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MBBS IV - Junior Clerkship WCS > JC48 (Medicine) - Hemolytic anaemia, Aplastic anaemia, Inherited anaemia > Flashcards

JC48 (Medicine) - Hemolytic anaemia, Aplastic anaemia, Inherited anaemia Flashcards

1
Q

Inherited causes of haemolytic anaemia

A

RBC Membrane defect:

  • Hereditary spherocytosis
  • Hereditary elliptocytosis

RBC enzyme deficiency

  • G6PD deficiency
  • Pyruvate kinase/ glycolytic enzyme deficiency
  • Pyrimidine 5’ nucleotidase deficiency

Haemoglobin defect

  • Thalassaemia
  • Abnormalities: e.g. Sickle cell disease
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2
Q

acquired causes of haemolytic anaemia

A

Immune

  1. Autoimmune - Warm or Cold
  2. Alloimmune: Transfusion reaction or Hemolytic disease of Newborn
  3. Drug induced hemolysis

Non-immune:

  • Mechanical: Prosthetic valves, microangiopathic (DIC, TTP)
  • Infection: bacteria (C. perfringens) and parasites (malaria)
  • Chemical: Wilson’s disease, Heat, venom, Oxidative drugs, chemicals >>> damage Hb, cell membrane

Acquired intrinsic red cell defect:
- Paroxysmal nocturnal hemoglobinuria

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3
Q

Paroxysmal nocturnal hemoglobinuria

Pathogenesis

A

PIGA gene mutation > deficiency of glycophosphatidylinositol > Deficiency of CD55, CD59 > RBC membrane defect > complement mediated lysis of RBC

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4
Q

Features of haemolytic anaemia on Lab tests: CBC, Serum, PBS

A

Evidence of RBC destruction:

  • High LDH
  • High unconjugated bilirubin
  • Low haptoglobin
  • High methaemalbumin

RBC changes:

  • Fragmentation (microangiopathic hemolysis)
  • Agglutination (cold agglutinin disease)
  • Spherocytes (hereditary or immune-mediated)
  • Positive DAT

Bone marrow compensation:

  • Reticulocytosis/ Polychromasia on PBS
  • Bone marrow erythroid hyperplasia
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5
Q

History taking for hemolytic anaemia

A
  1. Age, Sex, Ethnicity
  2. Infections (HIV, C. perfringens, Mycoplasma), Travel History (Malaria)
  3. Drug use (L-dopa, methyldopa, mefenamic acid, penicillin, quinidine)
  4. Haematological malignancies, autoimmune diseases
  5. Transfusion history
  6. Metabolic disease/ Wilson disease/ IEMs (enzyme defects)
  7. Surgical history: prosthetic valves/ filters
  8. Gallstone history (portal hypertension, hypersplenism)
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6
Q

General clinical features of hemolytic anaemia

A

Pallor

Jaundice (no obstructive jaundice signs as unconjugated bilirubin only)

Haemoglobinuria (intravascular hemolysis/ G6PD…etc)

Splenomegaly

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7
Q

Immune haemolytic anaemia

  • Cause
  • Categorize causative antibodies
  • Pathogenesis of drug-induced haemolysis
A

Autoimmune antibodies against self RBC

Autoimmune:

  • Warm IgG
  • Cold IgM

Alloimmune: previous sensitization to foreign antigen

  • Hemolytic disease of newborn: Rh- or ABO-incompatibility between mother/ child
  • Hemolytic transfusion reaction: ABO-incompatibility

Drug induced:

  • Alteration of RBC antigen causing AutoAb cross-reaction with normal antigens
  • Hapten reaction: associate RBC structures forming part of antigen
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8
Q

Compare underlying causes of Warm and Cold type autoimmune haemolytic anaemia

A

Warm antibodies (80%): binds best at 37oC, majority IgG, often against Rhesus antigens

  • Idiopathic (50%)
  • Preceding viral infection: usually in children
  • Autoimmune disease, eg. SLE, ALPS
  • Immunodeficiencies, eg. CVID
  • Lymphoproliferative disease, eg. CLL, NHL

