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.

Figure 6.2 Typical blood film in chronic iron deficiency anaemia. Note the pale red cells with pencil (elongated) cells.

Other causes include:

• Poor diet

• Multiple pregnancies

• Regular blood donation.

Further reading

Provan D. Mechanisms and management of iron deficiency anaemia. British Journal of Haematology. 1999;105(Suppl 1):19–26.

The findings indicate a severe macrocytic anaemia with a moderate neutropenia and thrombocytopenia. The diagnosis could be pernicious anaemia.

Vitamin B₁₂ or folate deficiency impairs DNA synthesis and affects all rapidly dividing cells, particularly in the bone marrow, resulting in pancytopenia when severe. The anaemia is slow to develop and elderly patients, in particular, often do not present until very late.

Avoid blood transfusion, if at all possible, because there is a risk of volume overload and acute left ventricular 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.

Remember

Drugs and rare metabolic defects can result in megaloblastic anaemia with normal vitamin levels:

• Methotrexate induces functional folate deficiency

• Transcobalamin II deficiency results in intracellular vitamin B₁₂ deficiency (but is very rare).

Bone marrow aspiration (not generally necessary since modern analysers can provide rapid vitamin B₁₂ levels):

• Confirms megaloblastic erythropoiesis

• Documents pretreatment iron stores

• Excludes other conditions – myelodysplasia, acute leukaemia and aplastic anaemia – all of which can present with a macrocytosis and pancytopenia.

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

• Alcohol excess

• Infertility

• Autoimmune endocrine disease

• Family history of pernicious anaemia

• Drug therapy, particularly anti-convulsants.

Diagnosis.

This patient had megaloblastic anaemia secondary to severe vitamin B₁₂ deficiency.

Pernicious anaemia

• Serum B₁₂: 25 ng/L (NR 160–960 ng/L)

• Serum folate: 14.6 µg/L (NR 4.0–18.0 µg/L)

• Red cell folate: 86 µg/L (NR 160–640 µg/L).

Management

Whenever possible, treat with one haematinic only. In this patient, treat with hydroxocobalamin 1000 µg IM daily for 3 days.

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.

Do full blood counts + reticulocytes and urea and electrolytes initially daily (in a severely anaemic patient – as in this case) to look for:

• 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:

• Incorrect diagnosis and/or treatment: review laboratory data

• Coexistent iron deficiency: check iron stores, e.g. ferritin levels

• Intercurrent infection: review patient – chest infection? urinary tract infection?

• Coexistent hypothyroidism.

Remember

Pernicious anaemia is an autoimmune disease; 1–2% of patients will also develop thyroid disease. Gastric cancer is also slightly more common (1–3% of cases).

The majority of patients with vitamin B₁₂ deficiency have vitamin B₁₂ malabsorption and require life-long treatment with vitamin B₁₂.

Treatment.

Hydroxocobalamin 1000 µg IM every 3 months is given but high doses of vitamin B₁₂ (2 mg) daily by mouth are also effective.

Nutritional deficiency of vitamin B₁₂ is rare and confined to vegans.

Further reading

Lahner E, Annibale B. Pernicious anaemia; new insights. World J Gastro. 2009;15:5121–5128.

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.

A normocytic anaemia can be due to:

• Acute blood loss

• Lack of erythropoietin – chronic kidney disease

• Bone marrow infiltration, e.g. carcinoma

• Haemolysis.

The patient described is anaemic and jaundiced with splenomegaly, suggesting a haemolytic anaemia. To confirm this you need to demonstrate:

• Increased red cell production

• A reduced red cell lifespan.

Increased red cell production

• Reticulocytosis: reticulocytes are immature red cells newly released from the bone marrow. They are larger than mature red cells, contain mRNA and appear polychromatic on standard blood films.

• Bone marrow aspiration: erythroid hyperplasia.

Remember

Cortisol, androgens and thyroxine are all required for optimal erythropoiesis.

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

• Malaria parasites.

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.

Diagnosis.

Autoimmune haemolytic anaemia (secondary to underlying CLL).

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.

Remember

AHA can develop acutely with a rapid fall in haemoglobin. This patient has a short history. Check the haemoglobin concentration at least once a day.

Progress.

This patient went into remission on the steroids. Steroids are effective in about 80% of cases. The haematologists gradually reduced her steroids over 3 months and she was started on azathioprine. A year later her CLL became active and she is now on rituximab and fludarabine.

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.

Questions to ask patients presenting with sickle-cell crises

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

• Continuous infusion: 0–10 mg/h

• PCA bolus dose: 2–10 mg

• Dose duration: 1 minute

• Lockout time: 20–30 minutes.

When using diamorphine or other parenteral opiates the following parameters must be monitored regularly on an hourly basis:

• Pain score

• Respiratory rate

• O₂ saturation on air

• Analgesia consumption.

Adjuvant oral analgesia

• Paracetamol 1 g 6-hourly

• +/− Ibuprofen * 400 mg 8-hourly

• or Diclofenac * 50 mg 8-hourly

Supplementary analgesia may be provided by:

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)

• Aggressive pain relief

• Intravenous antibiotic therapy.

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.

Remember

Other complications of SCD include:

• Pneumococcal septicaemia

• Splenic sequestration

• Erythrovirus infection associated with marrow aplasia

• Acute folate deficiency

Progress.

This patient’s current crisis was more severe than her previous ones and she went on to develop the acute chest syndrome from which she died.

Types of sickle-cell disease

• Sickle-cell anaemia HbSS

• Sickle-cell–haemoglobin C disease HbSC

• Sickle-cell beta thalassaemia

• Rare compound heterozygotes, e.g. HbSD.

Diagnosis in A&E/MAU

• Information from patient

• UK Haemoglobinopathy card

• Blood count, reticulocyte count and blood film review

• Serum bilirubin

• Sickle solubility test (commercial kits are available).

Later:

• Haemoglobin electrophoresis (Fig. 6.5) on cellulose acetate membrane (CAM) at an alkaline pH

Figure 6.5 Patterns of haemoglobin electrophoresis.

• High-performance liquid chromatography (HPLC).

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).

Figure 6.6 Blood film in sickle-cell disease showing numerous sickle-shaped red cells.

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.

Further reading

Rees DC, Williams TN, Gladwin MT. Sickle cell disease. Lancet. 2010;376:2018–2031.

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.

On examination he was not breathless at rest. Pulse was 82/min with no evidence of cardiac failure. Auscultation of the chest showed scattered wheeze and a few crackles at both bases. Peak flow was 350 L/min.

Initial investigations have shown Hb 230 g/L, PCV 0.62, WCC 12 × 10⁹/L, a mild neutrophilia and platelets 200 × 10⁹/L.

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.

On examination he looked well. Pulse and blood pressure were normal. There were no abnormal signs in the cardiac or respiratory systems.

Investigations show his Hb was 220 g/L with PCV 0.58, WBC 20 × 10⁹/L and platelets 600 × 10⁹/L. Lactic dehydrogenase 740 U/L.

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).

Figure 6.7 Alteration of haemoglobin in relation to plasma.

How to visualise the Hb level:

• Hb is expressed as a concentration, i.e. g/dL blood but blood = plasma + solids (RBCs mainly). Thus Hb level must be related to the level of the plasma.

Preliminary management

• Ensure no hyperviscosity symptoms or signs:

• Confusion

• Visual disturbance

• Peripheral circulatory disturbance.

• Ensure patient is adequately hydrated.

• Infection (if present) must be treated.

• Identify correctable causes, e.g. chronic hypoxia.

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.

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).

• Bone marrow (see Remember box).

• Erythropoietin levels (normal or low in PV).

Remember

From: Tefferi et al. Blood (2007) 110:1092. American Society of Haematology.

^*EEC. This is not routinely available but colony formation in the absence of exogenous erythropoietin in vitro is 100% specific and sensitve in patients without previous treatment.

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.

• Erythropoietin levels raised.

NB It is now not necessary to do blood viscosity and red cell volume studies.

Secondary polycythaemia

• As above, but generally with no hepatosplenomegaly, no thrombocytosis.

• Usually secondary cause found, such as cyanotic heart disease, lung disease, renal disease.

Apparent (or relative) polycythaemia

• Red cell mass normal

• Reduced plasma volume

• No hepatosplenomegaly.

Management and progress

This is where knowledge of the underlying cause becomes crucial.

Your FIRST patient has secondary polycythaemia due to lung disease

This is a physiological rise in Hb. Reducing the Hb to normal could have serious consequences because the rise in Hb is a compensatory mechanism.

The initial aim is to reduce the Hb to a safe level. Generally this is achieved by venesection (removal of ~400–500 mL blood) every 2 days. In males the PCV is reduced to < 0.5 and in females to < 0.45.

ALL cases of secondary polycythaemia should be treated with venesection and treatment of the underlying cause if possible. This patient’s raised Hb was due to chronic lung disease, with the high Hb due to hypoxia.

Your SECOND patient has polycythaemia vera (Remember box)

• Venesect 400–500 mL weekly.

• Then control marrow activity with hydroxycarbamide.

• Targeted therapy with JAK1 and JAK2 agonists is becoming available.

Long-term complications

Up to 30% of patients with PV will develop intense marrow fibrosis and 5% develop acute myeloid leukaemia. The other polycythaemias do not transform.

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.

