Anaemia and leukaemia
Red and white cell disorders: anaemia, haemoglobinopathies, polycythaemia, leukaemia and lymphoma
Anaemia is classified by red cell size and explained by too little production, ineffective production or too much destruction; the haemoglobinopathies are common in Pakistan and leave marks on the skeleton. CPSP asks you to read blood indices and iron studies, explain sickle and thalassaemia complications, separate types of polycythaemia, and recognise haematological malignancy on film, genetics and imaging.
Classifying anaemia by MCV
| Microcytic | Normocytic | Macrocytic |
|---|---|---|
| Iron deficiency (hookworm, menstruation, poor diet) | Chronic kidney disease (low erythropoietin) | B12 or folate deficiency (megaloblastic) |
| Thalassaemia trait | Anaemia of chronic disease | Brisk reticulocytosis (reticulocytes are large) |
| Lead poisoning (basophilic stippling; surma) | Acute blood loss, haemolysis | Liver disease, alcohol, hypothyroidism |
| Anaemia of chronic disease (late) | Marrow failure or infiltration | Myelodysplasia |
- Megaloblastic anaemia: faulty DNA synthesis in all precursors, so pancytopenia; hypersegmented neutrophils are an early sign. Precursors die in the marrow (ineffective erythropoiesis), raising LDH and unconjugated bilirubin. Pernicious anaemia destroys parietal cells (achlorhydria, high gastrin).
- A dimorphic film suggests combined iron and folate deficiency.
Iron studies and thalassaemia trait
| Test | Iron deficiency | Chronic disease | Thalassaemia trait |
|---|---|---|---|
| Ferritin | Low | Normal or high (acute phase protein) | Normal |
| TIBC (transferrin) | High | Low | Normal |
| Transferrin saturation | Low | Low | Normal |
| Red cell count | Low | Low | High (MCV ÷ RBC below 13) |
- Anaemia of chronic disease: IL-6 raises hepcidin, which traps iron in macrophages and blocks gut absorption. Soluble transferrin receptor rises only with true iron deficiency.
- β-thalassaemia trait: HbA₂ above 3.5% on HPLC. Iron deficiency lowers HbA₂ and can mask it. α-thalassaemia trait: microcytosis with normal ferritin and normal HbA₂. Antenatal screening uses MCH below 27 pg.
Thalassaemia and sickle cell disease
| Feature | β-thalassaemia major | Sickle cell disease (HbSS) |
|---|---|---|
| Defect | Reduced β-chain synthesis; excess α-chains precipitate and kill precursors in the marrow | Glu to Val at β6; deoxygenated HbS polymerises |
| Onset | After about 6 months, as γ-chain (HbF) output falls | Same, protected by HbF early |
| Skeleton | Marrow expansion in the diploe: hair-on-end skull, frontal bossing, maxillary overgrowth | Infarcts: H-shaped vertebrae (central end-plate), avascular necrosis of femoral head, Salmonella osteomyelitis |
| Spleen | Hypersplenism increases transfusion needs | Autosplenectomy: Howell–Jolly bodies, pneumococcal sepsis |
| Other | Iron overload (heart, liver, endocrine); after splenectomy, plasma haemoglobin scavenges nitric oxide (pulmonary hypertension) | Acute chest syndrome (fat emboli from infarcted marrow), stroke (screen with transcranial Doppler), dilute urine and enuresis (vasa recta damage), placental sickling with growth restriction |
- α-thalassaemia: loss of all four genes gives Hb Barts hydrops fetalis; loss of three gives HbH disease.
- Sickle trait: usually well, but papillary necrosis with painless haematuria, splenic infarction at altitude and urinary infection in pregnancy. Haemoglobin electrophoresis or HPLC separates trait from disease (the solubility test cannot).
Haemolysis
- Features: anaemia, reticulocytosis, unconjugated bilirubin, raised LDH, low haptoglobin; pigment gallstones.
| Type | Examples and clues |
|---|---|
| Intravascular | ABO-incompatible transfusion (plasma haemoglobin plus hypotension injure tubules), mechanical valve (fragments; haemosiderin in proximal tubules), paroxysmal cold haemoglobinuria (biphasic IgG anti-P after a viral illness) |
| Extravascular (spleen) | Hereditary spherocytosis (raised MCHC; splenectomy raises infection risk), warm IgG autoimmune haemolysis (SLE; positive DAT), drug hapten (penicillin) |
- In malaria, uninfected cells are cleared too, so anaemia exceeds the parasitaemia. Fetal anaemia from Rh disease causes high-output heart failure and hydrops.
Marrow failure and infiltration
- Aplastic anaemia: pancytopenia, fatty hypocellular marrow, no splenomegaly. Inherited forms: Fanconi anaemia (DNA cross-link repair defect, short stature, café-au-lait spots, thumb anomalies); Diamond–Blackfan (ribosomal protein, red cells only, macrocytic). Pure red cell aplasia is linked with thymoma.
- Myelofibrosis: teardrop cells, dry tap, massive spleen (megakaryocyte growth factors drive fibrosis). Metastatic infiltration gives a leucoerythroblastic film.
