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FRACP Written Exam 2023 > Haematology > Flashcards

Haematology Flashcards

1
Q

Hereditary haemachromatosis - mode of inheritance?

A

Autosomal recessive

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2
Q

Causes of microcytic anaemia

A

Iron deficiency
Thalassaemia
Anaemia of inflammation (aka anaemia of chronic disease) - not anaemia of CKD

Hyperthyroidism (rare)
Lead poisoning (rare)
Congenital sideroblastic anaemia (rare)

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3
Q

Actions of hepcidin

A

Blocks ferroportin gate in:
- Gut (decreased iron absorption)
- Macrophages (sequestration of iron)

Iron then unavailable for Hb synthesis > microcytic anaemia

This is what occurs in anaemia of chronic disease in setting of infection/inflammation > leading to IL-6

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4
Q

What does basophilic stippling suggest on a blood film?

A

Lead toxicity, especially if also microcytic anaemia

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5
Q

What is alpha thalassaemia?

A

Impaired production of alpha chains leading to excess beta chains > haemolysis

HbH disease > 3 gene deletion
Barts hydrops fetails > 4 gene deletion

Excess beta chains form beta tetramers > HbH bodies (“golf balls”)

Excess gamma chains form gamma tetramers - can be detected immunochromatographic strips

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6
Q

Typical presentation of alpha thalassaemia silent carrier?

A

Heterozygous for one gene deletion
Common in Maori, SE Asia, Africa
Hb normal/slightly reduced
MCV borderline, 75-85
HbH bodies rare
Gamma tetramers detected in 70%
No reproductive issues

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7
Q

Typical presentation of alpha thalassaemia 2 gene deletion (alpha trait)?

A

Either a-/a- or –/aa
Hb - slightly reduced, mild anaemia
MCV 65-75
HbH bodies usually detected in –/aa
Gamma tetramers detected in 80% of trans, 100% of cis
Use DNA testing
Reproductive implications
In cis - more common in SE Asia, worse

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8
Q

Typical presentation of alpha thalassaemia 3 gene deletion (HbH disease)?

A

Excess beta chains = beta tetramers = Hbh precipitates
Membrane damage and chronic haemolysis
Moderate anaemia (Hb 70-100)
MCV 50-65
Require transfusions and/oor gets iron overload

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9
Q

Typical presentation of alpha thalassaemia 4 gene deletion (Hb Barts)?

A

Hb Barts = gamma tetramers
Fetal or early post natal deatchh
Complications to mother as well - large placenta

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10
Q

What is beta thalassaemia?

A

Reduced synthesis of beta globin chains leading to excess alpha chains

Usually caused by mutations that cause: reduced expression or absent expression
Large deletions uncommon

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11
Q

Key diagnostic testing in beta thalassaemia?

A

HbA2 (>3.5% in beta thalassaemia)

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12
Q

Typical presentation of beta thalassaemia trait (beta thalassaemia minor)?

A

Asymptomatic - mild anaemia
MCV <72
Blood film: normal-mild microcytosis with anisocytosis, hypochromia, poikilocytosis
HbA2 3.6-5% (normal <3.5%)
HbF often elevated but variable

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13
Q

Typical presentation of beta thalassaemia major?

A

Hb 30-70
MCV 50-70
HbF ~90%
Expanded bone marrow, bony deformities
Hypersplenism
Hypercoaguable
Dependent on blood transfusions
Complications of iron overload subsequently
- Cardiac failure, delayed growth

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14
Q

Main difference between beta thalassaemia intermedia vs. major?

A

Major is transfusion dependent
Intermedia - Hb 70-100

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15
Q

Combination of alpha & beta thalassaemia?

A

Ok outcome - improves condition as it corrects globin chain imbalance - fewer precipitates of excess chains

Worse outcomes with things that affect both beta chains
- HbE + beta thal - variable but severe since few/normal beta chains
- HbS + beta thal - worsens sickle trait, closer to sickle disease

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16
Q

What does hypersegmented neutrophils suggest?

A

B12/folate deficiency

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17
Q

Causes of macrocytosis?

A

EtOH
Liver disease (esp. cholestatic)
Myelodysplastic syndrome
B12/folate deficiency
Drugs (phenytoin, cytotoxics, antivirals, MTX)
Reticulocytosis (haemolytic anaemia, bleeding)
- Reticulocytes are ~20% bigger!
Myeloma (25% of cases)
Haemochromatosis (causes macrocytosis, but not anaemic)

Aplastic anaemia (causes cytopenia with macrocytosis)
Hypothyroidism

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18
Q

Causes of normocytic anaemia?

A

Decreased production/reticulocytes:
- Inflammatory process (tends towards microcytic)
- Lack of nutrients (micro/macro)
- Lack of EPO (CKD)
- Infiltration of bone. marrow
- Marrow disease such as MDS (often macro)
- Chemotherapy

Increased loss/destruction:
- Acute bleeding
- Haemolysis (sometimes macrocytic)

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19
Q

Causes of extravascular and intravascular haemolysis?