On examination his tonsils were enlarged and inflamed; he had palatal petechiae and cervical lymphadenopathy.

Investigations showed an Hb of 124 g/L, an MCV of 98 fL, WBC of 16 × 10⁹/L with abnormal lymphocytes in the peripheral blood. A monospot test is positive.

Diagnosis: Infectious mononucleosis.

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

A thorough history and examination will usually allow you to determine the cause of the elevated WBC. ‘Alert’ features suggesting a possible malignant cause include:

• Ill patients

• Those with bleeding/bruising

• Fever

• Enlargement of liver or spleen or lymphadenopathy

• Weight loss

• Lymphocytes or bizarre/abnormal cells on blood film.

Is it glandular fever or acute leukaemia?

The atypical lymphocytes seen in this patient with an infectious mononucleosis can be confused with leukaemic blasts because the lymphocytes are large, often have nucleoli and resemble lymphoblasts. Specific tests, such as the ‘Monospot’, help confirm the diagnosis. In general, the haematology department will advise on further investigation, e.g. cell marker analysis to exclude leukaemia.

Further reading

Stock W, Hoffman R. White blood cells 1: non-malignant disorders. Lancet. 2000;355:1351–1357.

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.

Other significant features in this patient:

• Evidence of weight loss

• Splenomegaly 4 cm below the costal margin.

You need to decide whether the marked elevation of the platelet count is likely to be reactive to some underlying process/disorder, or whether she has a primary marrow disorder, because the management is dictated by the underlying cause.

Why does the platelet count rise in a reactive manner?

In simplistic terms, any acute stress (bleeding, operative surgery, severe infection) causes intense marrow activity with elevation of white cells and platelets in a non-specific way.

Reactive thrombocytosis does not usually exceed 1000 × 10⁹/L, whereas primary thrombocytosis is often > 1000 × 10⁹/L, but do not rely on platelet count alone. A reactive thrombocythaemia will resolve when the underlying problem, e.g. infection, is treated.

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.

Figure 6.10 Large numbers of platelets (small purple cells) in blood film of patient with essential thrombocythaemia.

Information

Myeloproliferative disorders associated with thrombocytosis

• Primary (essential) thrombocythaemia

• Polycythaemia vera

• Chronic myeloid leukaemia

• Myelofibrosis

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.

Complications

• Primary thrombocythaemia: generally indolent course but might transform to polycythaemia myelofibrosis in ~5% (occasionally transforms to acute myeloid leukaemia).

Progress.

This patient was referred to the Vascular Surgical Department who carried out Doppler and Duplex imaging of his peripheral arteries but found no lesion amenable to surgery.

Glucose-6-phosphate dehydrogenase deficiency

Definition

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the hexose-monophosphate pathway. It is responsible for generating NADPH. In the red cell, NADPH is a major source of reducing the potential required to maintain the iron atoms of haemoglobin in the ferrous state and to prevent membrane lipid peroxidation.

Case history

A 30-year-old Nigerian man was brought to A&E having collapsed in the street. He had returned from a 3-month holiday in Nigeria 6 days previously. Two days before admission he had developed central colicky abdominal pain and diarrhoea; 1 day before admission he began to feel weak and noticed his urine was discoloured red.

On examination he was pyrexial (37.8°C), anaemic and jaundiced. There was no hepatosplenomegaly.

Dipstix testing of urine was negative for bilirubin but positive for urobilinogen and blood. Urine microscopy revealed no red cells.

Investigations

• Hb 54 g/L

• MCV 91 fL

• WBC 15.8 × 10⁹/L

• Platelets 249 × 10⁹/L

• Reticulocytes 11.61%

Blood film showed polychromasia, irregularly contracted and bitten-out red cells. There were no malaria parasites or Heinz bodies.

The patient has a normocytic anaemia with a reticulocytosis suggesting acute haemolysis or haemorrhage.

Polychromasia refers to the appearance of reticulocytes, or immature red cells, when stained by using standard stains.

The appearance of the red cells is compatible with oxidative red cell damage. It is unusual to see Heinz bodies when patients have a functional spleen.

Differential diagnosis (see Table 6.4)

Malaria is a common cause of haemolysis in patients returning from the tropics. Other evidence to suggest acute intravascular haemolysis is shown in Table 6.2.

Table 6.2 Evidence to show intravascular haemolysis

Test	Result
Serum bilirubin	65 mmol/L
Serum haptoglobins	Undetectable
Serum LDH	587 iu/L
Schumm’s test	Positive

Hb electrophoresis on cellulose acetate membrane (CAM) and agar gel demonstrates sickle-cell trait but no other structural haemoglobin variant. Sickle-cell trait does not result in a haemolytic anaemia.

The negative isopropanol stability test excludes an inherited, unstable haemoglobin variant.

The negative DAT (or Coombs’ test) excludes immune-mediated red cell destruction.

G6PD was assayed by two methods that confirmed G6PD deficiency. The most common G6PD variant in individuals of African descent is G6PD A^–.

Remember

• G6PD deficiency will be present in all (homozygous) males who carry an affected X chromosome

• Heterozygous females will have a dual population of red cells

• Because X chromosome inactivation is random (lyonisation), some heterozygous females will demonstrate clinical G6PD deficiency.

Deficiency of G6PD arises from a large number of different mutations in the G6PD gene, the majority of which are point mutations resulting in single amino acid substitutions. G6PD deficiency is widespread in many tropical and subtropical populations where malaria was, or is, endemic. Frequencies of 20% of the population in Southern Europe and Africa and 40% in south east Asia and the Middle East have been reported.

G6PD deficiency can present as:

• Neonatal jaundice

• Chronic haemolytic anaemia

• Acute haemolytic anaemia.

An acute haemolytic crisis is the most common presentation and most affected individuals are asymptomatic until this happens. Acute haemolysis occurs when an exogenous factor imposes an extra oxidative stress, which overwhelms the limited supply of NADPH in the red cells. Acute haemolysis can be precipitated by:

• Infection

• Drugs

• Fava beans (either lightly cooked food or as a pollen).

Many drugs (Table 6.3) have been implicated in attacks of acute haemolysis in susceptible individuals.

Table 6.3 Drugs that commonly cause acute haemolysis in patients with G6PD

Type	Example
Anti-malarials	Primaquine
	Pamaquine
	Chloroquine
	Quinine
Sulfonamides	Sulfasalazine
	Dapsone
	Co-trimoxazole
Other antibiotics	Nitrofurantoin
	Nalidixic acid
	Quinolones, e.g. ciprofloxacin
Analgesics	Aspirin (> 1 g per day)
Miscellaneous	Vitamin K analogues
	Naphthalene
	Probenecid
	Dimercaprol
	Methylene blue

Remember

• Some drugs (e.g. primaquine, aspirin and vitamin K) can be given safely in reduced doses

• Some agents (e.g. Dapsone and naphthalene) in sufficient amounts will cause haemolysis in individuals with normal levels of G6PD.

Favism is a form of severe, acute, intravascular haemolysis, often with massive haemoglobinuria, precipitated by exposure to fava beans (Vicia faba) in individuals with G6PD deficiency. It is most common in children, following the ingestion of fresh, raw beans. Haemolysis is probably precipitated by divicine, a glucoside constituent in fava beans, which generates free oxygen radicals when oxidised.

Diagnosis of G6PD deficiency

Laboratory features

Blood count:

• Normocytic anaemia

• Reticulocytosis

• Bitten-out and irregularly contracted red cells.

The spleen ‘bites out’ Heinz bodies, which are aggregates of oxidised methaemoglobin, from affected red cells.

Features of intravascular haemolysis

• Decreased haptoglobins

• Increased LDH

• Haemoglobinaemia

• Haemoglobinuria

• Positive Schumm’s test due to methaemalbumin.

One of the isoenzymes of lactate dehydrogenase (LDH) is found in high concentrations in red cells and is released in red cell damage.

Rapid depletion of haptoglobin with the formation of methaemalbumin is typical of intravascular haemolysis. In the absence of other scavenging serum proteins excess haem binds to albumin and the ferrous iron is subsequently oxidised to ferric iron to give methaemalbumin and a positive Schumm’s test. The cause of the intravascular haemolysis was established by further tests, as shown in Table 6.4.

Table 6.4 Test results confirming the cause of intravascular haemolysis

Test	Result
Haemoglobin electrophoresis	HbA + HbS
Direct antiglobulin test (DAT)	negative
Isopropanol stability test	negative
G6PD assay	1.9 IU/gHb

Haemoglobinuria might result in acute kidney injury, particularly in adults – monitor urine output, urea and creatinine.

Remember

• Old red cells have less G6PD than young red cells and are destroyed first during a haemolytic attack

• Newly formed reticulocytes have relatively high concentrations of G6PD

• As a result of these two factors the concentration of G6PD in an affected individual may rise during an acute haemolytic episode to within the normal range

• If in doubt retest 1 month later.

Assessment of G6PD activity

• Qualitative screening test, e.g. cresyl blue decolorisation test

• Quantitative enzyme assay by spectrophotometry.

What had precipitated a haemolytic crisis in this man with G6PD deficiency?

