Haematology Flashcards
Peripheral blood smear morphology
• IDA: McHc cells, pencil cells
• G6PD deficiency: bite cells, Heinz
bodies
• Microangiopathies/ DIC:
schistocytes (fragmented RBC)
• HS, AIHA: spherocytes
• SCD: sickle cells, target cells
• Thalassemia: target cells, tear drop
cells, nucleated RBC
• Pb poisoning: ringed sideroblasts,
basophilic stippling
• Megaloblastic anaemia (B12/ folate):
oval macrocytes, hypersegmented
neutrophils (≥5% with 5 lobes or ≥1%
with ≥6 lobes)
• MDS: Howell-Jolly bodies, leucoerythroblastic blood picture
Microcytic anemia
Important differentials: Fe deficiency anemia, thalassemia, anemia of chronic disease, sideroblastic anemia
Workup: peripheral blood smear, Fe profile (serum Fe, TIBC) + ferritin, Hb pattern, clotting profile
Iron deficiency anemia
Physiology of iron:
• Absorption as Fe2+ in duodenum: by
amino acids and vitamin C
• Bound to transferrin in plasma (TIBC
measures capacity of binding)
• Broken down by reticuloendothelial
system: liver, spleen
Causes:
• ↑Demand: pregnancy, growth spurts
• ↓Supply: vegetarian diet, post-
gastrectomy, malabsorption (e.g. IBD,
celiac disease)
• ↑loss: haemorrhage (GI bleed,
menorrhagia, trauma), chronic haemolysis,
haemodialysis, hookworm infestation
Specific clinical features
• Brittle hair and nails, koilonychia (spoon-shaped nails)
• Mucosal changes: glossitis, angular cheilitis, esophageal webs (PWS)
• Pica (appetite for non-food substance, e.g. dirt)
• Restless leg syndrome
Laboratory findings
• CBC: McHc anemia, reactive thrombocytosis (EPO stimulates platelet precursors)
• Fe study: low ferritin (higher threshold if inflammation/ liver disease), high TIBC, low TSAT, low serum Fe (not diagnostic)
• PBS: pencil cell, anisopoikilosis
• Workup for underlying cause: e.g. occult GI bleed (FOBT x 3 —> top-and-tail endoscopy)
Management
• Diet: iron-rich food (meat, egg, green veg), vit C (promote absorption)
• PO FeSO4 300mg BD
o 65mg elemental Fe/ 100mg tablet; expect Hb increase 1g/dL every 7-10 days
o Give with vitamin C and without food (2h before, 4h after)
o S/E: n/v, constipation, epigastric discomfort, metallic taste, black stool
- Switch to elixir form
- Take with meals (note decrease absorption)
• IV Fe: for those who cannot tolerate oral iron / severe ongoing blood loss
o Effective, no GI side effects
• Refractory IDA: consider poor compliance, ongoing blood loss, low absorption, alternative cause of anemia
Anaemia of chronic disease
Pathogenesis: no total body Fe deficiency, just that body is not utilizing iron
• Dysregulated homeostasis: increase hepcidin (induced by IL-6) —> decrease ferroportin expression —> decreased Fe absorption & release
• Immune-mediated: decreased EPO secretion
Causes:
• Infection: e.g. TB
• Inflammatory diseases: RA, SLE
• Cancer: especially haematological malignancy
• Chronic organ impairment: heart failure, COPD, CKD
Laboratory findings
• CBC: NcNc anemia (MC) / McHc anemia, low reticulocyte count
• Fe study: low TIBC (low Fe utilization), high ferritin (inflammatory marker)
• PBS: normal
Management: treat underlying disease (Fe supplement not particularly useful)
Thalassemia
Most common single gene defect in HK (a-carrier: 5%; b-carrier: 3.5%)
Alpha thalassemia
- Genetics:
AR gene deletions (Chr 16: 2 pairs) – MC is SEA deletion
• 1-2 deletions: trait
• 3 deletions: HbH (beta 4)
• 4 deletions: Hb Barts (gamma 4)
- S/S:
Hb Barts (4): non-viable in utero (hydrops fetalis)
HbH disease (3): transfusion- dependent, severe anemia present at birth
- Lab finding:
• CBC: NcNc if mild, McHc if more severe; ↑RBC to compensate for ↓Hb
• Fe profile: rule out concomitant IDA, risk of iron overload if regular transfusion
• Hb pattern: HbH inclusion bodies
• Alpha-IC strip for Hb Barts
• Alpha genotyping
- Mx:
• Hb Barts: in-utero transfusion
• HbH disease: transfusion (esp. during acute illness), folic acid supplement
Beta thalassemia
- Genetics:
AR point mutations (Chr 11: 1 pair, each can be b0 or b+)
• Major (b0/b0)
• Intermedia (b0/b+, b+/b+)
• Minor / Trait: (b/b0, b/b+)
- S/S:
Major/ intermedia: present at 3-6 months (gamma-beta shift)
• Severe transfusion-dependent anemia
• Growth retardation
• Extramedullary haematopoiesis (prevented by early transfusion)
o Hepatosplenomegaly
o BM expansion: Cooley’s facies (frontal bossing, maxillary overgrowth)
• Jaundice, gallstones (bilirubin)
• S/S of iron overload (GI absorption + transfusion + ineffective erythropoiesis): cirrhosis, cardiomyopathy, hypogonadism, DM
- Lab finding:
• CBC: NcNc if mild, McHc if more severe; ↑RBC to compensate for ↓Hb
• Fe profile: rule out concomitant IDA, risk of iron overload if regular transfusion
• Hb pattern: HbA2 >3.5%, HbF
• Genetic test
• X-RAY skull: hair on end appearance, thinning of cortex
- Mx:
Lifelong transfusion: leukodepleted, extended crossmatched
• Goal: pre-transfusion Hb 9-10, post-transfusion Hb 13-14
• Risk of iron overload - Fe chelating agents (refer to [Fe overload] for details), regular liver and cardiac MRI
Folic acid supplement (less store c.f. B12)
Hydroxyurea: stimulate gamma chain —> HbF production
Luspatercept: target TGF-β ligand —> block aberrant Smad2/3 signalling —> correct ineffective erythropoiesis [BELIEVE trial]
Splenectomy (rarely done)
HSCT (for b thal-major only)
Sideroblastic anaemia
Causes
• Hereditary (XR): rare
• Acquired: idiopathic (subtype of MDS), lead poisoning, drugs (isoniazid)
Lab findings:
• Fe profile: ↑ferritin, TSAT
• PBS: ringed sideroblasts (iron granules surrounding nucleus), basophilic stippling
Management:
• X-linked: high-dose pyridoxine (co-enzyme for the mutated enzyme)
• Acquired: treat underlying cause, EPO, G-CSF, transfusion
Normocytic anaemia
Important differentials:
acute blood loss, anemia of chronic disease, haemolytic anemia, marrow failure (e.g. cancer, AA), chronic renal insufficiency
Haemolytic anaemia
Classification: intrinsic vs extrinsic, inherited vs acquired, intravascular vs extravascular
- Intracvascular
- Haemolysis inside bloodstream —> Free Hb released into blood —> bind to haptoglobin —> excess Hb excreted in urine
- Causes:
Enzyme: G6PD / PK deficiency
Fragmentation syndromes: MAHA (microangiopathic hemolytic anaemia)
C’-mediated lysis: Cold AIHA (IgM),
alloimmune HA, PNH
- S/S:
Jaundice, gallstones, Dark urine, AKI (hemoglobinuria)
- Lab findings:
CBC: MCV can be N/high/low depending on amount of reticulocytes (↑MCV) & spherocytes (↓MCV)
Markers of haemolysis: high LDH, high unconjugated bilirubin, N/decrease haptoglobin
Compensatory erythroid hyperplasia: retic > 2%, polychromasia and nucleated RBC on PBS
Urine Hb / haemosiderin
Serum free Hb, metHb, decrease haptoglobin
- Mx:
Folate replacement
Cholecystectomy - Extravascular haemolysis
- Haemolysis by reticuloendothelial system
- Causes:
Membrane: HS, HE
Hb: thalassemia, sickle cell
Warm AIHA (IgG)
- S/S:
Jaundice, gallstones, Splenomegaly
- Lab findings:
CBC: MCV can be N/high/low depending on amount of reticulocytes (↑MCV) & spherocytes (↓MCV)
Markers of haemolysis: high LDH, high unconjugated bilirubin, N/decrease haptoglobin
Compensatory erythroid hyperplasia: retic > 2%, polychromasia and nucleated RBC on PBS
- Mx:
Folate replacement, splenectomy, cholecystectomy
G6PD deficiency* (prevalence: 4.5% male, 0.5% female)
- XR disorder (for production of glutathione against oxidative stress)
- Precipitants: infection, drugs (anti-malarials, analgesics, dapsone, nitrofurantoin, quinolones, sulphonamides (e.g. Septrin)), DKA, hepatitis
- S/S; Abdominal pain, jaundice, pallor, dark urine during acute attack