Cold antibodies (20%): binds best at 4oC, usually IgM and binds complement

  • Idiopathic
  • Infections, esp M. pneumoniae, EBV
  • Lymphoid malignancies, eg. monoclonal gammopathies, NHL, CLL
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9
Q

Investigations for diagnosis of AIHA

A

CBC - Anaemia, usually normocytic
PBS - Reticulocytosis + spherocytosis
Serum - High unconjugated bilirubin, High LDH, Low hepatoglobin
Direct antiglobulin test/ Coombs’ test: positive

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10
Q

Compare direct and indirect antiglobulin tests (/)

A

Direct Coombs test: useful in detecting prior Ab binding to RBC using anti-IgG, anti-C3

  • Autoimmune hemolytic anaemia
  • Hemolytic disease of newborn
  • Transfusion reactions

Indirect Coombs test: useful in detecting autoreactive Ab in serum

  • Antibody screening in pre-transfusion tests
  • Screening for HDN during pregnancy
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11
Q

Clinical presentation of warm AIHA (/)

A

Typical S/S of extravascular haemolytic anaemia

Presents as part of:
- Evans syndrome: co-occurrence of ≥2 immune cytopaenias, most often AIHA + ITP
- Lymphoproliferative disease: most commonly in CLL, present with systemic symptoms (eg. LOW/LOA, fever, LN)

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12
Q

Clinical presentation of cold AIHA (/)

A

Asymptomatic when not exposed to cold

Cold-induced symptoms:
→ Acrocyanosis
→ Livedo reticularis
→ Raynaud phenomenon
→ Cutaneous ulcer/necrosis
→ Pain/discomfort on swallowing cold food/liquids

Haemolytic anaemia: generally extravascular
→ Variable severity from compensated haemolysis to severe haemolytic anaemia requiring transfusion
→ Precipitant: cold ambient temperature, febrile illness

High risk of VTE

Lymphoid malignancy S/S

Mycobacterium pneumoniae infection/ Infectious Mononucleosis S/S

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13
Q

Management of warm AIHA

A
  1. Folate supplement
  2. Decrease further hemolysis/ immunosuppress:
    - Oral prednisolone
    - Rituximab
    - Splenectomy
    - Alternative immunosuppressants: azathioprine, cyclophosphamide
  3. Transfusion: test for allo-Ab (T/S)
  4. Treat underlying causes (e.g. lymphoproliferative diseases)
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14
Q

Management of Cold AIHA

A
  1. Folate supplement
  2. Avoid cold temperature: eg. avoid cold liquid, warm clothing, pre-warmed IV fluid
  3. Therapy for anaemia:
    - Transfusion with prior T/S
  4. Decrease antibody production
  • Rituximab/bortezomib-based chemotherapy for idiopathic cases
  • Plasmapheresis, IVIg
  • Treat underlying lymphoid malignancy
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15
Q

Aplastic anaemia

  • Definition
  • Causes
A

Bone marrow hypoplasia/ aplasia causing pancytopenia

  • *Primary aplastic anaemia:**
  • Primary idiopathic (80%)
  • Inherited bone marrow failure syndromes: Fanconi anaemia, Shwachman-Diamond syndrome, Dyskeratosis congenita
  • *Secondary aplastic anaemia:**
  • Drugs: alcohol, NSAIDs
  • Toxins: benzenes, pesticides
  • Ionizing radiation
  • Infection: sero-negative hepatitis, HIV, EBV
  • Acquired clonal abnormalities (PNG, MDS)
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16
Q

List drugs that cause secondary aplastic anaemia (/)

A

Cytotoxic drugs: anticipated effect with nadir d7-10
Antibiotics, eg. chloramphenicol, sulphonamide
DMARDs, eg. penicillamine, gold
NSAIDs, eg. phenylbutazone, indomethacin, diclofenac
Thionamides, eg. carbimazole, propylthiouracil
Anticonvulsants, eg. carbamazepine, phenytoin

