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Ovid: Oxford Handbook of Clinical Medicine

Editors: Longmore, Murray; Wilkinson, Ian B; Turmezei, Tom; Cheung, Chee Kay Title: Oxford Handbook of Clinical Medicine, 7th Edition Copyright ©2007 Oxford University Press > Table of Contents > 9 – Haematology 9 Haematology

Fig 1. The old methodology: a naked haematologist works alone hammering a red cell into shape. “Every space larger than a red globule of man’s blood is visionary, and it is created by the Hammer of Los.” Image from the Song of Los, William Blake.image1
Fig 2. The new methodology: teamwork in action, as haematologist, geneticist, and lab staff deal with a troublesome spherocyte.image2 (×3000)

P.309
On the taking of blood and of holidays This is not one of those pages about how you should be kind to the patient, explain in full what you are going to do, talk him or her through venepuncture, label the bottles carefully, and make a plan for communicating the results. Be all this as it may, there is something else which needs communicating about the act of taking blood. It is partly to do with the fact that as blood is life, and, because, as Ruskin taught us, ‘there is no wealth but life’, we are led to the conclusion that what is special about taking blood is that for once we are being given something valuable by the patient. What is this wealth? The answer is time. For while the blood is flowing into our tube we cannot be disturbed. We are excused from answering our bleeps, and from making polite conversation (a few grunts in reply to patients’ enquires about the colour of their blood is quite sufficient)— and we can indulge in that almost unimaginable luxury, at least as far as life on the wards is concerned, of being alone with our own thoughts. Thinking of this sacred time as a sort of hypnotic holiday is excellent. For however many nights we have been awoken, and through however many wards we have traipsed to this bedside, this little holiday will be worth an hour’s sleep—if our mind is furnished and ready to empty itself of all objectivity. The best sight in haematological practice is, during venepuncture, to watch for those occasions when, owing to some chance characteristic of flow, the jet of blood streaming into our tube breaks up into countless globules, and before coalescing again, these globules jostle together like the overcrowded chain of events which led us to this bedside. During this time, allow your own thoughts to coalesce into a more peaceful order if you can, and let William Blake help you in the task of furnishing your mind to banish objectivity, for he knew some truths about haematology unknown to strictly rational practitioners of this art: The Microscope knows not of this nor the Telescope: they alter The ratio of the Spectators Organs but leave Objects untouch’d For every space larger than a red globule of Mans blood Is visionary, and it is created by the Hammer of Los:1 And every space smaller than a Globule of Mans blood opens Into eternity of which this vegetable Earth is but a shadow. The red Globule is the unwearied Sun by Los created To measure Time and Space to mortal Men …

Fig 1. A normal blood film, with a neutrophil, normal red cells, and platelets (arrows).image3

P.310
Anaemia Anaemia is defined as a low haemoglobin (Hb) concentration, and may be either due to a low red cell mass, or increased plasma volume (eg in pregnancy). A low Hb (at sea level) is <13.5g/dL for men and <11.5g/dL for women. Anaemia may be due to reduced production or increased loss of RBC and has many causes. These will often be distinguishable by history, examination, and inspection of the blood film. Symptoms Due to the underlying cause or to the anaemia itself: fatigue, dyspnoea, faintness, palpitations, headache, tinnitus, anorexia—and angina if there is pre-existing coronary artery disease. Signs May be absent even in severe anaemia. There may be pallor (eg conjunctivae, although this is not a reliable sign). In severe anaemia (Hb <8g/dL), there may be signs of a hyperdynamic circulation, eg tachycardia, flow murmurs (ejection-systolic loudest over apex), and cardiac enlargement; or retinal haemorrhages (rarely). Later, heart failure may occur: here, rapid blood transfusion may be fatal. Types of anaemia The first step in diagnosis is to look at the mean cell volume (MCV, normal MCV is 76-96 femtolitres, 1015 fL = 1L). Low MCV (microcytic anaemia)

  • Iron-deficiency anaemia (IDA, most common cause): p312.
  • Thalassaemia (suspect if the MCV is ‘too low’ for the level of anaemia and the red cell count is raised): p328.
  • Sideroblastic anaemia (very rare): p312.

NB: The last two are conditions where there is an accumulation of iron, and so tests will show serum iron↑, ferritin↑, and a low total iron-binding capacity (TIBC). Normal MCV (normocytic anaemia)

  • Acute blood loss
  • Anaemia of chronic disease (or ↓MCV)
  • Bone marrow failure
  • Renal failure
  • Hypothyroidism (or ↑MCV)
  • Haemolysis (or ↑MCV)
  • Pregnancy

If wcc↓ or platelet↓, suspect marrow failure: see p348. High MCV (macrocytic anaemia)

  • B12 or folate deficiency
  • Alcohol excess—or liver disease
  • Reticulocytosis (eg with haemolysis)
  • Cytotoxics, eg hydroxycarbamide
  • Myelodysplastic syndromes
  • Marrow infiltration
  • Hypothyroidism
  • Antifolate drugs (eg phenytoin)

Haemolytic anaemias: (p322). These disorders do not fall elegantly into the above classification as the anaemia may be normocytic, or, if there are many young (hence larger) RBCs and reticulocytes, macrocytic. Suspect if there is a reticulocytosis (>2% of RBCs; or reticulocyte count >100×109/L), mild macrocytosis, haptoglobin↓, bilirubin↑ & urobilinogen↑. Often mild jaundice (but no bilirubin in urine as haemolysis causes pre-hepatic jaundice). Blood transfusion The decision on whether to transfuse depends on a number of factors: the onset (acute or chronic), the severity of anaemia (one review suggests that transfusion is not essential for most patients unless Hb <7g/dL)image4, if there is co-morbidity (have a lower threshold to transfuse in ischaemic heart disease) and whether the patient is symptomatic. If there is an acute cause (eg haemorrhage with active peptic ulcer), transfuse up to 8g/dL. Chronic anaemia is better tolerated, and it is important to ascertain the cause eg in iron deficiency anaemia, iron supplements will raise the haemoglobin in a safer and less costly way. In severe anaemia with heart failure, transfusion is vital to restore Hb to safe level, eg 6-8g/dL, but must be done with great care. Give packed cells slowly with 10-40mg furosemide IV/PO with alternate units (dose depends on previous exposure to diuretics; do not mix with blood). Check for rising JVP and basal crackles. If CCF gets worse, stop and treat. If immediate transfusion is essential, a 2-3 unit exchange transfusion can be tried, removing blood at same rate as it is transfused. P.311

Fig 1. ‘Conjunctival pallor’, the classic sign of anaemia, is a confusing term as the conjunctiva is translucent, transmitting the colour of the structures under it. The ‘pallor’ in fact refers to the vasculature on the inner surface of the lid which lacks haemoglobin.

It is this colourimage, whereas it should be more like this:image. P.312
Iron-deficiency anaemia (IDA) This is common (seen in up to 14% of menstruating women). Causes:

  • Blood loss eg menorrhagia or GI bleeding (upper p244; lower p70).
  • Poor diet may cause IDA in babies or children (but rarely in adults), those on special diets, or wherever there is poverty.
  • Malabsorption (eg coeliac disease) is a cause of refractory IDA.
  • In the Tropics, hookworm (GI blood loss) is the most common cause.

Signs: Chronic IDA (signs now rare): koilonychia (fig 1 and p27), atrophic glossitis, angular cheilosis (fig 2), and rarely, post-cricoid webs (Plummer-Vinson syndrome). Tests: Microcytic, hypochromic anaemia with anisocytosis and poikilocytosis (fig 3 and 4). ↓MCV, ↓MCH & ↓MCHC. Confirmed by ferritin↓ (also serum iron↓ with ↑total iron binding capacity—TIBC, but these are less reliable). ↑red cell protoporphyrin. NB: Ferritin is an acute phase protein and ↑ with inflammation eg infection, malignancy. Serum transferrin receptors are also ↑ in IDA but are less affected by inflammation. If MCV↓, and good history of menorrhagia, oral iron may be started without further tests. Otherwise investigate for GI blood loss: gastroscopy, sigmoidoscopy, barium enema or colonoscopy, stool microscopy for ova if foreign travel. Faecal occult blood is not recommended as sensitivity is poor. ▶Iron deficiency without an obvious source of bleeding mandates a careful GI workup.1 1 In one study, 11% presenting to their GP with IDA had GI carcinoma.image Consider both upper and lower GI investigation as in another study, 29% (n=89) had abnormalities on both.image Treatment: Treat the cause. Oral iron eg ferrous sulfate 200mg/8h PO. SE: nausea, abdominal discomfort, diarrhoea or constipation, black stools. Hb should rise by 1g/dL/week, with a modest reticulocytosis (ie young RBC, p314). Continue until Hb is normal and for at least 3 months, to replenish stores. Intravenous iron is almost never needed, but may be indicated if the oral route is impossible or ineffective, eg functional iron deficiency in chronic renal failure, where there is inadequate mobilization of iron stores in response to the acute demands of erythropoietin therapy. The usual reason that IDA fails to respond to iron replacement is that the patient has rejected the pills. Negotiate on concordance issues (p3). Is the reason for the problem GI disturbance? Altering the dose of elemental iron with a different preparation may help. There may be continued blood loss, malabsorption, anaemia of chronic disease; or there is misdiagnosis, eg when thalassaemia is to blame. The anaemia of chronic disease This is associated with many diseases, including chronic infection (eg TB, osteomyelitis), vasculitis, rheumatoid arthritis, malignancy, renal failure. There is cytokine driven inhibition of red cell production. Investigations: Mild normocytic anaemia (eg Hb >8g/dL), ferritin normal or ↑. Treatment: Treat the underlying disease. The anaemia of renal failure is partly due to erythropoietin deficiency and recombinant erythropoietin is effective in raising the haemoglobin level (SE: ‘flu-like symptoms, hypertension, mild rise in the platelet count). It is also effective in raising Hb and improving quality of life in those with malignant disease.image5 Sideroblastic anaemia Characterized by ineffective erythropoiesis, leading to ↑iron absorption, iron loading (bone marrow) and occasionally haemosiderosis (endocrine, liver and cardiac damage due to iron deposition). It may be congenital (rare, X-linked) or acquired—usually idiopathic as one of the myelodysplastic disorders, but can follow chemotherapy, irradiation, alcohol or lead excess, anti-TB drugs or myeloproliferative disease. Hypochromic RBCs are seen on the blood film with ring sideroblasts in the marrow (erythroid precursors with iron deposited in mitochondria in a ring around the nucleus). Treatment: Remove the cause if possible. Pyridoxine may be of benefit. Repeated blood transfusion may be needed in severe anaemia. P.313
Interpretation of plasma iron studies

Iron

TIBC

Ferritin

Iron deficiency

↓

↑

↓

Anaemia of chronic disease

↓

↓

↑

Chronic haemolysis

↑

↓

↑

Haemochromatosis

↑

↓ (or ↔)

↑

Pregnancy

↑

↑

↔

Sideroblastic anaemia

↑

↔

↑

TIBC: total iron binding capacity.

Fig 1. Koilonychia. Spoon-shaped nails, found in iron deficiency anaemia.
Fig 2. Angular cheilosis, ulceration at the side of the mouth, in iron deficiency anaemia. Also a feature of Vitamin B12 and B2 (riboflavin) deficiency.image6 COURTESY OF PROFESSOR THOMAS HABIF
Fig 3. Microcytic hypochromic cells in iron deficiency anaemia.image7 COURTESY OF PROF KRZYSZTOF LEWANDOWSKI
Fig 4. Poikilocytosis and anisocytosis seen in iron deficiency anaemia.image8 COURTESY OF PROF CHRISTINE LAWRENCE
Fig 5. Pathological ring sideroblasts in the bone marrow, with a perinuclear ring of iron granules, found in sideroblastic anaemia.image9

P.314
The peripheral blood film ▶Many haematological (and other) diagnoses are made by careful examination of the peripheral blood film. It is also necessary for interpretation of the FBC indices. Anisocytosis is variation in RBC size, eg megaloblastic anaemia, thalassaemia, IDA. Acanthocytes: (fig 1) RBCs show many spicules due to an unstable red cell membrane lipid structure (eg in abetalipoproteinaemia). Basophilic RBC stippling: (fig 2) Denatured RNA found in RBCs, indicating accelerated erythropoiesis or defective Hb synthesis. Seen in lead poisoning, megaloblastic anaemia, myelodysplasia, liver disease, haemoglobinopathy eg thalassaemia. Blasts: Nucleated precursor cells. They are not normally in peripheral blood, but are seen in myelofibrosis, leukaemia or malignant infiltration by carcinoma. Burr cells: Irregularly shaped cells occurring in uraemia. Dimorphic picture: Two populations of red cells. Seen after treatment of Fe, B12 or folate deficiency, in mixed deficiency (↓Fe with ↓B12 or folate), post-transfusion, or with primary sideroblastic anaemia, where a clone of abnormal erythroblasts produce abnormal red cells, alongside normal red cell production. Howell-Jolly bodies: DNA nuclear remnants in RBCs, which are normally removed by the spleen (fig 8). Seen post-splenectomy and in hyposplenism (eg sickle cell disease, coeliac disease, congenital, UC/Crohn’s, myeloproliferative disease, amyloid). Also in dyserythopoietic states: myelodysplasia, megaloblastic anaemia. Hypochromia: (p312). Less dense staining of RBCs due to ↓Hb synthesis, seen in IDA, thalassaemia, and sideroblastic anaemia (iron stores unusable). Left shift: Immature neutrophils are sent out of the marrow, eg in infection. Leucoerythroblastic anaemia: Immature cells (myelocytes, promyelocytes, metamyelocytes, normoblasts) seen in film. Due to marrow infiltration (eg malignancy) when these cells are displaced; also seen in anorexia, sepsis, severe haemolysis. Leukaemoid reaction: A marked leucocytosis (WCC>50×109/L). Seen in severe illness eg with infection or burns, and also in leukaemia. Pappenheimer bodies: (fig 5) Granules of siderocytes containing iron. Seen in lead poisoning, carcinomatosis, and post-splenectomy. Poikilocytosis is variation in RBC shape, eg in IDA, myelofibrosis, thalassaemia. Polychromasia: RBCs of different ages stain unevenly (young are bluer). This is a response to bleeding, haematinic replacement (ferrous sulfate, B12, folate), haemolysis, or marrow infiltration. Reticulocyte count is raised. Reticulocytes: (normal range: 0.8-2%; or <85×109/L) fig 6. Young, larger RBCs (contain RNA) signifying active erythropoiesis. Increased in haemolysis, haemorrhage, and if B12, iron or folate is given to marrow that lack these. Right shift: Hypermature white cells: hypersegmented polymorphs (>5 lobes to nucleus) seen in megaloblastic anaemia, uraemia, and liver disease. See p318, fig 1. Rouleaux formation: (fig 7) Red cells stack on each other (it causes a raised ESR; p356). Seen with chronic inflammation, paraproteinaemia and myeloma. Spherocytes: Spherical cells found in hereditary spherocytosis and autoimmune haemolytic anaemia. See p324. Schistocytes: Fragmented RBCs sliced by fibrin bands, in intravascular haemolysis. (p324, fig 4) Look for microangiopathic anaemia, eg DIC (p336), haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura (TTP: p300), or pre-eclampsia. Target cells: (also known as Mexican hat cells, fig 8). These are RBCs with central staining, a ring of pallor, and an outer rim of staining seen in liver disease, hyposplenism, thalassaemia—and, in small numbers, in iron-deficiency anaemia. P.315

Fig 1. Acanthocytosis.image10
Fig 2. Basophilic stippling.image11
Fig 3. Burr cells.image12
Fig 4. Left-shift: presence of immature neutrophils in the blood.image16
Fig 5. Pappenheimer bodies.image14image15
Fig 6. Reticulocytes. RNA in RBCs; supravital staining (azure B; cresyl blue) is needed.image13
Fig 7. Rouleaux formation.image17
Fig 8. Film in hyposplenism: target cell (short arrow), acanthocyte (long arrow) and a Howell-Jolly body (arrow head).image18
Fig 9. A Cabot ring; these red/purple-staining filamentous figure-of-8 rings are often seen in RBCs with basophilic stippling.image19 They may be microtubules from mitotic spindles or nuclear remnants. They occur in severe or megaloblastic anaemia, leukaemia, and lead poisoning. It is easy to confuse them with malaria parasites, p385 (especially if stippling gives a ‘chromatin dot’ artefact, as here).image20

P.316
The differential white cell count Neutrophils 2-7.5 × 109/L (40-75% of white blood cells: but absolute values are more meaningful than percentages). Increased in:

  • Bacterial infections.
  • Inflammation eg myocardial infarction, polyarteritis nodosa.
  • Myeloproliferative disorders.
  • Drugs (steroids).
  • Disseminated malignancy.
  • Stress eg trauma, surgery, burns, haemorrhage, seizure.

