1. HAEMATOLOGY
HAEMATOLOGY

2. Haematology
Phase 2a Revision Session Benjamin Ward & Hannah Talwar
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3. Content: Anaemia: Microcytic: Normocytic: Macrocytic: Iron-deficiency
Thalassaemia
Sickle cell
(Anaemia of chronic disease & sideroblastic anaemia)
Normocytic:
Haemolytic anaemia
Aplastic
(Acute blood loss & chronic disease)
Macrocytic:
Normoblastic  ALCOHOL
Megaloblastic  Folate & Vitamin B12 deficiency (including pernicious anaemia
Other causes of normoblastic macrocytic:
Reticulocytosis (eg. In heamolysis)
Liver disease
Hypothyroidism
Pregnancy
Megaloblastic: folate, b12 and cytotoxic drugs.
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4. Content continued: Polycythaemia DVT and thromboembolism Bleeding:
Over-anticoagulation
DIC
Platelet disorders  ITP, TTP
Cancers:
Leukaemia
Lymphoma
Myeloma
Infections  malaria
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5. Anaemia
Definition
= DECREASE in Hb in blood below reference level for age and sex of the individual.
Normal Values:
Hb? ☞ g/dL
Decrease = anaemia, increase = polycthaemia
- Mean corpuscular volume (MCV)? ☞ 82-96fl
Classification:
Classified by MCV into:
Microcytic = MCV<80
Normocytic = MCV
Macrocytic = MCV >100
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6. Anaemia SIGNS: SYMPTOMS: (non-specific) Pallor Tachycardia
Systolic flow murmur
Cardiac failure
Pale mucous membranes and palmar creases
Specific signs for each anaemia include nail signs and bone deformities.
Clinical Features
SYMPTOMS: (non-specific)
Fatigue, headache, faintness
Breathlessness
Angina
Intermittent claudication
Palpitations
Reduced exercise tolerance
NB: Exacerbates cardio-respiratory issues, especially in elderly.
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7. MICROCYTIC ANAEMIAS We will talk about: Iron-deficiency anaemia
Thalassaemia
Sickle cell anaemia
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8. Iron Deficiency Anaemia
Low Hb and MCV<80fl
Causes:
USE MORE, LOSE MORE OR DON’T GET ENOUGH
Bleeding (= most common)
Increased demand
Malabsorption
Dietary/reduced intake
Microcytic hypochromic cells
Iron is one of the haematinics. Can anyone name others? (folate and B12)
These are required to make RBC, therefore, decreased iron  decreased RBC production.
BLEEDING: occult GI (ulcer/malignancy)/hookworm, or menorrhagia
INCREASED DEMAND: growth or pregnancy
MALAB: small bowel disease (coeliac, crohns), gastrectomy
DIETARY: v. rare in western world/developed countries
Only 10% of body’s iron comes from dietary sources, the rest comes from breakdown of RBCs, therefore dietary deficiency rarely causes anaemia.
NB: the most common cause of iron deficiency anaemia worldwide is HOOKWORM --> causes GI blood loss
Low serum ferritin (=how excess iron is stored, along w. haemosiderin). Hypochromic microcytic.
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9. Symptoms as in general anaemia.
Iron Deficiency – Symptoms and Signs
Symptoms as in general anaemia.
Specific Signs
Koilonychia (= spoon-shaped nails)
Brittle hair and nails
Angular stomatitis
Atrophic glossitis
Symptoms: tired, malaise, SOB, decreased exercise tolerance, angina, IC
Signs:
Decreased epithelial cell iron  brittle hair and nails, stomatitis and glossitis.
Koilonychia
Angular stomatitis = inflam at corners of mouth, assoc. w. wrinkled/fissured epithelium.
Atrophic glossitis = an erythematous, edematous & painful tongue that appears smooth due to loss of filiform and sometimes fungiform papillae secondary to certain nutritional deficiencies.
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10. Iron Deficiency – Investigations and Treatment
FBC & film:
MCV<80
Variation in size (anisocytosis) & shape (poikilocytosis) of cells.
Low serum iron & ferritin
Low reticulocytes (due to reduced Hb production)
High TIBC
Ix of GI tract
Coeliac serology
Treatment
Treatment of underlying cause
Ferrous sulphate 200mg  NB: compliance often an issue.
Ix:
NB: don’t be fooled by normal/high ferritin! Ferritin is an acute phase reactant so is raised in any chronic inflam./malig. Disease, so levels may be normal even though patient has iron deficiency anaemia.
High total iron binding capacity  transferring saturation (= serum iron ÷ TIBC) <19%.