- Ix: PBS —> bite cels, Heinz bodies
G6PD assay (may be normal during acute
haemolysis, repeat after recovery)
- Mx: Avoid drugs, mothball, fave beans
- Classes of G6PD deficiency: Class I (severe with nonspherocytic hemolytic anemia), Class II (severe with intermittent hemolysis), Class III (moderate to mild)
Hereditary spherocytosis
- AD mutation (75%), Sporadic (25%)
- S/S: highly variable. Chronic haemolytic anaemia
- Ix:
PBS: spherocytosis
DCT: rule out AIHA
Flow cytometry: low EMA binding
Osmotic fragility test
- Mx: Oral folic acid supplement, Splenectomy, Cholecystectomy
Autoimmune haemolytic anaemia (AIHA)
1. Warm (90%, IgG mediated, extravascular haemolysis):
- primary
- secondary (lymphoproliferative disorders e.g. CLL, autoimmune e.g. SLE, drug-
induced e.g. methyldopa / L-DOPA, other CA)
- S/S:
Evans syndrome: warm
AIHA + ITP
Splenomegaly
- Ix:
PBS: spherocytosis
DCT for anti-IgG*
- Mx:
Treat underlying cause
1st line: Steroids (oral pred 1mg/kg/d)
2nd line: rituximab, IVIG, splenectomy
3rd line: azathioprine, cyclophosphamide
- Cold* (10%, IgM mediated, intravascular haemolysis):
- primary
- secondary (lymphoproliferative disorders esp. lymphoma, infection e.g. EBV,
mycoplasma pneumoniae)
- S/S:
Anaemia aggravated by cold
Acrocyanosis
Livedo reticularis
Raynaud phenomenon
- Ix:
PBS: RBC agglutination
DCT for anti-C3d* ± cold agglutinin titre
- Mx:
Avoid cold (e.g. pre- warmed IV fluids)
Rituximab, plasmapheresis / IVIG - Paryoxsmal nocturnal hemoglobinuria
(PNH)
- Patho: lack of GPI anchor (glycerylphosphatidyl inositol) —> ↓anchoring of CD55/59 —> loss of
protection from complement lysis
- S/S:
Nocturnal haemolysis: blood during first void urine in morning
Venous thrombosis (Plt hypersensitive to C’): Budd-Chiari, mesenteric ischemia, DVT/PE
Aplastic anemia (AA)
- Ix:
Flow cytometry: loss of expression of CD55/59 ±BM for AA
Sucrose lysis test
- Mx:
Transfusion
Eculizumab: anti-C5
Treat AA: immunosuppressive therapy
Definitive: allogenic HSCT
Macrocytic anaemia
- Megaloblastic
- Nuclear-cytoplasmic
maturation asynchrony
- Aetiology:
B12 deficiency
Folate deficiency
Drugs: immunosuppressants (MTX/AZA), TKI (imatinib, sunitinib)
- PBS:
Oval macrocytes
Hypersegmented neutrophils
- Ix:
Active B12 and folate levels ± RBC folate (B12 deficiency falsely serum folate levels) - Non-megaloblastic
- Membrane abnormalities with abnormal cholesterol metabolism
- Aetiology:
Alcoholism (MC)
Liver disease
Hypothyroidism
Haemolytic anemia (∵reticulocytosis)
Aplastic anemia / Myelodysplastic syndrome
- PBS:
Round macrocytes
Normal neutrophils
- Ix:
Haemolytic screen: LDH, haptoglobin, bilirubin, reticulocyte
LFT, TFT
B12 deficiency
Source:
Diet (Meat, fish, egg, dairy products) + microbes
Storage:
Liver store sufficient for 3 years of use + enterohepatic circulation —> YEARS to manifest S/S
Absorption:
Complex with intrinsic factor (IF) made by parietal cells —> absorbed in terminal ileum
Binding:
Transcobalamin: active B12 (10-30% of total B12)
Haptocorrin: inactive B12
Biochemical roles:
Methyl-B12: cofactor of methionine synthase (homocysteine —> methionine) for DNA synthesis
Ado-B12: convert MMA to succinyl CoA for Kreb’s
Aetiology:
Diet e.g. strict vegetarian, alcoholic
Stomach:
• Pernicious anaemia (anti-parietal cell / IF Ab —> impaired IF secretion and achlorhydria; a/w other autoimmune disease e.g. vitiligo, thyroid)
• Post-total gastrectomy
Intestine:
• Ileal resection: e.g. Crohn’s, TB
• Blind loop syndrome: bacterial overgrowth
• Malabsorption: e.g. celiac disease
• Fish tapeworm (Diphyllobothrium latum)
Drugs (e.g. PPI, metformin)
Specific S/S:
- Mucosal changes: atrophic glossitis, oral ulcers, angular stomatitis
- Sensory-predominant peripheral neuropathy (reversible)
- Cerebral: delirium, dementia (reversible), optic atrophy (rare)
- Spinal cord: subacute combined degeneration (SCD)
- (irreversible): motor (pyramidal tract) + sensory (DCML)
- increase knee jerk (SCD) + decrease ankle jerk (peripheral neurop.)
Ix:
Anti-parietal cell (more sensitive), anti-IF (more specific): any ONE positive = pernicious anemia
OGD for atrophic gastritis and r/o CA stomach
Mx:
- Diet
- Vitamin B12 1mg PO daily / IM Q3m (if absorption problem)
• Monitor K due to resumption of erythropoiesis
• Monitor Fe: rapid Fe depletion
Folate deficiency
Source:
Diet only (Green vegetables, liver, nuts):
destroyed by cooking
Storage:
Body store sufficient for 3 months of use
Absorption:
Convert to methyl-THF —> absorbed in
upper small intestine
Binding:
Weakly to albumin
Biochemical roles:
DNA synthesis
(note: B12 traps folate into cells)
Aetiology:
Diet: poor nutrition e.g. old age, alcoholic
Drugs
• Anti-folate (e.g. methotrexate,
trimethoprim, pentamidine)
• Induced malabsorption e.g.
phenytoin, valproate, OCP
• Alcohol: poor nutrition + direct decreased folate level
Increased demand: pregnancy, turnover
(haemolysis, exfoliative dermatitis,
dialysis)
Specific S/S:
- Mucosal changes: atrophic glossitis, oral ulcers, angular stomatitis
- Sensory-predominant peripheral neuropathy (reversible)
- Cerebral: delirium, dementia (reversible), optic atrophy (rare)
- Neural tube defect
Further Ix:
- Anti-parietal cell (more sensitive), anti-IF (more specific): any ONE positive = pernicious anemia
- OGD for atrophic gastritis and r/o CA stomach
Mx:
- Diet
- Folic acid PO 5mg daily (after r/o B12
deficiency: risk of exacerbating SCD)
Haemochromatosis
Pathogenesis: each unit of blood contains 250mg Fe —> excess iron load saturates transferrin —> non-transferrin-bound
iron NTBI (e.g. bound to albumin / citrate) —> Haber-Weiss reaction (iron catalyses H2O2 —> reactive oxygen species)
Causes:
• Hereditary hemochromatosis (HH)
• Transfusion overload (e.g. TDT, AA/MDS, haematological malignancies)
• Others (rare): Ineffective erythropoiesis, liver disease, diet
Clinical features: often asymptomatic
• Liver: deranged LFT, cirrhosis
• Heart: dilated cardiomyopathy (à heart failure)
• Endocrine: delayed growth, hypothyroidism, hypogonadism (pituitary), DM (pancreas)
• Skin: hyperpigmentation (“bronze diabetes”)
• Joint: arthropathy, esp. 2nd & 3rd MCP joints (squared off bone ends, hook-like osteophytes)
Investigations:
• CBC, LFT
• Iron profile: likely if both +ve
o TSAT > 45%
o Serum ferritin >200mcg/L(M), >150mcg/L(F) – note false positive (acute phase reactant)
• Liver and cardiac MRI
• ± Gene testing if FHx: HFE gene - C282Y, H63D mutation
• ± Liver biopsy, endomyocardial biopsy
Treatment:
• Dietary adaptation: avoid Fe supplement / red meat, hepatotoxic drugs / alcohol / uncooked seafood
• Chelation therapy: indicated if ferritin > 1000mcg/L, positive findings in MRI T2 for liver/ heart
- Deferoxamine —> SC 3-5x/week —> Compliance issue, S/E: ototoxicity, retinal changes, ARDS
- Deferiprone —> PO—> Less effective, S/E: agranulocytosis
- Deferasirox —> PO —> S/E: GI upset, LRFT derangements, hypotension, hypersensitivity
• Venesection
Porphyria
Definition: metabolic disorders caused by altered activities of 8 different enzymes involved in haem biosynthesis —>
buildup of porphyrin (precursor of haem) in tissues and blood
Many subtypes, including:
• Acute intermittent porphyria (AIP) – most common form of acute porphyria
• Porphyria cutanea tarda (PCT) – most common form of cutaneous porphyria
Clinical features
• Neuropsychiatric: peripheral neuropathy, psychosis, etc
• Cutaneous: bullae / blisters, changes in skin colour, photosensitivity, etc
• Abdominal pain, n/v/d
• Red-wine urine
Investigations: urine for porphobilinogen (PBG)