Decreased in: (see p336)

  • Viral infections.
  • Drugs eg post-chemotherapy, cytotoxic agents, carbimazole, sulfonamides.
  • Severe sepsis.
  • Neutrophil antibodies (SLE, haemolytic anaemia)—↑ destruction.
  • Hypersplenism eg Felty’s syndrome (p357).
  • Bone marrow failure—↓ production (p348).

Lymphocytes 1.5-4.5 × 109/L (20-45%). Increased in:

  • Acute viral infections.
  • Chronic infections eg TB, Brucella, hepatitis, syphilis.
  • Leukaemias and lymphomas, especially chronic lymphocytic leukaemia.

Large numbers of abnormal (‘atypical’) lymphocytes are characteristically seen with EBV infection: these are T-cells reacting against EBV-infected B-cells. They have a large amount of clearish cytoplasm with a blue rim that flows around neighbouring RBCs. Other causes of ‘atypical’ lymphocytes: see p389. Decreased in:

  • Steroid therapy; SLE; uraemia; Legionnaire’s disease; HIV infection; marrow infiltration; post chemotherapy or radiotherapy.

T-lymphocyte subset reference values: CD4 count: 537-1571/mm3 (low in HIV infection). CD8 count: 235-753/mm3; CD4/CD8 ratio: 1.2-3.8. Eosinophils 0.04-0.4 × 109/L (1-6%).image21 Increased in:

  • Drug reactions eg with erythema multiforme, p546.
  • Allergies: asthma, atopy.
  • Parasitic infections (especially invasive helminths).
  • Skin disease: especially pemphigus, eczema, psoriasis, dermatitis herpetiformis.

Also seen in malignant disease (including lymphomas and eosinophilic leukaemia), PAN, adrenal insufficiency,image22 irradiation, Löffler’s syndrome (p696), and during the convalescent phase of any infection. The hypereosinophilic syndrome1 is a disease of unknown cause, with a sustained eosinophil count >1.5 × 109/L for more than 6wks, leading to end-organ damage (endomyocardial fibrosis causing restrictive cardiomyopathy, skin lesions, thromboembolic disease, pulmonary disease, neuropathy, and hepatosplenomegaly). 1 Many previously diagnosed with this have been recently found to have monoclonal genetic abnormalities consistent with chronic eosinophilic leukaemia, with improved molecular techniques.image Monocytes 0.2-0.8 × 109/L (2-10%). Increased in: Post chemo- or radiotherapy, chronic infections (eg malaria, TB, brucellosis, protozoa), malignant disease (including M4 and M5 acute myeloid leukaemia—(p340), and Hodgkin’s disease), myelodysplasia. Basophils 0-0.1 × 109/L (0-1%). Increased in: Myeloproliferative disease, viral infections, IgE mediated hypersensitivity reactions (eg urticaria, hypothyroidism), and inflammatory disorders (eg UC, rheumatoid arthritis). P.317

Fig 1. Neutrophil. These ingest and kill bacteria, fungi and damaged cells.image23
Fig 2. Lymphocyte: divided into T & B types, which have important roles in cell mediated immunity & antibody production.image24
Fig 3. Eosinophil: these play a role in allergic reactions, and in defence against parasitic infections.image25
Fig 4. Monocyte: precursors of tissue macrophages.image26
Fig 5. Basophil. The cytoplasm is filled with dark staining granules, containing histamine, myeloperoxidase and other enzymes. On binding IgE, histamine is released from the basophil.image27

P.318
Macrocytic anaemia Macrocytosis (MCV >96fL) is common, often due to alcohol excess without any accompanying anaemia. Although only ~5% are due to B12 deficiency, pernicious anaemia is the most common cause of a macrocytic anaemia in Western countries. B12 and folate deficiency are megaloblastic anaemias. A megaloblast is a cell in which nuclear maturation is delayed compared to the cytoplasm. This occurs with B12 and folate deficiency, as they are both required for DNA synthesis. Causes of macrocytosis

  • Megaloblastic: B12 deficiency, folate deficiency, cytotoxic drugs.
  • Non-megaloblastic: Alcohol, reticulocytosis (eg in haemolysis), liver disease, hypothyroidism, pregnancy.
  • Other haematological disease: Myelodysplasia, myeloma, myeloproliferative disorders, aplastic anaemia.

Tests: B12 and folate deficiency result in similar blood film and bone marrow biopsy appearances. Blood film: Hypersegmented polymorphs in B12 and folate deficiency, (target cells if liver disease). Other tests: LFT (include γGT), TFT, serum B12 and serum folate (or red cell folate—a more reliable indicator of folate status, as serum folate only reflects recent intake). Bone marrow biopsy is indicated if the cause is not revealed by the above tests. It is likely to show one of the following four states:

  • Megaloblastic.
  • Normoblastic marrow (eg in liver disease, hypothyroidism).
  • Abnormal erythropoiesis (eg sideroblastic anaemia, leukaemia, aplasia).
  • Increased erythropoiesis (eg haemolysis).

Folate is found in green vegetables, nuts, yeast & liver; it is synthesized by gut bacteria. Body stores can last for 3-4 months. Maternal folate deficiency may cause neural tube defects in the fetus. It is absorbed by duodenum and proximal jejunum. Causes of deficiency

  • Poor diet: eg poverty, alcoholics, elderly.
  • Increased demand: eg pregnancy or ↑cell turnover (seen in haemolysis, malignancy, inflammatory disease and renal dialysis).
  • Malabsorption: eg coeliac disease, tropical sprue.
  • Drugs: eg alcohol, antiepileptics (phenytoin, sodium valproate), methotrexate, trimethoprim.

Treatment: Assess for an underlying cause eg poor diet, malabsorption. Treat with folic acid 5mg/day PO for 4 months, ▶never without B12 unless the patient is known to have a normal B12 level, as in low B12 states, it may precipitate, or worsen, subacute combined degeneration of the spinal cord (p320). In pregnancy prophylactic doses of folate (400µg/day) are given from conception until at least 12 wks; this helps prevent spina bifida, as well as anaemia. NB: In ill patients with megaloblastic anaemia (eg with CCF), it may be necessary to treat before the results of serum B12 and folate are at hand. Do tests then treat with large doses, eg hydroxocobalamin 1mg/24h IM, with folic acid 5mg/24h PO. Blood transfusions are very rarely needed, but see p310. Folate and ischaemic heart disease Previous observational studies have indicated that higher homocysteine concentrations are associated with a greater risk of coronary heart disease. It has been suggested that folic acid supplementation may have a role in prevention of cardiac disease by lowering homocysteine levels. However, trial results have so far been disappointing (further studies awaited).image28 One meta-analysis also showed no causal relationship between high homocysteine concentrations and coronary heart disease risk in Western populations.image29 P.319

Fig 1. Megaloblastic anaemia: peripheral blood film showing many macrocytes and one hypersegmented neutrophil (normally there should be ≤5 segments).image30

P.320
B12 deficiency and pernicious anaemia Vitamin B12 is found in meat and dairy products, but not in plants. Body stores are sufficient for 4yrs. It is protein bound and released during digestion. B12 then binds to intrinsic factor in the stomach, and this complex is absorbed in the terminal ileum. In B12 deficiency, synthesis of thymidine, and hence DNA, is impaired, so red cell production is reduced. Causes of deficiency: • Dietary (eg vegans) • Malabsorption: Stomach (lack of intrinsic factor): pernicious anaemia, post gastrectomy; Terminal ileum: ileal resection, Crohn’s disease, bacterial overgrowth, tropical sprue, tapeworms (Dyphyllobothrium) • Congenital abnormalities in metabolism. Features: General: Symptoms of anaemia (p310), ‘lemon tinge’ to skin due to combination of pallor (anaemia) and mild jaundice (due to haemolysis), glossitis (beefy-red sore tongue), angular cheilosis (also known as stomatitis, p312). Neuropsychiatric: Irritability, depression, psychosis, dementia. Neurological: Paraesthesiae, peripheral neuropathy. Also: Subacute combined degeneration of the spinal cord: Onset is insidious (subacute) with peripheral neuropathy due to ↓B12. There is a combination of symmetrical posterior (dorsal) column loss, causing sensory and LMN signs, and symmetrical corticospinal tract loss, causing motor and UMN signs (p438). Joint-position and vibration sense are often affected first leading to ataxia, followed by stiffness and weakness if untreated. The classical triad is: • Extensor plantars (UMN) • Absent knee jerks (LMN) • Absent ankle jerks (LMN). It may present with falls at night-time, due to a combination of ataxia and reduced vision, which is also seen with ↓B12. Pain and temperature sensation may remain intact even in severe cases, as the spinothalamic tracts are preserved. ▶Neurological signs with B12 deficiency can occur without anaemia. Pernicious anaemia (PA) This is caused by an autoimmune atrophic gastritis, leading to achlorhydria and lack of gastric intrinsic factor secretion. Incidence 1 : 1000; ♀:♂≈1.6:1; usually >40yrs; higher incidence if blood group A. Associations Other autoimmune diseases (p539): thyroid disease (~25%), vitiligo, Addison’s disease, hypoparathyroidism. Carcinoma of stomach is ~3-fold more common in pernicious anaemia, so have a low threshold for upper GI endoscopy. Tests • Hb↓ (3-11g/dL) • MCV↑ •WCC & platelets ↓ in severe cases • Serum B12↓1 • Reticulocytes ↓ or normal as production impaired • Hypersegmented polymorphs (p318) • Megaloblasts in the marrow • Specific tests for PA: 1 Parietal cell antibodies: found in 90% with PA, but also in 3-10% without. 2 Intrinsic factor (IF) antibodies: specific for pernicious anaemia, but lower sensitivity. These target B12 binding sites (in 50%) or ileal binding sites (in 35%). 3 Schilling test (BOX). Treatment Treat the cause if possible. Most cases are due to malabsorption so injections are required. Replenish stores with hydroxocobalamin (B12) 1mg IM alternate days eg for 2wks (or, if CNS signs, until improvement stops). Maintenance: 1mg IM every 3 months for life (child’s dose: as for adult). If the cause is dietary, then oral B12 can be given after the initial acute course. Initial improvement is heralded by a transient marked reticulocytosis and hence ↑MCV, after 4-5 days. Practical hints

  • Beware of diagnosing PA in those under 40 yrs old: look for GI malabsorption (small bowel biopsy, p272).
  • Watch for hypokalaemia as treatment becomes established.
  • Transfusion is best avoided, but PA with high output CCF may require exchange transfusion (p310), after doing tests for FBC, folate, B12, and marrow sampling.
  • As haemopoiesis accelerates on treatment, additional iron may be needed.
  • Hb rises ~1g/dL per week, WCC and platelet count should normalize in 1wk.

Prognosis Supplementation usually improves peripheral neuropathy within the first 3-6 months, but has little effect on cord signs. Patients do best if treated as soon as possible after the onset of symptoms: don’t delay! P.321

Fig 1. Glossitis in B12 deficiency.

Schilling test image31 If there is B12 deficiency, and the parietal cell and intrinsic factor antibodies do not give the answer, consider a Schilling test to help to identify the cause. This determines whether a low B12 is due to malabsorption from the terminal ileum or due to a lack of intrinsic factor—by comparing the proportion of an oral dose (1µg) of radioactive B12 absorbed and hence excreted in urine, with and without the concurrent administration of intrinsic factor (the blood must be saturated by giving an IM dose of 1000µg of B12 first). If intrinsic factor enhances absorption leading to increased urine B12, then lack of intrinsic factor, ie pernicious anaemia, is likely to be the cause. Note that the Schilling test is rather cumbersome, and some labs have stopped offering this test, hoping to rely on serology testing for parietal cell and intrinsic factor antibodies, and the plasma response to oral or IM B12. P.322
An approach to haemolytic anaemia1 Haemolysis is the premature breakdown of RBCs, before their normal life span of ~120d. It occurs in the circulation (intravascular) or in the reticuloendothelial system ie macrophages of liver, spleen and bone marrow (extravascular). In sickle-cell anaemia, lifespan may be as short as 5d. Haemolysis may be asymptomatic, but if the bone marrow does not compensate sufficiently, a haemolytic anaemia results. An approach is to first confirm haemolysis and then find the cause—try to answer these 4 questions:

  • Is there increased red cell breakdown?
    • Anaemia with normal or ↑MCV.
    • ↑Bilirubin: unconjugated, from haem breakdown (prehepatic jaundice).
    • ↑Urinary urobilinogen (no urinary conjugated bilirubin).
    • ↑Serum lactic dehydrogenase (LDH), as released from the RBC.
  • Is there increased red cell production?
    • ↑Reticulocytes, causing ↑MCV (reticulocytes are large immature RBCs) and polychromasia.
  • Is the haemolysis mainly extra- or intravascular? Extravascular haemolysis may lead to splenic hypertrophy and splenomegaly. Features of intravascular haemolysis are:
    • ↑Free plasma haemoglobin: released from RBCs.
    • Methaemalbuminaemia: some free Hb is broken down in the circulation to produce haem and globin; haem combines with albumin to make methaemalbumin.
    • ↓Plasma haptoglobin: mops up free plasma Hb, then removed by the liver.
    • Haemoglobinuria: causes red-brown urine, in absence of red blood cells.
    • Haemosiderinuria: occurs when haptoglobin binding capacity is exceeded, causing free Hb to be filtered by the renal glomeruli, absorption of free Hb via the renal tubules and storage in the tubular cells as haemosiderin. This is detected in the urine in sloughed tubular cells by Prussian blue staining ~1 week after onset (implying a chronic intravascular haemolysis)
  • Why is there haemolysis? Causes are on p324.

History Family history, race, jaundice, dark urine, drugs, previous anaemia, travel. Examination Jaundice, hepatosplenomegaly, gallstones (pigmented, due to ↑bilirubin from haemolysis), leg ulcers (due to poor blood flow). Investigation FBC, reticulocytes, bilirubin, LDH, haptoglobin, urinary urobilinogen. Thick and thin films for malaria screen if history of travel. The blood film may show polychromasia and macrocytosis due to reticulocytes, or point to the diagnosis:

  • Hypochromic microcytic anaemia (thalassaemia).
  • Sickle cells (sickle cell anaemia).
  • Schistocytes (microangiopathic haemolytic anaemia).
  • Abnormal cells in haematological malignancy.
  • Spherocytes (hereditary spherocytosis or autoimmune haemolytic anaemia).
  • Elliptocytes (hereditary elliptocytosis).
  • Heinz bodies, “bite” cells2, (glucose-6-phosphate dehydrogenase deficiency).

Further tests:

  • Direct antiglobulin (Coombs’) test (DAT) identifies red cells coated with antibody or complement. A positive result indicates an immune cause of the haemolysis.
  • RBC lifespan may be determined by chromium labelling and the major site of RBC breakdown may also be identified. This test is rarely done now.