Alcohol

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17
Q

Idiopathic aplastic anaemia

  • Pathogenesis
A

Immune-mediated, T-cell suppression of marrow stem cells

Autoimmunity due to over-expression of HLA-DR2, polymorphisms in perforin gene or TNF-α

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18
Q

Clinical features of Aplastic anaemia

A

Pancytopenia: recurrent infections, mucocutaneous bleeding, anaemic symptoms
→ Infections: typically bacterial (sepsis, pneumonia, UTI) but invasive fungal infection is deadly

NO lymphadenopathy, NO hepatosplenomegaly → suggestive of haematological malignancies

± Dysmorphic features in the young, eg. thumb abnormality in Fanconi syndrome

± Haemolytic anaemia, thrombosis → suggestive of associated PNH

19
Q

Aplastic anaemia

First-line investigations and expected results

A

□ CBC: pancytopenia with normocytic/macrocytic anaemia, reticulocytopenia

□ PBS: NO abnormal cells

□ R/LFT, haemolysis markers, serum B12, RBC folate to r/o alternative causes

□ BM examination: required for diagnosis
→ Profoundly hypocellular marrow with decrease in all elements and replacement by fat/stromal cells
→ Morphologically normal residual haematopoietic cells without megaloblastic haematopoiesis
→ NO BM infiltration by fibrosis/malignancy

□ Other Ix:
→ Autoimmune markers
→ Flow cytometry (↓CD55/59) for PNH
→ Chromosome breakage with diepoxybutane for Fanconi anaemia esp for children

20
Q

Severity grading for aplastic anaemia
Purpose of grading?

A

Non-severe:
BM cellularity < 25% + peripheral pancytopenia not as severe as ‘severe grade’

Severe:
BM cellularity <25% + 2 out of 3 of following:
1. Neutrophil < 0.5
2. Platelet < 20
3. Reticulocytes < 20

Very severe:
BM cellularity <25% + 2 out of 3 of following:
1. Neutrophil < 0.2*******
2. Platelet < 20
3. Reticulocytes < 20

Purpose: Severe and very severe need cytotoxic drug treatment

21
Q

Treatment of aplastic anaemia **

A

Allogeneic HSCT: 1st line for young adult + matched donor or refractory disease

Immunosuppressive therapy: Tx for >50y or ineligible for HSCT:
- eltrombopag (TPO-agonist) + antithymocyte globulin (ATG) + Cyclosporine A + steroids

Manage cytopaenia:
- Transfusion for packed cells, platelet concentrate +/- iron chelation/phlebotomy

Infection prophylaxis: antifungals, antibiotics

22
Q

List inherited marrow failure syndromes causing anaemia and pancytopenia

A

Anaemia only

  • Diamond-Blackfan anaemia
  • Congenital dyserythropoietic anaemia

Pancytopenia:

  • Fanconi anaemia
  • Dyskeratosis congenita
  • Schwachman-Diamond syndrome
23
Q

Compare the inheritance patterns between 5 inherited marrow failure syndromes (/)

A
24
Q

Compare between pancytopenia vs anaemia only inherited marrow failure syndromes:

  • Consequence of BM failure
  • Presence of malignancies
  • Presence of short telomeres and chromosomal instability
  • Number of genes involved
A
25
Q

Fanconi anaemia (FA) (/)

  • Genetic cause
  • Clinical features
  • Diagnosis
  • Treatment
A

Cause: mutation in ≥17 FA genes (FANCA-Q, majority AR but FNACB/R XLR)
→ ↓repair of DNA crosslinks
→ ↑genomic instability
→ premature loss of HSCT
→ High risk of CA - MDS (6000×), AML (700×), SCCs

Clinical features: Congenital malformations

  • Skin: hyper-/hypopigmentation, café-au-lait spots
  • Thumb/radial abnormality: absent/hypoplastic/bifid thumb, absent/hypoplastic radii
  • Axial skeleton: microcephaly, triangular facies, short stature
  • VACTERL association: vertebral anomalies, anal, congenital heart (usu VSD), trachea-esophageal, renal, limb defects
  • BM failure with pancytopenia