Management: hemin (reduce production of porphyrins)
Platelet disorder
Quantitative (thrombocytopenia)
1. Congenital
- Bernard-Soulier syndrome
- Wiskott-Aldrich syndrome
- May-Hegglin anomaly
2. Acquired:
• decrease Platelet production: malignancy, megaloblastic anemia, MDS, AA, ITP
• increase Platelet destruction: ITP, MAHA (e.g. HUS, TTP, DIC), drug-induced (e.g. heparin), SLE
• Hypersplenism: chronic liver disease, myelofibrosis
Qualitative (platelet dysfunction)
1. Congenital
- Bernard-Soulier syndrome (GP1b)
- Glanzmann’s thrombasthenia (GP2b/3a)
2. Acquired
• Antiplatelets: aspirin, P2Y12i, GP2b/3a inhibitors, NSAIDs
• Uremia: increase NO —> inhibit platelet
• MPN: acquired vWF deficiency
Investigations
• CBC: EDTA can cause platelet clumping
• PBS: rule out platelet clumping, look for signs of etiology (e.g. MAHA)
• Fundoscopy: assess risk of ICH
• ± BM examination
Clotting profile
- High PT, normal APTT
- Extrinsic pathway defect (7)
• Vit K deficiency (e.g. cholestasis) / warfarin use*
• Liver disease - Normal PT, high APTT
- Intrinsic pathway defect (8, 9, 11, 12)
• Improved after mixing study (1:1 mix with normal plasma): haemophilia, vWD
• Unchanged after mixing study: heparin use*, lupus anticoagulant, other acquired
inhibitors (e.g. hemophilia on factor infusion, autoimmune diseases) - High PT, high APTT
- Common pathway defect (factors 5, 10, 2)
• NOAC use* / high level heparin
• Severe vit K deficiency (e.g. cholestasis) / warfarin use*
• Liver disease: ↓clotting factors except factor 8 (produced by endothelium)
• DIC: ↓platelet, ↓fibrinogen, ↑D-dimer
Immune thrombocytopenia
Most common cause of isolated thrombocytopenia
Pathogenesis: autoantibodies against platelets (increase platelet destruction) and megakaryocytes (decrease platelet production)
Types
• Primary: occur in isolation
• Secondary: associated with other diseases
o Infection: H. pylori, HCV, HIV
o Autoimmune: SLE, APLS, Evans syndrome
o Drug induced: heparin-induced thrombocytopenia (HIT)
o Lymphoproliferative disorders
Investigations
• CBC: platelet < 100, anaemia possible (prolonged bleeding), leucocytosis possible (infection)
• Clotting profile
• Pre-Tx workup: LRFT, Ig pattern, HBsAg, CMVpp65/PCR, G6PD
• Peripheral blood smear: to rule out pseudothrombocytopenia (due to clumping) and other DDx (e.g. leukaemia)
• Bone marrow: not mandatory
o Indicated if: age > 60 (to r/o MDS), uncertain diagnosis, poor response to steroid, before splenectomy
• Screening for secondary causes: HCV, HIV, HP testing, ANA
• CT brain: rule out ICH
Management
• Supportive: activity restriction, avoid antiplatelet & IM injection, tranexamic acid, withhold offending drugs
• “Watch and wait” unless Plt < 30 or symptomatic bleeding
o Initial therapy
- Steroids (first-line, but take time for onset, maximum give 8 weeks)
—> Dexamethasone 40mg/day for 4 days (or: Prednisolone 1mg/kg/day for 2 weeks)
—> Taper over 1 week if no response; taper and stop at 6 weeks if Plt > 50
- IVIG (0.4g/kg/day x 5 days): if acute life-threatening bleeding
- IV anti-D: only for Rh+ patients, Ab-coated RBC compete with Ab-coated Plt for clearance
o Subsequent therapies
- TPO-R agonist (eltrombopag / avatrombopag PO, romiplostim SC): >60% response
- Rituximab
- Fostamatinib: inhibit phagocytosis of Ab-coated platelets
- ± Immunosuppressant, e.g. azathioprine, MMF
- Splenectomy: failed medical Tx + 12-24 months from Dx (chance of spontaneous remission), risk of infections and thrombosis
• Platelet transfusion: only if life-threatening bleeding
Drug induced thrombocytopenia
Pathogenesis: multiple mechanisms
• IgG antibodies recognize a neo-epitope created by binding of drugs to platelet glycoprotein —> Form immune
complex which binds to platelet Fc receptor
Examples:
• Antibiotics: sulphonamides, vancomycin, rifampicin, penicillin & beta-lactams
• 1st generation anti-epileptics: carbamazepine, phenytoin, valproate
• Methyldopa, H2 blockers
• Others: heparin, procainamide, quinidine, quinine
Management:
• Discontinue offending drugs
• Platelet concentrate if dangerous bleeding
Heparin-induced thrombocytopenia (HIT)
Type 1
- Non-immune mediated: direct effect of heparin causing platelet aggregation
- Time: Day 1-4 after initiating heparin
- Platelet count: Mild, transient drop
- Mx: Spontaneously return to normal
with continued heparin
Type 2
- Immune mediated: IgG to platelet factor 4 (PF4) complexed with heparin to form “HIT antibodies” —> bind FcgR on Plt —>
immune-mediated platelet activation —> paradoxical thrombosis with thrombocytopenia
- Time: Days 5-14 after initiating heparin
- Platelet count: Fall >50%
- Mx: STOP heparin and switch to non-heparin anticoagulant e.g. direct thrombin inhibitor (e.g. argatroban, lepirudin)
‘4T’ scoring system: each item 0/1/2 points —> high (6-8) vs intermediate (4-5) vs low (≤3) probability of HIT
• Thrombocytopenia: 2 points if Plt decrease 50% and nadir ≥20
• Timing of platelet count fall: 2 points if clear onset at Day 5-14
• Thrombosis / other sequalae: 2 points if confirmed new thrombosis / skin necrosis at heparin injection sites /
anaphylactoid reaction after IV heparin bolus
• Other causes: 2 points if none apparent
Vitamin K deficiency
Aetiology
• Poor diet, e.g. alcoholics
• decrease Store: chronic liver disease
• Malabsorption, e.g. biliary obstruction, fat malabsorption
• Drugs: warfarin (vit K epoxide reductase inhibitor), antibiotics (eradicate gut flora)
Investigations
• Clotting: ↑INR
• Reduced factors 2, 7, 9, 10
Reversal of anticoagulant: see separate section
Haemophilia
Patho:
Factor VIII activates factor X with factor IX in intrinsic pathway —> prolonged APTT
Lab:
Clotting: ↑APTT, improved by mixing test
Factor level assay (FVIII:C/ FIX:C): <40%
vWF antigen: normal
Ristocetin cofactor activity (vWF activity): Normal
Cause:
Type A: Factor 8 deficiency (XR)
Type B (Christmas disease): Factor 9 deficiency (XR)
Type C (Rosenthal syndrome): Factor 11 deficiency (AR, rare)
S/S:
Type A & B clinically indistinguishable
Haemarthrosis: painful joint swelling, loss of bony landmarks,
hemophilic arthropathy (e.g. contracture)
Soft tissue haematoma: muscle atrophy, compartment syndrome
Severity: factor level
• Severe: < 1% (spontaneous bleeding)
• Moderate: 1-5% (bleeding with mild injury)
• Mild: >5 - 40% (bleeding after surgery/ trauma)
Mx:
Education
• Avoid contact sports, injury prevention (e.g. pads on furniture), maintain good dental hygiene
• Avoid IM injection, aspirin/ NSAID
• Early recognition of bleeding: tingling sensation / refuse to move affected limb —> RICE
• Learn storage, preparation and injection of factors
• Physiotherapy: preserve joint function and muscle strength
Tranexamic acid
DDAVP:
• MOA: stimulate endogenous release of FVIII & vWF
• Indication: mild haemophilia A (before dental extraction), vWD
• S/E: water retention (hypoNa), facial flushing, headache (vasodilation)
Factor concentrate replacement (3x/week for Type A, 2x/week for Type B)
• Through IV access e.g. CVC, Port-a-catheter
• Types: recombinant (preferred), plasma-derived, combined
• Indications:
o Primary prophylaxis: severe haemophilia
o Secondary prophylaxis (MC): after ≥2 large joint bleeding
o Tertiary prophylaxis: Evidence of joint damage
o On-demand: before invasive procedures
• S/E: inhibitor formation (usually first 10-20 days)
o Low titre: higher dose factor concentrate
o High titre: activated Factor VII (Novoseven), bypassing agent (e.g. FEIBA), emicizumab (SC monthly; link up
Factor X and IXa)
o Others: tissue factor pathway inhibitor (TFPI, e.g. marstacimab, concizumab), immunotolerance induction (ITI)