The cause may now be obvious, but further tests may be needed. Membrane abnormalities are identified on the film and can be confirmed by osmotic fragility testing. Hb electrophoresis will detect haemoglobinopathies. Enzyme assays are reserved for situations when other causes have been excluded. P.323
P.324
Causes of haemolytic anaemia Acquired—these are divided into immune and non-immune causes.

  • Immune mediated (=direct antiglobulin test +ve).
    • Drug-induced Causing formation of RBC autoantibodies from binding to the RBC membrane (eg penicillin) or production of immune complexes (eg quinine).
    • Autoimmune haemolytic anaemia (AHA) Mediated by autoantibodies causing mainly extravascular haemolysis and spherocytosis. They are divided by their optimal binding temperature to RBCS. Warm AHA: IgG-mediated, bind at body 37°C. Treatment: Steroids/immunosuppressants (± splenectomy). Cold AHA: IgM-mediated, bind at lower temperature (<4°C), activating cell surface complement. Causes a chronic anaemia made worse by cold, often with Raynaud’s or acrocyanosis. Treatment: Keep warm. Chlorambucil may help. Causes: Most are idiopathic; secondary causes of warm AHA include lymphoproliferative disease (eg CLL, lymphoma), drugs, autoimmune disease eg SLE. Cold AHA may follow infections eg Mycoplasma pneumoniae, EBV.
    • Paroxysmal cold haemoglobinuria is seen with viruses/syphilis. It is caused by the Donath-Landsteiner antibodies, which stick to RBCs in cold, and cause complement-mediated haemolysis on rewarming. Haemolysis is self-limiting.
  • Isoimmune Acute transfusion reaction (p571); haemolytic disease of newborn.
  • Microangiopathic haemolytic anaemia (MAHA) A mechanical disruption of RBCs in circulation, causing intravascular haemolysis and schistocytes. Causes include haemolytic-uraemic syndrome (HUS), TTP (p300), DIC, pre-eclampsia, eclampsia. Treat the underlying disease; transfusion or plasma exchange may be needed. Also caused by intravascular devices eg prosthetic heart valves.
  • Infection eg malaria (p382): RBC lysis and ‘blackwater fever’ (haemoglobinuria).
  • Paroxysmal nocturnal haemoglobinuria RBCs (also platelets, neutrophils) are sensitive to complement-mediated lysis due to an inherited loss of surface glucosylphosphatidylinositol (GPI). There is chronic intravascular haemolysis (especially at night→haemoglobinuria), pancytopenia, and ↑thrombosis (eg Budd- Chiari syndrome, p688). Diagnosis: Urinary haemosiderin +ve. Cellular immunophenotype shows altered GPI. Ham’s test +ve (in vitro acid-induced lysis, but rarely done now). Â: Anticoagulation. Stem cell transplant may be curative.

Hereditary Is there a defect in RBC enzymes, membrane, or Hb? Enzyme defects:

  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest RBC enzyme defect. Inheritance is X-linked, affecting 100 million mainly û in Africa, Mediterranean and Middle/Far East. Most are asymptomatic, but are susceptible to oxidative crises due to ↓glutathione production, precipitated by many drugs (eg primaquine, sulfonamides, aspirin), exposure to the broad bean Vicia fava (favism) or illness. During an attack, there is rapid anaemia and jaundice, with bite cells and blister cells on the film. Diagnosis: Enzyme assay. Don’t do until ~2- 3 months after a crisis: young RBCs may have sufficient enzyme so results may appear normal. Â: Avoid precipitants; transfuse if severe.
  • Pyruvate kinase deficiency Autosomal recessive, ↓ATP production causing shortened red cell survival. Homozygotes have neonatal jaundice; later, chronic haemolysis with splenomegaly and jaundice. Diagnosis: Enzyme assay. Â: Often the condition is well tolerated. No specific therapy—splenectomy may help.

Membrane defect—Hereditary spherocytosis Autosomal dominant RBC membrane defect.image32 Less deformable spherical RBCs, so trapped in spleen → extravascular haemolysis. Signs: Splenomegaly, jaundice. δ: Mild anaemia. Film (p314): many spherocytes. Osmotic fragility tests: RBCs show ↑fragility in hypotonic solutions.

  • Hereditary elliptocytosis Autosomal dominant, most are asymptomatic. Treatment: Folate, splenectomy is curative but reserved for severe cases.
  • Haemoglobinopathy: Sickle-cell disease p326.
  • Thalassaemia p328.

Factors exacerbating haemolysis Infection leads to ↑haemolysis. The anaemia may be exacerbated by parvoviruses (OHCS p142), producing a cessation of marrow erythropoiesis, ie aplastic anaemia, with no reticulocyte formation (p348). P.325

Fig 1. Autoimmune haemolytic anaemia: antibody coated red cells undergoing phagocytosis by monocytes.image33
Fig 2. A ‘bite’ cell in G6PD, following removal of Heinz bodies by the spleen. Heinz bodies are formed from oxidized, denatured Hb during oxidative crises.image34
Fig 3. ‘Blister’ cells (arrows) in G6PD, following removal of Heinz bodies. Also contracted red cells (arrowheads).image35
Fig 4. Microangiopathic anaemia eg from DIC: numerous cell fragments (schistocytes) are present.image36
Fig 5. Fibrin strands, deposited in HUS & TTP (p300), slice up passing red cells (microangiopathic anaemia).image37
Fig 6. Hereditary spherocytosis.image38
Fig 7. Hereditary elliptocytosis.image39

P.326
Sickle-cell anaemia Sickle-cell anaemia is an autosomal recessive disorder causing production of abnormal β globin chains. An amino acid substitution in the gene coding for the β chain (Glu ↑ Val at position 6), results in the production of HbS rather than HbA. HbA2 and HbF are still produced. It is common in people of African origin. The homozygote (SS) has sickle-cell anaemia (HbSS), and heterozygotes (HbAS) have sickle-cell trait, which causes no disability (and protects from falciparum malaria) except in hypoxia, eg in unpressurized aircraft or anaesthesia, when vaso-occlusive events may occur, so all those of African descent need a sickle cell test pre-op. Symptomatic sickling also occurs in heterozygotes with genes coding other Hb variants (eg HbC leading to HbSC, or β-thalassaemia trait leading to HbS/βthal). Pathogenesis HbS polymerizes when deoxygenated, causing RBCs to deform. This produces sickle cells, which are fragile and haemolyse, and also block small vessels. Tests Haemolysis is variable. Hb ≈ 6-9g/dL, ↑reticulocytes 10-20%, ↑bilirubin. Film: sickle cells and target cells. Sickle solubility test: +ve, but does not distinguish between HbSS and HbAS. Hb electrophoresis: Confirms the diagnosis and distinguishes SS, AS states, and other Hb variants. Aim for diagnosis at birth (cord blood) to aid prompt pneumococcal prophylaxis (vaccine, p152, or penicillin V). Signs and symptoms are highly variable. There is a chronic haemolytic anaemia, usually well tolerated unless there is a supervening crisis (below and see BOX). Vaso-occlusive ‘painful’ crises: Common, due to micro-vascular occlusion. Often affects the bone marrow, causing severe pain. Precipitated by cold, dehydration, infection or hypoxia. Hands and feet are affected in children <3yrs leading to dactylitis. Occlusion may also cause mesenteric ischaemia, mimicking an acute abdomen. Cerebral infarction occurs in ~10% of children, leading to stroke, seizures or cognitive defects. Transcranial Doppler ultrasonography indicates risk of impending stroke, and blood transfusions can be used to prevent this, by reducing HbS.image40 Priapism may occur; if >12h, arrange prompt cavernosus-spongiosum shunting—prevents future erectile dysfunction (also occurs in CML, p342). Aplastic crises: This is due to Parvovirus B19, with sudden reduction in marrow production, especially RBCs. Usually self-limiting <2wks, transfusion may be needed. Sequestration crises: Mainly affects children as the spleen has not yet undergone atrophy. There is pooling of blood in the spleen ± liver, with organomegaly, severe anaemia and shock. Urgent transfusion is needed. Complications •Splenic infarction occurs before 2yrs old, due to repeated microvascular occlusion, leading to ↑susceptibility to infection (p357) •Growth impairment •Bone necrosis due to ↓blood supply, especially the femoral head •Chronic renal failure •Chronic leg ulcers •Gallstones •Retinal disease and visual impairment •Multiple blood transfusions may lead to iron overload or blood-borne infection •Long-term lung damage—hypoxia, fibrosis and pulmonary hypertension, partly preventable by incentive spirometry—10 maximal inspirations/2h.image41 Management of chronic disease

  • Consider hydroxycarbamide (hydroxyurea) if frequent crises.1
  • Splenic infarction leads to hyposplenism. Prophylaxis, in terms of antibiotics and immunization should be given (p357).
  • Febrile children risk septicaemia: repeated admission may be avoided by outpatient ceftriaxone (eg 2 doses, 50mg/kg IV on day 0 and 1). Admission may still be needed, eg if Hb <5g/dL, WCC <5 or >30 × 109/L, T° >40°C, severe pain, dehydration, lung infiltration. Seek expert advice.
  • Bone marrow transplant can be curative, but remains controversial.

1 Long-term hydroxycarbamide causes ↑production of fetal haemoglobin (HbF) and decreased Hb polymerization, causing reduction in painful crises, acute chest syndrome, admissions, blood transfusions and mortality.imageimage This may result from fewer episodes of bone marrow ischaemia and embolization. Prevention Genetic counselling; prenatal tests (OHCS p152-3). Parental education can help prevent 90% of deaths from sequestration crises.image42 P.327
Management of sickle-cell crisis1 ▶Seek expert help early.

  • Give prompt, generous analgesia, eg IV opiates (see p560).
  • Crossmatch blood. FBC, reticulocytes, blood cultures, MSU ± CXR if fever or chest symptoms.
  • Rehydrate with IVI and keep warm.
  • Give O2 by mask if PaO2↓ or O2 sats <95%.
  • ‘Blind’ antibiotics (eg cephalosporin, p372) if fever T° >38°, unwell, or chest symptoms, after sending infection screen.
  • Measure PCV, reticulocytes, liver, and spleen size twice daily.
  • Give blood transfusion if Hb or reticulocytes fall sharply. Match blood for the blood group antigens Rh(C, D, E) and Kell, to prevent formation of antibodies. Red cell transfusion improves oxygenation, and is as good as exchange transfusion, which is reserved for those who are rapidly deteriorating.image43Exchange transfusion is a process where blood is removed and donor blood is given in stages. Indications: severe chest crisis, suspected CNS event or multiorgan failure—when the proportion of HbS should be reduced to <30%.

The acute chest syndrome: Entails pulmonary infiltrates involving complete lung segments, causing pain, fever, tachypnoea, wheeze, and cough. It is a serious condition. Incidence: ~0.1 episodes/patient/yr. 13% in the landmark Vichinsky study needed ventilation, 11% had CNS symptoms, and 9% of those over 20 years old died. Prodromal painful crisis occur ~2.5 days before any abnormalities on CXR in 50% of patients. The chief causes of the infiltrates are fat embolism from bone marrow or infection with Chlamydia, Mycoplasma, or viruses.image44Â: Oxygen, analgesia, empirical antibiotics (cephalosporin + macrolide) until culture results known. Bronchodilators (eg salbutamol, p167) have proved to be very effective in those with wheezing or obstructive pulmonary function at presentation. Blood transfusion (exchange if severe). Take to ITU if PaO2 cannot be kept above 9.2kPa (70mmHg) when breathing air. Patient-controlled analgesia (PCA): An example with paediatric doses. First try warmth, hydration, and oral analgesia: ibuprofen 5mg/kg/6h PO (codeine phosphate 1mg/kg/4-8h PO up to 3mg/kg/d may also be tried, but is relatively ineffective). If this fails, see on the ward and offer prompt morphine by IVI—eg 0.1mg/kg. Start PCA with morphine 1mg/kg in 50mL 5% dextrose, and try a rate of 1mL/h, allowing the patient to deliver extra boluses of 1mL when needed. Do respiration and sedation score every 1/4h + pulse oximetry if chest/abdominal pain.image45 For further advice, liaise with the local pain service. 1 Brit. Committee for Standards in Haem. Management of the acute painful crisis in sickle cell disease.image

Fig 1. Blood film in sickle-cell anaemia: there are sickle cells, target cells, and a nucleated red cell.image46
Fig 2. Leg ulcers in sickle cell disease.image47

P.328
Thalassaemia The thalassaemias are genetic diseases of unbalanced Hb synthesis, as there is underproduction (or no production) of one globin chain (BOX). Unmatched globins precipitate, damaging RBC membranes, causing their haemolysis while still in the marrow. They are common in areas from the Mediterranean to the Far East. The β thalassaemias are usually caused by point mutations in β-globin genes on chromosome 11, leading to ↓β chain production (β+) or its absence (β0). Various combinations of mutations are possible (eg β0/β0, β+/β+, or β+/β0). Tests FBC, MCV, film, iron, HbA2, HbF, Hb electrophoresis. β thalassaemia minor or trait (eg β/β+; heterozygous state): This is a carrier state, and is usually asymptomatic. Mild, well-tolerated anaemia (Hb >9g/dL) which may worsen in pregnancy. MCV <75fL, HbA2 >3.5%, slight ↑HbF. Often confused with iron deficiency anaemia. β thalassaemia intermedia describes an intermediate state with moderate anaemia but not requiring transfusions. There may be splenomegaly. There are a variety of causes including mild homozygous β thalassaemia mutations eg β+/β+, or co-inheritance of β thalassaemia trait with another haemoglobinopathy eg HbC thalassaemia (1 parent has the HbC trait, and the other has β+). Sickle-cell β+ thalassaemia produces a picture similar to sickle-cell anaemia. β thalassaemia major (Cooley’s anaemia) describes abnormalities in both β-globin genes, and presents within the 1st year, with severe anaemia and failure to thrive. Extramedullary haematopoiesis (production of RBCs outside the bone marrow) occurs in response to the anaemia, causing characteristic facial deformities eg skull bossing (fig 1) and hepatosplenomegaly (also due to haemolysis). Skull x-ray shows a ‘hair on end’ appearance due to increased marrow activity. Life-long blood transfusions are needed, with resulting iron overload and deposition occurring after ~10yrs as endocrine failure (pituitary, thyroid, pancreas↑diabetes mellitus), liver disease, and cardiac toxicity. Long-term infusion of desferrioxamine helps to prevent iron loading. The film shows very hypochromic, microcytic cells with target cells and nucleated RBCs. HbF↑↑, HbA2 variable, HbA absent. Treatment image48

  • Folate supplements.
  • Regular (~2-4 weekly) life-long transfusions to keep Hb >9g/dL, to suppress the ineffective extramedullary haematopoiesis and to allow normal growth.
  • Iron-chelators to prevent iron deposition, eg desferrioxamine infusions given SC for 8-12 hours per day. SE: pain, hearing loss, cataracts, retinal damage, ↑risk of Yersinia infection. Compliance can be a problem. The role of newer oral iron-chelators, eg deferiprone, are under study (neutropenia may be a problem).
  • Large doses of ascorbic acid also increase urinary excretion of iron.
  • Splenectomy if hypersplenism persists with increasing transfusion requirements (p357)—this is best avoided until >5 yrs old due to risk of infections.
  • Hormonal replacement or treatment for endocrine complications eg diabetes mellitus, hypothyroidism. Growth hormone treatment has had variable success.image49
  • A histocompatible marrow transplant can offer the chance of a cure.image50

Prevention Approaches include genetic counselling or antenatal diagnosis using fetal blood or DNA, then ‘therapeutic’ abortion. The α thalassaemias There are two separate α-globin genes on each chromosome 16 ∴ there are four genes (termed αα/αα). The α thalassaemias are mainly caused by gene deletions. If all 4 α genes are deleted (—/—), death is in utero (Bart’s hydrops). Here, HbBarts (γ4) is present, which is physiologically useless. HbH disease occurs if 3 genes are deleted (—/-α), there may be moderate anaemia and features of haemolysis: hepatosplenomegaly, leg ulcers and jaundice. In the blood film, there is formation of β4 tetramers (=HbH) due to excess β chains, HbBarts, HbA and HbA2. If 2 genes are deleted (—/αα or -α/-α), there is an asymptomatic carrier state, with ↓MCV. With one gene deleted, the clinical state is normal. P.329
Structure of haemoglobin The three main types of Hb in adult blood are:

Type

Peptide chains

% in adult blood

% in fetal blood

HbA

α2 β2

97

10-50

HbA2

α2 δ2

2.5

Trace

HbF

α2 γ2

0.5

50-90

Adult haemoglobin (HbA) is a tetramer of 2 α- and 2 β-globin chains each containing a haem group. In the first year of life, adult haemoglobin replaces fetal haemoglobin (HbF). It might be thought that because the molecular details of the thalassaemias are so well worked out they represent a perfect example of the reductionist principle at work: find out exactly what is happening within molecules, and you will be able to explain all the manifestations of a disease. But this is not so. We have to recognize that two people with the identical mutation at their β loci may have quite different diseases. Co-inheritance of other genes and conditions (eg α thalassaemia) is part of the explanation, as is the efficiency of production of fetal haemoglobin. The reasons lie beyond simple co-segregation of genes promoting the formation of fetal Hb. The rate of proteolysis of excess α-globin chains may also be important—as may mechanisms that have little to do with genetic or molecular events. So the lesson the thalassaemias teach is more subtle than the reductionist one: it is that if you want to understand the whole picture, you must look at every level: genetic, molecular, physiological, social, and cultural. Each level influences the other, without necessarily determining them.