This was initially obscure. He denied any drug ingestion but, on repeated questioning, admitted drinking approximately 50 mL of an oily liquid he had obtained from his church in Nigeria where it was used for anointing the faithful. When he produced the bottle it smelt strongly of mothballs and ultraviolet spectrophotometry confirmed the presence of naphthalene. Naphthalene is well known to cause acute haemolysis. It was first described in the 19th century after the introduction of beta-naphthol to treat hookworm infestations. Many cases of affected infants have been described where the naphthalene was used as a moth repellant in clothes. The presence of G6PD deficiency greatly increases sensitivity to the oxidative red cell damage mediated by naphthalene.

Progress.

The patient’s haemoglobin concentration did not fall any further but rose slowly, reaching 92 g/L 7 days later. The reticulocyte count peaked at 17.4% on the fifth day, and the jaundice had resolved by 14 days. Re-assay 6 weeks later confirmed G6PD deficiency.

Bleeding disorders

These can be due to inherited or acquired causes. Disorders are due to haemolysis (either intra or extra-vascular) or coagulation disorders. Always take a good history and use your common sense, as illustrated in the case below.

Case history (1)

You are phoned by a surgical specialist registrar asking for your advice. He has just finished a bilateral hernia repair on a 50-year-old man and the right side is bleeding briskly. The patient has required a transfusion with two units of blood in the last 30 min. The surgeon tells you that the surgery has gone well and wants you to sort out his clotting.

What do you think about this case?

This patient is most likely to be bleeding from a surgical cause: 2 units in 30 min is far in excess of what you would expect to give in a patient with a clotting disorder, and he is only bleeding from one of the repair sites, not both. Best to advise the registrar to find the bleeding vessel!

Although this might seem like a somewhat silly example, it shows that not all bleeding is due to abnormal clotting. Look at the whole picture before jumping in with fresh frozen plasma (FFP).

Inherited bleeding disorders

You are far more likely to see acquired bleeding disorders than inherited. Inherited disorders are uncommon, but must be identified.

Remember

Management of inherited disorders is complex: always seek specialist support.

How can I identify the inherited disorders?

Most inherited disorders of any severity present in childhood and hence most, if not all, patients will be able to tell you about their problem. They should carry a medical card with them, identifying the problem and their haematology consultant. It should be easy to sort out these patients and get in touch with the appropriate specialist. Always take any suggestion of an inherited bleeding disorder seriously (see Figs 6.11 and 6.12).

Figure 6.11 Gross arthritis in a patient with haemophilia (inherited factor VIII or IX deficiency).

Figure 6.12 This patient with haemophilia A has bled into his foot (note the discoloration of the foot below the medial malleolus).

How can I identify milder forms?

Milder inherited disorders might not present until later in life and usually do so after surgery or other interventions.

Acquired bleeding disorders

As mentioned, these are far more common than inherited problems and are usually seen in particular clinical settings. These common scenarios will be outlined later. Most acquired disorders involve multiple and complex defects of coagulation.

What should I request?

You request a basic coagulation screen:

• Full blood count to check platelet count

• Prothrombin time (PT)

• Activated partial thromboplastin time (APTT).

Remember

Even a 2-second prolongation might indicate an inherited clotting problem of significance and should be investigated more fully.

These are the minimum number of tests to start with. If you really want to check that a clotting disorder exists, then the following should also be performed:

• Fibrinogen level

• Thrombin time (TT).

These tests form your baseline investigations or screening tests.

Acquired disorders are relatively easy because clotting times are usually notably prolonged.

There are a whole range of specialist investigations for the complete study of a coagulation disorder: it is best to seek specialist advice.

Case history (2)

You are called to see a patient in A&E who is bleeding excessively from a dental extraction. The doctor in A&E thinks that the patient has liver disease and asks you for some help. There is nothing in the history to indicate what the liver problem might be and the patient denies excess alcohol consumption.

On examination you notice spider naevi, liver palms and splenomegaly. You agree that the excess bleeding is probably due to liver disease.

Bleeding in liver disease

This causes widespread coagulation and bleeding problems. Always be aware that significant liver dysfunction can result in a potentially severe bleeding disorder. The components of liver-related bleeding are:

• Reduced synthesis of coagulation factors: the liver is the source of all coagulation factors (apart from Factor VIII).

• Associated vitamin K deficiency: coagulation proteins might be synthesised but will not be active because of vitamin K deficiency.

• Thrombocytopenia: frequently secondary to splenomegaly from portal hypertension.

• Chronic low-grade disseminated intravascular coagulation (DIC): see p. 112.

• Abnormal fibrinogen synthesis: in liver disease, excess sialic acid residues are added to fibrinogen and hence an acquired dysfibrinogenaemia occurs.

The classic laboratory defects would be:

• PT prolonged due to decrease in factor II, V, VII or X

• APTT prolonged due to decrease in all factors

• TT prolonged due to abnormal fibrinogen

• Fibrinogen degradation products (FDPs) increased (due to failure to remove from circulation ± chronic DIC).

Information

Causes of vitamin K deficiency

• Biliary obstruction

• Oral anti-coagulants

• Liver disease

• Malabsorption states

• Inflammatory bowel diseases (with ileal resection)

Diagnosis: Chronic kidney disease

Anyone with significantly impaired renal function can have an acquired bleeding disorder. The major cause is toxic metabolites impairing platelet function, as is the case in this patient.

Is the APTT or PT abnormal in renal disease?

No. As mentioned above, the major defect is an acquired platelet disorder. The clotting times are usually normal.

Should the bleeding time be measured regularly in patients with renal disease?

No, but remember that renal disease is a cause of an acquired bleeding disorder and if you are planning surgery on the patient they might have a bleeding problem.

What can we do in renal failure?

There are several approaches to treatment but sorting out the renal problem first is the best option. Dialysis will improve platelet function; this is why few stable dialysed/controlled patients actually bleed. The real risk group is those with a very high serum creatinine/urea.

Other treatments for bleeding include:

• Synthetic vasopressin analogue (desmopressin)

• Cryoprecipitate

• Platelet transfusion.

These are all used in bleeding episodes.

Disseminated intravascular coagulation (DIC)

This is the most complex of the acquired bleeding disorders.

DIC is inappropriate and continued activation of coagulation that leads ultimately to both bleeding and thrombosis.

The initial phase of DIC is thrombosis. This is why DIC is associated with end-organ damage leading to multi-organ failure.

Remember

DIC is always secondary to some other major clinical problem.

Bleeding arises as a secondary phenomenon due to consumption of coagulation factors and platelets (due to continued activation of clotting) and the activation of fibrinolysis (breaking down any fibrin that gets laid down).

Case history (4)

A 29-year-old man is brought to the Trauma Unit with severe injuries to his abdomen and legs as a result of a road traffic accident. Initial examination and CT scanning confirm that he has fractured both femurs and has a fractured pelvis. He has fluid in his abdomen on CT, suggesting internal organ damage.

He is resuscitated and taken to ITU where he needs ventilation, volume replacement and cardiovascular support with inotropes. His leg fractures are stabilised and he undergoes emergency laparotomy with resection of damaged small bowel. He initially improved but then his renal and liver function deteriorated and he was diagnosed as having multi-organ failure. He was then noted to be bleeding from his laparotomy wound.

Action

• Always think about DIC in a bleeding patient

• Try to make the diagnosis.

Causes

• Infection

• Obstetric complications

• Transfusion reactions.

If someone is bleeding and you always think about DIC you won’t go wrong. In many ways the long list of causes is academic when you first see the patient – but if they have got DIC you must identify the cause.

How do I make the diagnosis?

Send off all the screening tests and fibrinogen degradation products (FDPs). The pattern is:

• Platelets low: consumption

• PT prolonged: consumption

• APTT prolonged: consumption

• TT prolonged: consumption of fibrinogen and FDPs

• Fibrinogen low: consumption

• FDPs high: breakdown of fibrin.

Why are FDPs measured?

FDPs tell you that fibrin is being broken down. The most specific test is the D-dimer, which tells you that cross-linked fibrinogen has formed and has then been broken down.

How do I manage DIC?

• Treat the underlying disorder.

• Treat the underlying disorder!

• Treat the underlying disorder!!

• Support with FFP, cryoprecipitate and platelets.

Remember

People die from their underlying disorder rather than the DIC per se.

You must aim to treat the underlying disorder! DIC is always secondary. As mentioned earlier, it is due to inappropriate and continued activation of clotting. Until you stop this by treating the underlying problem it won’t get better.

Blood component therapy is purely supportive. Give:

• 10–20 mL/kg FFP + cryoprecipitate

• Platelets

• Blood as required.

Aim to get the fibrinogen concentration to normal and the PT/APTT to within 4 s of normal.

Progress.

Despite all efforts the patient died.

Case history (5)

A 50-year-old patient has carcinoma of the lung with a prolonged PT, APTT, TT, low fibrinogen and platelet count and high FDPs, but he isn’t bleeding.

Has this patient got DIC?

This is the picture of subclinical DIC – laboratory abnormalities but no bleeding. It is seen in chronic DIC, e.g. in liver disease, malignancy. DIC ranges from florid bleeding to abnormalities that are picked up only by laboratory testing.

Remember

People die from their underlying disorder rather than the DIC per se.

Anti-coagulant overdosage

An obvious cause of bleeding. Don’t forget to look for warfarin/heparin usage.