Gene therapy: introduce deficient gene by adeno-associated virus (AAV) e.g. Roctavian (2022), efanesactocog alfa (2023)
Note: Acquired haemophilia A (autoAb against Factor 8) classically presents with retroperitoneal hematoma
Von Willebrand disease
Patho:
Roles of vWF
• Carrier protein for FVIII: protect FVIII from
degradation
• Facilitate platelet adhesion to damaged
endothelium
Lab:
Clotting: Normal/ ↑APTT
Factor level assay: normal / decrease (Type 3)
vWF antigen: decrease
RiCof (vWF activity): decrease
Ristocetin-induced plt aggregation: abnormal
Cause:
Inherited:
• Type 1 (AD): partial quantitative deficiency
• Type II (AD/AR): qualitative abnormalities
• Type III (AR): complete quantitative
deficiency
Acquired: antibody-mediated
(lymphoproliferative, SLE), shear stress-induced (Heyde syndrome in AS)
S/S:
Mucocutaneous bleeding e.g. epistaxis,
menorrhagia, postpartum bleeding
Haemarthrosis only in type 3 (complete absence of vWF —> low Factor VIII level)
Mx:
Education
• Avoid contact sports, injury prevention (e.g. pads on furniture), maintain good dental hygiene
• Avoid IM injection, aspirin/ NSAID
• Early recognition of bleeding: tingling sensation / refuse to move affected limb à RICE
• Learn storage, preparation and injection of factors
• Physiotherapy: preserve joint function and muscle strength
Tranexamic acid
DDAVP:
• MOA: stimulate endogenous release of FVIII & vWF
• Indication: mild haemophilia A (before dental extraction), vWD
• S/E: water retention (hypoNa), facial flushing, headache (vasodilation)
- Plasma-derived FVIII containing vWF
(recombinant form contains no vWF)
- Cryoprecipitate / vWF concentrates
Thrombophilia screening
• Indications:
o Young patients with idiopathic venous thrombosis
o Suspected APLS, e.g. recurrent miscarriage
o Unusual sites of thrombosis, e.g. mesenteric, renal, portal vein, cerebral venous sinus
o Warfarin-induced skin necrosis (protein C/S deficiency)
• Tests:
o Protein C, protein S, activated protein C resistance (APCR), anti-thrombin (AT)
o Factor V Leiden PCR, prothrombin G20210A mutation
o APLS: Anti-cardiolipin, lupus anticoagulant, anti-β2-glycoprotein I antibody (anti-β2 GPI)
• Timing of testing:
o Do not test at time of VTE event, or while patients arereceiving anticoagulants (withhold warfarin x 2 weeks, DOAC x at least 2 days)
Disseminated intravascular coagulation
Pathophysiology
Mechanism: Release of procoagulant materials / Widespread endothelial damage and collage exposure
—> Widespread intravascular thrombosis (organ ischemia)
—> Bleeding due to consumption coagulopathy
- Acute (decompensated DIC)
- Causes: Trauma, sepsis, APL, transfusion reaction
- S/S: Tends to bleed (consumption coagulopathy), Oozing from trauma / catheter / drain sites
- Lab features:
Platelet: decrease
Clotting: PT increase, APTT increase
Fibrinogen: decrease
D-dimer: increase
PBS: schistocytes - Chronic (compensated DIC)
- Causes: Malignancy (CA pancreas, stomach, ovaries, prostate)
- S/S: Tends to clot (production of procoagulant factors keep pace with ongoing thrombosis)
• Unprovoked venous / arterial thromboembolism
- Lab features:
Platelet: normal / mild decrease
Clotting: normal / mild increase PT/APTT
Fibrinogen: normal / increase
D-dimer: increase
PBS: schistocyte
Aetiology (OMIT HSR)
• Obstetrics (amniotic fluid embolism, eclampsia / HELLP, placenta abruptio)
• Malignancy (AML-M3, CA pancreas)
• Infections (sepsis, meningococcaemia)
• Trauma (shock, burns, crush injury)
• HSR (snake bite, incompatible transfusion)
Clinical features
• Bleeding, e.g. intracranial bleeding, petechiae, haematuria, mucosal bleeding (e.g. epistaxis)
• Thrombosis, e.g. ischaemic stroke, MAHA, VTE
• Purpura fulminans: due to protein C deficiency
• Organ dysfunction:
o AKI
o Liver dysfunction: jaundice
o Acute lung injury: pulmonary haemorrhage, ARDS
o Neurological dysfunction: coma, delirium
o Adrenal failure: Waterhouse-Friderichsen syndrome
Management
• Treat underlying causes
• Supportive treatment: platelet, FFP, cryoprecipitate
• ?Heparin: to reduce thrombin, but increase bleeding
• AVOID tranexamic acid (antifibrinolytic) / PCC —> promote thrombosis
Thrombotic thrombocytopenia purpura
Pathogenesis:
ADAMTS13 deficiency —> cannot cleave ultra-large vWF multimers —> ↑platelet adhesion
S/S:
Classical pentad (35%)
• Fever
• Anemia (MAHA):
• Thrombocytopenia: petechiae
• Renal impairment: microthrombi in kidney
• Neuro fluctuating signs: microthrombi in brain
Ix:
CBC, LRFT, retic / LDH / haptoglobin, DAT (-ve)
Clotting profile: normal (r/o DIC)
Blood film: schistocytes
↓ADAMTS13 (usually ≤10%)
PLASMIC score: pre-test probability
Mx:
Plasmapheresis (remove large vWF multimers) + Replace by FFP (ADAMTS13) / cryo-reduced plasma (CRP
Immunosuppressants: high-dose steroids + rituximab
C/I to platelet transfusion: add to clot formation
Haemolytic uraemia syndrome
Pathogenesis:
Verotoxin from EHEC (O157:H7) damages endothelial cells
S/S:
Triad of AKI, MAHA & thrombocytopenia
Types:
• Typical (EHEC, Shigella)
• Atypical (S. pneumoniae) – poorer prognosis
Compared to TTP:
• More severe renal impairment
• Minimal neuro symptoms
Mx:
Same as TTP, but
Normal ADAMTS13
Microbiology: blood and urine culture, stool OCP, etc.
Approach to pancytopenia
Etiology
• decrease synthesis:
o “Empty factory”: AA
o Raw materials: Fe, B12/folate (megaloblastic anemia)
o Ineffective production: MDS
o Marrow infiltration: lymphoma, myeloma, myelofibrosis, carcinoma, TB
• destruction:
o DIC
o Hypersplenism (e.g. Felty’s syndrome)
o SLE
o PNH
Clinical features
• Fatigue (anaemia)
• Recurrent infections (leukopenia)
• Mucocutaneous bleeding (thrombocytopenia)
Investigations
• CBC, CRP/ESR, ferritin, B12/folate, TFT, clotting
• PBS: hypercellular disease may show
leucoerythroblastic blood picture*
• Bone marrow exam: usually indicated unless splenomegaly
Bone marrow study
• Usual indication: unexplained pancytopenia
• Site: posterior superior iliac crest (sternum if obese, tibia if infant)
• Aspiration:
o Cytological abnormalities
o Special tests: immunophenotyping (CD), cytogenetics, immunohistochemistry (FISH), molecular study
(specific gene rearrangement)
• Trephine biopsy: histological abnormalities
Leucoerythroblastic blood picture
Presence of myeloid precursors and nucleated RBC in PBS (i.e. something displace them out from BM):
• Myelofibrosis
• BM infiltration: leukemia/lymphoma, TB,
metastatic cancers
• Marrow stress: severe hemolysis, severe sepsis
Approach to neutropenia
Etiology
• Selective neutropenia
o Congenital: Kostmann’s syndrome
o Acquired:
- Drug-indued agranulocytosis: e.g. carbimazole, chloramphenicol, clozapine, deferiprone, co-trimoxazole, phenytoin, chlorpromazine
- Immune: SLE
- Infections: viral (e.g. hepatitis, HIV), fulminant bacterial infection
o Benign / Cyclical
• Part of pancytopenia (see above): bone marrow failure, splenomegaly
Management
• Check for S/S of infection, PMHx, DHx, any hepatosplenomegaly / lymphadenopathy / autoimmune features
• Likely benign / cyclical: Regular monitoring (CBC), BM exam only if symptomatic / pancytopenia
• Agranulocytosis: stop offending drugs, protective isolation, septic work-up, broad spectrum Abx, G-CSF
Aplastic anaemia
Definition: destruction of haematopoietic cells of bone marrow
• Severe AA: BM cellularity <25% + ≥2 of 3 criteria:
o Absolute reticulocyte count < 20
o Platelet < 20
o ANC < 0.5
• Very severe AA: severe + ANC < 0.2
• Non-severe AA: not fulfilling criteria for severe AA
Aetiology
• Congenital:
o Fanconi’s anaemia (AR/XR): Dx: diepoxybutane (DEB) instability test, risk of malignancy (MDS, AML)
o Dyskeratosis congenita (XR usually): mutation in telomere-related genes
o Schwachman-Diamond syndrome
• Acquired
o Idiopathic (MC)
o Chemical: benzene
o Drugs: chloramphenicol, sulphonamide, cytotoxic drugs
o Ionizing radiation
o Infection: viral hepatitis
o Pregnancy
Laboratory findings
• CBC: pancytopenia with normocytic/macrocytic anemia, decrease reticulocytes
• PBS: normal
• BM biopsy: hypocellular with fat infiltration (>90%), no malignant infiltration
Management of idiopathic AA
• Supportive care: discontinue offending drugs, transfusion, growth factors (G-CSF), broad-spectrum antibiotics
• Triple therapy immunosuppression: anti-thymocyte globulin + cyclosporin A ± eltrombopag x 6 months
• Definitive treatment: allogenic HSCT (if <40yo + HLA-matched sibling)
• Consider androgens
• Screen for developing other clonal disorders: MDS, PNH, AML
Myelodysplastic syndrome
Definition: heterogenous group of clonal diseases characterised by ineffective / dysmorphic haematopoiesis
Clinical features
• Increased incidence with age (median age ~65); M>F
• Trilineage failure S/S: progressive decline in cell counts
• Pre-leukaemia: may transform to acute leukaemia
• NO hepatosplenomegaly
Classification
Principles
• Number of dysplastic lineages
• Percentage of ring sideroblasts (erythroid precursor, ≥5 iron granules encircling ≥1/3 of nucleus)
• Percentage of blast cells in BM and PB: must be ≤20% to r/o AML
• Del (5q): good prognosis
Investigations
• CBC: pancytopenia
• PBS: oval macrocytes, basophilic stippling, Howell-Jolly bodies, hypersegmented neutrophils
• Bone marrow exam (mandatory): hypercellular marrow with single / trilineage dysplasia
Management
No curative treatment
Risk stratification by IPSS-R score
• Low risk:
o Asymptomatic: observe
o Symptomatic: supportive care (e.g. transfusion, antibiotics)
- ± EPO (e.g. darbepoietin), TPO-RA (e.g. eltrombopag), targeted therapy as below
• High risk:
o Medically fit:
- Allogenic HSCT
- Hypomethylating agents (e.g. azacitidine, 5-aza-2’ deoxycytidine): may achieve response in 50-60% through epigenetic mechanisms
- Targeted therapy: e.g. lenalidomide for del(5q), luspatercept for ring sideroblasts, IDH inhibitors
o Medically unfit: supportive care
Approach to erythrocytosis
Definitions
• Cytosis: increase in counts
• Cythaemia: increase in counts due to primary bone marrow disorder
• Erythrocytosis: Hb > 16.5 (male) or > 16 (female)
Aetiology
• Relative erythrocytosis (haemoconcentration): dehydration, diuretics, burns, stress
• Absolute erythrocytosis:
o Primary: polycythaemia rubra vera (PV)
o Secondary:
- Appropriate increased production of EPO
—> Respiratory: COPD, sleep apnoea, pulmonary hypertension, CO poisoning
—> CVS: Eisenmenger syndrome, methaemoglobinaemia
- Inappropriate increased production of EPO:
—> Paraneoplastic: RCC, HCC, adrenal tumors, cerebellar haemangioblastoma, uterine fibroma
—> Renal: PKD, hydronephrosis
Clinical features
• Facial plethora
• Thrombosis (DVT/ PE, stroke) or bleeding (MPN)
• Hyperviscosity: headache, visual disturbance, etc
Investigations
• Pulse oximetry
• EPO level: to differentiate primary (low) vs secondary (elevated)
• If primary: JAK2 mutation, ferritin level
Management
• PV: see separate section
• Secondary: treat underlying cause
Approach to thrombocytosis
Definition: platelet > 400
Aetiology
• Primary: essential thrombocythaemia (ET)
• Secondary/ reactive: acute phase reactant
o Inflammation/ infection/ malignancy
o Iron deficiency, acute bleeding
o Post surgery
o Rebound thrombocytosis (recovery from B12/folate deficiency or splenectomy)
Investigations
• Bloods: CBC, PBS, CRP/ESR, ferritin (TPO level is not widely available)
• Bone marrow exam: if reactive thrombocytosis unlikely
Management
• Compare with previous blood results
• Primary: aspirin +/- cytoreductive agents (e.g. hydroxyurea)
• Reactive: treat underlying cause
Polycythaemia Vera
Definition:
Stem cell disorder characterised by erythrocytosis +/- increased while cell and platelet production
S/S:
- Facial plethora
- Erythromelalgia (burning pain in hand and feet)
- Aquagenic pruritis (pruritis after warm bath)
- Thrombosis / bleeding
- Hypeviscosity: headache, BOV
- Splenomegaly
CBC:
- high Hb (M >16.5, F > 16), ↑WBC & Plt
- high Hct (M > 49, F > 48)
BM exam:
- Hypercellularity with trilineage growth (panmyelosis)
Genetics:
- JAK2 V617F mutation (97%)
- JAK2 exon 12 mutation (3%)
Mx:
Venesection: aim Hct <45%
Low-dose aspirin (80mg) daily/BD
High thrombotic risk (Hx of thrombosis / age > 60):
Hydroxyurea 500mg BD
Alternative: IFN / busulfan
Refractory: ruxolitinib (JAKi)
Essential thrombocytopenia
Definition:
- increased platelet production in the absence of recognisable stimulus
S/S:
- Vasomotor: headache, dizziness
- Thrombosis: chest pain, stroke, PVD
- Bleeding (non-functional platelet, acquired vWD)
CBC:
- increase platelet (>450)
BM:
- Hypercellularity with megakaryocyte lineage
Genetics:
JAK2 mutation (50%)
CALR mutation (20%)
MPL mutation (5%)
Mx:
Manage CV risk factors
Low-dose aspirin
High thrombotic risk (prior thrombosis, age > 60, JAK2 mutation):
Hydroxyurea / IFN / anagrelide
Primary myelofibrosis
Definition:
Excessive marrow fibrosis leading to marrow failure
S/S:
- severe fatigue
- Constitutional symptoms
- Anaemic symptoms
- Massive splenomegaly +/- hepatomegaly, portal HT
- Bone and joint pain: osteosclerosis, gout
CBC:
↓Hb, variable WBC & Plt
PBS: leucoerythroblastic picture, tear drop cell
BM:
- Aspirate: dry tap
- biopsy: megakaryocytic proliferation and atypia, fibrosis
Genetics:
JAK2 mutation (65%)
CALR mutation (30%)
MPL mutation (8%)
Mx:
High-risk + eligible:
allogenic HSCT
Symptomatic relief:
Ruxolitinib (regardless of JAK2
status), fedratinib
Hydroxyurea, splenectomy
Transfusion, folic acid, EPO
Gout prophylaxis: allopurinol
*Risk stratification systems for primary myelofibrosis: IPSS (at
diagnosis), DIPSS / DIPSS-Plus (at follow-up)
• IPSS & DIPSS used 5 parameters à classified into low, Int-1,
Int-2, high risk
• DIPSS-Plus takes into account 3 more factor
S/E f hydroxyurea
myelosuppression, mucocutaneous ulcer, peripheral neuropathy, teratogenicity
Acute leukaemia
Risk factors
• Genetics: Down’s syndrome, Fanconi anemia, Bloom’s syndrome
• Exposure to chemotherapy, radiation, benzene
• Hx of pre-leukemic conditions: e.g. MDS, MPN
Clinical features
• Pancytopenia
o Anaemia: fatigue, pallor
o Thrombocytopenia: bleeding tendency, DIC (APL)
o Neutropenia (despite increased WBC): infection
• Organ infiltration: more in ALL
o Hepatosplenomegaly
o Lymphadenopathy
o Orchidomegaly
o Eyes: haemorrhage, Roth spots, cotton wool spots
o Gum hypertrophy (AML-M5)
o Mediastinal involvement (T-ALL): SVCO
o CNS involvement (esp. ALL): headache, neurological S/S
• Leucostasis/ hyperviscosity syndrome: headache, vision change, SOB
Classification (for reference)
1. AML
• AML with recurrent genetic abnormalities
e.g. t(15;17), inv(16), mutated NPM1
• AML with myelodysplasia-related changes
• Therapy-related AML
• AML not otherwise specified (NOS)
• Myeloid sarcoma
• Myeloid proliferation related to Down’s
syndrome
2. ALL
• B-cell ALL (85%)
o Not otherwise specified (NOS)
o Recurrent genetic abnormalities e.g. t(9;22)
• T-cell ALL (10-15%)
• ALL of ambiguous lineage
• AML: Prognosis depends on
o Age (>60 = poor prognosis)
o Genetic / molecular abnormalities
o Initial response to chemotherapy (initial remission rate 70-80%, but half of them might relapse
Investigations (SAQ!)