Most iron deficiency anaemia in ♂ & post-menopausal ♀ due to occult GI blood loss  ix w. scope/bloods/US/etc
Tx:
Ferrous sulphate – 200mg 6m/until anaemia treated, then give for further 3m to replenish stores that will have been depleted
Compliance with ferrous sulphate = big issue due to Aes, including constipation.
May have prescribe laxatives with them.
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11. Anaemia of Chronic Disease
= MICROCYTIC ANAEMIA
Due to chronic inflam./infection/malignancy. (e.g. TB, Crohn’s, SLE, RA)
May be due to increased levels of hepcidin production.
Serum iron low, TIBC low, and serum ferritin normal/raised.
Doesn’t respond to iron therapy, tx is by control/mx of the chronic underlying pathology.
Common in hospital patients
Ferritin increases due to inflammatory process.
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12. Thalassaemia What is it?
Autosomal recessive condition, where there is decreased Hb production.
Normally: balanced 1:1 production of α & ß chains in Hb molecule.
Thalassaemia: gene defect  defective synthesis of globin chains  imbalanced globin chain production  precipitation of globin chains in red cells/precursors.
2 types:
α-thalassaemia (decreased α chain synthesis)
ß-thalassaemia (decreased ß chain synthesis)
Autosomal rec.
Normal HbA has equal numbers of a and b chains - 4 alpha and 4 beta chains - per molecule (1:1 ratio)
Thalassaemia = decreased rate of production of one of more globin chain  precipitation (depositing) of globin chains in red cell precursors/mature red cells.
Precipitation of globin chains in red cell precursors and causes ineffective erythropoiesis (=production of red blood cells).
Precipitation of globin chains in mature red cells  haemolysis (=rupture/destruction of red blood cells).
Put simply: get faulty production and premature destruction of RBCs.
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13. α- thalassaemia
Normally we have 4 α globin chains, clinical manifestation depends on number of deletions:
4 deletions: Hb Barts, infants are STILLBORN (hydrops fetalis).
3 deletions: SEVERE anaemia.
2 deletions: often ASYMP. carrier, may have mild anaemia.
1 deletion: close to normal.
Presentation varies from mild anaemia to severe condition incompatible with life.
Caused by gene deletions (unlike B which is due to gene defects)
4 deletions = no a-chain synth, only Hb Barts present. Hb Barts CANNOT CARRY OXYGEN and is incompatible with life.
Infants stillborn  they are pale, oedematous w. huge livers and spleens.
3 deletions: HbH disease. Common in parts of Asia. Pts have low levels of HbA and Hb Barts, HbA2 normal/reduced. Moderate anaemia, and splenomegaly. Not usually transfusion dependent.
2: microcytosis w or w/o mild anaemia.
1: blood picture normal.
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14. ß- thalassaemia What is it?
In homozygous ß-thalassaemia, little/no normal ß chain production  EXCESS α chains.
α chains combine w. whatever ß, 𝛿 or γ chains available  increased production of HbA2 & HbF.
Genetics
Caused by genetic defects in transcription, RNA splicing & modification, and translation  mutations.
These cause production of unstable and unusable ß chains.
B chain production very reduced, meaning there are excess a chains avaialble to bind.
These a chains bind to delta, gamma and beta chains where available  increased formation of HbA2 HbF.
A chains also precipitate in erythroblasts & RBCs  ineffective erythropoiesis and haemolysis,
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15. ß- thalassaemia Clincal syndromes: 3 main forms
ß- thal. minor (trait): asymp. heterozygous carrier state.
Mild/absent anaemia, low MCV & MCH.
Iron stores & ferritin normal.
ß- thal. Intermedia:
Moderate anaemia – DON’T REQUIRE TRANSFUSIONS.
Splenomegaly, bone abnormalities, recurrent leg ulcers & gallstones.
ß- thal. Major: HOMOZYGOUS ß- thal.
Presents in 1st year of life w. SEVERE ANAEMIA (Cooley’s anaemia), failure to thrive & chronic infections.
Bony abnormalities – e.g. skull bossing, thalassemic facies.
Hepatosplenomegaly.
Major:
Presents in first year of life because up to ~6m we use HbF. At 6m normally we switch to HbA, and this is when symptoms begin to occur.
Bony abnormalities occur due to hypertrophy of bone marrow.
Hepatosplenomegaly due to resumption of haematopoiesis in liver and spleen.
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16. ß- thalassaemia – Ix & Tx
Investigations:
FBC & film  hypochromic & microcytic anaemia
Irregular and pale RBCs.