Fig 1. β thalassaemia major: bossing due to extra-medullary haematopoiesis.image51
Fig 2. Thalassaemia major: skull X-ray.image52

Further Reading: Drew Provan and John G Gribben 2004 Molecular Hematology 2e, Blackwell Publishing. P.330
Bleeding disorders After injury, 3 processes halt bleeding: vasoconstriction, gap-plugging by platelets, and the coagulation cascade. Disorders of haemostasis fall into these 3 groups. The pattern of bleeding is important—vascular and platelet disorders lead to prolonged bleeding from cuts, bleeding into the skin (eg easy bruising and purpura), and bleeding from mucous membranes (eg epistaxis, bleeding from gums, menorrhagia). Coagulation disorders cause delayed bleeding into joints and muscle. 1 Vascular defects Congenital: Osler-Weber-Rendu syndrome (p700), connective tissue disease (eg Ehlers-Danlos syndrome OHCS p642, pseudoxanthoma elasticum). Acquired: Senile purpura, infection (eg meningococcal, measles, dengue fever), steroids, scurvy (perifollicular haemorrhages), Henoch-Schönlein purpura (p694), painful bruising syndrome—women who develop tingling under the skin followed by bruising over limbs/trunk, resolving without treatment. 2 Thrombocytopenia ↓ marrow production: Aplastic anaemia (p348), megaloblastic anaemia, marrow infiltration (eg leukaemia, myeloma), marrow suppression (cytotoxic drugs, radiotherapy). Excess destruction: Immune: Immune thrombocytopenic purpura (ITP), other autoimmune causes eg SLE, CLL, drugs eg heparin, viruses; Non-immune: DIC p336, thrombotic thrombocytopenic purpura (TTP) or HUS (p300), sequestration (in hypersplenism). ITP is caused by antiplatelet autoantibodies leading to phagocytic destruction. It is acute (usually in children, 2wks after infection with sudden self-limiting purpura: OHCS p197) or chronic (seen mainly in adult women). Chronic ITP runs an indefinite fluctuating course of bleeding, purpura (especially dependent pressure areas), epistaxis and menorrhagia. There is no splenomegaly. Tests: ↑megakaryocytes in marrow, antiplatelet autoantibodies may be present although not always. Â: Mild disease may not need treatment. If symptomatic or platelets <20 × 109/L, prednisolone 1mg/kg/d, and reduce after remission; aim to keep platelets >30 × 109/L—takes a few days to work. If relapse, splenectomy cures ≤80%. If this fails: immunosuppression, eg azathioprine or cyclophosphamide. Platelet transfusions are not used (except during splenectomy or life-threatening haemorrhage) as these are destroyed quickly by the autoantibodies. IV immunoglobulin may temporarily raise the platelet count eg for surgery, pregnancy. Causes of ↓platelet function Myeloproliferative disease, NSAIDs, urea↑. 3 Coagulation disorders Congenital: Haemophilia, von Willebrand’s disease (p704). Acquired: Anticoagulants, liver disease, DIC (p336), vitamin K deficiency.

  • Haemophilia A: Factor VIII deficiency; inherited in an X-linked recessive pattern in 1:10,000 male births—usually due to a ‘flip tip’ inversion in the Factor VIII gene in the X chromosome. There is a high rate of new mutations (30% have no family history). Presentation depends on severity and is often early in life or after surgery/trauma—with bleeds into joints leading to crippling arthropathy, and into muscles causing haematomas, which may lead to nerve palsies and compartment syndrome due to pressure. Diagnose by ↑APTT and ↓factor VIII assay. Management: Seek expert advice. Avoid NSAIDs and IM injections. Minor bleeding: pressure and elevation of the part. Desmopressin (0.3µg/kg/12h IVI over 20min) raises factor VIII levels, and may be sufficient. Major bleeds (eg haemarthrosis) require factor VIII levels to be ↑ to 50% of normal and life-threatening bleeds (eg obstructing airway) need levels of 100%, eg with recombinant factor VIII. Genetic counselling: OHCS p154.
  • Haemophilia B (Christmas disease): Factor IX deficiency (inherited, X-linked recessive); behaves clinically like haemophilia A.
  • Liver disease produces a complicated bleeding disorder with ↓synthesis of clotting factors, ↓absorption of vitamin K, and abnormalities of platelet function.
  • Malabsorption leads to less uptake of vitamin K (needed for synthesis of factors II, VII, IX, and X). Treatment is IV vitamin K (10mg) or FFP for acute haemorrhage.

P.331
The intrinsic and extrinsic pathways of blood coagulation

Fig 1. Mild haemophilia after an IM injection image53. Give vaccines etc SC.

Fibrinolysis The fibrinolytic system causes fibrin dissolution and acts via the generation of plasmin. The process starts with the release of tissue plasminogen activator (t-PA) from endothelial cells, a process stimulated by fibrin formation. t-PA converts inactive plasminogen to plasmin which can then cleave fibrin, as well as several other factors. t-PA and plasminogen both bind fibrin thus localizing fibrinolysis to the area of the clot. Mechanism of fibrinolytic agents Alteplase (=rt-PA=Actilyse®; from recombinant DNA) is a fibrinolytic enzyme imitating t-PA, as above. Plasma t½ ≈ 5min. Streptokinase is a streptococcal exotoxin and forms a complex in plasma with plasminogen to form an activator complex, which forms plasmin from unbound plasminogen. Initially there is rapid plasmin formation which can cause uncontrolled fibrinolysis. However, plasminogen is rapidly consumed in the complex and then plasmin is only produced as more plasminogen is synthesized. The activator complex binds to fibrin, so producing some localization of fibrinolysis. P.332
An approach to bleeding There are 3 sets of questions to be answered: Is there an emergency? —needing immediate resuscitation or senior help?

  • Is the patient about to exsanguinate (shock, coma, p774-9)?
  • Is there hypovolaemia (postural hypotension, oliguria)?
  • Is there CNS bleeding (meningism, CNS, and retinal signs)?

Why is the patient bleeding? Is bleeding normal, given the circumstances (eg surgery, trauma, parturition), or does the patient have a bleeding disorder?

  • Is there a secondary cause eg drugs (warfarin), alcohol, liver disease, sepsis?
  • Is there unexplained bleeding, bruising, or purpura?
  • Past or family history of excess bleeding eg during trauma, dentistry, surgery?
  • Is the pattern of bleeding indicative of vascular, platelet, or coagulation problems (p330)? Are venepuncture or old cannula sites bleeding (DIC, p336)? Look for associated conditions (eg with DIC).
  • Is a clotting screen abnormal? Check FBC, platelets, PT, APTT and thrombin time. Consider D-dimers, bleeding time, and a factor VIII assay.

In the case of a bleeding disorder, what is the mechanism? Coagulation tests (Sodium citrate tube; false results if under-filled)

  • Prothrombin time (PT): Thromboplastin is added to test the extrinsic system. PT is expressed as a ratio compared to control [International Normalized Ratio (INR), normal range = 0.9-1.2]. It tests for abnormalities in factors I, II, V, VII, X. Prolonged by: warfarin, vitamin K deficiency, liver disease, DIC.
  • Activated partial thromboplastin time (APTT): Kaolin is added to test the intrinsic system. Tests for abnormalities in Factor I, II, V, VIII, IX, X, XI, XII. Normal range 35-45s. Prolonged by: heparin treatment, haemophilia, DIC, liver disease.
  • Thrombin time: Thrombin is added to plasma to convert fibrinogen to fibrin. Normal range: 10-15s. Prolonged by: heparin treatment, DIC, dysfibrinogenaemia.

D-dimers: These are a fibrin degradation product, released from cross-linked fibrin during fibrinolysis (p331). This occurs during DIC, or in the presence of venous thromboembolism—deep vein thrombosis (DVT) or pulmonary embolism (PE). D-dimers may also be raised in inflammatory states eg with infection or malignancy. Bleeding time: This is a test of haemostasis, carried out by making two small incisions into the skin of the forearm. Normal time <7 minutes. NB: This test is seldom performed now, as results are very operator dependent. Interpretation

  • Platelets: If low, do FBC, film, clotting.
  • PT: If long, look for liver disease or anticoagulant use.
  • APTT: If long, consider liver disease, haemophilia (factor VIII or IX deficiency), or heparin.
  • Bleeding time: Raised in von Willebrand’s disease (p704), or platelet disorders. Aspirin also prolongs the bleeding time.
  • If both PT & APTT are very raised, with low platelets, and ↑D-dimers, consider DIC.

Management depends on the degree of bleeding. If shocked, resuscitate (p778). If bleeding continues, in the presence of a clotting disorder, or a massive transfusion, discuss the need for FFP and platelets with a haematologist. In ITP (p330), steroids ± IV immunoglobulin may be used. Especially in pregnancy (OHCS p88), consult an expert. Is there overdose with anticoagulants (p826)? In haemophiliac bleeds, consult early for coagulation factor replacement. Never give IM injections. P.333

Disorder1

INR

APTT

Thrombin time

Platelet count

Bleeding time

Notes

Heparin

↑

↑↑

↑↑

↔

↔

DIC

↑↑

↑↑

↑↑

↓

↑

↑D-d, p336

Liver disease

↑

↑

↔/↑

↔/↓

↔/↑

AST↑

Platelet defect

↔

↔

↔

↔

↑(↑)

Vit K deficiency

↑↑

↑

↔

↔

↔

Haemophilia

↔

↑↑

↔

↔

↔

see p330

von Willebrand’s

↔

↑↑

↔

↔

↑(↑)

see p704

Special tests may be available (factor assays: ▶consult a haematologist).

1 After OTS, p215. D-d = D-dimer.

P.334
Anticoagulants Main indications

  • Therapeutic: Venous thromboembolic disease: DVT and PE.
  • Prophylactic: Prevention of DVT/PE in high-risk patients (p359), eg post-op. Prevention of stroke, eg in chronic AF or prosthetic heart valve.

Heparin 1 Low molecular weight heparin (LMWH) Given SC. Molecular weight ~5000 Daltons (Da), eg dalteparin, enoxaparin, tinzaparin. Inactivates factor Xa (but not thrombin). T½ is 2-4-fold longer than standard heparin, and response is more predictable, and so only needs to be given once or twice daily, and no laboratory monitoring is usually required. It has replaced unfractionated heparin (UFH) as the preferred option in the prevention and treatment of venous thromboembolism and in acute coronary syndrome. See BNF for doses. It accumulates in renal failure: lower doses are used for prophylaxis, or UFH for therapeutic doses. 2 Unfractionated heparin (UFH) IV or SC. ~13,000Da. A glycosaminoglycan, which binds antithrombin (an endogenous inhibitor of coagulation), increasing its ability to inhibit thrombin, factor Xa, and IXa. Rapid onset and has a short T½. Monitor and adjust dose with APTT (p332). SE for both: ↑Bleeding (eg at operative site, gastrointestinal, intracranial), heparininduced thrombocytopenia (HIT), osteoporosis with long-term use. HIT and osteoporosis are less common with LMWH than UFH. Beware hyperkalaemia. CI: Bleeding disorders, platelets <60×109/l, previous HIT, peptic ulcer, cerebral haemorrhage, severe hypertension, neurosurgery. Warfarin is used orally once daily as long-term anticoagulation. The therapeutic range is narrow, varying with the condition being treated (see BOX)—and is measured as a ratio compared with the standard INR. Warfarin inhibits the reductase enzyme responsible for regenerating the active form of vitamin K, producing a state analogous to vit K deficiency. CI: Peptic ulcer, bleeding disorders, severe hypertension, pregnancy (teratogenic, see OHCS p640). Use with caution in the elderly and those with past GI bleeds. In the UK, warfarin tablets are 0.5mg (white), 1mg (brown), 3mg (blue), or 5mg (pink). ▶Interactions: p740. Others: Fondaparinux is a pentasaccharide Xa inhibitor and may be used in place of LMWH for prophylaxis in certain situations.image54 Ximelagatran, a direct thrombin inhibitor, may provide an alternative to warfarin that does not require monitoring. Beginning therapeutic anticoagulation (follow local guidelines, and see BNF). For treatment of venous thromboembolism, LMWH or UFH are used initially, and warfarin is given in combination usually from day 1. Heparin should be continued until INR has reached target therapeutic range (see BOX) and until day 5, as warfarin has an initial prothrombotic effect. LMWH Dose according to weight (see BNF). UFH IV infusion:

  • Give heparin 5000iu IV bolus over 30min. (10000iu in severe PE).
  • Prepare syringe pump: Add 25,000iu to 50mL 0.9% saline (=500iu/mL).
  • Start infusion at 1000-2000iu/h IVI (2.8mL/h=1400iu/h). Check APTT at 6h, aim for APTT ratio 1.5-2.5 (see BOX). Measure APTT daily or 10h after dose change.

Warfarin is given daily; start with 10mg stat at 18.00. Do INR 16h later.

  • If INR <1.8 (as is likely) the 2nd dose of warfarin is 5 or 10mg at 18.00 (24h after first dose). Give the lower dose if >60yrs, liver disease, or cardiac failure. But if INR >1.8 (warfarin sensitivity; rare) give just 0.5mg.
  • Do INR daily for 5d and adjust dose (see BOX—use 5mg, not 10mg dose 3 if over 60, or liver disease, or cardiac failure).
  • Stop heparin after 5d and when INR >2 for 2d. Tell lab when stopped.
  • Measure INR on alternate days until stable, then weekly or less often.

Antidotes If UFH overdose: stop infusion. If there is bleeding, protamine sulphate counteracts UFH: discuss with a haematologist. Warfarin: see Box 2. P.335
Warfarin guidelines and target levels for INR1

  • Pulmonary embolism and DVT. Aim for INR of 2-3; 3.5 if recurrent.
  • Atrial fibrillation2: for stroke prevention (p116). Target INR 2-3. An alternative is aspirin (but less effective), if the risk of bleeding with warfarin is high (eg falls with risk of intracranial bleed, or difficulty with monitoring).
  • Prosthetic metallic heart valves: for stroke prevention. Target INR 3-4.

Duration of anticoagulation in DVT/PE

  • If the cause will go away (eg post-op immobility):
    • At least 6 weeks for below knee DVT.
    • At least 3 months for above knee DVT or PE.
  • At least 6 months if no cause found.
  • Indefinitely for identified, enduring causes, eg thrombophilia (p358).