• Bloods: CBC, clotting, fibrinogen/ D-dimer (DIC), RFT, LFT, CaPO4, urate, glucose, LDH (TLS), T&S X-match
• Pre-treatment: G6PD (rasburicase / Septrin), viral serology (HBsAg, anti-HBc ± HBV DNA, anti-HCV, anti-HIV),
anti-CMV IgG (if HSCT)
• PBS and bone barrow aspiration + trephine biopsy:
1. AML
- CBC: pancytopenia with blasts
- PBS:
myeloblast (high N:C ratio, Auer rods)
AML-M3: Faggot cells (promyelocyte with multiple Auer rods)
- BM exam:
>20% blast
Cytochemistry: MPO +ve, Sudan black +ve
Immunophenotyping: CD34, HLA-DR, CD117, CD13, CD33
Cytogenetics, e.g. PML-RARA (AML-M3)
Molecular genetics (e.g. FLT3-ITD/TKD, NPM1)
2. ALL
- CBC: pancytopenia with blasts
- PBS: Lymphoblastic (scanty cytoplasm without granules / Auer rods)
- BM exam:
>20% blasts
Immunophenotyping: Tdt, CD3 (T-ALL), CD19, CD20 (B-ALL)
Cytogenetics, e.g. Ph+ (B-ALL)
Molecular genetics
• Additional workup for ALL: LP (CNS involvement), CT thorax with contrast (if T-ALL: mediastinal mass)
Initial Mx:
1. Blood product support
• RBC if symptomatic anaemia (but C/I in leukostasis)
o If HSCT is considered, give CMV-negative blood or leukodepleted blood
• Platelet: if Plt ≤10 or ≤20 if fever/bleeding (keep ≥50 for APL due to high risk of DIC)
• FFP if evidence of bleeding due to DIC
2. Leucostasis
• Leucopharesis if WCC very high / symptomatic
3. Infection
• Full septic workup
• Reverse isolation +/- empirical antibiotics if evidence of infection
• PCP prophylaxis (Septrin 960mg 3 days/ week) for ALL (higher risk in T cell
depletion)
4. TLS prophylaxis
• Aggressive fluid hydration (2-3L/day)
• Allopurinol / febuxostat
• Consider rasburicase in high-risk patients (C/I: G6PD)
5. Nausea and vomiting
• Adequate antiemetics and analgesics prn
• Consult haematologist if emergency:
o Hyperleucocytosis (WBC >100): chemotherapy ± leucophoresis, avoid blood transfusion until WBC lowered
o APL: early use of ATRA (refer below)
• Other preparations:
o HSCT: arrange HLA typing for patient’s siblings
o Chemo: arrange Hickmann catheter insertion
Definitive management
Principles (important)
• Induction: high-intensity chemotherapy to destroy bulk of tumor
• Consolidation: multiple courses of chemotherapy to attack residual disease
• ± Maintenance (ALL): low-intensity chemotherapy to maintain remission
• ± CNS prophylaxis (ALL)
• ± HSCT if poor prognosis
- AML-M3 (APL)
Initiate treatment based on clinical + morphological criteria (Faggot cells), before definite cytogenetic
diagnosis (t(15;17) —> PML-RARA fusion)
• Correct coagulopathy and control DIC:
o Aggressive platelet transfusion (target > 50)
o Cryoprecipitate/ FFP (fibrinogen target > 150, PT/APTT aim normal)
• Induction: Early use of ATRA (All-trans retinoic acid) 45mg/m2/day PO (promote differentiation)
o Low risk (WBC ≤ 10): ATRA + arsenic trioxide (promote apoptosis of leukemic cells)
o High risk (WBC > 10): ATRA + conventional chemotherapy (7+3)
o Caution for ATRA differentiation syndrome (50%): cytokine release due to further differentiation of promyelocytes; S/S fever, hypotension, SOB (DDx sepsis)
- Mx supportive + steroid (e.g. dexamethasone IV 10mg Q12h x ≥ 3 days)
• Consolidation therapy: ATRA + ATO or ATRA + anthracycline (depend on what was used) - AML non-M3
Induction therapy: 7+3 regimen (Day 1-7 cytarabine continuous infusion + Day 1-3 IV anthracycline)
• Cytarabine (cytosine arabinoside) 100mg/m2: S/E flu-like syndrome, myelosuppression
• Anthracycline (e.g. daunorubicin) 45mg/m2: S/E cardiotoxicity, red urine
• Post-Tx BM biopsy 7 days after final dose to evaluate need of 2nd induction course
• Consider allogenic HSCT if high relapse risk, young patients with little comorbidities
- Consolidation therapy: intermediate dose of cytarabine (IDAC) - ALL
Induction (4-6 weeks): vincristine (weekly, S/E: neuropathy) + high-dose steroids + asparaginase
• ± Rituximab (if CD20+), ± TKI (if Ph+), ± anthracycline (T-ALL)
• Start CNS prophylaxis: intrathecal methotrexate / RT
- Consolidation (4-8 months) ± late intensification: vincristine, steroids, other combination of drugs
- Maintenance (3 years for boys, 2 years for girls): vincristine (monthly), pulse steroids, daily 6-MP
Definition of remission in AML/ALL: no circulating blasts + normal PB count + <5% blasts in BM
Chronic myeloid leukaemia
Definitions
• Clonal proliferation of granulocytic cell line
• Defined by Philadelphia (Ph) chromosome t(9,22) causing production of BCR-ABL1 fusion protein
Clinical features
• Massive splenomegaly: infiltrative disease
• Hypercatabolism: bone pain, weight loss, fever, fatigue, sweating
• Hyperleukostasis: blurred vision, SOB, chest pain
Clinical phases
- Chronic phase (3-4 years) —> Blast < 10% —> 90% of patients at any time point
Asymptomatic
- Accelerated phase (18 months) —> Blast 10-19% —> Acquisition of additional molecular lesions, Increasing symptoms
- Blast crisis (1-2 months) —> Blast ≥ 20% —> Acute leukaemia (2/3 AML > 1/3 ALL)
Investigations
• CBC d/c: decrease Hb, increase WBC (basophilia, myelocyte > metamyelocyte), N/ increase Plt
• Peripheral blood film: complete spectrum of myeloid cells (left shift)
• BM biopsy:
o Hypercellular with granulopoietic predominance
o Cytogenetic study: Ph chromosome
o FISH study / PCR: BCR-ABL fusion protein
Management
• Tyrosine kinase inhibitor (TKI)
o 1st gen: imatinib
o 2nd gen: nilotinib, dasatinib
o 3rd gen: ponatinib (for T315I mutation)
o S/E: rash, ↑QT (nilotinib), pleural/pericardial effusion (dasatinib), thrombosis / dLFT (ponatinib)
• Hydroxyurea ± busulfan: cytoreduction for symptomatic relief
• Allogenic HSCT (if failed TKI)
• Monitoring of BCR-ABL fusion level: CBC (haematological response), cytogenetics (FISH) (cytogenetic response CyR), qPCR (molecular response MR – most sensitive)
o Optimal response: ≤10% at 3mo, ≤1% (CyR) at 6mo, ≤0.1% (MMR) at 12mo
Chronic lymphocytic leukaemia
Definitions
• Most common leukemia in adults (Western»_space; Chinese)
• Monoclonal proliferation of non-functional mature B cells (T cells very rare)
• More resemble lymphoma than ALL
• Pathologically equivalent to small lymphocytic lymphoma (SLL)
Clinical features
• Asymptomatic (MC)
• B symptoms: Fatigue, weakness, fever, night sweats, weight loss, bone pain
• Lymphadenopathy, hepatosplenomegaly
• Anemic symptoms (AIHA, bone marrow)
• Bleeding symptoms (thrombocytopenia)
• Risk of “Richter transformation”: transformation of CLL/SLL into DLBCL or HL
Investigations
• CBC D/C: leukocytosis with↑lymphocytes ± anaemia ± thrombocytopenia
• PBS (diagnostic): smear cells / smudge cells (fragile lymphocytes damaged during slide preparation)
• PB flow cytometry: CD5+, CD19+, CD20+, CD23+, sIg+
• ± BM biopsy: not required for diagnosis, but useful in monitoring treatment response
• ± LN biopsy
• ± cytogenetics: Del 13q (55%), Del 11q (25%)
Staging: RAI / Binet
- RAI: 5
- Binet: A, B, C
Management
• Supportive care: blood products, leukapheresis for leukostasis
• Close observation for early stage asymptomatic CLL (i.e. Rai 0 / Binet A)
• Chemotherapy:
o Indications of treatment
- Advanced stage: Rai stage III/ IV
- Symptomatic: Severe B symptoms, bulky lymphadenopathy / splenomegaly
- Active disease progression: Lymphocytosis ≥50% increase over 2 months / doubling time ≤ 6 months
- Disease-related complications: Refractory AIHA / ITP, recurrent infections, Richter’s transformation
o Choice of regimen
- Young patients: FCR (fludarabine, cyclophosphamide, rituximab) / bendamustine-based Tx
- Old patients: chlorambucil
- Newer agents: ibrutinib (BTK inhibitor), idelalisib (P13K blocker), venectoclax (BCL-2 inhibitor), rituximab / obinutuzumab (anti-CD20)
- Allogenic stem cell transplant
Lymphoma
Classification: histology, immunophenotyping (B/T/NK), cytogenetics / molecular genetics
- Hodgkin’s lymphoma
- 10%
Reed-Sternberg (RS) cells
Strong association with EBV
- Classical: CD15+ CD30+
• Nodular sclerosing (MC)
• Mixed cellularity
• Lymphocyte-rich
• Lymphocyte-depleted
Nodular lymphocyte- predominant (NLP): “popcorn cells”, CD20+, best prognosis
- Superficial (70% cervical LN)
Contiguous spread
Few extranodal disease
- S/S: non-tender lymphadenopathy
B symptoms, Pruritis, Alcohol-induced pain, Splenomegaly +/- hepatomegaly - Non-hodgkin’s lymphoma
- 90% in which:
• B cell neoplasm: 90%
• T/NK cell neoplasm: 10%
- Indolent subtypes: incurable (not chemosensitive)
• Follicular lymphoma: t(14;18)
• MALToma
Aggressive subtypes: potentially curable
• DLBCL (MC, 30%)
o Germinal centre B-cell like (GCB) t(14;18)
o Activated B-cell like (ABC) t(3;14) – worse Px
• Mantle cell lymphoma: t(11;14)
Highly aggressive subtype: potentially curable (very chemosensitive)
• Burkitt’s lymphoma - related to EBV/ HIV, “starry sky appearance”, t(8;14) / t(2;8) / t(8;22)
- Diffuse spread
Nodal +/- extranodal disease with non-contiguous spread
- S/S:
Non-tender lymphadenopathy
“B” symptoms*
Extranodal disease: GI tract (MALToma), skin, brain (e.g. headache, seizures), tonsil (e.g. sore throat, dysphagia)., etc
Investigations
• Bloods: CBC, clotting, RFT/ LFT, CaPO4, ESR & LDH (prognostic), urate (TLS), PBS, glucose, DAT, serum Ig, SPE
• Pre-treatment: HBV, HCV, HIV, G6PD, lung function test (bleomycin), pregnancy test
• Pathology:
o LN: Excisional biopsy / core biopsy for histology, cytogenetics & immunophenotyping (FNA not adequate!)
