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HIS > HIS32 Practical Approach To The Investigation Of Haematological Disorders > Flashcards

HIS32 Practical Approach To The Investigation Of Haematological Disorders Flashcards

1
Q

Approach to anaemia

A

Traditional approach (only reliable for a few causes, lacks mechanistic insight)

  1. Microcytic (MCV <80)
    - Fe deficiency, Thalassaemia, Inherited sideroblastic anaemia
  2. Macrocytic (MCV >120)
    - Pernicious anaemia (Megaloblastic anaemia), MDS
  3. Normocytic (MCV 85-95) / Mildly macrocytic anaemia (MCV 95-110)
    - a lot of causes

Modern approach:

***Hyperproliferative (↑ Reticulocytes / Polychromasia)
- BM react normally ↑ to compensate anaemia
—> no abnormal marrow infiltration / nothing suppressing BM erythropoiesis

  1. Thalassaemia / Haemoglobinopathy (↑ Reticulocytes + RBC count)
  2. Haemolytic anaemia (haemolysis outside BM —> ↓ RBC, but ↑ Reticulocyte)

***Hypoproliferative (↓ / inappropriately normal Reticulocytes)
- something suppressing erythropoiesis
—> e.g. abnormal BM infiltration / lack key factors for erythropoiesis (e.g. Fe, vit B12)

  1. Haematinic deficiencies
    —> Fe deficiency
    —> B12, folate deficiency
    —> other nutrient deficiency (e.g. Cu)
  2. Primary marrow failure syndromes (HSC defect —> Pancytopenia)
    —> Aplastic anaemia
    —> Inherited BM failure syndromes
3. Primary BM pathology
—> MDS
—> Leukaemia
—> Lymphoma
—> Myeloma
—> Fibrotic phase of PMF (MPN)
—> CML (MPN)
  1. Drugs / toxins
  2. Infections (e.g. Parvovirus)
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2
Q

Investigations for anaemia

A
  1. History + Physical examination
    - previous blood counts
    - family history
    - detailed drug, past medical history
  2. CBC + D/C + PB film + ***Reticulocyte count

Aim of investigations:
- Mechanism of anaemia + underlying cause

Hypoproliferative anaemia:

  1. B12/folate
  2. Fe status (microcytic, isolated anaemia)
  3. BM exam + Cytogenetics

Hyperproliferative anaemia:

  1. Hb pattern
    - if RBC count raised with low MCV —> Thalassaemia
    - RBC raise with normal MCV —> Haemolysis

Haemolysis:

  1. Direct/indirect bilirubin
  2. LDH
  3. Haptoglobin
  4. Methaemalbumin

Cause of haemolysis:

  1. PB film
    - RBC morphology
    - spherocytosis (immune cause)
    - fragmentation (MAHA)
    - signs of oxidative haemolysis (Heinz body)
  2. Direct, Indirect antiglobulin tests (DAT, IAT) —> immune cause
  3. G6PD assay (need to repeat 6-8 weeks later)

Immune haemolysis:

  • Cold vs Warm
  • Underlying cause (autoimmune / alloimmune, LPD, infections, drugs)
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3
Q

Case 1:

  • 76 yo man
  • old TB
  • CA pyriform fossa with OT done (Total laryngectomy, pharyngectomy with free jejunal flap) done in 7/2009
  • adjuvant chemotherapy + RT
  • post-RT hypothyroidism on replacement
  • admitted with anaemic symptoms
  • Hb 6.7
  • MCV 111.6
  • Platelet 196
  • WBC 2.72
A

Differential diagnosis:

  • MDS (possible post-chemotherapy)
  • B12, folate deficiency
  • Acute leukaemia (unlikely as leukopenia, platelet normal)

Further investigation:

  • Gradual worsening of anaemia over 6 months (baseline Hb 11)
  • pale, malnourished, no palpable LN / organomegaly, other systems unremarkable

PB film:

  • Macrocytosis
  • Absent Polychromasia —> Reticulocytopenia —> suggest BM problem (i.e. Hypoproliferative anaemia)
  • No hypersegmented neutrophil —> No B12 folate deficiency
  • No dysplastic neutrophils —> CANNOT exclude MDS (dysplastic neutrophil can be present in BM only)
  • Reticulocyte 0.5% —> Low, normal >=2%
  • LRFT —> normal
  • LDH 280 —> normal
  • B12/folate —> normal —> No B12 folate deficiency
  • Fe status —> Fe normal, Transferrin saturation ↑ (i.e. Fe accumulating), TIBC 53

