular.
Case history
A 60-year-old woman presents with a history of feeling tired and exhausted for the last week. She is normally well but is under the care of the haematologists with chronic lymphatic leukaemia (CLL). She knows all about the condition, having been diagnosed 4 years ago. She is not on any treatment but is under regular follow-up.
She has a normocytic anaemia with a raised white cell count and a reticulocytosis.
A normocytic anaemia can be due to:
The patient described is anaemic and jaundiced with splenomegaly, suggesting a haemolytic anaemia. To confirm this you need to demonstrate:
Increased red cell production
Reduced red cell lifespan
• Acholuric jaundice: unconjugated hyperbilirubinaemia, urobilinogen but no bilirubin in the urine.
• Abnormal red cell morphology: this might also indicate the specific cause of the haemolytic anaemia (see below).
• Directly by radioactive isotope studies: reduced survival of 51Cr-labelled autologous red cells (only performed if diagnosis of haemolysis is in doubt).
There are many specific causes of haemolysis. The diagnosis can often be made by review of the blood film. Speak to the haematology medical staff.
Features of haemolysis on blood film
• Spherocytes: autoimmune haemolytic anaemia, hereditary spherocytosis, Clostridium welchii septicaemia, extensive burns
• Red cell fragments: leaking mechanical heart valve, disseminated malignancy
• Sickled cells: sickle-cell anaemia, sickle-cell–HbC disease
• Bitten-out red cells: glucose-6-phosphate dehydrogenase deficiency, unstable haemoglobin, oxidative drug therapy, e.g. Dapsone
Investigations
• Antibody screen and direct anti-globulin test (DAT): in autoimmune haemolytic anaemia autoantibodies to red cell membrane antigens are present in serum and on the red cell surface
• Urinary haemosiderin: positive in chronic intravascular haemolysis such as paroxysmal nocturnal haemoglobinuria (PNH, very rare) and leaking mechanical heart valves
• Flow cytometry with antibodies against CD55 and CD59 antigens for PNH
• Glucose-6-phosphate dehydrogenase assay: common enzyme deficiency in particular ethnic groups (African, Mediterranean, SE Asian)
This patient had a strongly positive direct anti-globulin test (DAT) with anti-IgG (see Fig. 6.13, p. 129). The antibody eluted from her red cells was also present free in her serum and did not have any easily definable antigen specificity. She therefore has autoimmune haemolytic anaemia (AIHA) due to an IgG red cell autoantibody active at 37°C. AIHA can be primary or secondary. This patient is known to have CLL and has lymphadenopathy and a lymphocytosis with small, mature lymphocytes. Her AIHA is secondary to the underlying chronic lymphocytic leukaemia (CLL); 10–15% of patients with CLL develop AIHA.
Management
• Start oral prednisolone 60 mg/day. This usually produces a remission. Corticosteroids reduce the production of antibodies and also destroy antibody coated red cells.
• Blood transfusion is necessary if the haemoglobin continues to fall. Compatibility testing is complex because the autoantibody interferes with the cross-match; the laboratory could carry out autoabsorption studies to exclude additional alloantibodies. Transfuse slowly.
• Refer patient to her Consultant in Haematology to discuss further management.
Sickle-cell disease
Case history
An 18-year-old female of African origin came to A&E with severe pains in her right leg, left hip, chest and back. She was well known to many of the staff as she had attended on many occasions with painful sickle crises. She had been out all night at a club.
The examination should initially be brief until adequate pain control has been achieved.
Investigations
Performed in medical assessment unit (MAU), aimed at assessing the severity of the crisis and determining any treatable cause:
Questions to ask patients presenting with sickle-cell crises
Any precipitating factors?
