Haem - Anaemia and Haemolytic anaemia

Question 1

What investigations should be done in a pancytopenia

Answer 1

Examination for splenomegaly (myelofibrosis and lymphoproliferative disorders)

Bloods:
- B12/folate/iron
- Reticulocyte count (low implies aplastic anaemia/BM failure)
- Blood film: ?blasts, ?hairy cell leukaemia, ?LGL leukaemia, ?dysplasia (myelodysplasia)
- Myeloma screen
- Parvovirus PCR

Bone marrow biopsy for diagnosis

Question 2

What are the causes of anaemia according to impaired synthesis vs destruction

Answer 2

Synthesis
Inefficient: marrow infiltration, iron deficiency, EPO deficiency, myelofibrosis
Ineffective: SCD, thalassaemia, B12/folate def, sideroblastic anaemia

Destruction
Congenital: SCD/thalassaemia, G6PD-D, PKD, spherocytosis/elliptocytosis
Acquired: Immune (CLL, SLE, mycoplasma, EBV) or non-immune (malaria, trauma, MAHA)

Question 3

What are the causes of microcytic anaemia

Answer 3

Iron deficiency
Thalassaemia
Anaemia of chronic disease
Lead poisoning
Sideroblastic anaemia

Question 4

What would the iron studies show for iron deficiency, thalassaemia and anaemia of chronic disease

Answer 4

Iron deficiency: Low iron, ferritin, transferrin saturation | high TIBC
Thalassaemia: low iron | normal ferritin, TIBC and transferrin saturation
Chronic disease: low iron and TIBC| normal ferritin (Or raised if inflammation), normal transferrin saturation | raised ferritin

Question 5

What is a hallmark feature of lead poisoning on blood film

Answer 5

Basophilic stippling

Question 6

What are the features of sideroblastic anaemia on blood film

Answer 6

Sideroblastic cells
Hypochromic, dimorphic RBCs

Question 7

What are the causes of macrocytic anaemia

Answer 7

Megaloblastic: B12 deficiency, folate deficiency, cytotoxic drugs.

Non-megaloblastic: Alcohol (most common cause of macrocytosis without anaemia), reticulocytosis (e.g. in haemolysis), liver disease, hypothyroidism, and pregnancy.

Other haematological disease: Myelodysplasia, myeloma, myeloproliferative disorders, aplastic anaemia.

Question 8

What are the features of megaloblastic anaemia on blood film

Answer 8

Hypersegmented polymorphs
Leucopenia
Macrocytosis
Anaemia
thrombocytopenia
Megaloblasts (RBC precursors with immature nucleus but mature cytoplasm)

Question 9

What are the causes of vitamin B12 deficiency

Answer 9

Dietary (e.g. vegans) - B12 found in meat and dairy
Malabsorption:
- Stomach (lack of intrinsic factor which is produced by gastric parietal cells) → Pernicious anaemia, post gastrectomy
- Terminal ileum (absorption) due to ileal resection, Crohn’s disease, bacterial overgrowth, tropical sprue and tapeworms.

Question 10

What are the clinical features of B12 deficiency

Answer 10

Mouth: Glossitis, angular cheilosis
Neuropsychiatric: Irritability, depression, psychosis, dementia.
Neurological: Paraesthesiae, peripheral neuropathy (loss of vibration and proprioception first, absent ankle reflex, spastic paraperesis, subacute combined degeneration of spinal
cord)

Question 11

What is pernicious anaemia and what investigations should be done for diagnosis

Answer 11

Autoimmune atrophic gastritis → achlorhydria and lack of gastric intrinsic factor
Most common cause of a macrocytic anaemia in Western countries (Usually >40yrs)
Specific tests: Parietal cell antibodies (90%), Intrinsic factor antibodies (50%), Schilling qtest (outdated)

Question 12

What are the causes of folate deficiency

Answer 12

Poor diet
Increased demand: pregnancy or ↑ cell turnover (haemolysis, malignancy, inflammatory disease and renal dialysis).
Malabsorption: coeliac disease, tropical sprue.
Drugs: alcohol, anti-epileptics (phenytoin), methotrexate, trimethoprim

Question 13

What is the management for B12 and folate deficiencies

Answer 13

B12: Replenish stores with IM hydroxocobalamin (B12) with 6 injections over 2 weeks. (if pernicious anaemia → 3-monthly IM injection)

Folate: oral folic acid (B12 is checked and replaced prior to folic acid otherwise folic acid may exacerbate the neuropathy of B12 deficiency)

Question 14

What are the features of intravascular haemolytic anaemia on blood results

Answer 14

Raised free plasma Hb
Reticulocytosis (unless aplastic)
Raised unconjugated bilirubin and urobilinogen
Raised LDH
Low haptoglobins
May have pigmented gallstones
Haemoglobinuria (dark red urine)
Methaemalbuminaemia (Haem + albumin in blood)

Question 15

What are the features of extravascular haemolytic anaemia on blood results

Answer 15

Anaemia
Reticulocytosis (unless aplastic)
Raised unconjugated bilirubin and urobilinogen
Raised LDH
May have pigmented gallstones
Splenomegaly