Increased reticulocytes and nucleated RBCs
Dx by Hb electrophoresis – shows increased HbF & absent/low HbA.
Treatment:
BLOOD TRANSFUSIONS
NB: risk of iron overload
Give iron chelation
e.g. desferrioxamine, deferipone  decrease iron loading.
Ascorbic acid  increased urinary excretion of iron.
Long term folic acid supplements.
Other: bone health, endocrine supplements and psychological support.
PROMOTE FITNESS & HEALTHY DIET!
Blood trasnfusions – mainstay of treatment. = regular (~2-4wkly)
Allow normal development by replenishing HbA levels to normal.
Beware Iron overload! – give chelators/ascorbic acid
IRON OVERLOAD: results from repeated transfusions and  damage of endocrine/major organs (liver, pancreas & heart + endocrine glands)
NB: if excess iron not removed it is deposited in liver and spleen  liver fibrosis and cirrhosis.
Splenectomy if hypersplenism persists w increasing transfusion requirements.
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17. Sickle Cell Anaemia Pathophysiology
Substition of valine for glutamic acid  production of HbS not HbA.
Cells become rigid, sickle shaped & dehydrated.
Anaemia = homozygous state (HbSS), whereas heterozygous state (HbAS) = sickle cell trait which is protective against malaria.
Sickling of cells causes:
Premature haemolysis (destruction) of RBCs
Obstruction of microcirculation (vaso-occlusion)  tissue infarction.
NB: Sickling precipitated by hypoxia, infection,
dehydration & cold.
Haemolysis of cells usually at ~30 days (normal RBC lifespan = 120)  lifespan can be as short as 5d.
Vaso-oclusion can  vaso-occlusive crisis = acute pain in hands, feet & chest
Earlier presentation may be pain in hands & feet (dactylitis)
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18. Sickle Cell – Clinical Features
Manifests clinically when HbF swaps to HbA at ~6m old.
Vaso-occlusive Crises
In children: acute pain in hands & feet (dactylitis)
In adults: bone pain (mainly long bones – ribs, spine & pelvis).
Pain often accompanied by FEVER.
Acute Chest Syndrome
Occurs in up to 30%.
Caused by infection/fat emboli/pulmonary infarction.
SOB, chest pain, hypoxia & new CXR changes (consolidation).
Gradual/very rapid presentation, can  death in few hours.
Mx: pain relief, high flow oxygen and ABX.
Vaso-occlusion:
HbF production not affected, therefore sickling only occurs to HbA and symptoms only occur once Hb swapped from HbF to HbA at around 6m.
Get extreme phenotypic variation – some are asymptomatic, others have recurrent crises and decreased life expectancy.
Crises vary in frequency greatly – but roughly, someone with moderate-severe sickle cell would have ~3 hospital admissions/year from painful vaso-occlusive crises
Dactylitis due to vessel occlusion & avascular necrosis of bone marrow.
ACS
Pulm. HTN & chronic lung disease are the most common causes of death in adults with sickle cell.
Caused by inf/fat emboli from necrotic bone marrow/pulmonary infarction due to sequestration of sickle cells.
ABX = cefotaxime and clarithromycin should be started immediately
If treatment above doesn’t work, exchange transfusion and ventilation may be necessary
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19. Sickle Cell – Clinical Features
Anaemia
Chronic haemolysis produces stable Hb level (~60-80g/dL).
Therefore pts often don’t have symptoms of anaemia.
If Hb falls suddenly then get sx, possible causes:
Splenic sequestration
Bone marrow aplasia  destroys erythrocyte precursors.
Further haemolysis – drugs/acute infection
Long-term complications:
Cardiac problems
Bones: avascular necrosis & spinal cord compression
Stunted growth/development
Infections
CKD
Leg ulcers
Pulm. HTN
Pigment stones (cholelithiasis)
Also don’t get anaemia sx as HbS releases oxygen to tissues more easily than HbA.
Splenic sequestration = spleen engorged with RBCs pooling (also get hypovolaemia)  acute drop in Hb and rapid painful enlargement of spleen  damage.
Eventually leads to fibrotic, non-functioning spleen.
Liver sequestration can also occur.
Bone marrow aplasia normally due to infection w. erythrovirus B19  destruction of precursors.
Further haemolysis may be due to: drugs, acute infection, or assoc w. G6PD deficiency
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20. Sickle Cell – Ix & Tx Investigations:
Screen neonate  blood/heel prick test
FBC   Hb,  reticulocyte count
Blood film  SICKLED erythrocytes
Hb ELECTROPHARESIS for dx  HbSS present and absent HbA.