Action

Confirm anti-coagulant overdosage by finding a prolonged PT (warfarin) or APTT (heparin). The treatment of bleeding depends on the problem, but in essence:

If due to warfarin: STOP WARFARIN

• Minor bleeding: If INR > 6.0: restart warfarin when INR < 5.0; check INR daily. If INR > 8.0 give vitamin K 2.5 mg oral or 0.5 mg IV.

• Major bleeding: give prothrombin complex concentrate 50 units/kg or FFP 15 mL/kg; give vitamin K 5 mg IV.

Remember

High prothrombin time (due to warfarin) without bleeding usually requires no treatment apart from stopping warfarin.

If due to heparin: STOP HEPARIN

If bleeding is excessive or uncontrolled:

• Protamine reversal (1 mg IV neutralises 100 units heparin – maximum dose 40 mg). Protamine has no effect on low molecular weight heparin.

• Seek advice.

• Heparin excess will correct in a few hours.

Remember

New thrombin inhibitors that are now being used for anti-anti-coagulation, e.g. dabigatran, apixaban and rivaroxaban have no antidotes.

Surgical cause

Suspect if rapid blood loss at operation. Don’t understimate the number of times this is forgotten and people chase a medical cause for bleeding when a vessel has a hole in it.

If you have a hole in a vessel bleeding won’t stop until the hole is fixed, however good the coagulation system is.

Remember

Surgical and medical bleeding might coexist. If you correct the coagulation and the patient is still bleeding, think surgical whatever the surgeon says!

Platelet disorders

Case history (1)

You are asked to see a 24-year-old woman who is in A&E. She has presented with petechiae scattered over her body. The casualty officer has found that she has a platelet count of 10 × 10⁹/L. This woman seems very well and tells you that she has had the petechiae for at least a week. She has no other symptoms. She is on the contraceptive pill and is taking no other tablets. She does not smoke and drinks wine (6 units) at the weekend only.

On examination she has petechiae over her trunk, arms and legs. She has no other abnormal signs.

Investigations

You note the platelet count and also that all the other parameters in her blood count are normal. She also has normal routine biochemistry.

Remember

Meningococcal septicaemia has a purpuric rash and/or petechiae.

There are multiple causes of thrombocytopenia (Table 6.5). Thrombocytopenia may be the presentation of another disorder rather than a primary platelet disorder. All patients with severe thrombocytopenia (defined as < 20 × 10⁹/L, which produces spontaneous haemorrhage) require admission for investigation/treatment.

Table 6.5 Causes of thrombocytopenia

Failure of platelet production

Marrow aplasia

Metabolic defects

Vitamin B₁₂/folate deficiency

Uraemia

Alcohol excess

Liver disease

Drugs

Chemotherapy ± radiation

Marrow infiltration:

Leukaemia

Lymphoma

Myeloma

Myelofibrosis

Carcinoma

Decreased platelet survival

Immune:

Immune thrombocytopenic purpura (ITP)

Systemic lupus erythematosus (SLE)

Chronic lymphatic leukaemia (CLL)

Hodgkin’s lymphoma

Drug related

Infection

Malaria

Virus infection

Consumption:

DIC

Extracorporeal circulation

Haemolytic uraemic syndrome

Thrombotic thrombocytopenic purpura (TTP)

Loss from circulation:

Splenomegaly

Massive transfusion

Remember

The list of causes (Table 6.5) is not comprehensive and excludes inherited thrombocytopenia or causes that would present in childhood.

Questions that need to be answered immediately

• Does this patient have immune thrombocytopenic purpura (ITP)?

• Does she have acute leukaemia?

• Does she have aplastic anaemia?

• ITP: normal Hb, normal WCC, no hepatosplenomegaly or lymphadenopathy.

• Acute leukaemia (see p. 132): high WCC, abnormal white cells on film, lymphadenopathy, hepatosplenomegaly (occasionally).

• Aplastic anaemia: low Hb, low WCC, no lymphadenopathy, no hepatosplenomegaly.

The diagnosis appears to be ITP. You are called back to see the patient 20 minutes later as she has had a massive haematemesis. You think the diagnosis is ITP as there are no other features to make you think it is aplastic anaemia or acute leukaemia.

Major bleeding in ITP is not common but can be a serious complication. Treatment approaches should be decided by a haematologist.

Learning points

• High-dose immunoglobulin elevates the platelet count by macrophage Fc receptor blockade of the reticuloendothelial system.

• Endogenous platelets usually rise after 24–48 h; the survival of exogenous platelets is improved.

• Platelet transfusion is usually not necessary in ITP except in the situation of life-threatening haemorrhage, such as in this case.

• 75% of patients respond to oral steroids but the full therapeutic effect may take 2–4 weeks to develop.

Remember

ITP might become chronic and might require long-term treatment ± splenectomy. Romiplostim and eltrombopag, thrombopoeitin receptor agonists, are now being used if splenectomy has no effect.

Further reading

Provan D, Newland A. Fifty years of idiopathic thrombocytopenic purpura (ITP): management of refractory ITP in adults. British Journal of Haematology. 2002;118:933–944.

Imbach P, Crowther M. Thrombopoietin receptor agonists for primary immune thrombocytopenia. N Engl J Med. 2011;365:734–741.

Case history (2)

You are asked to see a 50-year-old man on a surgical ward who has come into hospital for an elective hernia repair. He is found on a routine preop FBC to have a platelet count of 90 × 10⁹/L. His Hb and WCC count are normal.

This chronic presentation of mild thrombocytopenia is reasonably common. To establish the cause you should systematically go through the causes of thrombocytopenia from an initial clinical history and examination.

Can he go ahead and have his hernia repair?

It might take a while to get to the bottom of his thrombocytopenia. Elective surgery can be performed as the platelet count is greater than 80 × 10⁹/L.

Avoid any NSAIDs as postop analgesia; make sure aspirin has not been taken within the last 10 days.

This man was discharged following a successful surgical repair and one week later his platelet count was 96 × 10⁹/L. By 1 month the platelet count was normal. No clear reason for the thrombocytopenia was found but a viral cause seemed the most likely.

Case history (3)

A 28-year-old woman has had a D&C for long-standing menorrhagia. She is now 5 days after the procedure and still bleeding. She has been back in theatre and no local defect is found. She says she had problems in the past with bleeding after dental extractions. Her PT and APTT and platelet count are normal.

Diagnosis

This is the typical picture of an inherited platelet disorder. Severe platelet function disorders present in childhood but milder versions do not usually present until surgery in adulthood. Clues here are bleeding after dental extraction and long-standing menorrhagia.

Management

Assess the extent of bleeding. Treatment options include:

• Tranexamic acid 1 g × 4 daily if mild bleeding

• Platelet transfusion if severe bleeding.

In a classic platelet function disorder the bleeding time is prolonged, but this test is difficult to perform. If you suspect a platelet function disorder organise platelet function studies with your haematological laboratory.

Progress.

This patient stopped bleeding following a platelet transfusion. She was referred to the Haematology Department for follow-up.

Thrombosis

Case history (1)

You are asked to see a 24-year-old woman who has had a life-threatening pulmonary embolus. She received fibrolytic therapy (p. 286) on the ICU. Her condition stabilised and she is now on warfarin following initial treatment with low molecular weight heparin. She wants to know why she has had a pulmonary embolus. She has a family history of DVT.

Are investigations indicated?

Thrombosis is common but relatively uncommon under the age of 45 years unless there is a precipitating event (see below). In such patients with a family history, about 50% have a definable underlying prothrombotic state. It is well worth formally investigating her for a prothrombotic state.

Attempt to identify any precipitating event, such as:

• Taking combined oral contraceptive pill

• Immobility and/or recent surgery/fracture/injury

• Long-haul flight

• Obesity

• Malignancy.

Should she be investigated now or later?

She is on warfarin, which can interfere with thrombotic investigations. Identifying an underlying thrombotic state acutely will not change the immediate management.

Remember

• An abnormal result after an acute thrombosis does not mean an abnormality genuinely exists

• It must be rechecked

• However, a normal result is normal.

She is on warfarin so formal studies must be delayed. Refer her on to a specialist for follow-up and investigation.

What investigations will be requested after stopping warfarin?

These aim to look for an inherited deficiency of natural anti-coagulants, mutations leading to increased thrombin generation or acquired causes of a prothrombotic state.

Progress.

This woman has Factor Leiden deficiency. She is referred on to a specialist for long-term follow-up and counselling and family studies.

Case history (2)

You are asked to see a 70-year-old man who had a DVT after a knee replacement despite DVT prophylaxis. He has no family history of venous thrombosis. He is at present on warfarin following treatment with LMW heparin.

Should he be investigated for thrombophilia? No!

It is likely that at this age a DVT in this setting has been precipitated by the surgery. The pick-up rate for a significant thrombotic disorder is very low in this setting. When asked to assess the thrombotic status, balance the likelihood of finding a defect against the value of identifying the exact defect.

Case history (3)

You are called to see a 45-year-old man who is being anti-coagulated for acute iliofemoral vein thrombosis with heparin. His APTT remains normal on 28 000 units heparin per 24 h. The dose of heparin has been progressively increased over the last 3 days but his leg swelling is worse.

What do you advise?

The target APTT for heparin for an acute thrombosis is 1.5–2.5 times the mid-point of the normal range. The most common reasons for failure are:

• Under-monitoring

• Underdosing

• Not actually receiving dose of heparin prescribed.

Action

• Ensure prescribed dose is being given.