- Marrow imaging: chronic anaemia reconverts yellow to red marrow; radiotherapy leaves fatty marrow; G-CSF causes diffuse marrow FDG uptake.
Polycythaemia
| Type | Mechanism | Example |
|---|---|---|
| Primary | JAK2 V617F; high cells of all lines, low EPO | Polycythaemia vera |
| Secondary, appropriate | Hypoxia raises EPO | Altitude, lung disease, high-affinity haemoglobin |
| Secondary, inappropriate | Tumour secretes EPO | Renal cell carcinoma, hepatoma |
| Relative | Contracted plasma volume | Diuretics, smoking, obesity |
- On unenhanced CT, a high haematocrit makes dural sinuses uniformly dense; anaemia makes blood darker than the interventricular septum.
Leukaemia
| Disease | Clues |
|---|---|
| AML | Myeloperoxidase-positive blasts, Auer rods; monocytic type infiltrates gums; megakaryoblastic type in Down syndrome; therapy-related after alkylating agents and topoisomerase inhibitors |
| APL | t(15;17); faggot cells; DIC; treated with ATRA and arsenic |
| ALL | Children; bone pain and limp; testicular relapse (blood–testis barrier blocks drugs) |
| CML | t(9;22); massive spleen; low neutrophil alkaline phosphatase (high in a leukaemoid reaction) |
| CLL | Smudge cells, CD5 and CD23 B cells; hypogammaglobulinaemia |
| Hairy cell | BRAF V600E, dry tap, few monocytes, big spleen |
| Adult T-cell leukaemia | HTLV-1, hypercalcaemia |
Lymphoma and myeloma
- Hodgkin lymphoma: Reed–Sternberg cells are a small minority; most of the mass and its FDG uptake are reactive cells. Nodular sclerosis (young women, mediastinum) is commonest; mixed cellularity has many classic RS cells; nodular lymphocyte-predominant has popcorn cells.
- Non-Hodgkin: DLBCL commonest; Burkitt t(8;14) MYC (starry sky); follicular t(14;18) BCL-2; mantle cell t(11;14) cyclin D1; MALT lymphoma from H. pylori or Sjögren syndrome; enteropathy-associated T-cell lymphoma in coeliac disease; T-lymphoblastic anterior mediastinal mass in children; anaplastic large cell lymphoma with textured breast implants.
- Imaging: bulky homogeneous mesenteric nodes encasing vessels without obstruction; primary CNS lymphoma (HIV) enhances homogeneously and shrinks on steroids (lymphocyte apoptosis), so steroids are withheld before biopsy. Lymphoma can cause hypercalcaemia by making calcitriol.
- Myeloma: hypercalcaemia, renal failure (light-chain cast nephropathy), anaemia, punched-out lytic lesions; the bone scan is often normal because osteoblasts are suppressed. MGUS lacks CRAB features. Ann Arbor stage III = nodes on both sides of the diaphragm.
Remember Microcytosis with a high red cell count and normal ferritin is thalassaemia trait until proven otherwise.
Exam trap Ferritin is an acute phase protein: a normal value during infection does not exclude iron deficiency.
Exam trap Sickle cell disease and β-thalassaemia major are silent at birth because fetal haemoglobin is still high.
Test yourself on this topic
5 of the 120 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A 9-year-old boy finished treatment for acute lymphoblastic leukaemia a year ago and has been in remission. He now has a painless, firm, enlarged left testis, and his blood count is normal. Why does relapse occur at this site?
Answer: Blood-testis barrier blocks drugs
Leukaemic blasts lodge in many tissues, but in the testis they lie behind the blood-testis barrier formed by tight junctions between Sertoli cells. Many systemic chemotherapy drugs penetrate poorly, so blasts survive there while the marrow is cleared. The testis, like the central nervous system, is therefore a 'sanctuary site' for relapse. Biopsy shows blasts infiltrating between the seminiferous tubules.
Sanctuary sites in ALL
- Testis and CNS
- Barriers keep drugs out
- Blasts survive and relapse
- Painless testicular enlargement
Remember Painless testicular swelling after ALL: think relapse.
Exam trap A normal blood count does not exclude an isolated testicular relapse.
Why the other options are wrong
- Testis has a higher temperature The testis is cooler than the body, and this is not the reason.
- Blasts are attracted by testosterone Not a recognised mechanism.
- Testicular lymphatics drain to the marrow Testicular lymph drains to para-aortic nodes, not to the marrow.
- Radiotherapy damaged the testis Not the explanation; he has not had testicular radiotherapy.
A 52-year-old obese man who smokes and takes bendroflumethiazide for hypertension has a haematocrit of 0.54 on two occasions. JAK2 testing is negative, he has no splenomegaly, and isotope studies show a normal red cell mass. What is the cause of his raised haematocrit?