Warfarin dosage and excessive anticoagulationimage55 Below is a guide to warfarin dosing, for target INR of 2-3:

INR

<2

2

2.5

2.9

3.3

3.6

4.1

3rd dose

10mg

5mg

4mg

3mg

2mg

0.5mg

0mg

Maintenance

≥6mg

5.5mg

4.5mg

4mg

3.5mg

3mg

*

* Miss a dose; give 1-2mg the next day (if INR >4.5, miss 2 doses). Lower doses are given in certain groups of patients (see TEXT).

In cases of raised INR (see BNF):

INR 4.5-6

Reduce warfarin dose or omit. Restart when INR <5.

6-8

Stop warfarin. Restart when INR <5.

>8, no bleed or minor bleed

If no bleeding: stop warfarin. 0.5-2.5mg vitamin K (oral) if risk factors for bleeding. Check INR daily.

Major bleed, (including intracranial haemorrhage)

Stop warfarin. Give prothrombin complex concentrate (50units/kg; discuss with a haematologist). If unavailable, give FFP (15mL/kg ≈ 1L for a 70kg man). Also give 5-10mg vitamin K IV.

Minor bleeding includes epistaxis.

Vitamin K may take several hours to work, and can cause prolonged resistance when restarting warfarin, so should be avoided if possible when long-term anticoagulation is needed. Prothrombin complex concentrate contains a concentrate of Factor IX, and provides a more complete and rapid reversal of warfarin than FFP. IV heparin dosing

APTT ratio

>5

4-5

3-4

2.5-3

1.5-2.5

1.2-1.4

<1.2

Change rate (iu/h) by

Stop* -500

-300

-100

-50

0

+200

+400

* Stop for 1 hour then recheck APTT. Reduce dose by 500iu/h and restart if <5. image56

P.336
Leukaemia and the house officer Leukaemic patients often fall ill suddenly and deteriorate quickly. Prompt appropriate treatment is essential. Major concerns are infection, bleeding and hyperviscosity (p356). Take non-specific confusion/drowsiness seriously: do blood cultures, exclude hypoglycaemia, measure renal function, LFT, and Ca2+. Check clotting screen. Consider CNS bleeding—CT/MRI of brain if any doubt. Correct any haemostatic defect urgently with platelets/FFP. (See p476 for delirium.) Neutropenic regimen (for patients with a neutrophil count ¢1.0 × 109/L). ▶Close liaison with a microbiologist and haematologist is essential.

  • Full barrier nursing if possible, but simple hand-washing is probably most important. Use a side room.
  • Avoid IM injections (danger of an infected haematoma).
  • Look for infection (mouth, axilla, perineum, IVI site). Take swabs.
  • Check: FBC, platelets, INR, U&E, LFT. Take cultures (blood×3—peripherally ± Hickman line; urine, sputum, stool if diarrhoea) and request a CXR.
  • Wash perineum after defecation. Swab moist skin with chlorhexidine. Avoid unnecessary rectal examinations. Oral hygiene (eg hydrogen peroxide mouth washes/2h) and Candida prophylaxis are important (p230).
  • TPR 4-hrly. High-calorie diet; avoid foods with high risk of microbial contamination. Vases containing cut flowers pose a Pseudomonas risk.

Use of antibiotics in neutropenia ▶Treat any known infection promptly.

  • If T° >38°C or T° >37.5°C on separate occasions, 1-2h apart, or the patient is toxic, assume septicaemia and start blind broad spectrum antibiotics, eg antipseudomonal penicillin/cephalosporin and aminoglycoside. Vancomycin (p371) may be added if suspected Hickman line sepsis. Check local preferences.
  • Continue antibiotics until afebrile for 72 hours or 5d course, and until neutrophils recover (>0.5×109/L). If fever persists despite antibiotics, consider CMV or fungal infection (eg Candida or Aspergillus, p428).
  • May need to consider treatment for Pneumocystis (see p399 eg co-trimoxazole =trimethoprim 20mg/kg with sulfamethoxazole 100mg/kg per day PO/IV in 2-4 divided doses). Also remember TB.
  • Genetically engineered recombinant human granulocyte-colony stimulating factor (G-CSF) may be used to stimulate neutrophil production. Follow local guidelines, and seek expert advice.

Other dangers • Tumour lysis syndrome: Caused by a massive destruction of cells leading to K+↑, urate↑ and renal impairment. Prevent by giving a high fluid intake + allopurinol pre-cytotoxics. For patients at high risk of cell lysis, eg children with high count ALL, recombinant uricase (rasburicase) may be given. Seek advice. • Hyperviscosity: (p356). If WCC is >100 × 109/L WBC thrombi may form in brain, lung, and heart (leucostasis). Avoid transfusing before lowering WCC, eg with hydroxycarbamide or leucopheresis, as viscosity rises (risk of leucostasis ↑). • Disseminated intravascular coagulation (DIC): This is pathological widespread activation of coagulation, due to release of procoagulant agents into the circulation. Clotting factors and platelets are consumed, with ↑risk of bleeding. Fibrin strands fill small vessels, haemolysing passing RBCs, and fibrinolysis is also activated. Causes: Malignancy, sepsis, trauma, obstetric: OHCS p88. Signs: Extensive bruising, bleeding anywhere eg recent venepuncture sites, renal failure. Tests: Platelets↓; PT↑; APTT↑; fibrinogen↓ (correlates best with severity); fibrin degradation products (D-dimers) ↑↑. Film: broken RBCs (schistocytes). [prescription take]: Treat the cause. Give replacement therapy: platelets if <50×109/L, cryoprecipitate to replace fibrinogen, FFP to replace coagulation factors. Heparin is controversial. Activated protein C reduces mortality in DIC with severe sepsis or multi-organ failure.image57 The use of alltransretinoic acid (ATRA) has significantly reduced the risk of DIC in acute promyelocytic leukaemia (the commonest leukaemia associated with DIC). P.337
Leukaemias These are divided into 4 main types depending on the cell line involved and the speed of disease progression:

Lymphoid

Myeloid

Acute

Acute lymphoblastic leukaemia (ALL)

Acute myeloid leukaemia (AML)

Chronic

Chronic lymphocytic leukaemia (CLL)

Chronic myeloid leukaemia (CML)

Fig 1. The appearance of DIC on the sole.image58

P.338
Acute lymphoblastic leukaemia (ALL) This is a malignancy of lymphoid cells, affecting either B or T lymphocyte cell lines, arresting maturation and promoting uncontrolled proliferation of immature blast cells, with bone marrow failure and tissue infiltration. It is thought to develop from a combination of an environmental trigger in the presence of genetic susceptibility. In most cases these are unknown, but predisposing factors include ionizing radiation (eg X-rays) during pregnancy, and syndromes including Down’s.image59 It is the commonest cancer of childhood, and is rare in adults. CNS involvement is common. Classification is based on 3 systems:

  • Morphological The FAB1 system divides ALL into 3 types (L1, L2, L3) by microscopic appearance. Provides limited information.
  • Immunological Surface markers are used to classify ALL into:
    • Precursor B-cell ALL
    • T-cell ALL
    • B-cell ALL.
  • Cytogenetic Chromosomal analysis. Abnormalities are detected in up to 85%, which are often translocations . Useful for predicting prognosis eg poor with Philadelphia chromosome (see below), and for detecting disease recurrence.

Signs and symptoms are due to:

  • Marrow failure: Anaemia (↓Hb), infection (↓WCC), and bleeding (↓platelets).
  • Infiltration: Hepato- and splenomegaly, lymphadenopathy—superficial or mediastinal, orchidomegaly, CNS involvement—eg cranial nerve palsies, meningism.

Common infections: Especially chest, mouth, perianal and skin. Bacterial septicaemia, Zoster, CMV, measles, candidiasis, Pneumocystis pneumonia (p398). Tests

  • Characteristic blast cells on blood film and bone marrow. WCC usually high.
  • CXR and CT scan to look for mediastinal and abdominal lymphadenopathy.
  • Lumbar puncture should be performed to look for CNS involvement.

Treatment

  • Supportive care: Blood and platelet transfusions, IV fluids and allopurinol to prevent tumour lysis. Insert a Hickman line for venous access.
  • Infections: These are dangerous, due to neutropenia caused by the disease and treatment. Immediate IV antibiotics for infection. Start the neutropenic regimen (p336): prophylactic antivirals, antifungals and antibiotics (eg co-trimoxazole to prevent Pneumocystis pneumonia (p336), but beware: can worsen neutropenia).
  • Chemotherapy: Patients are entered into national trials. A typical programme is:
    • Remission induction: This may be achieved with vincristine, prednisolone, L-asparaginase, and daunorubicin.
    • Consolidation: High/medium-dose therapy in ‘blocks’ over several weeks.
    • CNS prophylaxis: Intrathecal (or high-dose IV) methotrexate ± CNS irradiation.
    • Maintenance: Prolonged chemotherapy, eg mercaptopurine (daily), methotrexate (weekly), and vincristine + prednisolone (monthly) for 2yrs. Relapse is common in blood, CNS, or testis (so examine these sites at follow-up). More details: OHCS p194.
  • Marrow transplant: (p340) Consider if poor prognosis or relapse. This is the only way to cure those with Philadelphia chromosome—see below.image60

Haematological remission means no evidence of leukaemia in the blood, a normal or recovering blood count, and < 5% blasts in a normal regenerating marrow. Prognosis: Cure rates for children are 70-90%; for adults only 35% (<5% if >65yrs old, where there is a 2nd peak in incidence). Poor prognosis if adult, male, Philadelphia chromosome (p342): BCR-ABL gene fusion due to translocation of chromosomes 9 & 22, presentation with CNS signs, WCC >100×109/L or B-cell ALL. PCR is used to detect minimal residual disease, undetectable by standard means. Prognosis is poor if seen in high amounts at presentation or during remission. The future may lie in tailoring therapy to the exact gene defect, and according to the individual’s metabolism. Monoclonal antibodies, gene-targeted retinoids, cytokines, vaccines, and T-cell infusions are all being studied.image61 P.339

Fig 1. Blood film in ALL, L1 subtype. Small blasts with scanty cytoplasm.image62
Fig 2. Bone marrow in ALL, L1 subtype.image63
Fig 3. Blood film in ALL, L2 subtype. Larger blast cells with greater morphological variation, and more abundant cytoplasm.image64
Fig 4. Bilateral parotid infiltration in ALL.image65 (Enlarged parotid glands are also seen in mumps and sarcoidosis.)

P.340
Acute myeloid leukaemia (AML) This neoplastic proliferation of blast cells is derived from marrow myeloid elements. It is a very rapidly progressive malignancy (death in ~2 months if untreated; ~20% 3-yr survival after chemotherapy). Incidence 1/10,000/yr. Increases with age, and is the commonest acute leukaemia of adults. Seen increasingly as a long-term complication of chemotherapy, eg for lymphoma. Also associated with myelodysplastic syndromes (see BOX), ionising radiation and syndromes eg Down’s. Morphological classification now based on WHO histological classification, which is complex and requires specialist interpretation. It recognizes the important prognostic information from cytogenetics and molecular genetics. 5 main types:

  • AML with recurrent genetic abnormalities.
  • AML, other.
  • AML multi-lineage dysplasia (usually 2° to preexisting myelodysplastic syndrome).
  • AML, therapy related.
  • Acute leukaemias of ambiguous lineage (both myeloid and lymphoid phenotype).

Symptoms

  • Marrow failure: Patients usually present with symptoms of anaemia, infection or bleeding. DIC occurs in acute promyelocytic leukaemia, a subtype of AML, where there is release of thromboplastin. Use of all-transretinoic acid with chemotherapy reduces the risk of DIC (see p336).
  • Infiltration: Hepato- and splenomegaly, gum hypertrophy, skin involvement. CNS involvement at presentation is rare in AML.

Diagnosis WCC is often ↑, but can be normal or even low. Blast cells may be few in the peripheral blood, so diagnosis depends on bone marrow biopsy. Differentiation from ALL may be by microscopy (Auer rods are diagnostic of AML), but is now based on immunophenotyping and molecular methods. Cytogenetic analysis (eg type of mutation) affects treatment recommendations, and guides prognosis. Complications

  • Infection is the major problem, related to both the disease and during treatment. Be alert to septicaemia (p336). Infections may be bacterial, fungal or viral, and prophylaxis is given for each during treatment. Pitfalls: AML itself causes fever, common organisms present oddly, few antibodies are made, rare organisms—particularly fungi (especially Candida or Aspergillus).
  • Chemotherapy causes ↑plasma urate levels (from tumour lysis)—so give allopurinol with chemotherapy, and keep well hydrated with IV fluids.
  • Leucostasis (p336) may occur if WCC ↑↑.

Treatment

  • Supportive care As for ALL.
  • Chemotherapy is very intensive, resulting in long periods of marrow suppression with neutropenia + platelets↓. The main drugs used include daunorubicin, and cytosine arabinoside, with ~5 cycles given in 1 week blocks to achieve remission.
  • Bone marrow transplant (BMT) Pluripotent haematopoietic stem cells are collected from the bone marrow. Allogeneic transplants from HLA-matched siblings or from matched unrelated donors (accessed via international databases) is indicated during first remission in disease with poor prognosis. The idea is to destroy leukaemic cells and the immune system by cyclophosphamide + total body irradiation, and then repopulate the marrow by transplantation from a matched donor infused IV. BMT allows the most intensive chemotherapy regimens because marrow suppression is not an issue. Ciclosporin ± methotrexate may be used to reduce the effect of the new marrow attacking the patient’s body (graft vs host disease). Complications: Graft vs host disease (may help explain the curative effect of BMT); opportunistic infections; relapse of leukaemia; infertility. Prognosis: Lower relapse rates ~60% long-term survivors, but significant mortality of ~10%. Autologous BMT where stem cells are taken from the patient themselves, is used in intermediate prognosis disease, although some studies suggest better survival rates with intensive chemotherapy regimes.
  • Supportive care, or lower dose chemotherapy for disease control, may be more appropriate in elderly patients, where intensive therapies have poorer outcomes.