Treatment:
Prophylactic ABX  daily penicillin.
Pneumococcal & influenza vaccine
Folic acid
Pain relief for crisis  NSAIDs/paracetamol
Hydroxyurea (hydroxycarbamide)   conc. of HbF
Screening in children from high risk couples/adults from high prev. areas before undergoing surgery.
Electropharesis shows 80-95% HbSS, and absent HbA.
Treatment:
Avoid precipitating factors
Prophylactic ABX – hyposplenism  more prone to infections
NB: pneumococcal vaccine important as pneumococcal infection is LETHAL in hyposplenism.
Folic acid in pts with haemolysis
Transfusions not routinely needed, but sometimes required
Pts often carry cards with their analgesic routine for painful crises as they are fairly regular often. If pain not managed with nsaids/paracetamol, pt will be hospitalised for mx.
Hydroxycarbamide used in patients with recurrent crises to reduce/prevent these. It breaks down cells that are prone to sickling.
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21. Normoplastic Anaemias
We will discuss:
Haemolytic anaemia
Aplastic anaemia
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22. Haemolytic Anaemias
Haemolysis = premature breakdown of RBCs, before normal lifespan (~120 days).
Occurs in bloodstream (intravascular) OR in reticuloendothelial system – ie macrophages of liver, spleen & bone marrow – (extravascular)splenomegaly.
Haemolysis may be asymp, but if BM doesn’t compensate  haemolytic anaemia.
See increased reticulocytes  increased MCV.
Either acquired/hereditary:
ACQUIRED: split into immune mediated & non-immune causes
Immune: drug induced, AI haemolytic anaemia
Non-immune: microangiopathic (MAHA), infection,
HEREDITARY: split into enzyme defects, membrane defects & haemaglobinopathy:
ENZYME: G6PD deficiency, pyruvate kinase deficiency
MEMBRANE: hereditary spherocytosis, hereditary eliptocytosis, etc.
HAEMAGLOBINOPATHY: thalassaemia & sickle cell.
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23. Haemolytic Anaemia Presentation
HISTORY: fhx, race, jaundice, dark urine, drugs, previous anaemia, travel.
EXAMINATION:
Jaundice
Gallstones
Hepatosplenomegaly
Leg ulcers
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24. Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
X-linked
Affects mainly males, in Mediterranean, Africa & Middle/Far East.
Most = asymptomatic! May get oxidative crisis.
Precipitated by drugs, Vicia fava, or illness.
In attacks: rapid anaemia & jaundice.
Film: bite & blister cells
Dx w ENZYME ASSAY.
Mx:
Avoid precipitants  eg. HENNA
Transfuse if severe.
HEREDITARY  X-linked
Affects 100 million
Oxidative crises due to decreased glutathione prod.
Precipitated by:
Drugs (primaquine, sulfonamides, aspirin)
Vicia fava (fava beans/favism)
Illness.
NB: pyruvate kinase deficiency is another enxyme deficiency = autosomal recessive.  ATP prod  RBC survival.
Homozygotes have neonatal jaundice. Later: haemolysis w. splenomegaly +/- jaundice.
Also dx by enzyme assay
Often don’t need tx  splenectomy may help.
MEMBRANE DEFECTS
= all Coombs –ve, all need folate, splenectomy helps some.
HEREDITARY SPHEROCYTOSIS: autosomal dominant. 1/3000. less deformable, spherical RBCs, so get trapped in spleen  extravascular haemolysis.
Signs: splenomeg., jaundice.
Dx mild if Hb>110 & reticulocytes <6%, film  osmotic fragility tests: RBCs show  fragility in hypotonic solutions.  bilirubin ( gallstones).
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25. Aplastic Anaemia What is it?
= PANCYTOPENIA w. HYPOCELLULARITY (aplasia) of the bone marrow.
 no of pluripotent stem cells.
BM replaced by fat.
Causes: mostly AI, triggered by drugs, irradiation, Fanconi anaemia (=inherited form), infections.
Clinical features
anaemia, infections & bleeding.
Physical findings: bruising, bleeding gums, epistaxis.
General background:
BM responsible for haematopoiesis. Normally in central skeleton in adults (vertebrae, ribs, sternum & skull) & proximal long bones.
Some anaemias  demand  extramedullary haematopoiesis (in liver & spleen)  ORGANOMEGALY.
All blood cells arise from pluripotent stem cells & progenitor cell.