Diagnosis: peripheral blood T cells for chromosomal breakage following exposure to diepoxybutane (DEB)

Tx: allogeneic HSCT with androgen Tx

26
Q

Dyskeratosis Congenita (short telomere syndrome) (/)

  • Genetic cause
  • Clinical features
  • Diagnosis
  • Treatment
A

Cause: mutation in telomere-related genes → premature cell death or genomic instability

Clinical features:
→ Mucocutaneous findings: classical triad of nail dystrophy, lacy reticular hyperpigmentation of upper chest and neck, oral leukoplakia
→ BM failure
→ Lung fibrosis
→ Cancer predisposition: H&N SCC, gastro/oesophageal, anorectal, skin…etc

Dx: clinical + telomeric length analysis + BM hypocellularity

Mx: supportive + allogeneic HSCT if available

27
Q

Diamond-Blackfan anaemia (/)

  • Genetic cause
  • Clinical features
  • Diagnosis
  • Treatment
A

Cause: genetic mutation affects ribosome synthesis → ↓activation of TP53 tumour suppressor pathway

Clinical features:
Congenital anomalies: mainly in H&N + UL areas
- Craniofacial: hypertelorism, microcephaly, congenital cataract/glaucoma, micro-ophthalmos, blue sclera, high-arched palate, ear malformation
- Thumb: bifid, duplication, hypoplasia, absence, flat hypoplastic thenar eminence
- Urogenital: dysplastic/horseshoe kidney, duplex ureter, RTA
- Others: A/VSD, hypogonadism, mental retardation

Pure red cell aplasia (PRCA) - isolated anaemia

Diagnosis:
isolated macrocytic anemia with onset <1y, no other cytopenias, reticulocytopenia, normal BM cellularity

Tx: transfusion + oral steroid from 6-12mo

28
Q

History taking for inherited anaemia *

A

Family history - Pattern of inheritance

Age of onset

Drug Hx

Symptoms of haemolysis

Transfusion requirement

Complications

29
Q

List 5 inherited RBC membrane defects

A

Hereditary spherocytosis

Hereditary elliptocytosis and hereditary pyropoikilocytosis

Southeast Asian ovalocytosis

Hereditary acanthocytosis

Hereditary Stomatocytosis

30
Q

Outline the underlying membrane proteins associated with inherited RBC defects (/)

A
31
Q

Hereditary spherocytosis

Definition
Inheritance, genetic defects, pathogenesis

A

Definition:
hereditary RBC membrane defect characterized by spherocytes on RBCs

AD inheritance

Ankyrin- spectrin complex defect >> abnormal vertical cytoskeleton-membrane interaction >> primary loss of membrane (due to microvesiculation) → progressive spherocytosis

Poor deformability → inability to pass through splenic microcirculation → confers liability to haemolysis

32
Q

Hereditary spherocytosis

Clinical presentation

A

Chronic haemolytic anaemia: moderate, with jaundice

Crises of anaemia exacerbation/ Aplastic crisis:
→ Haemolytic crisis due to ↑severity of haemolysis ma/w infections
→ Megaloblastic crisis due to folate deficiency, a/w during pregnancy
→ Aplastic crisis** due to parvovirus B19 infection → severe anaemia with low reticulocyte count

Complications of haemolysis:

  • Neonatal jaundice
  • splenomegaly
  • pigmented gallstones **
33
Q

Investigations and typical findings of Hereditary Spherocytosis

A

CBC: anaemia, MCV variable, MCHC ≥36g/dL

Blood film: spherocytes, polychromasia

Bone marrow: erythroid hyperplasia

Markers of extravascular haemolysis:
- ↑LDH, ↑unconj bilirubin

Flow cytometric analysis
- ↓ eosin 5’ melamide (EMA) binding** on red cell skeletal proteins

  • *Osmotic fragility test**** (± pre-incubation) when EMA binding N/A:
  • ↑fragility compared to normal RBCs when exposed to hypotonic solutions
34
Q