P.341

Fig 1. Auer rods found in AML myeloblast cells, representing crystals of coalesced granules.image66
Fig 2. AML with monoblasts and myeloblasts on the peripheral blood film.image67
Fig 3. Gum hypertrophy, in AML.image68
Fig 4. Bone marrow in AML: multiple monoblasts.image69

Myelodysplastic syndromes (myelodysplasia) These are a group of diseases where there is a neoplastic clonal disorder of multipotent haematopoietic stem cells, leading to progressive bone marrow failure and ineffective haematopoiesis. This produces functional abnormalities of myeloid cells and peripheral cytopenias, with reduced numbers of red blood cells, neutrophils, and platelets. A proportion of patients later undergo transformation to AML. In most cases, these are primary disorders, but they may also develop secondary to chemotherapy or radiotherapy, given for other malignancies. Clinically, around half present >70 years old. There may be no symptoms with detection on blood tests, or they may present with anaemia, infections (neutropenia), or easy bruising and bleeding (↓platelets). Tests show a pancytopenia (p348), with a reduced reticulocyte count. Bone marrow cellularity is usually increased due to the ineffective haematopoiesis. Ring sideroblasts may also be seen in the marrow. There are different subtypes, grouped according to WHO classification. Treatment differs according to disease prognosis, and the individual. Allogeneic stem cell transplantation offers a cure, but is associated with a risk of mortality, and is thus reserved for younger patients (<55yrs) with poor prognosis disease. Alternatively, intensive combination chemotherapy may be used. In those where there is a better prognosis, or in older patients where intensive treatment is associated with poorer outcomes, single agent chemotherapy may be used to try to obtain disease control. Multiple transfusions of red cells or platelets are often required. Erythropoietin ± human granulocyte colony stimulating factor (G-CSF) may be used to lower the transfusion requirement. Immunosuppressive agents may also be used, eg ciclosporin or antithymocyte globulins. Prognosis Median survival: from 6 months to 6 years according to disease type. P.342
Chronic myeloid leukaemia (CML) CML is characterized by an uncontrolled clonal proliferation of myeloid cells. It accounts for 15% of leukaemias. It is a myeloproliferative disorder (p350) having features in common with these diseases eg splenomegaly. It occurs most often between 40-60yrs, with a slight male predominance, and is rare in childhood. Philadelphia chromosome (Ph) Present in >80% of those with CML. It is a hybrid chromosome comprising reciprocal translocation between the long arm of chromosome 9 and the long arm of chromosome 22—t(9;22) forming a fusion gene BCR/ABL on chromosome 22, which has tyrosine kinase activity. Those without Ph have a worse prognosis. Some patients have a masked translocation—cytogenetics do not show the Ph, but the rearrangement is detectable by molecular techniques. Symptoms Mostly chronic and insidious: weight↓, tiredness, fever, sweats. There may be features of gout (due to purine breakdown), bleeding (platelet dysfunction), and abdominal discomfort (splenic enlargement). ~30% are detected by chance. Signs Splenomegaly (>75%)—often massive. Hepatomegaly, anaemia, bruising. Tests WBC ↑↑ (often >100 × 109/L) with whole spectrum of myeloid cells ie ↑neutrophils, myelocytes, basophils, eosinophils. Hb↓ or normal, platelets variable. Urate↑, B12↑. Neutrophil alk phos score↓ (seldom performed now). Bone marrow is hypercellular. Ph found on cytogenetic analysis of blood or bone marrow. Natural history Variable, median survival 5-6yrs. There are three phases: chronic, lasting months or years of few, if any, symptoms → accelerated phase, with increasing symptoms, spleen size, and difficulty in controlling counts → blast transformation, with features of acute leukaemia ± death. Treatment See BOX. Chronic lymphocytic leukaemia (CLL) This is a monoclonal proliferation of non-functional mature B lymphocytes (T cell CLL occurs rarely). CLL constitutes 25% of all leukaemias. ♂:♀ 2:1. It is a disease of the elderly, median age at diagnosis is ~65 years. Staging correlates with survival:

Stage 0

Lymphocytosis alone.

Median Survival >13yrs

I

Lymphocytosis + lymphadenopathy.

8yrs

II

Lymphocytosis + spleno- or hepatomegaly.

5yrs

III

Lymphocytosis + anaemia (Hb <11g/dL).

2yrs

IV

Lymphocytosis + platelets <100 × 109/L.

1yr

Symptoms (none in 25%) Infection, anaemia. If severe: weight↓, sweats, anorexia. Signs Enlarged, rubbery, non-tender nodes. Splenomegaly, hepatomegaly. Tests ↑Lymphocytes—may be marked. Later: autoimmune haemolysis (p324), marrow infiltration: ↓Hb, ↓neutrophils, ↓platelets. Complications

  • 1 Autoimmune haemolysis.
  • 2 ↑Infection due to hypogammaglobulinaemia (=↓IgG), bacterial, viral especially herpes zoster.
  • 3 Marrow failure.

Natural history Some remain in status quo for years, or even regress. Usually nodes slowly enlarge (± lymphatic obstruction). Death is often due to infection (commonly pneumococcus, haemophilus, meningococcus, Candida or aspergillosis), or transformation to aggressive lymphoma (Richter’s syndrome). Treatment If asymptomatic, the patient can be monitored. Chlorambucil is used to ↓lymphocyte count, improve marrow function, and reduce node size. Dose: eg 0.1- 0.2mg/kg daily PO. The purine analogue fludarabine is an alternative. Steroids are used in autoimmune haemolysis. Radiotherapy: For relief of lymphadenopathy or splenomegaly. Supportive care: Transfusions, IV human immunoglobulin if recurrent infections. Bone marrow transplant is currently experimental. Prognosis Current treatments are mainly non-curative at present. Prognosis is often good: depends on stage and molecular/immunological factors. P.343
Treatment of CML Chemotherapy

  • Imatinib (Glivec®), a specific BCR/ABL tyrosine kinase inhibitor, has revolutionized CML therapy. It is more effective than the previous gold standard of ×- interferon—± cytarabine in chronic phase patients, in terms of preventing disease progression. It is likely that this will be translated into a survival advantage; long term data are awaited. The drug may also be effective in accelerated phase and blast crises. Imatinib gives high haematological response rates (>90%). Cytogenetic remissions are also common, but complete eradication of the Philadelphia clone, as detected by the most sensitive molecular methods, is unusual (<5% patients). SE: usually mild: nausea, cramps, oedema, skin rash, headache, arthralgia. May cause myelosuppression.
  • Hydroxycarbamide may still be used in patients intolerant of imatinib, or where imatinib has proved ineffective. Busulfan is very rarely used now.
  • The use of ×-interferon in CML has declined dramatically with the introduction of imatinib, but ×-interferon may still have a role in combination therapy.
  • Treatment of CML blast crisis is problematic. Patients not previously treated with imatinib may respond temporarily to this. Those with lymphoblastic transformation may benefit from treatment as for ALL. Treatment of myeloblastic transformation with chemotherapy rarely achieves lasting remission and allogeneic transplantation offers the only hope of long-term survival.

Stem cell transplantation

  • Allogeneic transplantation from a HLA matched sibling or unrelated donor is the only curative treatment but carries significant morbidity and mortality. Guidelines suggest that this approach should be used 1st line only in young patients where mortality rates are lower. Other patients should be offered imatinib. Patients are then reviewed annually to decide whether to continue imatinib, or to offer combination therapy or stem cell transplantation.
  • The role of autologous transplantation, if any, in CML, remains to be defined.
Fig 1. Hepatosplenomegaly in CML.
Fig 2. CML: Numerous granulocytic cells at different stages of differentiation.image70
Fig 3. Bilateral cervical lymphadenopathy in CLL.
Fig 4. CLL: Numerous lymphocytes and a typical ‘smear’ cell: a fragile cell damaged in preparation.image71

P.344
Hodgkin’s lymphoma [Thomas Hodgkin, Guy’s,UK 1798-1866] Lymphomas are disorders caused by malignant proliferations of lymphocytes. These accumulate in the lymph nodes causing lymphadenopathy, but may also be found in peripheral blood or infiltrate organs. Lymphomas are histologically divided into Hodgkin’s and non-Hodgkin’s types. In Hodgkin’s lymphoma, characteristic cells with mirror-image nuclei are found, called Reed-Sternberg cells. Hodgkin’s lymphoma: 2 peaks of incidence: young adults and elderly. ♂:♀≈2:1; Symptoms Often presents with enlarged, painless, non-tender, ‘rubbery’ superficial lymph nodes, typically cervical (60-70%), also axillary or inguinal nodes. The size of the nodes may increase and decrease spontaneously, and nodes can become matted. 25% have constitutional upset, eg fever, weight loss, night sweats, pruritus, and lethargy. There may be alcohol-induced lymph node pain. Mediastinal lymph node involvement can cause features due to mass effect eg bronchial or SVC obstruction (p514), or direct extension eg causing pleural effusions. Pel-Ebstein fever implies a cyclical fever with long periods (15-28 days) of normal or low temperature: it is, at best, rare—and some have called it mythical.1 1 Pel-Ebstein fever is dismissed by Richard Asher (Talking Sense), as existing only thanks to its having been exotically named (the 1885 patients of Dr P Pel had no histology, and fevers in Hodgkin’s are usually non-specific). Another unfair reason for consigning it to myth is that the paper proving its existence and its relation to cyclical changes in node size doesn’t come up in literature searches as Wilhelm Ebstein was spelled Epstein throughout.image Signs Lymph node enlargement. Also, cachexia, anaemia, spleno- or hepatomegaly. Tests Tissue diagnosis Lymph node excision biopsy if possible. Image guided needle biopsy, laparotomy or mediastinoscopy may be needed to obtain a sample. Bloods FBC, film, ESR, LFT, LDH, urate, Ca2+. ↑ESR or ↓Hb indicate a worse prognosis. LDH is raised as it is released during cell turnover. Staging (Ann Arbor system) Influences treatment and prognosis. Done by CXR, CT of thorax, abdo, pelvis ± bone marrow biopsy if B symptoms, or stage III-IV disease.

I

Confined to single lymph node region.

II

Involvement of two or more nodal areas on the same side of the diaphragm.

III

Involvement of nodes on both sides of the diaphragm.

IV

Spread beyond the lymph nodes eg liver or bone marrow.

Each stage is subdivided into ‘A’—no systemic symptoms other than pruritus; or ‘B’—presence of B symptoms: weight loss >10% in the last 6 months, unexplained fever >38°C, or drenching night sweats (requiring change of clothes). ‘B’ indicates more extensive disease. Localized extra-nodal extension does not advance the stage, but is indicated by subscripted ‘E’, eg I-AE . Treatment This is with chemotherapy, radiotherapy or both. Radiotherapy ± short courses of chemotherapy for stages I-A and II-A (eg with ¢3 areas involved). Longer courses of chemotherapy for II-A with >3 areas involved through to IV-B. The standard regime is ‘ABVD’: Adriamycin, Bleomycin, Vinblastine, and Dacarbazine. More intensive regimens are used if poor prognosis or advanced disease. In relapsed disease, where disease recurs after treatment, high dose chemotherapy with peripheral stem-cell transplantation may be used, involving autologous (or occasionally allogeneic) transplantation of peripheral blood progenitor cells to restore marrow function after therapy.image72 Complications of treatment See p516-9: Radiotherapy may ↑ risk of second malignancies—solid tumours (especially lung and breast, also melanoma, sarcoma, stomach and thyroid cancers), ischaemic heart disease, hypothyroidism and lung fibrosis due to the radiation field. Chemotherapy SE include myelosuppression, nausea, alopecia, infection. AML (p340), non-Hodgkin’s lymphoma and infertility may be due to both chemo- or radiotherapy—see page 519. 5-year survival Depends on stage and grade: >95% in I-A lymphocyte-predominant disease; <40% with IV-B lymphocyte-depleted. Emergency presentations Infection; SVC obstruction—JVP↑, sensation of fullness in the head, dyspnoea, blackouts, facial oedema (seek expert help; see p514). P.345

Classification (In order of incidence)

Prognosis

Classical Hodgkin’s lymphoma

Nodular sclerosing

Good

Mixed cellularity*

Good

Lymphocyte rich

Good

Lymphocyte-depleted*

Poor

NB: nodular lymphocyte predominant Hodgkin’s is recognized as a separate entity, behaving as an indolent B-cell lymphoma.

* Higher incidence and worse prognosis if HIV +ve.image73

Fig 1. A Reed-Sternberg cell, which contains 2 nuclei, characteristic of Hodgkin’s lymphoma.image74
Fig 2. Another Reed-Sternberg cell.image75
Fig 3. Cervical lymphadenopathy in Hodgkin’s disease.

P.346
Non-Hodgkin’s lymphoma This includes all lymphomas without Reed-Sternberg cells, and is a very diverse group of diseases. Most are derived from B-lymphocyte cell lines. Not all are centred on lymph nodes (extranodal tissues generating lymphoma include mucosaassociated lymphoid tissue—MALT. Gastric MALT is associated with H. pylori, and may regress when this is eradicated). The overall incidence of lymphoma has doubled since 1970 (to 1 : 10,000). Causes: congenital immunodeficiency, acquired immunodeficiency eg drugs, HIV infection (usually high grade lymphoma), infection (eg HTLV-1 p336, EBV, H. pylori) or environmental toxins. Signs and symptoms

  • Nodal disease (75% at presentation): superficial lymphadenopathy
  • Extranodal disease (25%) involving the oropharynx, skin (especially T cell lymphomas—p548), bone, gut, CNS, or lung. Disease of the oropharyngeal lymphoid tissue (Waldeyer’s ring) causes sore throat and obstructed breathing.
  • Systemic symptoms—fever, night sweats, weight loss (less common than in Hodgkin’s lymphoma, and indicates disseminated disease)
  • Pancytopenia due to marrow involvement—anaemia, neutropenia (infection) and ↓platelets (bleeding).

Tests As for Hodgkin’s disease with the Ann Arbor system (p344). Diagnosis Lymph node biopsy. Bloods FBC, U&E, LFT, LDH. ↑LDH indicates worse prognosis as it is released with cell turnover. Stage with CT or MRI of chest, abdomen, pelvis, and bone marrow aspiration. Send cytology of any effusion; lumbar puncture for CSF cytology if any CNS signs. Histology This is something of a quagmire as classification systems are complex and changing. The current classification is based on the WHO classification of lymphoid neoplasms. Discuss diagnosis and management as a multidisciplinary team, bringing together information available from clinical evaluation, histology, immunology, molecular genetics, and imaging. Generally:

  • Low-grade lymphomas are indolent, and are often incurable and widely disseminated at presentation. Include: follicular lymphoma, marginal zone lymphoma (includes MALT lymphomas), lymphocytic lymphoma (closely related to CLL and treated similarly), lymphoplasmacytoid lymphoma (associated with production of IgM = Waldenström’s macroglobulinaemia, p354).
  • High-grade lymphomas are more aggressive, but long-term cure may be achievable. There is often a short history of rapidly enlarging lymphadenopathy with systemic symptoms. Include: Burkitt’s lymphoma (childhood disease with characteristic jaw lymphadenopathy), lymphoblastic lymphomas (shares features with ALL), diffuse large B-cell lymphoma.

Treatment Depends on disease subtype. Low grade: If symptomless, none may be needed. Radiotherapy may be curative in localized disease. Chlorambucil is used in diffuse disease. Remission may be maintained by using ×-interferon or rituximab (see below). High grade: For diffuse large B-cell lymphoma (DLBCL), the ‘CHOP’ regime: Cyclophosphamide, Hydroxydaunorubicin, vincristine (Oncovin®) and Prednisolone plus rituximab may be used.1 The addition of rituximab, an anti-CD20 monoclonal antibody, to this regimen has produced the first major advance in the treatment of this disorder for 30yrs. Survival Histology is important. Prognosis is worse if at presentation:

  • Age >60yrs
  • Systemic symptoms
  • Bulky disease (abdominal mass >10cm)
  • ↑LDH
  • Disseminated disease. Typical 5-yr survival for treated patients: ~30% for high-grade and >50% for low-grade lymphomas, but the picture is very variable.

P.347

Fig 1. Burkitt’s lymphoma, with characteristic jaw lymphadenopathy.image76
Fig 2. Burkitt’s lymphoma, with 3 basophilic vacuolated lymphoma cells.image77
Fig 3. Cutaneous T cell lymphoma, which has caused severe erythroderma (Sézary syndrome) in a Caucasian woman.image78

P.348
Pancytopenia, and bone marrow failure The bone marrow is responsible for haemopoiesis. In adults, this normally takes place in the central skeleton (vertebrae, sternum, ribs, skull) and proximal long bones. In some anaemias (eg thalassaemia), increased demand produces haematopoiesis outside the bone marrow (extramedullary haematopoiesis), in the liver and spleen causing organomegaly. All blood cells arise from an early pluripotent stem cell, which divides in an asymmetrical way to produce another stem cell and a progenitor cell committed to a specific cell line. Committed progenitors undergo further differentiation under myeloid or lymphocyte lineage, before their release into the blood as mature cells. Pancytopenia is reduction in all the major cell lines: red cells, white cells and platelets. Causes are due to

  • ↓marrow production: aplastic anaemia, infiltration (eg acute leukaemia, myelodysplasia, myeloma, lymphoma, solid tumours, TB), megaloblastic anaemia, paroxysmal nocturnal haemoglobinuria (p324), myelofibrosis (p350), SLE.
  • ↑peripheral destruction: hypersplenism.