Aplastic anaemia:
= rare stem cell disorer  Pancytopenia (=deficiency of all the elements of the blood) due to hypocellularity of BM.
BM is HYPOPLASTIC (stops making cells)
 in pluripotent stem cells w faulty remaining ones/immune reaction against them  means unable to repopulate in BM
Low reticulocytes, -ve coombs, normal bilirubin. Absent RBC precursors on BM examination.
Causes:
Mostly idiopathic acquired (67%)
Congen – fanconis
Cytotoxic durgs/irradiation/drug reactions
Infections  HIV, hepititis, TB, etc.
Sx due to  RBC, WBCs & platelets  anaemia, infections & bleeding
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26. Aplastic Anaemia – Ix & Tx
BM exam for dx!  HYPOCELLULAR
FBC  pancytopenia.
Film.
Tx:
Withdrawal of offending agent, supportive care & some definitive tx:
Blood & platelet transfusions
Prophylactic ABX/prompt tx of infections
Bone marrow transplant if <40yo (curative)
>40yo  immunosuppression w. anti-thymocyte globulin & ciclosporin.
BM exam shows hypocellular marrow w.  fat spaces. Trephine bx.
Blood count  pancytopenia w. low/absent reticulocytes.
Blood film
Tx:
Nb: blood & plt transfusions used w caution in potential BM transplant pts to AVOID SENSITISATION.
Severe neutropenia = severe infection risk  need ABX prophylaxis/prompt tx of infections.  neutrophil regimen!
BMT = tx of choice in pts <40 from HLA identically matched sibling – can be curative.
Pts >40  immunosuppressive therapy w. antithymocyte globulin & ciclosporin.  may be effective, but not curative in most.
- No clear role for G-CSF.
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27. Macrocytic Anaemia 2) Vitamin B12 deficiency
Macrocytosis commonly due to ALCOHOL EXCESS.
Other causes we will look at include:
1) Folate deficiency
2) Vitamin B12 deficiency
 Incl. Pernicious anaemia
MCV > 100fl!!!
Macrocytosis due to alc excess may not have accompanying anaemia.
DDX for macrocytic anaemia: alcohol excess (most common in UK), liver disease, hypothyroid,  reticulocytes
Although only ~5% due to B12 deficiency, pernicious anaemia is the most common cause of macrocytic anaemia in Western countries.
B12 & folate both = MEGALOBLASTIC
Megaloblast = cell where nuclear maturation is delayed compared w cytoplasm.
Occurs w. B12 & folate as both are required for DNA synthesis
Megaloblastic anaemia characterised by developing RBCs in bone marrow w delayed nuclear maturation – due to defective DNA synthesis
NB: RBC folate = more accurate measure of folate levels than serum folate as serum only measures recent intake.
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28. Folate Deficiency The Facts:
Folate found in green vegetables, fruit & offal.
Body stores last up to 4m.
Absorbed in duo/jej.
Causes of deficiency:
Poor diet  poverty, alcoholics, elderly
 demand (e.g. pregnancy & cell turnover)
Malabsorption  e.g.?
Coeliac, tropical sprue
Drugs, alcohol, AEDs, methotrexate, trimethoprim
Found in veg, nuts, yeast & liver
Synthesized by gut bacteria.
Body stores can last up to 4m.
MATERNAL folate deficiency  NEURAL TUBE DEFECTS
Absorbed in duodenum/jejunum
Increased demand: cell turnover seen in haemolysis, malig, inflam disease, & renal dialysis.
Also get it w psoriasis
Poor diet – also w. eating disorders
Malab: coeliac, IBD, tropical sprue
Excess utilization:
Physiological – pregnancy, lactation, prematurity
Pathological – chronic haemolytic anaemia, malig & inflam disease, dialysis
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29. Folate Deficiency Clinical Features = symps & signs of anaemia!!
NB: maternal deficiency  NEURAL TUBE DEFECTS!
 Folate supplements recommended before conception & during pregnancy!
Ix:
RBC folate level
Tx  OF UNDERLYING CAUSE!
- Folic acid (5mg OD)
NB: don’t give folic acid alone in megaloblastic anaemia of unknown cause!!!  WHY?
Rbc folate levels more accurate than serum folate levels
If hx doesn’t suggest dietary deficiency  other ix  eg small bowel bx
don’t give folic acid alone as it aggrevates neuropathy of B12 deficiency
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30. Vitamin B12 Deficiency The Facts
Found in meat, fish & dairy products. NOT in plants!!
Body stores last 4yrs! (in liver)
Binds to intrinsic factor & absorbed in terminal ileum.