Treatment of Hereditary spherocytosis

A

**no specific treatment**

  • *Folic acid** supplementation
  • *Transfusion** if severe anaemia
  • *Splenectomy** for severe haemolysis
  • *EPO** for infants
  • *Cholecystectomy** if symptomatic gall-stones

(Allogeneic HSCT: NOT used due to unfavourable risk-benefit ratio)

35
Q

Categorize haemoglobin disorders with examples

A
36
Q

List Red Cell Enzymopathies

A

G6PD deficiency

Pyruvate kinase (PK) deficiency

Deficiencies of other glycolytic pathways

>>> Congenital non-spherocytic haemolytic anaemia

37
Q

PK deficiency enzymopathy (/)

  • Inheritance
  • Pathogenesis
  • Clinical features
  • Dx
  • Tx
A

AR inheritance

Pathogenesis: haemolysis due to PK def, tolerated due to ↑O2 delivery from ↑2,3-BPG

Clinical features: lifelong condition but age of presentation varies
→ Chronic, Coombs’-negative haemolytic anaemia: usually from birth
→ Haemolysis Cx: NNJ, gallstones, jaundice, variable splenomegaly, folate deficiency
→ Iron overload due to ineffective erythropoiesis or transfusional iron overload

Dx: by testing PK activity in RBC haemolysate or genetic testing

Mx: transfusion ± chelation, folate supplementation, splenectomy

38
Q

G6PD deficiency

  • Epidemiology
  • Inheritance
  • Pathogenesis
A
  • most common RBC enzymopathy, affects 400M worldwide
  • Inheritance: X-linked recessive
  • Mutation: most commonly G6PD-Canton in China

Haemolysis: occurs during exposure to oxidative stress
→ insufficient regeneration of glutathione due to deficient G6PD activity
→ oxidant accumulation within RBC → oxidization of Hb and other proteins
→ formation of Heinz bodies (clumps of denatured Hb) and bite cells as Heinz bodies are removed by macrophages in RES
→ rigid non-deformable RBC destroyed in RES (extravascular)

39
Q

5 classes of G6PD (/)

A
  • Class I: G6PD activity <10%, a/w chronic haemolytic anaemia
  • Class II: G6PD activity <10%, a/w intermittent haemolysis only with NNJ, Favism, drug-induced intravascular haemolysis
  • ****** most common in Chinese with Canton variant ********
  • Class III: G6PD activity 10-60%, a/w intermittent haemolysis only
  • Class IV (normal): G6PD activity >60%, a/w no clinical significance
  • Class V: G6PD activity >100%, a/w no clinical significance
40
Q

Clinical presentation of G6PD deficiency

A

Asymptomatic between episodes of haemolysis

  • *Acute haemolytic anaemia trigger by infection, critical illness, drugs >> Intravascular hemolysis**
  • classically sudden onset of jaundice, pallor, dark urine
  • abrupt ↓Hb by 3-4g/dL ± abdominal, back pain (due to haemoglobinuria)

Neonatal jaundice

41
Q

Triggers of acute hemolysis episodes of G6PD deficiency (/)

A
42
Q

Investigations for G6PD deficiency
- Acute hemolytic attacks

  • Screening tests in newborn
  • Confirmatory tests
A

Non-spherocytic intravascular haemolysis during attack
→ CBC/PBS: polychromasia with bite cells, hemighosts, ghost cells, Heinz bodies

→ Intravascular haemolysis: ↑LDH, ↑unconj bilirubin, ↓haptoglobin, ↑methaemalbumin, haemoglobinuria/haemosiderinuria ± AKI

Screening test: absence of fluorescence in UV light or failure to reduce methaemoglobin → indicate failure to generate NADPH (semiquantitative)

Confirmatory test: by G6PD assay - test activity directly

43
Q

Management of G6PD deficiency

A

□ Avoid haemolysis triggers

□ Transfusion ± aggressive hydration for acute intravascular haemolysis

(Folate supplementation: NOT necessary unless in class I variant a/w chronic haemolysis)

MBBS IV - Junior Clerkship WCS (131 decks)

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