Question 16

What are the causes of intravascular haemolytic anaemia

Answer 16

Malaria
G6PD and PK deficiencies
Mismatched ABO blood transfusion
Cold anti-body haemolytic syndromes
Drugs
Microangiopathic HA’s (i.e. TTP)
Paroxysmal nocturnal haemoglobinuria

Question 17

What are the causes of extravascular haemolysis

Answer 17

Autoimmune
Alloimmune
Hereditary spherocytosis [AD inheritance]

Question 18

What are the causes of acquired haemolytic anaemia

Answer 18

Immune:
- Warm: CLL, SLE
- Cold: mycoplasma, EBV

Non-immune:
- Mechanical: metal valves, trauma
- PNH, MAHA
- Infections e.g. malaria
- Drugs

Question 19

What are the causes of inherited haemolytic anaemia

Answer 19

Membrane defect: hereditary spherocytosis/eliptocytosis
Enzyme defect: G6PD deficiency, pyruvate kinase deficiency
Haemoglobinopathies: SCD, thalassaemia

Question 20

What are the features of hereditary spherocytosis (inheritance, pathology, presentation)

Answer 20

Autosomal dominant (25% recessive or de novo)
Norther Europe more common
Spectrin or ankyrin deficiency
S/S: susceptibility to parvovirus B19, gallstone development, splenomegaly (extravascular haemolysis)

Question 21

What investigations should be done to diagnose hereditary spherocytosis

Answer 21

Blood film: Spherocytes seen
Osmotic fragility test: raised (lysis in hypotonic solution)
Di-binding test
Flow cytometry (EMA binding test)
Cryohaemolysis test
DAT coombs NEGATIVE

Question 22

What is the management for hereditary spherocytosis

Answer 22

Folic acid
± splenectomy

Question 23

What is paroxysmal nocturnal haemoglobinuria

Answer 23

Acquired loss of protective surface GPI markers on RBCs → complement-mediated lysis → chronic intravascular haemolysis

Nocturnal haemolysis
Morning haemoglobinuria and Thrombosis (± Budd-Chiari syndrome)
Bone marrow failure

Question 24

What are the investigations and management for paroxysmal nocturnal haemoglobunuria

Answer 24

Ham’s test / Flow cytometry of GPI-linked proteins

Iron/folate supplements
Prophylactic vaccines/antibiotics
Eculizumab

Question 25

What are the consequences of haemolysis

Answer 25

Anaemia
Erythroid hyperplasia
Increased folate demand
Susceptibility to parvovirus B19. gallstones, iron overload, osteoporosis, and hepatic siderosis

Question 26

What is the difference between hereditary spherocytosis and hereditary elliptocytosis

Answer 26

Spherocytosis: vertical interaction, spectrin/ankyrin deficiency
Elliptocytosis: horizontal interaction, spectrin mutation

Question 27

What is haemolysis in G6PDD triggered by

Answer 27

Anti-malarials e.g. primaquine
Sulphonamides, ciprofloxacin, nitrofurantoin
Vitamin K
Fava beans
Henna
Naphthalene (moth balls)
Infections

Question 28

What is G6PDD

Answer 28

deficiency in G6PD which catalyses the first step in the pentose phosphate pathway to generate NADPH
Common in Mediterranean populations
X-linked
Untreated → neonatal jaundice → kernicterus

Question 29

What are the features of G6PDD on investigation

Answer 29

Film: bite cells, nucleated RBCs, Heinz bodies. (methyl violet stain)

Question 30

What is the testing and management for G6PDD

Answer 30

Testing:
- Fluorescent spot test (G6PD and NADP)
- Methaemoglobin (Methylene blue)
- Guthrie spot
- G6PD activity

management: folate supplements, phototherapy in neonates
Avoid precipitants
Transfuse if severe
Genetic screening

Question 31

What are the features of pyruvate kinase deficiency on blood film

Answer 31

Echinocytes (“hedgehog-like”)
Spherocytes

Question 32

What are the features of warm autoimmune haemolytic anaemias and what are the causes

Answer 32

37oc
IgG
Positive coombs test
Spherocytes seen on blood film
Causes: idiopathic, lymphoma, CLL, SLE, methyldopa

Question 33

What are the features and causes of cold agglutinin disease (autoimmune haemolytic anaemia)

Answer 33

<37oC
IgM
Positive Coombs test
Often with Raynaud’s
Causes: idiopathic, lymphoma, infections (EBV, mycoplasma)

Question 34

What is the management for warm AIHA

Answer 34

Steroids
Splenectomy
immunosuppression

Question 35

What is the management for cold AIHA

Answer 35

Treat underlying condition
Avoid cold
Lymphoma → chemotherapy

Question 36

What are Donath-Landsteiner antibodies

Answer 36

Stick to RBCs in cold → complement-mediated
haemolysis on rewarming (self-limiting as IgG so dissociate at higher temp than IgM)

Question 37

What are the causes of MAHA

Answer 37

HUS
TTP
DIC
Pre-eclampsia

Question 38

What is TTP

Answer 38

Antibodies against ADAMTS13 → long strands of vWF which shear RBCs (haem emergency)
Pentad:
1. MAHA
2. Fever
3. Renal impairment
4. Neuro abnormalities
4. Thrombocytopenia