• Exposure to cold/skin chilling (might apply to this patient)
Treatment of acute painful sickle-cell crises
Analgesia
Morphine/diamorphine
• 0.1 mg/kg IV/SC every 20 minutes until pain controlled, then
• 0.05–0.1 mg/kg IV/SC (or oral morphine) every 2–4 hours
• Patient controlled analgesia (PCA) when pain controlled
• NB Ask patient about previous morphine dosages. Check medical records and discharge summaries. Higher doses may be required in cases who have previously received opioids.
Patient controlled analgesia (PCA) (example for adults > 50 kg)
Diamorphine
When using diamorphine or other parenteral opiates the following parameters must be monitored regularly on an hourly basis:
Adjuvant oral analgesia
Supplementary analgesia may be provided by:
Supportive measures
• Hydration: aim for 3 L per 24 h – orally if possible
• Venous access is often very difficult in these patients; to conserve peripheral veins the repeated insertion of IV lines should be avoided
• IV hydration is indicated if:
• Oxygenation: aim for O2 saturation 95%
• Monitor the haemoglobin concentration daily and transfuse if it falls to 150 g/L. All transfused blood should be matched for minor blood group antigens Kell and Rh (C and e, as well as D antigens). Remember, do not use transfusions in this steady-state anaemia, in an uncomplicated painful episode and for minor surgery.
The acute chest syndrome
Treatment of acute chest syndrome
• Exchange blood transfusion to reduce the amount of HbS to < 20%
• Maintenance of oxygenation: this might include, for example, continuous positive airway pressure (CPAP) via a tight-fitting mask, or intermittent positive pressure ventilation (IPPV)
The majority of patients with a sickle-cell crisis present with severe, acute bone pain secondary to ischaemic bone marrow necrosis. Beware the patient with sickle-cell disease (SCD) who presents unwell but without pain. Such patients might have other, less common, complications of SCD, which can progress very rapidly (Figs 6.3 and 6.4).
Figure 6.3 (a) Osteomyelitis of the humerus in a sickle patient (pre-treatment). Note the elevation of the periosteum at the distal part of the humerus. (b) The same patient showing normal periosteum following treatment.
Figure 6.4 Avascular necrosis of the femoral head in a patient with homozygous sickle-cell disease. There is loss of joint space and distortion of the head of the femur and acetabulum.
Types of sickle-cell disease
Diagnosis in A&E/MAU
Later:
• Haemoglobin electrophoresis (Fig. 6.5) on cellulose acetate membrane (CAM) at an alkaline pH
Typically, the patient will be anaemic with evidence of haemolysis (elevated bilirubin and reticulocyte count). The blood film will show sickled red cells in variable numbers (Fig. 6.6). The sickle solubility test will be positive and CAM electrophoresis or HPLC will confirm the presence of HbS ± HbC or HbD with no HbA (except in HbS/β+ thalassaemia).
Beware
• In HbSC and HbS/β+ thalassaemia the haemoglobin concentration, reticulocyte count and serum bilirubin can be virtually normal.
• The sickle solubility test is a qualitative test only and will be positive in any individual where the amount of HbS is > 10%. This will include both sickle-cell trait and sickle-cell disease.
Elevated haemoglobin (polycythaemia)
Case history (1)
On your medical take you admitted a 70-year-old man with breathlessness, wheeze, fever and cough productive of sputum. As a long-standing smoker he suffers bouts of bronchitis but is otherwise in reasonable health.
Case history (2)
In the next bed a 54-year-old man has been admitted with chest pain and a suspected myocardial infarct. His general health is reasonable but he has developed severe night sweats and has lost 7 kg over the last 3 months. He denies smoking cigarettes and does not have any previous history of chest problems.
These two cases both have elevated Hb, but is their cause the same?
Haemoglobin (in red blood cells) is required for oxygen transport and, like most things, too much Hb has serious consequences and needs appropriate management (Fig. 6.7).
Preliminary management
• Ensure no hyperviscosity symptoms or signs:
• Ensure patient is adequately hydrated.
Having made sure that the patients are stable, the next step is to determine the cause of the high Hb concentration. Before carrying out extensive investigation, it is sensible to contact the haematology team, who will either advise on further tests or take over the patient’s care.