Prod of DNA impaired w deficiency   RBC prod.
Causes:
Dietary  vegans
Malabsorption
Congenital metabolic errors.
Excess stored in liver
Protein bound and released during digestion.
Intrinsic factor prod by gastric parietal cells, this binds to B12 and enables its absorption
Malab due to:
Stomach (lack of intrinsic factor): Pernicious anaemia, post gastrectomy
Terminal ileum: ileal resection, crohns, bacterial overgrowth, tropical sprue, tapeworms
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34. Haematological malignancies
We will discuss:
Myeloma
Lymphoma
Hodgkins & Non Hodgkins
Leukaemia
AML, ALL, CML, CLL
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35. Myeloma – What is it ?
Malignant disease of Bone Marrow plasma cells (differentiated B cells)
Clonal expansion of abnormal, proliferating plasma cells producing monoclonal paraprotein (55 % IgG, 25 % IgA)
Malignant plasma cells accumulate in BM causing BM failure
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36. Epidemiology and Course
MGUS: <10% plasma cells in BM, monoclonal paraprotein in serum
Asymptomatic: >10% plasma cells in BM BUT no Sx/no ROTI
Symptomatic: significant paraproteinemia/>10% plasma cells in BM AND ROTI (i.e. CRAB)
Who does it affect?
Elderly
Males
Coourse: Monoclonal Gammpopathy of Undetermined significance (not really ‘Myeloma’ but shows increased risk of developing it)
Epi: Typically affects elderly, with male predominance. Median age of presentation = 60-70, rare under 40s
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37. Clinical features EMERGENCY Presentations:
Remember … CRAB !!
Calcium (raised)
Renal Injury
Anaemia (Pancytopenia)
Bone Lesions
Other = INFECTIONS – as Antibodies abnormal
EMERGENCY Presentations:
- Hypercalcaemia, Hyperviscosity, and Spinal Cord Compression
High calcium – due to bone destruction
Renal Injury – combo of reasons: deposition of light chain Ig (AL amyloidosis) in tubules, hypercalcaemia, NSAIDs.
Anaemia (Pancytopenia) – Decreased RBC, Neut, Plts - Because BM infiltration. Clinical triad of Anaemia Sx (low RBC), bleeding (low plts), and infections (low neutrophils)
Bone Lesions/ destruction
Imbalance between bone formation bone resorption leads to rapid bone loss
Mainly due to increased osteoclast activity (because increased osteoclast activating factors e.g. RANK-L) and reduced osteoblasts (because increased inhibitory factors e.g. DKK-1)
Osteoporosis and bone destruction
Occurs especially in Long bones/skull/vertebra
Present predominantly with BACK PAIN but also increased fractures and spinal cord compression which is an EMERGENCY
Other = INFECTIONS – as Antibodies abnormal
Emergencies:
hypercalceamia – normally asymptomatic, or present with bone pain etc. and be picked up then and corrected. But if severe can lead to cardiac arrest.
Hyperviscosity – because increased protein in blood and bone marrow. Leads to blurred vision, gangrene and bleeding.
Spinal Cord compression – UMN muscle weakness, sensory level sensation loss, urinary incontinence?
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38. Investigations General Urine electrophoresis
FBC – Hb, Neut, Plts all low
U+E – Creatinine high
Serum Calcium – high
Urine electrophoresis
BENCE JONES PROTEIN – light chains (lambda or kappa)
Radiology (plain xray/CT/MRI)
‘PEPPER POT’ SKULL (AKA ‘Raindrop’), other bone lesions, cord compression?
Bone Marrow Aspirate
Increased BM plasma cells
Prognostic = Albumin, Beta 2 microglobulin, and LDH
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39. Management Supportive Anaemia – transfusion, EPO
Infection prophylaxis (pneumococcal/influenza)
Bone Pain – RT an systemic Chemo OR high dose dexamethasone
- Bisphosphonates
Kidney – dialysis?
Specific
Stem cell transplant
Combo chemo – Steroid + melphalan + thalidomide
NB: IN INCURABLE AND PATIENT’S ALWAYS RELAPSE!!
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40. Lymphomas - overview AIDS DEFINING ILLNESS
Neoplastic transformations of B + T cells predominantly in lymphoid tissue
Arise mainly in LNs but also extra nodal (blood, BM, liver, spleen)
Types: Non Hodgkins vs Hodgkins
Aetiology : immunodeficiency, infections (EBV, H.pylori)
Watch out for B symptoms !!