A

Extravascular - usually means splenic haemolysis
(MOST)

Intravascular - complement mediated in PNH, microangiopathic, heart valves (mechanical)

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20
Q

What does spherocytosis suggest?

A

Hereditary spherocytosis or autoimmune haemolytic anaemia

In AIHA - macrophages remove membrane from RBCs resulting in spherocytes

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21
Q

Haemolytic anaemia screen?

A

Hb
Blood film
Reticulocytes
Bilirubin (unconjugated)
Low haptoglobin
Direct antiglobulin test (DAT)
LDH

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22
Q

Blood film changes suggestive of post-splenectomy?

A

Howell Jolly bodies (nuclear remnant)
Target cells
Spherocytes
Odd cells
Thrombocytosis
Lymphocytosis

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23
Q

Causes of acquired hyposplenism?

A

(1) Infarction
- Sickle cells, essential thrombocythaemia, polycythaemia vera

(2) Atrophy/hypofunction
- Coeliac, fermatitis herpetiforms, IBD
- Autoimmune (SLE/RA/GN)
Bone marrow transplantation & GVHD
- HIV/AIDS

(3) Infiltration
- Amyloid, sarcoid, leukaemia, myeloproliferative

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24
Q

What type mutations occur in hereditary spherocytosis and inheritance?

A

In red cell membrane/skeleton proteins
E.g. Ankyrin, Band 3, Spectrin, Protein 4.2

Autosomal dominant inheritance

Can do DAT to test

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25
Q

Consequences of hereditary spherocytosis?

A

Anaemia
Life long excessive breakdown of Hb
Pigment gallstones (also occurs in other chronic haemolytic states, e.g. sickle cell)
Splenectomy may be indicated in certain situations

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26
Q

Blood film changes suggestive of G6PD deficiency?

A

Bite cells, keratocytes

X-linked

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27
Q

Role of G6PD and consequences

A

Precipitates of Hb (Heinz bodies) results in bite cells

Heinz bodies = Heinz beans = beans = G6PD def

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28
Q

Drugs that cause drug-induced oxidative haemolysis?

A

Sulphonamides
Dapsone
Antimalarials
Cotrimoxazole
Naphthalene
Etc.

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29
Q

Causes of rouleaux?

A

High globulins/fibrinogen
- Chronic infection/inflammation
- Monoclonal proteins

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30
Q

Causes of reactive lymphocytes?

A

EBV
CMV
Toxoplasmosis

Reactive lymphocytes = reactive CD8+ T cells

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31
Q

Causes of cold agglutinins?

A

EBV
Mycoplasma
Lymphoma

If cold agglutinin + haemolytic anaemia:
- Primary, Cold Agglutinin Disease
> Strongly associated with distinct lymphoma
- Secondary, Cold Agglutinin Syndrome
> 2’ infection, lymphoma etc.

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32
Q

Fragile cells, smear/smudge cells, basket cells - cause?

A

CLL

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33
Q

Hairy cells on blood film?

A

Hairy cell leukaemia

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34
Q

Hairy cells on blood film?

A

Hairy cell leukaemia

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35
Q

Clefted, cerebriform cells of Sezary syndrome

A

T cell lymphoma

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36
Q

Granular lymphocytes of large granular lymphocyte leukaemia

A

Associated with neutropenia/RA
Felty Syndrome

37
Q

Reed-Sternberg Cell

A

Hodgkin Lymphoma

38
Q

B cell surface markers

A

CD19, CD20
Kappa, lambda

39
Q

T cell surface markers

A

CD3, CD4
CD5, CD8

40
Q

Granulocyte surface markers

A

CD33, CD13, CD15

41
Q

Most common cause of TTP (thrombotic thrombocytopenic purpura)?

A

Transient auto antibody against ADAMTS13 (levels <10%)

Results in excessively long VWF multimers, which binds platelets and activates clotting. Red cells then fragmented by fibrin strands leading to microangiopathic haemolysis.

42
Q

Characteristic presentation of TTP?

A

All have thrombocytopenia and microangiopathic haemolytic anaemia.

Most common: non specific, abdo pain, nausea, vomiting and weakness
Microthrombi everywhere - esp. brain, kidneys

43
Q

Treatment of TTP?

A

Plasma exchange to replace ADAMTS13 and to remove antibodies

Mortality: 90> 20%

44
Q

Abnormalities of VWF?

A
45
Q

What is HUS (haemolytic uraemic syndrome)?

A

Like TTP but mainly affects kidneys

Usually in children
90% of cases caused by Shiga toxin
> Would have preceding bloody diarrhoea/abdo pain
5% due to strep pneumoniae
> Usually preceding pneumococcal disease
5% atypical HUS
> Inherited mutations in complement

Often requires dialysis

Binds quite specifically to receptors in kidneys (Gb3), kids/children tend to have high levels

46
Q

What is type 1/2/3 Von Willbrand Disease?

A

Reduction in VWF/function

Type 1 - reduced level

Type 2 - reduced function

Type 3 - very very low levels (both alleles affected)

47
Q

What are 4 functional tests of VWF?