Aplastic anaemia is a rare stem cell disorder leading to pancytopenia and a hypoplastic bone marrow (the marrow stops making cells). Presents with features of anaemia (↓Hb), infection (↓WCC) or bleeding (↓platelets). Incidence: ~5 cases per million/year. Causes: Most cases are autoimmune, triggered by drugs, (viruses eg Parvovirus, hepatitis) or irradiation. May also be inherited eg Fanconi anaemia (p690). Tests: A bone marrow examination is required for the diagnosis. Treatment: Support the blood count (below). Asymptomatic patients do not require specific treatment, but supportive treatment (eg neutropenic regimen) may be required. The treatment of choice in young patients who are severely affected is an allogeneic marrow transplantation from an HLA matched sibling, which can be curative. Otherwise, immunosuppression with ciclosporin and antithymocyte globulin may be effective, although is not curative in most. Marrow support Red cells survive for ~120d, platelets for ~8d, and neutrophils for 1-2d, so early problems are mainly from neutropenia and thrombocytopenia. Red cell transfusion: Transfusing 1U should raise Hb by ~1-1.5g/dL (p570). Transfusion may drop the platelet count (you may need to give platelets before or after). Platelets: Traumatic bleeds, purpura and easy bruising occur if platelets <50×109/L. Spontaneous bleeding may occur if platelets <20 × 109/L, with intracranial haemorrhage rarely. Platelets are stored at room temperature (22°C; not in the fridge). In marrow transplant or if severely immunosuppressed, platelets may need irradiation before use, to prevent transfusion-associated graft-versus-host disease (GVHD). Platelets should be ABO compatible. They are not used in ITP (p330). Indications:

  • Platelets <10×109/L
  • Haemorrhage, including DIC (p336)
  • Before invasive procedures (eg biopsy, lumbar puncture) to increase count to >50 × 109/L. 4U of fresh platelets should raise the count to >40×109/L in adults; check dose needed with lab.

Neutrophils: Use a ‘neutropenic regimen’ if the count <0.5 × 109/L. See p336. Bone marrow biopsy may provide diagnostic information where there are abnormalities in the peripheral blood, and is also an important staging test in the lymphoproliferative disorders. Ideally an aspirate and trephine should be taken, usually from the posterior iliac crest (aspirates can also be taken from the anterior iliac crest or sternum). The aspirate provides a film which is examined by microscope. The trephine is a core of bone which allows assessment of bone marrow cellularity, architecture and the presence of infiltrative disease. Coagulation disorders may need to be corrected pre-biopsy. Apply pressure afterwards (lie on that side for 1-2h if platelets are low). P.349
P.350
The myeloproliferative disorders These form a group of disorders caused by proliferation of a clone of haematopoietic myeloid stem cells in the marrow. While the cells proliferate, they also retain the ability to differentiate into RBCs, WBCs or platelets. Classification is by the cell type which is proliferating

RBC

→

Polycythaemia rubra vera (PRV).

WBC

→

Chronic myeloid leukaemia (CML, p342).

Platelets

→

Essential thrombocythaemia.

Fibroblasts

→

Myelofibrosis.

Polycythaemia may be relative (↓plasma volume, normal RBC mass) or absolute (↑RBC mass). Relative polycythaemia may be acute and due to dehydration (eg alcohol or diuretics). A more chronic form exists which is associated with obesity, hypertension, and a high alcohol and tobacco intake. Absolute polycythaemia is distinguished by red cell mass estimation, using radioactive chromium (51Cr) labelled RBCs. Causes are primary (polycythaemia rubra vera) or secondary due to hypoxia (eg high altitudes, chronic lung disease, cyanotic congenital heart disease, heavy smoking) or inappropriately ↑erythropoietin secretion (eg in renal carcinoma, hepatocellular carcinoma). Polycythaemia rubra vera This is a malignant proliferation of a clone derived from one pluripotent marrow stem cell. The erythroid progenitor offspring are unusual in not needing erythropoietin to avoid apoptosis (p499). There is excess proliferation of RBCs, WBCS, and platelets, leading to thrombotic complications due to hyperviscosity. Usually affects older patients >60yrs. Signs May be asymptomatic and detected on FBC, or present with vague signs due to hyperviscosity (p356): headaches, dizziness, tinnitus, visual disturbance. Itch after a hot bath, and erythromelalgia, a burning sensation in fingers and toes, are characteristic. Examination may show facial plethora and splenomegaly (in 60%). Gout may occur due to ↑urate from RBC turnover. Features of arterial (cardiac, cerebral, peripheral) or venous (DVT, cerebral, hepatic) thrombosis may be present. Investigations

  • FBC: ↑RCC, ↑Hb, ↑HCT, ↑PCV, often also ↑WBC and ↑platelets
  • B12↑
  • Marrow shows hypercellularity with erythroid hyperplasia
  • Neutrophil alkaline phosphatase (NAP) score is ↑ (↓ in CML)
  • ↓serum erythropoietin
  • Raised red cell mass on 51Cr studies and splenomegaly, in the setting of a normal PaO2, is diagnostic.

Treatment: Aim to keep HCT <0.45 to ↓risk of thrombosis. In younger patients at low risk, this is done by venesection. If higher risk (age >60yrs, previous thrombosis), hydroxycarbamide (=hydroxyurea) is used. ×-interferon is preferred in women of childbearing age. Low dose aspirin 75mg daily PO is also given. Prognosis: Variable, many remain well for years. Thrombosis and haemorrhage (due to defective platelets) are the main complications. Transition to myelofibrosis occurs in ~30% or acute leukaemia in ~5%. Monitor FBC every 3 months. Essential thrombocythaemia A clonal proliferation of megakaryocytes leads to persistently ↑platelets, often >1000 × 109/L, with abnormal function, causing bleeding or arterial and venous thrombosis, and microvascular occlusion— headache, atypical chest pain, light-headedness, erythromelalgia. Exclude other causes of thrombocytosis (see BOX). Treatment: Low dose aspirin 75mg daily. Hydroxycarbamide is given to ↓platelets if >60yrs old or if previous thrombosis. Myelofibrosis There is hyperplasia of megakaryocytes which produce platelet derived growth factor, leading to intense marrow fibrosis and myeloid metaplasia (haemopoiesis in the spleen and liver)→massive hepatosplenomegaly. Presentation: Hypermetabolic symptoms: night sweats, fever, weight loss; abdominal discomfort due to splenomegaly; or bone marrow failure (↓Hb, infections, bleeding). Film: Leucoerythroblastic cells (nucleated red cells, p314); characteristic teardrop RBCs (see fig 2). Hb↓. Bone marrow trephine for diagnosis. Treatment: Marrow support (see p662). Allogeneic stem cell transplant may be curative in young people but carries a high risk of mortality. Prognosis: Median survival 4-5 years. P.351
Causes of thrombocytosis ↑Platelets >450 × 109/L may be a reactive phenomenon, seen with many conditions including:

  • Bleeding
  • Infection
  • Chronic inflammation, eg collagen disorders
  • Malignancy
  • Trauma
  • Post-surgery
  • Iron deficiency
Fig 1. Essential thrombocythaemia: numerous platelets seen.image79
Fig 2. Tear drop cells, seen in myelofibrosis.image80
Fig 3. Bone marrow trephine in myelofibrosis: the streaming effect is caused by intense fibrosis. Other causes of marrow fibrosis include any myeloproliferative disorder, lymphoma, secondary carcinoma, TB, leukaemia, and irradiation.image81

P.352
Myeloma Myeloma is a malignant clonal proliferation of B-lymphocyte derived plasma cells (fig 1). Normally many different plasma cells produce different immunoglobulins (Igs) which are polyclonal. In myeloma, a single clone of plasma cells produce identical Igs. This can be detected as a monoclonal band, or paraprotein, on serum and/or urine electrophoresis (see p678). Classification is based on the Ig product, which is IgG in ~2/3 and IgA in ~1/3. The small remainder are IgM or IgD. The other Ig levels are low. This is termed immunoparesis, causing increased susceptibility to infection. In ~2/3 of cases, the urine contains Bence-Jones protein, which are free Ig light chains of either kappa (κ) or lambda (λ) type, filtered by the kidney. Incidence 5/100,000. Peak age: 70yrs.♂:♀≈1. Afro-Caribbeans:Caucasians≈2:1. Symptoms

  • Osteolytic bone lesions causing unexplained backache, pathological fractures eg long bones or ribs, and vertebral collapse. Hypercalcaemia may result with symptoms (p672). Lesions are due to ↑ osteoclast activation, from signalling by myeloma cells.
  • Anaemia, neutropenia, or thrombocytopenia may result from marrow infiltration by proliferating plasma cells, leading to symptoms of anaemia, infection and bleeding.
  • Recurrent bacterial infections due to immunoparesis, and also because of neutropenia due to the disease and from chemotherapy.
  • Renal impairment due to light chain deposition (p306 & p354).
  • Systemic AL amyloidosis occurs in 15% (p354).

Tests FBC—normocytic normochromic anaemia, film—rouleaux formation (p314), persistently ↑ESR or PV (p356), ↑urea and creatinine, ↑Ca2+ (in ~40%), alk phos usually normal (unless healing fracture). Screening test: Serum & urine electrophoresis. Ò2-microglobulin (as a prognostic test). Imaging X-rays show lytic ‘punched-out’ lesions, eg pepper-pot skull, vertebral collapse, fractures or osteoporosis. CT or MRI may be useful to detect lesions not seen on XR. Diagnosis: see BOX. Treatment Supportive:

  • Bone pain should be treated with analgesia (avoid NSAIDs due to risk of renal impairment). Give all patients a bisphosphonate (clodronate, zolendronate or pamidronate), as they reduce fracture rates and bone pain. Local radiotherapy can help rapidly in focal disease. Orthopaedic procedures (vertebroplasty or kyphoplasty) may be helpful in vertebral collapse.
  • Anaemia should be corrected with transfusion, and erythropoietin may be used.
  • Renal failure: Rehydrate, and ensure adequate fluid intake of 3L/day to prevent further renal impairment by light chains. Dialysis may be needed in acute renal failure
  • Infections: Treat rapidly with broad spectrum antibiotics until culture results are known. Regular IV immunoglobulin infusions may be needed if recurrent.

Chemotherapy: In elderly patients, either melphalan or cyclophosphamide are used with prednisolone. This is usually effective in controlling disease for about 1 year, reducing paraprotein levels and bone lesions. The disease may then become uncontrollable and often resistant to treatment. One randomized trial (2006) found the addition of thalidomide (a teratogenic immunomodulator) markedly improved event-free survival in the elderly.RCT82 Its use is non-standard. SE: birth defects; drowsiness; neuropathy; neutropenia; sepsis; thromboembolism (anticoagulation is probably wise); orthostatic hypotension. In younger or fitter people, a more aggressive approach is used (high-dose therapy and stem-cell rescue, HDT) with a VAD type regime: Vincristine, Adriamycin and Dexamethasone. Autologous stem cell transplant may then be done, which improves survival but is not curative. Allogeneic transplantation can be curative in younger patients, but carries ↑risk of mortality (~30%). Thalidomide or bortezomib may be tried in relapsed disease. Prognosis Median survival is 3-4 years. A raised Ò2-microglobulin is associated with a worse prognosis. Death is commonly due to infection or renal failure. P.353
Diagnostic criteria image83

  • Monoclonal protein band in serum or urine electrophoresis
  • Increased plasma cells found on bone marrow biopsy
  • Evidence of end organ damage from myeloma
    • Hypercalcaemia
    • Renal insufficiency
    • Anaemia
    • Bone lesions: a skeletal survey is performed after diagnosis to detect bone disease, consisting of X-rays of chest; cervical, thoracic, and lumbar spine; skull and pelvis.

Complications of myeloma

  • Hypercalcaemia (p672). Occurs with active disease ie at presentation or relapse. Rehydrate vigorously with IV saline 0.9% 4-6L/d (careful fluid balance). IV bisphosphonates, eg zolendronate or pamidronate are useful for treating hypercalcaemia acutely.
  • Spinal cord compression (p458 & p515). Occurs in 5% of patients with myeloma. Urgent MRI if suspected. Treatment is with dexamethasone 8-16mg/24h PO and local radiotherapy.
  • Hyperviscosity (p356), causes reduced cognition, disturbed vision, and bleeding. It is treated with plasmapheresis, to remove light chains.
  • Acute renal failure is treated with rehydration. Patients may require urgent dialysis.
Fig 1. The bone marrow in myeloma: large number of plasma cells with abnormal forms.image84
Fig 2. A bone marrow section in myeloma, stained with IgG kappa monoclonal antibody.image85
Fig 3. An IgG kappa paraprotein monoclonal band on electrophoresis (a control sample has run on the left).image86

P.354
Paraproteinaemia Paraproteinaemia denotes presence in the circulation of immunoglobulins produced by a single clone of plasma cells. The paraprotein is recognized as a monoclonal band (M band) on serum electrophoresis.1 There are 6 major categories:

  • Multiple myeloma: See p352.
  • Waldenström’s macroglobulinaemia: This is a lymphoplasmacytoid lymphoma producing a monoclonal IgM paraprotein. Hyperviscosity is common (p356), with CNS and ocular symptoms. Lymphadenopathy and splenomegaly are also seen. ↑ESR, with IgM paraprotein on serum electrophoresis. [prescription take]: None if asymptomatic. Chlorambucil, fludarabine or combination chemotherapy may be used. Plasmapheresis1 for hyperviscosity (p356).
  • Primary amyloidosis: See below.
  • Monoclonal gammopathy of uncertain significance (MGUS) is common (3% >70yrs). There is a paraprotein in the serum but no myeloma, macroglobulinaemia or lymphoma, with no bone lesions, no Bence-Jones protein and a low concentration of paraprotein, with <10% plasma cells in the marrow. A proportion of these patients develop myeloma or lymphoma in the future.
  • Paraproteinaemia in lymphoma or leukaemia: Eg seen in 5% of CLL.
  • Heavy chain disease: This is where neoplastic cells produce free Ig heavy chains. × chain disease is the most important, causing malabsorption from infiltration of small bowel wall. It may progress to lymphoma.

Amyloidosis image87 This is a group of disorders characterized by extracellular deposits of a protein in abnormal fibrillar form, resistant to degradation. The following are the systemic forms of amyloidosis. Amyloid deposition is also a feature of Alzheimer’s disease, Type 2 diabetes mellitus and haemodialysis-related amyloidosis. AL amyloid (primary amyloidosis): Due to clonal proliferation of plasma cells, with production of amyloidogenic monoclonal immunoglobulins. In most cases, it occurs on its own as a primary amyloidosis, with occult plasma cell proliferation. It is also seen in 15% of patients with myeloma, and smaller proportions with Waldenströms, MGUS, or lymphoma. Deposition may occur in

  • Kidneys: Glomerular lesions—proteinuria and nephrotic syndrome
  • Heart: Restrictive cardiomyopathy (‘sparkling’ appearance on Echo), arrhythmias, angina
  • Nerves: Peripheral and autonomic neuropathy, carpal tunnel syndrome
  • Gut: Macroglossia (big tongue), malabsorption, perforation, haemorrhage, obstruction, and hepatomegaly.
  • Vascular: Purpura, especially periorbital—a characteristic feature.

AA amyloid (secondary amyloidosis): The amyloid here is derived from serum amyloid A, an acute phase protein. It occurs with chronic inflammation in rheumatoid arthritis, inflammatory bowel disease, familial Mediterranean fever, and chronic infections—TB, bronchiectasis, osteomyelitis. It affects the kidneys, liver, and spleen, and commonly presents with proteinuria, nephrotic syndrome or hepatosplenomegaly. Macroglossia is not seen, and cardiac involvement is rare. Familial amyloidosis is a group of autosomal dominant disorder, most commonly caused by mutations in transthyretin, a transport protein produced by the liver. Usually causes a sensory or autonomic neuropathy ± renal or cardiac involvement. Diagnosis is made with biopsy of affected tissue, and positive Congo Red staining with red-green birefringence under polarized light microscopy. The rectum or subcutaneous fat are relatively non-invasive sites for biopsy and are +ve in 80%. [prescription take]: AA amyloidosis may improve if the primary disease is treated. AL may respond to therapy as for myeloma. Liver transplant can be curative in familial amyloidosis. Prognosis Median survival is 1-2 years. Patients with myeloma and amyloidosis have a shorter survival than those with myeloma alone. P.355

Fig 1. Periorbital purpura in amyloidosis.image88
Fig 2. Isotope scan in amyloidosis showing areas of amyloid deposition in the liver and spleen.