• Increase dose by 10% per 24 h.

• Recheck APTT in 4 h.

• If still low, repeat the 10% increase in heparin dose and recheck at 4-hourly intervals.

Heparin monitoring is notoriously bad in most hospitals. If IV heparin is being used it should be monitored as follows:

• Check APTT every 4 h until target reached.

• Increase dose in 10% increments.

• Once target APTT reached, repeat at 4 h.

• If stable APTT, repeat 12-hourly.

Remember

• Outcome is dependent on the effectiveness of anti-coagulation within the first 48 h

• Heparin resistance is rare; poor heparin control is very common

For how long should a patient with venous thromboembolic disease be anti-coagulated with warfarin?

The duration and target INRs for various thrombotic conditions are listed in Table 6.6.

Table 6.6 Duration and target INRs for thrombotic conditions

	Duration	INR target
Uncomplicated DVT	6 months	2.5
Complex DVT	6 months	2.5
Pulmonary embolus	6 months	2.5
Recurrent VTE	Indefinite	2.5 – if the recurrent event occurs whilst taking warfarin the intensity of anti-coagulation is increased, target 3.5
AF	Indefinite	2.5
Mechanical heart valves	Indefinite	3.5

AF, atrial fibrillation; DVT, deep vein thrombosis; INR, international normalised ratio; VTE venous thromboembolism

Recurrent VTE is essentially two or more events. The more events, the greater the likelihood of recurrence.

Long-term anti-coagulation carries the risk of major haemorrhage (4% per annum) and death (~0.5% per annum). These must be balanced against recurrence prevention. Complications are far more common in older patients.

Recurrence is much higher in patients anti-coagulated for 6 weeks rather than 6 months.

Remember

• Drug interactions with warfarin

• Need to amend dosage in patients undergoing invasive procedures

• Regular anti-coagulant clinic follow-up.

New orally active anti-coagulant drugs

A number of orally active direct thrombin and Xa inhibitor drugs (dabigatran, rivaroxaban) are being used in clinical trials for prevention and treatment of thrombosis. Such drugs have a much broader therapeutic window than warfarin and offer the prospect of fixed drug dosing without the need to monitor coagulation. They do not, however, have specific antidotes.

Case history (4)

You are asked to see a 36-year-old woman with an acutely swollen calf. Clinical diagnosis is a distal DVT. She has no complicating problems.

How should she be treated?

Initially, the diagnosis should be confirmed by venous compression ultrasonography (sensitivity 97% for proximal and 73% for calf veins). An acutely swollen leg has a range of causes:

• DVT

• Ruptured Baker’s cyst

• Rupture of head of gastrocnemius

• Acute knee injury

• Haematoma

• Infection (e.g. cellulitis).

Action

If a DVT is confirmed:

• Give SC low molecular weight (LMW) heparin

• Warfarinise the patient.

This can be managed in outpatients with good nursing and laboratory support.

If the DVT is complex (i.e. iliofemoral):

• Admit

• IV unfractionated heparin or LMW heparin

• Warfarinise.

There is an increasing move to outpatient management of venous thromboembolism (VTE).

Dabigatran (see above) is being used instead of warfarin in some centres.

Case history (5)

You are phoned about a 36-year-old man with an acute right lower limb ischaemia due to an arterial thrombosis. He has a family history of thrombosis. There has been improvement in the ischaemic area over 24 hours. The patient is on intravenous heparin infusion and is being monitored by the vascular surgeons. The houseman wonders in view of the family history whether he should be investigated for thrombophilia. He has already sent off standard thrombophilia screen (see Investigations box, p. 118) and he asks if this is all that you need.

You tell him that thrombophilia is uncommon in arterial disease but there are a number of risk factors for arterial thrombosis. You suggest he requests:

• Plasma homocysteine

• Lipid profile

• Plasminogen activator inhibitor.

• Finding a cause in arterial disease is less likely than in venous thrombosis.

Progress.

No evidence of thrombophilia was found in this man but he is a smoker and his cholesterol was 7.4 mmol/L with risk factors for atherosclerosis. His lifestyle issues were addressed by the cardiac rehabilitation nurse specialist and he was started on a statin.

Case history (6)

You are asked to see a 60-year-old woman with a right leg DVT, who is on unfractionated heparin. She has been in hospital for 5 days and started warfarin therapy 48 hours previously. She has now developed a cold, painful leg on the left that is pulseless. You are told her platelet count has been falling since starting heparin.

What is the most likely diagnosis to consider?

This would be a good picture for heparin-induced thrombocytopenia with thrombosis (HIT) of the artery. The classic features are progressive platelet decline and new thrombosis. HIT is a clinical diagnosis and is diagnosed in any patient on heparin whose platelet count falls significantly.

Action

• Stop all heparin (including heparin flush).

• Contact haematologist.

• Alternative forms of anti-coagulation are not required for the DVT in this woman because she is on warfarin and the INR is 2.0 and heparin was about to be discontinued.

HIT is due to an immune induction of anti-heparin/PF4 antibodies which bind to and activate platelets via a Fc receptor. This results in a prothrombotic state with low platelets. There is usually a previous history of heparin exposure.

• Fatal thrombosis, both venous and arterial, can arise if heparin is not stopped immediately.

• HIT can occur after SC heparin use. It is becoming increasingly common with the widespread use of heparin prophylaxis.

Progress.

This woman has left acute ischaemic lower limb and required surgical removal of the thrombus in her popliteal artery. She fortunately made a good recovery although she still has a swollen, painful right leg (from the DVT) and ischaemic pain in the left leg after exertion.

Splenomegaly, splenectomy and hyposplenism

Case history (1)

A 55-year-old man presented with a 3-month history of discomfort in the left side of his abdomen. The discomfort is present most of the time and now seems to be getting worse.

He has had rheumatoid arthritis for many years but his condition has stabilised on methotrexate therapy and occasional use of diclofenac for pain in his knees.

On examination he looks pale, he has evidence of rheumatoid arthritis in his hands with ulnar drift and palmar subluxation of the MCPs. He has rheumatoid nodules in both elbows. Both knees are deformed. Examination of his abdomen shows a large spleen.

Investigations show a normochromic normocytic anaemia with low platelets and a neutropenia.

The diagnosis is Felty’s syndrome in a patient with rheumatoid arthritis.

Felty’s syndrome consists of splenomegaly and neutropenia in a patient with rheumatoid arthritis. A normochromic, normocytic anaemia of chronic disease is usually seen, although iron deficient and rare haemolytic (Coombs’ positive) anaemias are seen. Hypersplenism causing a pancytopenia may occur (see below).

Spleen size can be assessed by abdominal palpation or by imaging, e.g. ultrasound. CT, MRI and PET scans are also used to delineate the cause, e.g. lymphoproliferative disease.

There are many causes of splenomegaly, with the most frequent showing geographical variation. In temperate climates, malignant blood diseases, portal hypertension, haemolytic anaemias and infective endocarditis account for most cases, whereas in tropical countries malaria, leishmaniasis and the haemoglobinopathies are prevalent.

Information

Causes of splenomegaly

Enlargement of the spleen from any cause can be complicated by hypersplenism. This is characterised by:

• Splenomegaly

• Pancytopenia

• Normal or hypercellular bone marrow.

Pathophysiology of hypersplenism

Mature red cells, neutrophils and platelets ‘pool’, or are trapped, in the sinusoids of the large spleen and prematurely destroyed.

Hyposplenism may be due to:

• Congenital absence

• Splenectomy: surgical or by irradiation

• Splenic atrophy, e.g. coeliac disease, chronic inflammatory bowel disease

• Splenic infarction, e.g. sickle-cell anaemia (HbSS)

• Splenic infiltration.

The functional size of the spleen can be assessed by scanning with a scintillation counter following the injection of radiolabelled (99mTc), heat-damaged, autologous red cells. These cells are removed from the circulation solely by the spleen.

Progress.

This patient with RA was confirmed as having Felty’s syndrome as the cause of his splenomegaly. Over the following year he developed recurrent infections with a persistent, refractory neutropenia and eventually had a splenectomy.

Case history (2)

A 6-month-old baby boy of Nigerian parents was admitted to A&E, collapsed and unconscious. The family was travelling to the airport by taxi and diverted the car to hospital when the baby became suddenly unwell. Twelve hours before admission the child had been seen at a different A&E department with a short history of poor feeding, irritability and diarrhoea. He was noted to be febrile but not thought to be seriously unwell.

On examination the child was noted to be pale, with a GCS of 5. He was febrile at 39.5° with a firm spleen extending to below the umbilicus. Shortly afterwards, the child had a cardiorespiratory arrest and could not be resuscitated. The results of a blood count and blood film taken before death were:

Blood count	Blood film
Hb 24 g/L	Polychromasia
MCV 76 fL	Very reduced platelets
WBC 30.5 × 10⁹/L	Nucleated red cells
Platelets 27 × 10⁹/L	Occasional elongated sickle cells
Reticulocytes 7.0%	Diplococci both within neutrophils and macrophages and free in the plasma

Subsequent investigations demonstrated Streptococcus pneumoniae on blood culture.

Progress.

This baby presented moribund with splenomegaly, severe anaemia and thrombocytopenia. The reticulocytosis/polychromasia and nucleated red cells suggested a haemolytic anaemia. Haemoglobin electrophoresis subsequently confirmed sickle-cell anaemia (HbSS). The sickle-cell mutation affects the beta-globin gene and only assumes clinical importance 4 months after birth, when gamma-globin gene activity is suppressed and the beta-globin gene activated.