o BM aspiration and trephine biopsy: for staging
- HL: not indicated unless unexplained pancytopenia
- NHL: bilateral (∵non-contiguous spread)
• Imaging: CXR, PET-CT (preferred esp. DLBCL & HL), MRI brain / LP with cytospin (if suspect CNS lymphoma)
• Other investigations: e.g. Waldeyer’s ring exam, OGD for GI lymphoma
Staging:
Ann Arbor staging
Stage 1: Single LN group
Stage 2: ≥2 LN groups on same side of diaphragm
Stage 3: nodal involvement on both sides of diaphragm
Stage 4: extranodal involvement e.g. liver, BM (note that spleen is considered nodal)
Prognosis
International Prognostic Index (IPI) for aggressive NHL considers 5 factors
• Age > 60
• Performance status (ECOG) ≥ 2
• LDH elevated
• Extranodal sites ≥ 2
• Stage: III / IV
Management
• Supportive care
o TLS prophylaxis: IV fluid + allopurinol (or febuxostat)
o Manage complications: TLS, SVCO, cord compression, malignant hypercalcaemia
• Specific management
1. Hodgkin’s lymphoma
Early stage (I/II): ABVD + Involved field
radiotherapy (IFRT)
• Adriamycin (= Doxorubicin)
• Bleomycin (S/E: pulmonary toxicity)
• Vinblastine
• Dacarbazine
Advanced stage (III/IV): ABVD
Refractory:
• Salvage chemotherapy (e.g. DHAP, ICE)
• High-dose chemo + autologous HSCT
Novel therapy:
• Brentuximab vedotin (anti-CD30)
• Pembrolizumab / nivolumab (PD1 blockade)
2. Non-Hodgkin’s lymphoma
Indolent NHL: watchful waiting
Aggressive NHL: R-CHOP ± IFRT
• Rituximab
• Cyclophosphamide
• Hydroxydaunorubicin = Adriamycin = doxorubicin
• Oncovin/ Vincristine Sulfate
• Prednisolone
• ± CNS prophylaxis (IT methotrexate)
Refractory:
• Salvage chemotherapy (e.g. DHAP, ICE) ± rituximab
• High-dose chemo + autologous HSCT
Multiple myeloma
Definitions
- Monoclonal gammopathy: overproduction of ≥ 1 class of Ig from a single clone of plasma cells
- Plasma cell dyscrasia: neoplasm that arise from clonal expansion of plasma cells
Spectrum of plasma cell dyscrasias
• Multiple myeloma spectrum: multiple lesions of plasma cell proliferation
o Monoclonal gammopathy of undetermined significance (MGUS) – 1%/year progression to MM
o Smouldering multiple myeloma – 10%/year progression to MM
o Active multiple myeloma
• Plasmacytoma: solitary plasma cell tumour found in skeleton (medullary) or soft tissue (extramedullary)
• Waldenström macroglobulinaemia spectrum (arise from lymphoplasmacytoid cells but not plasma cells):
o IgM MGUS
o Smouldering WM
o WM: IgM paraproteinaemia + BM shows lymphoplasmacytoid cells
o Lymphoplasmacytoid lymphoma (LPL): solid tumour with LP cells
• Immunoglobulin deposition disease:
o Primary AL amyloidosis: organ deposition of amyloid proteins consisting of monoclonal light chains
o Light chain deposition disease: organ deposition of light chains that do not form amyloid fibrils
o Heavy chain deposition disease
• POEMS syndrome
Multiple myeloma
• 95% secrete M proteins (intact Ig, free light chain only or heavy chain only), IgG most common
• 5% are non-secretors
Clinical features
CRAB
• HyperCalcaemia/ Bone lesions: active osteoclasts
o Hypercalcaemia: confusion, constipation, polyuria/ polydipsia
o Bone lesions (osteolytic): pain, vertebral collapse, pathological fracture, cord compression
• Renal failure: important to know the cause (SAQ!)
o Cast nephropathy (MC): light chain casts obstructing distal tubules
o Hypercalcemia / hyperuricemia: nephrogenic DI —> dehydration —> pre-renal failure
o Amyloidosis (accumulation of FLC): present with nephrotic syndrome (require renal Bx)
o Other causes
- Drug-induced e.g. NSAID, bisphosphonate, chemoTx
- Local infiltration of tumor cells (myeloma kidney)
- Fanconi syndrome
- Recurrent UTI
• Anaemia (NcNc) / bleeding tendency: BM infiltration + acquired vWD
Other complications
• Hyperviscosity syndrome: rare c.f WM
• Cardiac failure: 2° to amyloidosis / anemia / hyperviscosity
• Sensory ± motor neuropathy: usually 2° to amyloidosis
• Recurrent infections: immunoparesis (decrease other Ig)
Investigations (SAQ!)
• Screening of monoclonal gammopathy:
o Serum and urine protein electrophoresis (SPE & UPE) with immunofixation (fig.)
- SPE: quantification of M protein
- Immunofixation: characterize type of M protein, e.g. IgGkappa (most common)
- Both SPE & UPE at diagnosis is mandatory: 50% LC MM is SPE -ve but UPE +ve
o Serum IgG/A/M levels
o Serum FLC: more sensitive for monoclonal FLC, k/l ratio (normal 0.26-1.65) also suggests monoclonal origin
o 24h urine: Bence Jones protein (FLC)
• Other investigations:
o Bloods: CBC (decrease Hb), increase ESR, LRFT (reversed A:G ratio, increase Cr), CaPO4 (increase Ca), urate, glucose, PBS (rouleaux)
o Pre-Tx: HBsAg, anti-HBc ± HBV DNA, G6PD
o BM aspiration and trephine biopsy, skeletal survey (e.g. MRI whole body)
o Prognostic: serum albumin, β2-microglobulin, LDH for staging (worse if higher)
- Must check these markers before induction therapy
MGUS vs SMM vs MM
- monoclonal component: <30g/L, >30g/L, Present
- Bone marrow plasma cells: <10%, 10-60%, >10%
- Myeloma defining events: Absent, Absent, Present
Myeloma defining events: SLiM CRAB
End-organ damage: CRAB
• Calcium: adjusted Ca > 2.75
• Renal insufficiency: Cr > 177 or CrCl < 40
• Anaemia: Hb < 10
• Bone disease: osteolytic “punched-out” lesions on CT / PET-CT / whole-body MRI; ALP usually normal
(∵osteoblastic activity normal)
Biomarkers of malignancy: SLiM
• Sixty: Clonal BM plasma cell ≥ 60%
• Involved/uninvolved serum free
Light chain ratio > 100
• >1 focal lesions on MRI
R- ISS staging
Original ISS: albumin, β2- microglobulin
Revised ISS: above + LDH
+ FISH cytogenetics
Management (SAQ!)