P.356
Erythrocyte sedimentation rate (ESR) Normal range: <20mm/h. The ESR is a sensitive but non-specific indicator of the presence of disease. It measures how fast RBCs fall through a column of anticoagulated blood over 1h. If certain proteins cover red cells, these cause RBCs to stick to each other in columns so they fall faster (the same phenomenon as rouleaux on the blood film, p314). The main causes of a raised ESR are any inflammation eg infection, rheumatoid arthritis, malignancy, myocardial infarction; or anaemia. In those with a slightly raised ESR, the best plan is probably to wait a month and repeat it. There is a group of patients whose vague symptoms would have prompted nothing more than reassurance—were it not for a markedly raised ESR— and in whom there are no pointers to specific disease. The same advice does not hold true for those with a very high ESR (>100mm/h), where there is a 90% predictive value for disease. In practice, most have signs pointing to the cause. In one survey, serious underlying disease later found in such patients included myeloma, giant cell arteritis, abdominal aneurysm, metastatic prostatic carcinoma, leukaemia, and lymphoma. Therefore, it would be wise (after history and examination) to consider these tests: FBC, plasma electrophoresis, U&E, PSA, chest and abdominal X-rays, ± biopsy of bone marrow or temporal artery. ESR also rises with age. A simple, reliableimage89 way to allow for this is to calculate the upper limit of normal, using the Westergren method, to be (for men) age in years ÷ 2. For women, the formula is (years+10) ÷ 2. Some conditions lower the ESR, eg polycythaemia (due to ↑red cell concentration), and sickle-cell anaemia. Even a slightly raised ESR in these patients should prompt one to ask: What else is the matter? Plasma viscosity (PV) Normal range: 1.50-1.72mPa/s. In many laboratories, this has replaced the ESR, as it is less affected by anaemia and results can be produced in 15min. The PV is affected by the concentration of large plasma proteins and is raised in the same conditions as the ESR. The PV and ESR are both raised in chronic inflammation and are less affected by acute changes under 24h in duration. The CRP is more sensitive in acute change (see p678). Hyperviscosity syndrome This occurs if the viscosity of blood rises enough to impair the microcirculation. It affects patients with a very high red cell count (haematocrit >50), white cell count (>100×109/L), or plasma components (usually immunoglobulins). Causes: Polycythaemia rubra vera (↑red cells), acute or chronic leukaemia (↑peripheral blast cells), myeloma (p352), Waldenström’s macroglobulinaemia (p354, as IgM is larger and so ↑ viscosity more than the same amount of IgG). Presentation: Features include lethargy, confusion, spontaneous bleeding: GU or GI, CNS disturbance, visual disturbance, and retinopathy: engorged retinal veins, haemorrhages, exudates, and a blurred disc. The visual symptoms (‘slow-flow retinopathy’) may be described as ‘looking through a watery car windscreen’. (Other causes of slow-flow retinopathy are carotid occlusive disease and Takayasu’s disease: p704). Treatment: Urgent treatment is needed which depends on the cause. Venesection is done in polycythaemia. Leucopheresis in leukaemias to remove white cells. Plasmapheresis in myeloma and Waldenström’s: blood is withdrawn via a plasma exchange machine, the supernatant plasma from this is discarded, and the RBCs returned to the patient after being re-suspended in a suitable medium. P.357
The spleen and splenectomy The spleen was a mysterious organ for many years; we now know that it plays a vital immunological role by acting as a reservoir for lymphocytes, and in dealing with bacteraemias. Splenomegaly is a commonish problem and its causes are divided into massive (into the RIF) and moderate. Causes of massive splenomegaly CML, myelofibrosis, malaria (hyperreactive malarial splenomegaly), leishmaniasis, ‘tropical splenomegaly’ (idiopathic—Africa, SE Asia), and Gaucher’s syndrome. Moderate splenomegaly: See p624.

  • Infection (eg EBV, endocarditis, TB, malaria, leishmaniasis, schistosomiasis)
  • Portal hypertension (liver cirrhosis),
  • Haematological (haemolytic anaemia, leukaemia especially CML, lymphoma)
  • Connective tissue disease (RA, SLE)
  • Others: sarcoidosis, primary antibody deficiency (OHCS p198), idiopathic.

Splenomegaly can be uncomfortable and may lead to hypersplenism: pancytopenia as cells become trapped in the spleen’s reticuloendothelial system, with symptoms of anaemia, infection, or bleeding. Splenectomy may be required if severe. When faced with a mass in the left upper quadrant, it is vital to recognize the spleen:

  • Dull to percussion
  • It enlarges towards the RIF
  • It moves down on inspiration
  • You may feel a medial notch
  • ‘You can’t get above it’ (ie the top margin disappears under the ribs). The last three features differentiate the spleen from an enlarged left kidney. Abdominal USS or CT are used to image the spleen. When hunting the cause for enlargement look for lymphadenopathy and liver disease, eg: FBC, ESR, LFT ± liver, marrow, or lymph node biopsy.

Splenectomy Main indications: splenic trauma, hypersplenism, autoimmune haemolysis: in ITP (p330) or warm autoimmune haemolytic anaemia (p324), congenital haemolytic anaemias. Splenectomy was historically performed for staging in Hodgkin’s disease, but CT and MRI have replaced this role. Mobilise early post-splenectomy as transient ↑platelets predisposes to thrombi. A characteristic blood film is seen following splenectomy, with Howell-Jolly bodies, Pappenheimer bodies and target cells (see p314). ▶The main problem post-splenectomy is lifelong increased risk from infection. The spleen contains macrophages which filter and phagocytose bacteria. Post-splenectomy infection is caused most commonly by encapsulated organisms: Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. Reduce this risk by giving:1

  • Immunizations:
    • Pneumococcal vaccine (p152), at least 2 weeks pre-op to ensure good response, or as soon as possible after emergency splenectomy eg after trauma. Re-immunize every 5-10yrs. Avoid in pregnancy.
    • Haemophilus influenzae type b vaccine (p381).
    • Meningococcal C vaccine.
    • Annual influenza vaccine (p390).
  • Lifelong prophylactic oral antibiotics (phenoxymethylpenicillin). Erythromycin if penicillin allergic.
  • Patient-held cards alerting health professionals to the infection risk.
  • Pendants or bracelets to alert medical staff.
  • Advice to seek medical attention if any signs of infection.
  • Urgent hospital admission if infection develops, for treatment with broad spectrum antibiotics.
  • If travelling abroad, warn of risk of severe malaria and advise meticulous prophylaxis, with nets, repellent, and medication.

The above advice also applies to hyposplenic patients, eg in sickle-cell anaemia or coeliac disease. P.358
Thrombophilia image90 Thrombophilia is an inherited or acquired coagulopathy predisposing to thrombosis, usually venous: DVT or PE (venous thromboembolism: VTE). Special precautions are needed in surgery, pregnancy, and enforced inactivity. Risk is further increased by obesity, immobility, trauma (accidents or surgery), pregnancy, and malignancy. NB: Thrombocytosis and polycythaemia may also cause thrombosis (p350). Note only ~50% of patients with thrombosis and a +ve family history have an identifiable thrombophilia: others may have abnormalities that are as yet unidentified. Inherited • Activated Protein c (APC) resistance/Factor V Leiden: Commonest cause of inherited thrombophilia. Present in ~5% population, although most will not develop thrombosis. Usually associated with a single point mutation in factor V (Factor V Leiden), so that this clotting factor is not broken down by APC. Risk of venous thromboembolism (DVT or PE) is increased 5-fold in patients who are heterozygous for the mutation, and 50-fold in homozygotes. Thrombotic risk is increased in pregnancy and those on oestrogens (OHCS p257 & p302). • Prothrombin gene mutation: Leads to high prothrombin levels and increased thrombosis due to down-regulation of fibrinolysis, by thrombin-activated fibrinolysis inhibitor. • Protein C and Protein S deficiency: These vitamin K-dependent factors act together to cleave and thus neutralize Factors V and VIII. Heterozygotes deficient for either protein risk thrombosis. Skin necrosis also occurs, especially if on warfarin. Homozygous deficiency for either protein causes neonatal purpura fulminans—fatal, if untreated. • Antithrombin deficiency: Antithrombin is a co-factor of heparin, and inhibits thrombin. Less common, affects 1 : 500. Heterozygotes’ thrombotic risk is greater than Protein C or S deficiency by ~4-fold. Homozygosity is incompatible with life. Acquired Causes: newer ‘3rd generation’ progesterones in the oral contraceptive pill and the antiphospholipid syndrome (APL: p540) when serum antiphospholipid antibodies are found (lupus anticoagulant ± anticardiolipin antibody)—predisposing to venous and arterial thrombosis, thrombocytopenia, and recurrent fetal loss in pregnant women. In most it is a primary disease, but it is also seen with SLE. Who to investigate? Consider special tests if:

  • Arterial thrombosis <50yrs (for APL)
  • Venous thrombosis <40y with no risk factors
  • Unexplained recurrent VTE
  • Unusual site, eg mesenteric/portal vein thrombosis
  • Familial VTE or with oral contraceptives/pregnancy
  • Recurrent fetal loss (≥3)
  • Neonatal thrombosis

Liaise with a haematologist. Do FBC, film, clotting tests: PT, thrombin time, APTT, and fibrinogen concentration. Further tests: APC resistance test, lupus anticoagulant and anticardiolipin antibodies, and assays for antithrombin and proteins C and S deficiency. Haematologists may advise DNA analysis by PCR for the Factor V Leiden mutation if the APC resistance test is +ve, and for prothrombin gene mutation. Ideally investigate while well, not pregnant, and not anticoagulated for 1 month. Treatment Treat acute thrombosis as standard—heparin, then warfarin to target INR of 2-3 (p335). If recurrence occurs with no other risk factors, lifelong warfarin should be considered. Recurrence whilst on warfarin should be treated by increasing target INR to 3-4. In antithrombin deficiency, high doses of heparin may be needed so liaise with a haematologist. In protein C or S deficiency, monitor treatment closely as skin necrosis may occur with warfarin. Prevention Life-long anticoagulation is not needed in asymptomatic patients. Patients should be advised of increased risk of VTE with the Pill or HRT, and counselled as regards to the best form of contraception. Patients should also be warned of other risk factors for VTE. Prophylaxis may be needed in pregnancy, eg in antiphospholipid syndrome. Get expert help: aspirin and prophylactic heparin are used, as warfarin is teratogenic. Prophylactic SC heparin may also be indicated in high risk situations, eg pre-surgery. P.359
Other risk factors for thrombosis Arterial

  • Smoking
  • Hypertension
  • Hyperlipidaemia
  • Diabetes mellitus

Venous

  • Surgery
  • Trauma
  • Immobility
  • Pregnancy, oral contraceptive pill, HRT
  • Age
  • Obesity
  • Varicose veins
  • Other conditions: heart failure, malignancy, inflammatory bowel disease, nephrotic syndrome, paroxysmal nocturnal haemoglobinuria (p324).

For thrombophilia in pregnancy, see OHCS p33; for anticoagulant use in pregnancy and thromboprophylaxis, see OHCS p16. P.360
Immunosuppressive drugs As well as being used in leukaemias and cancers, these are used in organ and marrow transplants, rheumatoid arthritis, psoriasis, chronic hepatitis, asthma, SLE, vasculitis (eg Wegener’s, giant cell arteritis, polymyalgia, PAN), inflammatory bowel and other diseases (so this page could figure in almost any chapter). Prednisolone Steroids can be life-saving, but a number of points should be taken into consideration before initiating treatment.

  • Certain conditions may be made worse by steroids, eg TB, hypertension, osteoporosis, diabetes: here careful monitoring is needed.
  • Growth retardation may occur in young patients, and the elderly frequently get more side effects from treatment.
  • Interactions: [Prednisolone]↓ by antiepileptics (below) and rifampicin.
  • Avoid pregnancy (may cause fetal growth retardation). If breast-feeding and prednisolone >40mg/day, see BNF.

Minimize side effects by using the lowest dose possible for the shortest period of time. Give doses in the morning, and alternate days if possible, to minimize adrenal suppression. Before starting long-term treatment (>3 weeks, or repeated courses) observe these guidelines:

  • Explain about not stopping steroids suddenly. Collapse may result, as endogenous production takes time to restart. ÕSee p818.
  • Inform about the need to consult a doctor if unwell, and increase the dose of steroid at times of illness/stress (eg flu or pre-op).
  • Encourage to carry a steroid card saying dose taken, and the reason.
  • You must warn patients about the listed side effects if they are receiving long-term treatment (over 6 weeks worth): see BOX.
  • Avoid over-the-counter drugs, eg NSAIDs: aspirin and ibuprofen (↑risk of DU).
  • Prevent osteoporosis if long-term use (p674): exercise, bisphosphonates, calcium and vitamin D supplements, smoking cessation advice.

Do not stop long-term steroids abruptly as adrenal insufficiency may occur. Once a daily dose of 7.5mg of prednisolone is reached, withdrawal should be gradual. Patients on short-term treatment (<3 weeks) can be stopped immediately, unless they have had repeated courses of steroids, a history of adrenal suppression, greater than 40mg daily, or doses at night, where withdrawal should be gradual. Azathioprine

  • SE: p533.
  • Interactions: mercaptopurine and azathioprine (which is metabolized to mercaptopurine) are metabolized by xanthine oxidase (XO). So azathioprine toxicity results if XO inhibitors are co-administered (eg allopurinol).

Ciclosporin This is a calcineurin inhibitor, as is tacrolimus which works in a similar way. It has an important role in reducing rejection in organ and marrow transplant. The main SE is dose-related nephrotoxicity. Doses are monitored by blood levels.

  • Other SE: Gum hyperplasia, tremor, BP↑ (stop if ↑↑), oedema, paraesthesiae, confusion, seizures, hepatotoxicity, lymphoma, skin cancer—avoid sunbathing.
  • Monitor U&E and creatinine every 2 weeks for the first 3 months, then monthly if dose >2.5mg/kg/d (every 2 months if less than this). ▶Reduce the dose if creatinine rises by >30% on 2 measurements even if the creatinine is still in normal range. Stop if the abnormality persists. Also monitor LFT.
  • Interactions are legion: [Ciclosporin]↑ by: ketoconazole, diltiazem, verapamil, the Pill, erythromycin, grapefruit juice. [Ciclosporin]↓ by: barbiturates, carbamazepine, phenytoin, rifampicin. Avoid concurrent nephrotoxics: eg gentamicin. Concurrent NSAIDs augment hepatotoxicity—monitor LFT.

Methotrexate An antimetabolite. Inhibits dihydrofolate reductase, which is involved in the synthesis of purines and pyrimidines. See p533. Cyclophosphamide An alkylating agent.

  • SE: marrow suppression (monitor FBC), nausea, infertility, teratogenic, haemorrhagic cystitis due to an irritative urinary metabolite. There is a slight ↑risk of later developing bladder cancer or leukaemia.

P.361
Side effects of steroid use

System:

Adverse reactions:

Gastrointestinal

Pancreatitis

Candidiasis

Oesophageal ulceration

Peptic ulceration

Musculoskeletal

Myopathy

Osteoporosis

Fractures

Growth suppression

Endocrine

Adrenal suppression

Cushing’s syndrome

CNS

Aggravated epilepsy

Depression; psychosis

Eye

Cataracts; glaucoma

Papilloedema

Immune

Increased susceptibility to, and severity of infections, especially chicken pox.

Steroids can also cause fever and leucocytosis; steroids only rarely cause leucopenia.image91 Explain side effects in terms that patients understand: document this in the notes.

Acknowledgements We thank Dr Drew Provan who is our Specialist Reader for this chapter.

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