BM:

  • Dyserythropoiesis
  • 50% ring-sideroblasts —> Dysplastic
  • Cytoplasmic vacuoles in erythroid / myeloid precursors —> Dysplastic
  • Megakaryocytes —> Unremarkable

Cytogenetics:

  • Karyotype —> normal (>80% MDS have abnormalities)
  • molecular studies —> no somatic mutation (>95% MDS have somatic mutations)

Other biochemistry:

  • Cu —> Low
  • Zinc —> normal (Zinc overload cause Cu deficiency)
  • Ceruloplasmin —> Low

Diagnosis:
- Cu-deficiency anaemia

Treatment:
- Oral Cu replacement —> recover

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4
Q

Causes of sideroblastic anaemia

A
  1. ***Acquired MDS (most common)
  2. Hereditary (rare)
  3. Reversible causes (require careful history-taking)
    - Alcoholism
    - Drugs (e.g. Isoniazid —> pyridoxine deficiency)
    - Cu deficiency (nutritional, chelation, zinc overload)
    - Pyridoxine deficiency (due to malnutrition / dialysis)
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5
Q

Deficiency in Pyridoxine and Heme synthesis (x exam)

A

Deficiency in Pyridoxine (B6)
—> Deficiency in Pyridoxal 5-phosphate (Cofactor for ALA synthase, important for Heme synthesis)
—> Inhibition of Fe incorporation into Porphyrin
—> Fe accumulate in Mitochondria
—> Fe complex formation
—> Ring Sideroblast

Isoniazid binds to Pyridoxal 5-phosphate
—> excreted in urine

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6
Q

Copper and anaemia

A

Copper store: 110mg total in body
Dietary copper: require 0.6-1.6mg / day

Absorption:
Small intestine
—> Blood
—> Cu bind to Albumin, Transcuprein
—> Liver
—> Cu released and binds to Ceruloplasmin
—> Cu-Ceruloplasmin can be delivered to tissues and enzymes
—> Cofactor for heme synthesis, erythropoiesis, haematopoiesis

Cu excretion: Biliary excretion

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7
Q

Haemolytic anaemia

A

Hyperproliferative anaemia

Immune causes (immune mediated RBC destruction):

  1. Autoimmune
    - Warm (primary vs secondary) - IgG mediated
    - Cold (primary vs secondary) - IgM mediated
    - Drug-induced (Methyldopa)

(secondary causes: SLE, RA —> warm / cold autoimmune haemolytic anaemia
CLL —> warm autoimmune haemolytic anaemia
Mycoplasma pneumoniae —> cold autoimmune haemolytic anaemia)

  1. Alloimmune
    - Acute haemolytic transfusion reaction (ABO incompatibility)
    - Delayed haemolytic transfusion reaction (other blood groups e.g. Anti-Jka/Jkb (Kidd system))

Non-immune causes:

  1. Membranopathy (damaged RBC membrane)
    - acquired (e.g. severe liver disease, TTP, acanthocytosis, Microangiopathic haemolytic anaemia)
    - inherited (e.g. hereditary spherocytosis, hereditary elliptocytosis)
  2. Enzymopathy
    - oxidative haemolysis (G6PD deficiency)
  3. Thalassaemia / Haemoglobinopathy
    - reduced RBC survival
    —> destroyed prematurely in spleen
    —> ***extravascular haemolysis
  4. Drugs
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8
Q

Case 2:

  • 60 yo female
  • good past health
  • family history: 2 younger sisters, 1 cousin with breast cancer diagnosed in late 30s
  • chief complain: syncope
  • 1st episode syncope: 1 min
  • tonic-clonic movement of upper/lower limbs (i.e. seizure)
  • urinary incontinence
  • post-ictal drowsiness, no focal weakness
  • no aura, palpitations, chest pain prior to event (rule out cardiac cause)
  • progressive SOB for 1 month prior to admission

P/E:

  • jaundice, multiple bruises
  • no palpable LN
  • raised JVP with giant v wave, loud pulmonary 2nd heart sound, grade 3/6 PSM over LLSB (tricuspid regurgitation murmur as a result of pulmonary hypertension)
  • chest clear
  • 2cm hard mass with surrounding induration over peri-areolar area of right breast —> breast cancer
A 
CBC:
Hb: 8.4 —> low
WBC: 8.64 —> normal
Platelet: 9 —> low
Serum creatinine: 94 (mildly impaired renal function)
LDH: high
Bilirubin: high (mainly indirect / unconjugated)
Normal clotting profile —> no DIC