Staging – Ann Arbor
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41. Hodgkins Epi: - YOUNG (20s) males>females Aetiology
- EBV has role in pathogenesis
Types:
- Classical – Reed-Sternberg cell (95%) ‘owls eyes’
- Nodular Lymphocyte Predominant – popcorn cell (5%)
CFs
- Cervical Lymphadenopathy (‘rubbery’ lump in neck)
- mediastinal lymphadenopathy causing cough
- Hepatosplenomegaly
- B Symptoms: night sweats, fever, weight loss
NB: some cases ALCOHOL RELATED PAIN
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42. Hodgkins
Ix:
- Dx = LN biopsy with histology showing reed-Sternberg cells
- CXR (mediastinal widening) - PET scan (staging)
- BM biopsy (if stage 3/4, B sx, HIV) - CT chest/abdo/pelvis (nodes)
Staging:
- PET scan - ANN ARBOR Tx
ABVD combo chemo
Then, Involved Field Irradiation
If this fails - BEACOPP
Very good cure rates (>80%)
BUT problems with Chemo:
Infertilty lung damage
Cardiomyopathy Peripheral Neuropathy
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43. Non- Hodgkins Epi: - Adults Types: - 80% B cell origin - 20% T cell
Aet:
- FH increases risk immunosuppression
- H. Pylori – Gastric MALT Lymphoma
- EBV – Burkitts Lymphoma - HTLV - 1
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44. Non-Hodgkins Pathogenesis:
- neoplasms of non-dividing mature lymphocytes = ‘indolent’ e.g follicular
- neoplasms of proliferating cells = ‘aggressive’ e.g. Diffuse Large B cell
CFs:
- painless peripheral lymphadenopathy
- extranodal involvement more common vs Hodgkins (skin, GIT,BM)
- BM involvement – pancytopenia (bleeding, infections, anaemia)
- B Sx
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45. Non-Hodgkins Ix: - mostly same as Hodgkins
- LDH + Beta 2 microglobulin = prognostic
- BM Aspirate/trephine
Mx – depends on type
Gastric Lymphoma
eradicate H.Pylori = cure H. Pylori triple therapy!!!
Aggressive e.g. Large B cell
- R CHOP (Rituximab + combo. Chemo)
good cure rates again 60-70%
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46. Leukaemias
Myeloid – RBS, plts, myeloblasts (prod baso, neut, eosino, macrophage)
Lymhoid – lymphocytes B + T cells
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47. Leukaemias Malignant proliferation of haemopoietic cells
4 types : AML, ALL, CLL, CML
ACUTE = BAD
- immature cells - rapid progression - fatal
Ix: Dx by exam. of blood and BM
Type – Immunophenotyping and cytogenetics
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48. Acute Myeloid
Clonal expansion of myeloblasts in BM, blood and other tissues.
Epi: Adults
Aet: Radiation, chemo, genetics
S + Sx:
BM failure – anaemia, infections, (GUM) BLEEDING
Other: leukostasis – hypoxia, red. GCS, visual dys.
Gum hypertrophy + BLEEDING
Myeloid sarcoma, Chloroma, hepatosplenomegaly
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49. Acute Myeloid Ix: BM asp – blast cells blood film – AUER RODS !!
Immunophenotyping cytogenetics – prog.
Mx:
Supportive – infections etc.
<60: Intense combo chemo – consolidation chemo – transplant
>60: Palliative chemo ?
Prog: depends on age and cytogentics – young = good
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50. Acute Lymphoblastic Clonal expansion of lymphoblasts Epi: CHILDREN
Aet: Radiation, Downs Syn.
S+Sx:
BM fail – Anaemia, Bleeding, Infections
Organs: CNS, hepatosplenomegaly, LN etc
Most common paed malig, 0
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51. Acute lymphoblastic Ix: BM aspirate – LYMPHOBLASTs >20% -LP (CNS ?)
Tx:
chemo: induction – intense consolidation – maintenance
CNS therapy
Stem cell transplant
Allopurinol – prevent tumour lysis syndrome
Prog:
Age and Cytogenetics – Old + Philadelphia chromo. = BAD
Children + young = good cure rates
Tumour lysis – in rapidly prolif neoplasms (Acute leuk) – fatal metab derangement – tumour cells breakdown releasing POTASSIUM (cardiac probs) and DNA (increased Urate and Ca/Phosphate – RENAL PROBS)
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52. Chronic Myeloid Epi: Only adults (40 – 60) Patho:
PHILADELPHIA CHROMOSOME t(9:22)  increases tyrosine kinase  cell division
Affects basophils, neuts, eosinophils (myeloproliferative neoplasm)
S+Sx:
insidious onset
systemic: weight loss, fever, night sweats (without Infection!!)