Information
The haematology registrar advises you to arrange some investigative tests.
Investigations
• Repeat FBC (to check the result is correct or that with some oral/IV fluid the Hb has normalised). High haematocrit.
• Biochemistry screen: renal function – is it normal? Uric acid – might be high in some types of polycythaemia.
• Blood film: these patients had elevated platelets and WBC – make sure these are normal peripheral blood cells, with no evidence of leukaemia.
• Presence of JAK 2 mutation (see Remember box).
Remember
Proposed criteria for PV
Modified from proposed revised WHO criteria for polycythaemia vera (PV).
From: Tefferi et al. Blood (2007) 110:1092. American Society of Haematology.
For diagnosis of secondary cases
• Blood gases or pulse oximetry (the latter is painless and quite adequate to exclude hypoxia only).
• CXR: emphysema, other lung pathologies.
• Abdominal ultrasound: is the spleen enlarged? Remember renal and uterine causes of polycythaemia.
• Bone marrow: not diagnostic in isolation but gives additional information.
NB It is now not necessary to do blood viscosity and red cell volume studies.
Classic features of polycythaemia vera (PV)
Elevated white blood cell count
Case history
A 17-year-old boy who has ulcerative colitis was admitted to MAU because he felt unwell with a headache, sore throat and a temperature. He had also developed diarrhoea but there was no blood in the stools. He was not on steroids but was on azathioprine 100 mg daily.
There are many causes of a raised WBC (Table 6.1) and there is overlap with haematological malignancies, many of which present with WBC elevation. As a non-specialist confronted with a patient who has an elevated WBC, the key question is: does this elevation represent a haematological malignancy or is it reflecting some other process?
Table 6.1 Causes of high white blood cell counts
| Patients with haematological malignancies likely to have high WBC | Situations in which a reactive high WBC occurs |
|---|---|
| Acute myeloid leukaemia | Infection |
| Acute lymphoblastic leukaemia | Corticosteroid therapy |
| Chronic lymphocytic leukaemia | Brisk GI tract bleeding |
| Chronic myeloid leukaemia | ‘Stress’, e.g. postoperative |
| Lymphoma | Post splenectomy |
| Other infiltrations: myeloma, myelofibrosis |
Elevated platelet count
Case history
A 75-year-old woman was admitted with acute ischaemia of the toes in both feet. On examination she was found to have dusky skin on both feet, with evidence of early gangrene in the toes. FBC showed normal Hb, WBC of 18 × 109/L (neutrophilia) and platelet count 1500 × 109/L.
Immediate action
If none obvious – check again for splenomegaly, as was found in this case.
Is there a test that will confirm a primary bone marrow pathology?
Unfortunately not. The JAK2 tyrosine kinase mutation is only present in 50% of cases (see polycythaemia vera). Bone marrow trephine biopsy can help because increases in the numbers of megakaryocytes (the cells that make platelets; Fig. 6.9) with clustering favour a diagnosis of essential thrombocythaemia (ET), but often it is a diagnosis of exclusion. Blood film examination may show marked variation in size and shape of the platelets (platelet anisocytosis; Fig. 6.10) in primary thrombocythaemia – but this is not diagnostic.
Figure 6.9 Bone marrow in essential thrombocythaemia: clusters of megakaryocytes (from which platelets bud off) are seen in the centre of the field.
Management
• Give low-dose aspirin 75–300 mg/day (or dipyridamole if aspirin contraindicated).
• Plateletpheresis (using cell separator) if organ function threatened and need rapid reduction in platelet count.
• Oral hydroxycarbamide (e.g. 2–3 g per day for 2–3 days, dropping thereafter to 500 mg/day) to suppress bone marrow production of platelets (but beware neutropenia if dose too high). Suggested regimen: 10–30 mg/kg/day. Anagrelide and Busulfan are also used.