This child’s death was due to overwhelming infection with Streptococcus pneumoniae, which was present in enormous numbers in the bloodstream. The thrombocytopenia was almost certainly related to DIC secondary to the bacterial infection. Severe hyposplenism is a characteristic feature of sickle-cell anaemia and is established by 4–6 months. Pneumococcal sepsis secondary to hyposplenism is a common cause of death in children less than 3 years old with sickle-cell anaemia.

The gross splenomegaly and severe anaemia were due to acute splenic sequestration of sickled red cells within the spleen, which often accompanies pneumococcal sepsis in this age group (see p. 126).

Overwhelming post-splenectomy infection (OPSI) is the most feared complication of hyposplenism.

Remember

• The greatest risk of OPSI following splenectomy is in the first 2 years but the increased risk is lifelong

• The mortality rate with OPSI due to Streptococcus pneumoniae is 50% despite treatment.

Pathophysiology

• Decreased antibody synthesis

• Decreased phagocytosis of opsonised bacteria.

The major pathogens involved in OPSI are:

• Streptococcus pneumoniae > 80%

• Haemophilus influenzae type B

• Neisseria meningitidis.

These are all encapsulated bacteria – the spleen is a vital first line of defence against encapsulated organisms. Severe infections in the hyposplenic patient can also occur in malaria and babesiosis (mosquito and tick bites, respectively) and following dog bites with Capnocytophaga canimorsus.

Remember

• Following vaccination check adequacy of antibody response

• Repeat antibody levels at 5 years post-vaccination and give booster doses if appropriate.

Prevention of OPSI depends on:

• Identification of the patient at risk

• Education of the patient about the risks of infection, dog bites and tropical travel

• Issue of a ‘post-splenectomy’ card and leaflet to the patient

• Lifelong prophylactic antibiotic therapy, e.g. penicillin V 250 mg × 2 daily

• Vaccination with a pneumococcal polysaccharide conjugate vaccine and the Hib vaccine.

Blood transfusion

The Blood Transfusion Department supplies red cells, platelets and plasma products, such as fresh frozen plasma, cryoprecipitate and human albumin.

The efficient and safe provision of blood products depends on good communication between you and the laboratory, and accurate patient identification.

Always

• Provide complete and accurate patient identification on the blood sample and request form.

• Tell the Blood Transfusion Department how much of what blood product is required and the urgency of the clinical situation.

Never

• Take blood from more than one patient at a time.

• Prelabel the blood sample tube.

Remember

When you request blood always make clear the urgency of the clinical situation:

• Very urgent: there is a life-threatening haemorrhage and blood is required in 1–5 min:

– ACTION: No pre-transfusion compatibility test. The laboratory will issue group 0 Rh(D) negative blood

• Urgent: blood required in 5–10 min:

– ACTION: ABO and Rh(D) group on patient sample. The laboratory will issue ABO and Rh(D) group compatible blood

• Non-urgent: blood required in 30–60 min:

– ACTION: Full pre-transfusion compatibility test. The laboratory will issue fully compatible blood.

To provide compatible red cells for transfusion the following procedures are undertaken by the Blood Transfusion laboratory:

• ABO and Rh(D) blood group:

• Major haemolytic transfusion reactions usually result from the transfusion of ABO incompatible blood.

• The Rh(D) antigen is very immunogenic and the development of anti-D must be avoided in women of childbearing age.

• Antibody screen: excludes the presence of clinically significant red cell alloantibodies in the patient’s plasma. These might result in an acute or delayed haemolytic transfusion reaction.

• Selection of appropriate donor units: wherever possible, blood of the same ABO and Rh(D) group as the patient is selected and will be negative for the appropriate antigen if an alloantibody has been identified.

• Cross-match: the patient’s plasma is reacted with the donor red cells in vitro. Incompatibility is indicated by agglutination or haemolysis.

A full compatibility procedure is always completed but this can be retrospective if the clinical demand for blood is urgent.

Case history (1)

You are asked to see a 72-year-old man with myelodysplasia who receives regular blood transfusions. One unit of blood was given uneventfully but 15 min into the second unit he began to shiver, felt unwell and developed a pyrexia and tachycardia.

A febrile transfusion reaction to HLA or granulocyte antigens is common in multi-transfused patients but cannot be safely distinguished from a haemolytic transfusion reaction due to red cell antibodies without appropriate laboratory tests.

Action

Figure 6.13 Antiglobulin (Coombs’) tests. The anti-human globulin forms bridges between the sensitised cells causing visible agglutination. The direct test detects patients’ cells sensitised in vivo. The indirect test detects normal cells sensitised in vitro. HDN, haemolytic disease of newborn.

Outcome

The red cell alloantibody was identified.

Progress.

An error in the collection of the blood from the laboratory led to the wrong blood being given in this man. The error was reported to the hospital as a serious event. The patient maintained his normal blood pressure and his symptoms settled, requiring no further treatment for this.

A major review of blood transfusion procedures was instituted. Fortunately with the prompt treatment, this man had no serious problems.

Other acute complications of blood transfusion can present with:

Remember

There are other longer-term complications of blood transfusion including:

• Post-transfusion purpura (PTP)

• Viral infection: hepatitis C, hepatitis B, HIV (Note: donor blood in many countries checked for these), CMV

• Iron overload (multiple transfusions)

• Graft versus host disease.

Case history (2)

A 64-year-old man with known severe chronic liver disease on the liver transplant list.

He has been admitted on a number of occasions with haematemesis due to variceal bleeding. Endoscopic banding of the varices has been undertaken and he is on propranolol therapy.

He is admitted on this occasion with a large haematemesis.

On examination he is cold, pale, pulse rate is 120/min and he has a blood pressure of 80/50.

He is in hypovolaemic shock and needs urgent resuscitation with fluid and blood and vasocontrictor therapy with terlipressin before urgent endoscopy.

Haemostasis failure is due to:

• DIC: secondary to hypovolaemic shock with additional liver failure, infection or tissue trauma

• Dilutional coagulopathy

• Stored blood is depleted of coagulation factors and contains few platelets.

Further reading

. Practical blood transfusion. Murphy MF, Pamphilon D, eds. 3rd edn. Oxford: Wiley-Blackwell; 2009.

Haematological oncology

This umbrella term covers a huge range of disorders. There are those that present dramatically and require urgent treatment and, at the other end of the spectrum, there are diseases that are indolent and chronic, often requiring no therapy. You should be able to recognise the low-grade (non-urgent) disease and high-grade (urgent) disorders and refer to your haematology department (outside normal hours do not be afraid to talk to the haematology registrar/consultant on call).

What main groups of disease are there?

• Leukaemias: can be acute (short duration, serious, rapidly fatal if not treated) or chronic. Generally have elevated WBC and other features (see below). These are marrow-/blood-based diseases.

• Lymphomas are lymph-node-based, sometimes involving blood and marrow. Some need urgent treatment and others can be sorted out at leisure.

• Myeloma is a low-grade, highly destructive disorder caused by malignant plasma cells, often presenting with bone pain, renal failure and hypercalcaemia.

Case history (1)

A 63-year-old cleaner is admitted to the medical assessment unit (MAU) with pyrexia and cough productive of sputum. Her general health has been reasonable until now.

On examination she has chest signs suggestive of pneumonia. In addition, she has generalised lymphadenopathy and a three-fingerbreadth spleen. Scarring over her trunk is, she claims, due to shingles 4 months earlier.

A full blood count shows mild anaemia (Hb 106 g/L), normal platelets, and a WBC elevated at 25 × 10⁹/L. The haematology technician phones to say most of the white cells are lymphocytes and there are smear cells on the film.

Remember

A smear cell is an artefact induced by making the blood film (the CLL cells are fragile and burst). There are no smear cells actually circulating in the patient’s blood.

You need to establish

• Whether this is an acute or chronic disease

• If urgent treatment is required

• What steps you would need to take to make a diagnosis.

The key features

• Lymphadenopathy/splenomegaly

• High WBC with smear cells.

This must be chronic lymphocytic leukaemia (CLL), the most common leukaemia in adults (Fig. 6.14). It is a slowly progressive disorder and is an incidental finding or presents with an infective complication. Shingles is a fairly common presenting feature.

Figure 6.14 Blood film in chronic lymphocytic leukaemia showing numerous smear cells (artefacts).

CLL is a disease mainly of the B lymphocytes (95%, the remaining 5% are T lymphocytes) – determined by checking cell markers. There is a reduction in immunoglobulin synthesis leading to the infective complications.

Other features

• Might be decreased Hb and platelets (depends on disease stage)

• Haemolytic anaemia (red cell autoantibodies)

• Other autoimmune complications.

Management

On day of admission

Start IV antibiotics (e.g. cefuroxime 750 mg × 3, erythromycin 500 mg × 4); rehydrate if necessary. Refer to the haematology department next day.

The prognosis in CLL is very variable and the disease may remain stable for several years. Many patients (approximately 30%) with CLL never need any treatment at all and lead normal lives.

Long-term treatment

Observation; the patient might require oral chemotherapy at a later stage (e.g. chlorambucil). Rituximab, in combination with chemotherapy, is now first line therapy.