• Supportive treatment
o TLS prophylaxis: IV fluid + allopurinol / febuxostat
o Hypercalcaemia / Bone disease: local RT for pain relief, aggressive hydration > 3L/day, bisphosphonates e.g.
pamidronate (osteoclast inhibitor), denosumab (RANKL inhibitor)
o Renal failure: hydration, avoid nephrotoxin (e.g. NSAID), dialysis prn
• Specific chemotherapy: only indicated in active MM
o Induction: triple therapy
- Proteasome inhibitor (e.g. bortezomib, carfilzomib) – S/E: peripheral neuropathy
- + Immunomodulatory agents (e.g. lenalidomide / thalidomide / pomalidomide)
- + Dexamethasone
o Determine transplant candidate: depend on patient’s risk (age < 60, co-morbidities)
- Eligible: 4 cycles of triple therapy —> high dose Melphalan + autologous HSCT
- Ineligible: 8-12 cycles of triple therapy
o Consolidation & maintenance therapy (lenalidomide monotherapy): ≥ 2 years
o Relapse / refractory: Anti-CD38 (daratumumab, isatuximab), SLAMF7 (elotuzumab)
o Immunotherapy against BCMA: Antibody-drug conjugate (ADC), Bi-specific T-cell engager (BiTE), CAR-T
Amyloidosis
Definition: fibrillar protein that is deposited in extracellular interstitial tissue, resulting in organ dysfunction by
pressure atrophy of adjacent cells (but not evoking inflammation)
Types
• Systemic:
o Primary AL amyloidosis: multiple myeloma
o Reactive AA amyloidosis: chronic inflammation (e.g. RA, AS, IBD)
o Dialysis-associated amyloidosis: long-term haemodialysis —> β2-microglobulin accumulation
o Senile systemic amyloidosis: transthyretin accumulation
o Hereditary amyloidosis
• Localised: Alzheimer’s disease [amyloid b], MTC [calcitonin]
Clinical features
• Kidney (MC): nephrotic syndrome
• CVS: restrictive cardiomyopathy
• Organomegaly: hepatomegaly, splenomegaly, macroglossia, pseudohypertrophy of muscles
Diagnosis: Congo red stain under polarised light – apple-green birefringence
Haematopoietic stem cell transplantation
Genetic basis of transplantation
• Major histocompatibility complex (MHC)/ human leukocyte antigen (HLA): important in HSCT as rejection occurs in both directions (host-versus-graft, graft-versus-host)
• Minor histocompatibility antigen (MiHA)
• ABO: less important in HSCT
Types
• Autologous: no risk of rejection or GVHD, but may contain contaminated stem cells
• Allogenic: potential graft-vs-tumour effect, but risk of rejection/ GVHD
Procedures
• Stem cell harvest: bone marrow (pelvis) or peripheral blood (G-CSF +/- chemotherapy to stimulate HSC growth)
• Conditioning regimens:
o Myeloablative (irreversibly destroy the haematopoietic function of BM)
o Non-myeloablative/ reduced intensity regimen (RIC): dose high enough to avoid graft rejection, and the remaining malignant cells eliminated by graft-vs-tumour effect
• Post-transplant recovery:
o Protective isolation, G-CSF, antibacterial/ antiviral/ antifungal prophylaxis, revaccination (infection)
o Immunosuppressant, e.g. steroid (rejection)
Complications
• Infection risk
o Early (< 100 days): neutropenia —> bacteria, Candida, Aspergillus, HSV reactivation
o Late (> 100 days): encapsulated bacterial infection, VZV
• Graft rejection
• Graft-versus-host disease (GVHD)
o Pathogenesis: T cell-mediated reaction against recipient tissues due to HLA mismatch or MiHA mismatch
(even HLA fully matched)
o Acute GVHD (< 100 days): skin (rash), GI (diarrhoea), liver (cholestatic hepatitis); Mx steroid
o Chronic GVHD (>100 days): sclerosis, multi-organ involvement ~ autoimmune diseases; Mx steroid (poor
response)
Blood product
Tests on donated blood: ABO, Rh, infections (HBsAg, anti-HCV, anti-HIV, anti-HLTV, syphilis, CMV, bacterial)
- Packed cells (250ml) / Whole blood (350ml / 450ml)
- Storage: 2-6°C
- Shelf life: PC: 42 days, WB: 35 days
- Dosage: 1 pc = 1g/dL, Give within 4h
- Indications:
No single Hb value - consider rate of
ongoing blood loss
• Hb < 7: transfusion usually
required
• Hb 7-10: consider if tolerate anaemia poorly, e.g. age > 65y, CV/respiratory disease
• Hb > 10: generally not required
- Emergency: O- (or O+)
- Packed cell preferred - Platelet concentrates (40-60ml)
- Storage: 20-24°C
- Shelf life: 5 days
- Dosage: 1 unit = 7- 10x109/L ,Standard dose: 4 units (adults)
- Indications:
Platelet < 10 in stable patients
Platelet < 20 in fever / sepsis
Platelet < 50 in invasive procedures (e.g.
laparotomy, LP, epidural, Bx)
Platelet < 100 in eye/ CNS operation
Extensive mucosal bleed or platelet
dysfunction (e.g. aspirin-induced):
immediate transfusion
- Emergency: Any - Fresh frozen plasma (FFP) (200-250mL)
- Storage: < -30°C (Thawed: 2-6°C)
- Shelf life: 1 year (Thawed: 24h)
- Dosage: 2-4 units, Give within 4h
- Indications:
Urgent reversal of anticoagulation
Clotting factor deficiency
Coagulopathy after massive transfusion
DIC with bleeding
- Emergency: AB - Cryoprecipitate* (10-40mL)
- Storage: < -25°C
- Shelf life: 1 year
- Dosage: 10 units/dose
- Indications:
Fibrinogen deficiency (< 100mg/dL) or
dysfunction
vWD (if DDAVP or factor concentrates is
inappropriate)
Thrombolytic overdose
Liver disease-induced coagulopathy
DIC
- Emergency: Any
*Prepared by thawing FFP and collecting the precipitate, which is then re-frozen
• Contain vWF, fibrinogen and fibronectin, factor VIII + XIII
• Small volume prevents volume overload
Interaction with IV fluids:
• Compatible: NS, plasmalyte, gelofusin
• NOT compatible: D5 (hypotonic —> hemolysis), lactated Ringer’s (calcium —> clotting)
Blood transfusion
Type & screen
• Type: ABO & Rh typing
• Screen: check patient serum against different RBC Ag by indirect Coomb’s test (5min)
• Crossmatch: if screen +ve; “trial transfusion” of patient’s serum with donor’s RBC (30-45 min)
• T&S only effective for 3 days
Management of adverse events (SAQ!)
• Stop transfusion & spigot off the unit
• Vitals & resuscitation
• Recheck identity: patient, blood unit and blood form
• Save blood bags and IV sets for investigations, but keep IV patent by normal saline
• Workup: CBC, clotting, RFT, haemolytic screen (LDH, haptoglobin, bilirubin, urine Hb), T&S, X-match, DAT
Major transfusion reaction
1. Acute haemolytic transfusion reaction (AHTR)
- Fever, abdominal pain, Shock, chills, SOB, Haemoglobinuria
- Blood culture: overlapping S/S with bacterial infection
- Supportive: NS infusion with target of urine output of 100ml/h
2. Septic reaction
- High fever (rise ≥1.5oC)
- Blood (from patient and blood unit) for Gram stain & C/ST
- Anti-pseudomonal antibiotics, e.g. Tazocin
• Pathogens: Pseudomonas fluorescens, Yersinia
3. Anaphylaxis
- Shock, bronchospasm, urticaria
- IM adrenaline, steroid, antihistamine
- Saline-washed RBC
4. Transfusion related Acute lung injury
(TRALI)
- SOB within 6h (donor anti-leucocyte
Ab vs recipient WCC)
- Ventilatory support
- Trial of diuretics (to differentiate from fluid overload)
5. Transfusion-associated Circulatory overload (TACO)
- SOB, APO
- Diuretics, Ventilatory support
• Delayed haemolytic transfusion reaction
o Pathology: destruction of transfused red cells by antibody not detectable during type & screen
- Note T&S is only valid for 3 days as new antibodies may form
o Clinical features: failed increase in Hb, jaundice, haemoglobinuria
o Management: supportive
Mid fever or rash only:
1. Febrile non-haemolytic transfusion reaction (FNHTR)
- Fever, chills, rigors Exclude AHTR & septic reaction
- Paracetamol, restart infusion at a slower rate
- Leucocyte-reduced blood products ± hydrocortisone prep
2. Mild allergic reaction (1-3%)
- Urticaria
- Exclude anaphylaxis
- Antihistamine ± steroid, restart infusion at a slower rate
- Saline-washed RBC if severe
Complications of long-term blood transfusion
• Iron overload: bronze pigmentation of skin, cardiomyopathy, cirrhosis, hypogonadism, DM
• Blood-borne infections: HBV, HCV, HIV, EBV, CMV
• Adverse events: allergic reactions, anaphylaxis
Complications of massive transfusion (>1 total blood volume in 24h)
• Electrolyte disturbances: hyperK (RBC lysis), hypoCa (EDTA takes up Ca in stored blood), acidosis
• Hypothermia
• Dilutional coagulopathy / thrombocytopenia