PB film:

  • Reticulocytosis —> Hyperproliferative anaemia
  • Schistocytes —> RBC fragmentation
  • Thrombocytopenia

Suggestion: RBC fragmentation —> Microangiopathic haemolytic anaemia
(Life-threatening causes: TTP)

Plasma exchange, high dose corticosteroid for Thrombotic Microangiopathy (TTP)
—> no response (platelet count, LDH)

BM exam:
- Marrow infiltration by non-haemic cells
—> breast cancer with marrow infiltration

Diagnosis: Metastatic cancer complicated by Thrombotic Microangiopathy

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9
Q

Microangiopathic haemolytic anaemia (MAHA)

A
  • Abnormal microcirculation
  • RBC fragmentation
  • Haemolysis

Causes:
1. DIC (microthrombi formation in microcirculation —> shear stress to RBC)

  1. TTP/TMA (~ DIC with normal clotting profile ∵ only use up platelets, vWF)
    - Immune (Ab against ADAMTS13)
    —> Idiopathic
    —> Secondary to AI disease
    - Secondary (endothelial damage)
    —> Disseminated malignancies
    —> Drugs, HSCT
  2. Haemolytic uraemic syndrome (HUS)
    - children after diarrhoea
  3. Malignant hypertension
  4. Systemic vasculitis
  5. Pregnancy-related complications, large hemangiomas
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10
Q

Drug-induced TTP

A
  1. Ticlopidine (antiplatelet)
  2. Clopidogrel
  3. Cyclosporin A
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11
Q

Approach to Bleeding tendency

A
  1. Acute vs Chronic (recurrent episodes)
    - onset
    - duration
    - progression
  2. Spontaneous vs Only on haemostatic stress (e.g. Trauma)
  3. Platelet type (more mucocutaneous) vs Coagulation type (more deep bleeding)
    - Clotting factor deficiency —> Coagulopathy (e.g. due to drugs, severe liver disease)
    - Platelet —> Quantitative / Qualitative (platelet function disorders due to Aspirin)
  4. Generalised (more platelet/coagulation systemic problem) vs Localised (local pathologies)
  5. Presence of acquired causes (antiplatelets, anticoagulants)
  6. Connective tissue / Collagen vascular disease

—> ALL need to distinguish between Acquired vs Inherited
—> do NOT forget drugs

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12
Q

Practical approach to Thrombocytopenia

A

Make sure Thrombocytopenia is genuine (exclude platelet clumping by PB film)

Investigation:

  1. PB film
  2. Clotting profile

Causes:

  1. Reduced production (BM causes —> >=1 lineage involved)
  2. Increased consumption (DIC, TTP/HUS)
  3. Increased sequestration / destruction (Hypersplenism/ Immune-mediated)
———> Isolated thrombocytopenia:
1. Peripheral causes (more common)
- Immune
—> primary vs secondary: autoimmune,LPD, infections, drugs
- Non-immune
—> Consumptive: DIC, TMA
—> Sequestration: hypersplenism (portal hypertension)
—> Drugs
  1. BM cause (BM pathology / failure)

———> Associated with other cytopenia:

  1. Peripheral
    - Hypersplenism
    - Active systemic autoimmune disease
    - Associated with MAHA - TMA, DIC
  2. BM cause (more common)
    - APL
  3. Hemantic (folate deficiency)
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13
Q

Case 3:

  • 38 yo woman
  • good past health
  • 1 week history of progressive SOB, on exertion
  • febrile, pale
  • easy bruising
  • spontaneous bruises on limbs, trunks
  • no limb/joint swelling
  • gum bleeding, heavy menses week before admission
  • mild mucositis
  • no gum swelling
  • no bleeding from other sites
  • no visual blurring / headache / neurological symptoms
  • sore throat —> may be leukopenia
  • no fever, bone pain, recent weight loss
  • no use of drugs, herbs
  • unremarkable family history
  • no palpable LN, hepatosplenomegaly
  • no focal neurological signs
  • no fundi haemorrhage
  • CVS / Resp normal
A

Acute spontaneous widespread bleeding tendency —> could be serious
Mucocutenous type —> Platelet problem