Case history (2)

You are called to see a 43-year-old accountant in A&E. This man went to see his doctor suffering from excessive tiredness. You are presented with an anxious, pale man, who has bruising over his lower limbs and arms. Temperature is 39°C. He is admitted urgently to MAU, where further examination reveals no other signs.

What tests would you arrange?

The Hb is 60 g/L, WBC 90 × 10⁹/L and platelets are 30 × 10⁹/L. Renal function is normal and CXR shows minimal increased shadowing at the right base.

Remember

Do not wait until the next morning – the patient may succumb before then!

Is this an acute or chronic disorder?

A short history in an ill patient with severe anaemia and thrombocytopenia indicates an acute disorder.

You must ask what the white cells are, morphologically. If they are neutrophils (neutrophilia), this might reflect an underlying infection; this is unlikely with such a high WBC.

However, the technician looks at the blood film and tells you they look like blasts.

Remember

Blasts are primitive white cells present in bone marrow in small numbers. They are never seen in peripheral blood in health.

This suggests an acute leukaemia (Fig. 6.15). In a patient of this age, acute myeloid leukaemia is likeliest (if he were a child then acute lymphoblastic leukaemia is more likely).

Figure 6.15 Bone marrow in acute myeloid leukaemia showing numerous large leukaemic blasts.

Investigations

• Specific diagnostic tests (performed by haematology department)

• Peripheral blood film examination (are there Auer rods? If so, their presence confirms AML; these are not all that common)

• Bone marrow aspirate and biopsy

• Cell marker analysis (determines pattern of antigens on white cells)

• Cytogenetic studies on marrow blasts: several karyotypic abnormalities are diagnostic

• Plus other tests, e.g. HLA typing

You should aim to perform only the initial treatment steps: IV fluids, empirical (blind) therapy of infection (send blood and urine cultures first) and then notify the haematology staff as soon as possible.

Case history (3)

A 72-year-old butcher is currently on the orthopaedic ward with collapse of one of his lumbar vertebrae. The orthopaedic SHO is concerned because some results have come back which he wishes to discuss with you.

The patient has mild anaemia with an elevated WBC (26 × 10⁹/L, mainly neutrophils). The ESR is 120 mm/h. Blood film comment: red cell rouleaux.

There is mild renal impairment and hypercalcaemia (corrected calcium is 3.21 mmol/L).

The patient appears quite uncomfortable and has lower back pain, pain in the left rib cage, right humerus and right thigh. His general health was excellent until about 4 months ago when he developed anorexia and mild weight loss. His wife, who is present, is concerned as he is forgetful and confused at times (this has been much worse over the past 1–2 weeks).

What possible diagnoses are there?

Although not in extremis, this man is ill:

• An ESR of 120 suggests serious underlying pathology (an ESR of 120 could be due to serious infection, autoimmune disease, rheumatoid disease, malignancy).

• Red cell rouleaux, renal impairment and hypercalcaemia in a patient with bone disease suggest either a primary bone disorder (such as myeloma) or possible infiltration by malignancy, e.g. carcinoma.

If outside working hours there is little else you can request. Your main objective is to treat the symptoms, e.g. rehydrate, start antibiotics if you think infection is present, correct the elevated calcium level (see p. 450). Alert the haematology team.

As soon as possible, check:

• Blood film.

• Immunoglobulin levels/serum protein electrophoresis/immunofixation.

• Repeat biochemistry to check renal function and calcium level.

• Send urine for Bence–Jones protein and plasma for free immunoglobulin light chains.

• Blood cultures if febrile.

• MSU.

• Arrange skeletal survey (plain radiology of skull, spine, pelvis, femora).

In this case the results are:

• Elevated total IgG with reduced IgA and IgM.

• Serum IgG M paraprotein (paraprotein = monoclonal immunoglobulin produced by the malignant clone of plasma cells).

• Bence–Jones protein present: kappa light chains.

• Widespread lytic lesions throughout skeleton.

• Subsequent bone marrow aspirate showed infiltration by abnormal plasma cells (Fig. 6.16).

Figure 6.16 Bone marrow aspirate in myeloma showing large numbers of plasma cells.

Diagnosis.

Multiple myeloma.

The patient should be referred for specialist advice, i.e. treatment for his myeloma. He also needs bisphosphonate treatment for his bone disease and orthopaedic referral for possible kyphoplasty, which involves inflating a balloon in the affected vertebral body and filling this, with methyl methacrylate cement in order to restore the vertebral shape.

Case history (4)

A 50-year-old bank manager is admitted with weight loss, sweats and splenomegaly.

On examination initial investigations show mild anaemia, WBC 200 × 10⁹/L and platelets 600 × 10⁹/L.

What further information do you require?

• White cells: are they blasts? No – there are neutrophils, eosinophils, basophils and early (i.e. immature) granulocytes (e.g. promyelocytes, myelocytes).

• How large is the spleen? Palpable to umbilicus (ultrasound = 24 cm).

Biochemical screen

• Normal apart from elevated serum uric acid level.

• Re-examine patient yourself. Are there any other abnormal findings?

• There is no lymphadenopathy.

• Liver edge is palpable.

• Chest is clear.

• Fundi: NAD.

What is the underlying diagnosis?

There are several significant findings, i.e. very high WBC, splenomegaly with weight loss and sweats. Could the patient have an underlying infection/neoplasm producing these features (i.e. reactive process)? Yes, but it is much more suggestive of an underlying primary blood disorder such as chronic myeloid leukaemia, because the white cell count is high with the whole spectrum of granulocytic cells present (Fig. 6.17). If the blood picture were ‘reactive’, a neutrophilia would be more likely.

Figure 6.17 CML blood film: note the large numbers of granulocytic cells, in particular neutrophils, at all stages of development.

What single investigation will confirm the diagnosis?

Cytogenetic analysis of peripheral blood white cells or bone marrow white cells.

The Philadelphia chromosome will be present (translocation of DNA between chromosomes 9 and 22) in most (95%) CML.

Remember

Philadelphia chromosome is present in some acute leukaemias but this patient does not have features of acute leukaemia, and the bone marrow will confirm this.

Does he need urgent referral to the haematology team?

Unless the patient is very unwell or has features of leucostasis (blood sludging in the lungs or brain due to high WBC) then there is no immediate need for urgent referral, but you should alert the haematology staff, who should take over the patient’s care next day. Leucostasis can result in:

• Confusion

• Visual disturbance

• Cough and dyspnoea.

Features suggestive of chronic/low-grade haematological malignancy

• Less dramatic onset

• Not particularly unwell

• Previous infection (e.g. chest infection or herpes zoster)

• Absence of blasts in blood

• Abnormal peripheral blood cells: lymphocytes with abnormal morphology or immature granulocytes. Generalised lymphadenopathy present for months.

Refer all suspected patients with acute leukaemia to the haematology team as soon as possible, for specialist management.

Remember

The WBC does not have to be high to diagnose acute (or chronic) leukaemia. In many cases acute leukaemia may present with normal or low WBC.

Not all patients with acute leukaemia are ill at presentation.

Further reading

Appelbaum FR, Rowe JM, Radich J, Dick JE. Acute myeloid leukemia. Hematology (American Society of Hematology Educational Program). 2001:62–86. Review

. The Lymphoid neoplasms. Magrath IT, Boffetta P, Potter M, eds. 3rd edn. London: Hodder Arnold; 2010.

Sawyers CL. Even better kinase inhibitors for chronic myeloid leukaemia. N Engl J Med. 2012;362:2314–2315.

Anaemia in rheumatoid arthritis

Case history

A 53-year-old woman with rheumatoid arthritis was admitted for investigation of anaemia.

On examination she had typical features of rheumatoid arthritis in her hands and arms. Her hands are grossly deformed, swollen with redness over the MCPs. She has tender, subcutaneous nodules on her elbows. All these features were indicative of an acute flare-up of her condition.

Investigations showed a Hb of 92 g/L, MCV 84 fL, WBC 11.4 × 10⁹/L and platelets 490 × 10⁹/L. Serum vitamin B₁₂, folate and ferritin were checked and found to be normal.

There are several possible causes for this anaemia:

• Bleeding (e.g. due to NSAIDs): the patient denies obvious GI bleeding. If she had been bleeding chronically her MCV would probably be reduced (iron deficiency). This woman’s MCV is normal, making chronic blood loss unlikely.

• Poor diet: can induce folate deficiency, but we know her folate level is normal.

• Autoimmune causes: e.g. pernicious anaemia (PA; she has rheumatoid arthritis (RA) and might possibly have PA, another associated autoimmune disease). However, her vitamin B₁₂ level is normal.

• Felty’s syndrome (p. 123): RA, splenomegaly and neutropenia. This woman has no features of this disorder.

• Infiltrations, myelodysplasia (MDS): difficult to exclude these in the absence of additional information, e.g. bone marrow. In MDS and marrow infiltration due to carcinoma in the presence of reduced Hb, it is likely (but not always the case) that the blood film would show morphological abnormalities such as red cell ‘tear-drop’ cells, nucleated red cells, hypogranular neutrophils, immature white cells. This woman’s blood film simply showed RBC rouleaux.

• Renal impairment, liver disease: again, morphological abnormalities are usually present on the film, and biochemical screen will assess liver and renal function.