anaemia Sx Splenomeg – abdo pain
pale lymphadenopathy
Philadelph causes BCR ABL fusion protein which causes tyrosine kinase activity and increased cell division
Stem cell transplant if imatinib resistant
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53. Chronic Myeloid Ix: FBC - increased Neut, Eosin, Baso
BM aspirate + cytogenetics: PHILADELPHIA CHROMO
Tx:
tyrosine kinase inhibitors e.g. Imatinib – blocks ABR CBL fusion protein
stem cell transplant – cure 70 %
Prog: survival >90% 5 yrs
Complications:
not treated – BLAST CRISIS + AML
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54. Chronic Lymphocytic Most common leuk
Clonal expansion of B cells (in blood/BM/LN)
Epi:
ELDERLY
RF: trisomies and pneumonia
S+Sx:
most ASYMPTOMATIC
recurrent infections (dec. Abs), Anaemia (BM fail), lymphadenopathy, splenomeg –abdo pain
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55. Chronic Lymphocytic Ix: FBC – LYMPHOCYTOSIS BM asp - lymphoctyes
Blood film – SMUDGE/SMEAR CELLS
Mx:
30% never need Tx
Supportive (transfusions, EPO, infection prophyl)
Specific:
- Purine Analogues, Monoclonal Abs (Rituximab), stem cell transplant
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56. Leukaemias – summary AML Adults Gum bleeding Auer rods CML
Philadelphia chromosome
ALL
Children
CNS
Blast cells
CLL
Elderly
Most common leuk.
Asymptomatic
Smear cells
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57. Platelet Problems Thrombocytopenia = too few platelets CFs:
Mucosal bleeding (nose bleeds, gum)
Easy bruising
Purpura
Causes
Reduced production: congenital, BM infiltration (heam. Malig), decreased BM production (low B12/folate, reduced TPO (liver dis.), Aplastic Anaemia, HIV/TB)
Increased destruction: Immune (ITP), hypersplenism, drugs (Heparin induced), consumption (DIC, TTP)
Platelets involved in clotting/haemostasis. Adhere to endothelium via collagen and vWF, release platelet granules (ADP/fibrinogen/thrombin) leading to FIBRIN prodn, and platelet aggregation.
TPO made in liver stimulates production.
Lifespan of platelets = 7-10 days, whenold removed by SPLENIC macrophages.
<150 X 10 to power of 9 = thrombocytopenia
Bleeding uncommon above 50, spontaneous bleeding uncommon above 20
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58. Immune Thrombocytopenic Purpura
Pathophysiology:
Immune destruction of platelets
IgG antibodies form to platelet/megakaryocyte surface glycoproteins.
Opsonised platelets removed by reticuloendothelial system
Aet:
Primary – after viral infection
Secondary – assoc. w. malignancies (CLL) and infections (HIV/HepC)
Ix: Dx of exclusion
Tx: cause, IV Ig, steroids
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59. DIC – Disseminated Intravascular Coagulation
A complication rather than condition itself
Pathophysiology
- increased/exposed tissue factor on endothelium
- massive activation of clotting cascade
Aet: sepsis, trauma, surgery/burns, promyelocytic leuk.
CFs:- activated clotting: microvascular CLOTS – organ failure
- consumption of plts/clotting factors: BLEEDING
Ix: - decreased plts, prolonged PT/APTT, increased D-dimers, decreased fibrinogen
Tx: Cause, supportive (plts/cryoprecipitate if bleeding)
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60. Heparin Induced Thrombocytopenia
Pathophys:
Complication of heparin (especially unfractionated hep.)
IgG antibody against platelet-heparin complex
IgG/plt/heparin complex causes plt activation and THROMBOSIS
RFs:
After Cardiac bypass surgery
CFs:
Sharp decrease in plts 5-10d after heparin
Thrombosis and skin necrosis
Tx:
immediately stop heparin, give alterntive anticoag, never expose pt to heparin again
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61. Polycythaemia Too many RBCs Aetiology:
Primary (BM problem) – Polycythaemia Rubra Vera (PRV)
Reactive/secondary (other problem but BM/blood affected)– EPO excess, altitude, lung disease
PRV
- myeloproliferative disorder of overactive BM
- increased RBCs (and WBCs + plts)
- CFs: hyperviscosity sx, thrombosis, itching, splenomeg, plethoric appearance
- Tx: Aspirin, venesection, BM suppression (hydroxycarbamide)
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