CBC:
Hb 6.3 —> low
MCV: 88.8
WBC: 3.72 —> low
Platelet: 5 —> low
Clotting profile:
PT: 15.5 —> prolonged
aPTT: 39 —> prolonged
Fibrinogen —> low
D-dimer —> high

Biochemistry:

  • LRFT normal
  • LDH high
  • urate high

PB film:
- medium size abnormal leukaemic cells
- bilobed nuclei + abundant azurophilic granules
—> Acute Promyelocytic leukaemia

Treatment:
All trans retinoic acid + Arsenic trioxide as frontline therapy

Diagnostic test:
BM exam: consistent with APL
Cytogenetic: t(15;17)(q24;q21)
RT-PCR positive for PML-RARA fusion transcript
PML: chromosome 15
RARA: chromosome 17

PML-RARA: causes differentiation block —> abnormal promyelocytes proliferation

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14
Q

Mechanisms of bleeding in APL

A
  1. Reduced platelet production
    - result of BM infiltration by abnormal promyelocytes
  2. Increased consumption due to DIC
    - APL cells express Tissue factor
    —> activate coagulation
    —> intense widespread DIC
    —> consume most clotting factors
  3. Hyper-fibrinolysis
    - APL cells express Annexin II
    —> activate plasminogen
    —> fibrinolysis
    —> hypofibrinogenaemia
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15
Q

Approach to suspected leukaemia

A
  1. Is this an acute leukaemia?
    —> can present with both high and low WBC
    —> APL: 90% low WBC (leukopenia)
  2. Is this acute promyelocytic leukaemia?
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16
Q

Approach to newly-diagnosed acute leukaemia

A

Initial approach to newly-diagnosed acute leukaemia:

  1. CBC
  2. ***Clotting profile
  3. Biochemistry

APL:

  • Start ATRA (all-trans retinoic acid) at first suspicion
  • Correct coagulopathy and thrombocytopenia (blood transfusion)
  • Treat any infection
  • Treatment and prevention of tumour lysis syndrome

Non-APL (ALL, AML):

  • Blood product support as indicated
  • Treat any infection
  • Treatment and prevention of TLS
  • Urgent chemotherapy only in symptomatic hyperleukostasis

Subsequent approach:

  1. Diagnostic
    - BM exam + Cytogenetics + Molecular genetics
  2. Pre-treatment assessment
    - HBsAg/Ab, Anti-HCV, HIV 1/2 Ab, G6PD assay, CXR, ECG, Echocardiogram
  3. HLA typing of patient and siblings
    - AML, ALL only (for HSCT potential)
    - NOT for APL (HSCT is obsolete)
17
Q

Monitoring and supportive care during treatment of APL

A
  1. CBC, LRFT, LDH, urate, electrolytes, clotting profile (daily)
  2. Keep platelet count >50, fibrinogen >1.5 (Ensure no spontaneous bleeding)
  3. ECG monitoring, QTc determination (Arsenic trioxide prolong QT interval)
  4. Avoid QTc prolonging agents if possible (quinolones, azoles)
  5. Correct electrolytes (K, Mg, Ca) (arrhythmia)
  6. Body weight, CXR monitoring
  7. Monitor for thromboses (esp. Central Venous Catheter-associated)
  8. Anti-fungal prophylaxis during neutropenic phase
18
Q

Things not to do in APL

A
  • No invasive / unnecessary procedures (except BM exam)
  • No CVC unless absolute necessary
  • Do not give G-CSF (induce uncontrolled myeloid proliferation, promote differentiation syndrome)
  • Do not stop ATRA/ATO as a measure for “treating ATRA-syndrome” (control WBC and give steroids instead)
19
Q

Side effects of ATRA, arsenic trioxide

A 
1. ***Differentiation syndrome (reversal of differentiation block)
—> capillary leak
—> pulmonary oedema, peripheral oedema
2. Headache
3. N+V
4. Skin rash
5. ***Hepatitis (ATO > ATRA)
6. ***Prolonged QTc (ATO)
7. Risk of ***Herpes zoster (ATO —> T cell dysregulation)
20
Q

Prevention and treatment of APL differentiation syndrome

A
  1. Early ***chemotherapy at presentation (esp. in patients with WBC >10 at presentation)
  2. Start ***dexamethasone early if signs and symptoms compatible
    —> Monitor for signs and symptoms

Rmb: Stopping ATRA / Arsenic trioxide is NOT treatment of differentiation syndrome

HIS (30 decks)

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