• Drug-induced anaemia: several mechanisms, e.g. haemolysis. There are no features suggesting this. Remember the bone marrow suppressive effect of gold and azathioprine.

This woman’s ESR was found to be > 100 mm/h with a high C-reactive protein. Her rheumatoid disease was very active (flare-up) and 3 months before admission her Hb was 110 g/L. The drop in Hb has coincided with the flare-up; a common finding, especially in patients with rheumatoid arthritis.

A major diagnostic pitfall in the assessment of anaemia in patients with inflammatory disease is in the determination of iron status. Patients can be iron deficient (confirmed by bone marrow aspirate stained for iron, the ‘gold standard’) yet have a normal serum ferritin: an acute-phase protein that rises to normal (or > normal) in such patients.

Assessment of iron status in patients with inflammatory disorders

• Ferritin: likely to be misleading for the reasons given above.

• Serum iron/TIBC: might show reduction of both in chronic disease. These tests are seldom performed now because they are unreliable. Ferritin is the preferred assay.

• Bone marrow: will determine iron status, but is expensive, painful and to be avoided if possible.

• Serum transferrin receptor assay: number of transferrin receptors on red cells rises in iron deficiency but remains normal in secondary anaemia. This test is replacing bone marrow aspirate in diagnosis of iron deficiency in patients such as this.

This woman had normal transferrin receptor levels, confirming anaemia of chronic disease. She failed treatment with sulfasalazine and methotrexate. She was therefore treated with Etanercept, a fully humanised p75 TNF α receptor IgG fusion protein subcutaneously, with a good response in her joints and the ESR. She is now attending the Rheumatology Clinic for follow-up.

Anaemia in chronic kidney disease (CKD)

The kidney is the body’s major site of erythropoietin (Epo) production. In renal disease Epo levels fall, leading to chronic anaemia.

Additional factors in development of anaemia in CKD

• Reduced RBC lifespan

• Iron deficiency (blood loss in dialysis tubing or GI tract blood loss)

• Folate loss due to dialysis.

What features should you look for?

• Low Hb

• Normal MCV

• Reticulocytes normal or reduced: low Epo reduces RBC production.

• Bizarre RBC shape on blood film: burr cells.

Management

Generally, Epo replacement given at dialysis improves the Hb in these patients (50–100 units/kg × 3 per week IV). Alternatively, darbepoietin alfa can be given weekly or pegzerepoietin alfa monthly. Might also require additional iron and folic acid. The Hb should be kept within the range of 100–120 g/L.

Anaemia in liver disease

Complex and multifactorial

Patients with chronic liver failure generally have moderate anaemia.

The red cells are often macrocytic and can have abnormal shapes – target cells and spur cells – owing to membrane abnormalities.

Vitamin B₁₂ levels are normal or high; folate levels are often low, owing to poor dietary intake.

• Bleeding produces a hypochromic, microcytic picture.

• Alcohol causes macrocytosis, sometimes with leucopenia and thrombocytopenia due to bone marrow suppression.

• Hypersplenism results in pancytopenia.

• Cholestasis can often produce abnormal-shaped cells and also deficiency of Vitamin K.

• Haemolysis accompanies acute liver failure and jaundice.

• Aplastic anaemia is present in up to 2% of patients with acute viral hepatitis.

• A raised serum ferritin with transferrin saturation (> 60%) is seen in hereditary haemochromatosis.

Anaemia in cancer

Information

Rouleaux

The tendency of red cells on the blood film to stack up like a ‘pile of coins’ relates to an increase in plasma proteins, particularly fibrinogen, as part of the acute-phase response.

This patient has a microcytic anaemia with rouleaux formation on the blood film. The anaemia of chronic disorder is common in disseminated malignancy and many other inflammatory and infective illnesses.

Anaemia of chronic disorder: pathophysiology

• Functional iron deficiency

• Reduced sensitivity to erythropoietin

• Reduced red cell lifespan.

She has a raised total white cell count with nucleated red cells and immature granulocytes seen on the blood film. This is a leucoerythroblastic picture; such cells are normally confined to the bone marrow. Bone marrow infiltration by disseminated malignancy disrupts the normal mechanisms controlling release of haemopoietic cells into the blood.

Leucoerythroblastic anaemia

• Bone marrow infiltration:

Remember

Most blood count analysers cannot distinguish nucleated RBCs (nRBCs) from white cells, and when nRBCs are present might give an inappropriately high white cell count. Ask for the blood film to be reviewed.

The reticulocyte count is not increased and no red cell fragmentation is present on blood film review. Microangiopathic haemolytic anaemia (MAHA), which sometimes complicates disseminated breast, prostate or gastric carcinoma, is not likely to be a feature in this patient. MAHA results from mechanical disruption of red cells in small blood vessels and can be complicated by chronic DIC, with a coagulopathy, reduced fibrinogen concentration, elevated fibrin breakdown products and thrombocytopenia.

Remember

Before accepting that a patient is thrombocytopenic:

• Ask for the blood film to be reviewed

• Repeat the blood count: fibrin formation or a small clot in the sample will result in a low platelet count.

This patient has thrombocytopenia. The aetiology of thrombocytopenia in disseminated malignancy is complex and can be due to:

• Bone marrow infiltration

• Folate deficiency secondary to anorexia

• Cytotoxic chemotherapy

• DIC.

However, review of the blood film in this patient reveals that the thrombocytopenia is spurious – platelets are clumped on the blood film. Platelet clumping is a common phenomenon related to the EDTA anti-coagulant that blood is collected into.

Progress and management

This lady was treated symptomatically with NSAIDs and started on bisphosphonates. She was referred to the Oncology Department for an MDT for discussion of further management.

Infection/sepsis

Bacterial sepsis

This results in a characteristic constellation of changes in the blood which provide confirmatory evidence of sepsis and, in occasional patients with occult infection, may direct appropriate investigations.

• Neutrophil leucocytosis: increased numbers of neutrophils.

• Immature granulocytes (= left-shift): occasional promyelocytes, myelocytes.

• Toxic granulation: coarse neutrophil granulation.

• Döhle bodies (these are white cells containing large RNA inclusions that are seen in, e.g., sepsis, malignancy, pregnancy).

Uncontrolled sepsis might be accompanied by:

• A falling white cell count/neutropenia

• Granulocyte vacuolation

• Bacteria visible on the stained blood film

• Thrombocytopenia

• DIC.

Anaemia is common in bacterial sepsis and is usually related to the acute-phase response. Occasionally, haemolysis and red cell fragmentation accompany DIC, and severe haemolysis might complicate Clostridium welchii septicaemia with spherocytosis on the blood film.

Malaria (see also case on p. 14)

This should be suspected in any individual with a fever who has recently visited/come from malarial parts of the world. Thrombocytopenia is a frequent accompaniment of malaria infection and haemolytic anaemia might develop, particularly if an individual also has G6PD deficiency.

Remember

If malaria is suspected:

• Ask for thick and thin blood film examination

• Repeat × 3–5 if the initial results are negative but clinical suspicion persists.

If malaria is diagnosed:

• Ask for the species of Plasmodium

• If P. falciparum, ensure you are given the parasite count. This indicates the severity of infection:

– A high parasite count > 5.0% indicates an increased risk of cerebral malaria

– Pre-schizont forms indicate an increased risk of cerebral malaria.

Some features of severe falciparum malaria

Remember

Treatment for severe malaria due to P. falciparum is a MEDICAL EMERGENCY. Give:

• Artesunate 2.4 mg/kg single bolus and then at 12 h and 24 h and then daily until oral medication can be tolerated.

• Quinine dihydrochloride 20 mg/kg IV over 4 h, then 10 mg/kg if artesunate unavailable.

See National Formulary for details; see p. 15 for other treatment.

Beware

The parasite count in falciparum malaria may underestimate the severity of the infection due to parasite sequestration. Always take a diagnosis of falciparum malaria seriously.

Viral infections

These produce a variety of specific and non-specific effects on the blood that might be helpful diagnostically.

Information

• Morphology of lymphoid cells

• Monospot or Paul–Bunnell test

• Immunophenotyping

Non-specific effects

These are common to many viral illnesses:

• Mild neutropenia and thrombocytopenia

• Occasional reactive lymphoid cells on blood film.

Specific effects

• Glandular fever is produced by Epstein–Barr virus infection (see p. 18). Similar features are seen in cytomegalovirus but also in toxoplasmosis. The reactive lymphocytosis must be distinguished from a malignant lymphoid proliferation.

• Erythrovirus B₁₉ causes Fifth’s disease and specifically infects erythroid progenitor cells, resulting in transient erythroid hypoplasia and failure of red cell production. This is of no consequence in otherwise healthy individuals but, in those with chronic haemolytic anaemia, it causes a sudden fall in the haemoglobin concentration, with absent reticulocytes. Urgent blood transfusion can be life saving.

Remember

Erythrovirus B₁₉ is infective, and chronic haemolytic anaemias can be inherited, e.g. sickle-cell disease. Ask about other family members with haemolysis, ‘Are they well?’

• HIV infection results in anaemia, thrombocytopenia and neutropenia in most patients. The severity of the cytopenia is related to the stage of the disease and is reflected by ineffective haemopoiesis with dysplastic changes in bone marrow precursor cells. It can be exacerbated by intercurrent infection and therapy.

^*Advised with NSAIDs in renal impairment.