Answer: Contracted plasma volume
Haematocrit is the fraction of blood volume made up of red cells, so it rises either when red cell mass increases or when plasma volume falls. In relative (apparent) polycythaemia the red cell mass is normal but plasma volume is reduced, here by diuretic use, with smoking, obesity and alcohol often contributing. Treatment is to remove the causes, for example stopping the thiazide and smoking. True polycythaemia, primary or secondary, would show a raised red cell mass.
Relative polycythaemia
- Red cell mass normal
- Plasma volume reduced
- Diuretics, smoking, obesity
- Treat the cause
Remember High haematocrit with normal red cell mass = low plasma volume.
Exam trap Dehydration from any cause raises the haematocrit; recheck once the patient is well hydrated.
Why the other options are wrong
- Erythropoietin from a renal tumour Would raise the red cell mass.
- Polycythaemia vera Would raise the red cell mass and usually carries a JAK2 mutation.
- Hypoxic lung disease Would raise red cell mass through erythropoietin.
- High-affinity haemoglobin Would raise red cell mass; P50 would be low.
A 22-year-old woman has a large anterior mediastinal mass and neck nodes. Biopsy shows classical Hodgkin lymphoma, but the pathologist notes that Reed-Sternberg cells make up only about 1% of the cells. What forms most of the mass?
Answer: Reactive non-tumour cells
In classical Hodgkin lymphoma the malignant Reed-Sternberg cells, derived from germinal centre B cells, are scattered and few. They secrete cytokines and chemokines such as IL-5, IL-13 and CCL17 that attract and activate a background of T cells, eosinophils, macrophages, plasma cells and fibroblasts, which make up most of the mass. This reactive background explains the large size of the nodes. In nodular sclerosis disease, collagen bands also divide the node.
Hodgkin lymphoma
- Reed-Sternberg cells: about 1%
- They secrete cytokines
- Background of reactive cells
- Explains the bulk of the nodes
Remember In Hodgkin lymphoma, most of the mass is not tumour.
Exam trap Because tumour cells are scarce, a small needle biopsy may miss the diagnosis.
Why the other options are wrong
- Necrotic tumour cells Necrosis is not the main component.
- Normal thymic tissue The mass replaces normal tissue; thymic remnants are minor.
- Metastatic carcinoma cells This is lymphoma, not carcinoma.
- Fibrin and blood clot The mass is cellular, not clot.
A 64-year-old man who is HIV negative has confusion and a periventricular brain mass thought to be lymphoma. He is given dexamethasone for oedema while awaiting biopsy, and a week later the mass has almost disappeared and the biopsy is non-diagnostic. Why did the mass shrink?
Answer: Steroids cause lymphoma cell apoptosis
Primary CNS lymphoma is usually a diffuse large B-cell lymphoma that forms solid, cell-dense masses near the ventricles. Glucocorticoids are directly lymphocytolytic: they trigger apoptosis of lymphoma cells as well as reducing oedema. The mass can therefore shrink dramatically within days, and a biopsy may then show only non-specific changes. For this reason steroids are withheld, when safe, until tissue has been taken.
Vanishing lymphoma
- Periventricular B-cell lymphoma
- Cell-dense mass
- Steroids cause apoptosis
- Biopsy before steroids if possible
Remember Steroids can make CNS lymphoma vanish and hide the diagnosis.
Exam trap Do not give steroids before biopsy unless raised pressure makes them essential.
Why the other options are wrong
- Steroids dissolved an abscess Steroids do not cure abscesses and may worsen infection.
- The lesion was an infarct that healed An infarct would not behave as a mass that shrinks this way.
- Steroids close the blood-brain barrier only Restoring the barrier reduces oedema, but the tumour cells themselves die.
- The mass was a demyelinating plaque A plaque is possible but does not fit a periventricular lymphoma in this setting.
A 30-year-old woman with warm autoimmune haemolysis has Hb 7.8 g/dL, an MCV of 104 fL and reticulocytes of 18%. Her B12 and folate are normal. Why is the MCV raised?
Answer: Reticulocytes are larger than mature cells
When red cells are destroyed, erythropoietin drives the marrow to release many reticulocytes. Reticulocytes still contain RNA and are about 20% larger than mature red cells, so a high reticulocyte count raises the mean cell volume. The film shows polychromasia (bluish, large cells). This macrocytosis is not megaloblastic, which is why the B12 and folate are normal.
Haemolysis and MCV
- Many reticulocytes released
- Reticulocytes are larger
- Polychromasia on the film
- MCV rises without B12 or folate lack
Remember High reticulocytes can raise the MCV.
Exam trap Chronic haemolysis uses up folate, so check it if the MCV stays high.
Why the other options are wrong
- Spherocytes are larger than normal cells Spherocytes are smaller in diameter and have a normal or low volume.
- Haemolysis blocks DNA synthesis Haemolysis does not affect DNA synthesis.
- Antibody coating increases cell size Antibodies on the surface do not enlarge cells.
- Liver damage enlarges the cells No liver disease is present.
Where this sits in the CPSP syllabus
- Diagnostic Radiology, Paper 2: General pathology and genetics, Red and white cell disorders; anaemia, polycythaemia and haemoglobin