A

(1) VWF activity assay
- GP1b binding

(2) Ristocetin co-factor acvitiy
- Alters conformation (mimicking shear forces) induces platelet binding

(3) Collagen binding assay

(4) Factor VIII levels

If VWF has decreased function (<0.7), then type II VWD

48
Q

Causes of acquired von Willbrand syndrome?

A

(1) Valvular disease - Heyde syndrome
CHD, shear-stress-induced proteolysis

(2) ET/PV/myeloproliferative disease
- Excessive binding to abnormal platelets + proteolysis

(3) Autoantibody-mediated loss of function in myeloma/lymphoma & SLE

49
Q

Mixing studies
- Results for deficiency + inhibitor?

A

Factor deficiency - haemophilia, warfarin, liver disease
> Mixing study will show correction

Inhibitor - heparin, antiphospholipid etc.
> Mixing study will not correct completely

50
Q

Management of triple positive (lupus anticoagulant, anti-cardiolipin, anti-beta2glycoprotein1)?

A

Needs wafarin rather than DOACs

51
Q

4T scoring system for HIT (heparin induced thrombocytopenia)?

A

Typical onset for HIT is 5-10 days post exposure

If re-exposed within 30 days, platelet count will drop within 1 day

52
Q

Most common mutation in haemophilia A?

A

Inversions of intron 22 (in 40-45% of severe patients)

> 2000 defects in F8

Point mutations 67%
Small insertions/deletions 25%

53
Q

Management of Haemophilia A

A

(1) Replacement/substitution therapy
Prophylactic therapy 2-3x/week with FVIII
30% of severe haemophilia A will develop inhibitors/alloantibodies within first 20-30 days

(2) Activated prothrombin complex concentration
- FEIBA (factor 8 inhibitor bypass activity)
- Contains II, VIIa, IX, X

(3) Recomobinant FVIIa Novoseven

(4) Emicizumab - bispecific antibody that mimics FVIII activity by binding to activated IX and X - mediating activation of X
- For patients with FVIII inhibitors + severe haemophilia A

54
Q

What is haemophilia B?

A

Deficiency in factor IX
“Christmas disease”

Factor IX on X chromosome
X-linked recessive

55
Q

If on warfarin, INR ≥1.5 and life threatening bleeding:

A

IV Vitamin K 5-10mg
Prothrombinex
+/- FFP

56
Q

Effect on DOACs on coagulation tests?

A

Not reliably… But can be helpful…

57
Q

Definition of febrile neutropenia

A

Fever >38 + neutrophils <0.5

58
Q

Tumour lysis syndrome - manifestations?

A

Increased uric acid
Hyperkalaemia
Hyperphosphataemia
Hypocalcaemia

Oedema, fluid overload, seizures, muscle cramps

(Phosphate binds to the calcium)

59
Q

Diseases at high, intermediate and low risk for TLS?

A

High risk:
- Burkitt Lymphoma, WBC >100, LDH 2x ULN

Intermediate risk:
- Early stage NHL, T cell lymphomas
- WBC 50-100
- LDH 2x ULN

Low risk:
- Indolent NHL, myeloma, CML
- WBC <25
- LDH <2x ULN

60
Q

Indications for CAR-T cells

A

Relapsed refractory ALL
Relapsed/refractory DLBCL after failure of ≥2 lines of therapy
Relapsed/refractory mantle cell lymphoma after failure of BTK inhibitor

61
Q

Complications of CAR-T cells

A

Cytokine release syndrome
- Fevers, chills, dyspnoea, nausea, headaches, tachycardia etc.
Neurotoxicity
- Headache, confusion/agitation, seizures

62
Q

Management of CRS/neurotoxiciity 2’ CAR-T cells

A

Symptomatic management - antibiotics, fluids, paracetamol
Tocilizumab (8mg/kg)
Dexamethasone 10-20mg

63
Q

DLBCL

A

Most common lymphoma
Biopsy: large and small cells, diffuse pattern, loss of normal architecture
Tend to grow quickly & infiltrate
B symptoms
Pedal oedema - 2’ pelvic lymphadenopathy
Generalised pruritus
Anorexia/fatigue
Splenomegaly

64
Q

DLBCL - standard therapy?

A

R-CHOP

Rituximab
Doxorubicin
Vincristine
Prednisone

65
Q

Indications for treatment for CLL?

A

Anaemia/thrombocytopenia (Hb/platelets <100)
Painful lymphadenopathy
B symptoms
Lymphocyte doubling <6 months
Rapidly enlarging lymph nodes/organs
AIHA/idiopathic TTP refractory to immunosuppressants

66
Q

Investigations for MM?

A

FBE - anaemia, thrombocytopenia
EUC - check renal function
Calcium
Skeletal survey
Protein electrophoresis
SFLC
BM biopsy - >10% plasma cells

67
Q

Indications for MM treatment?

A

CRAB or SliM criteria

> 60% plasma cells
SFLC >100
MRI lesions >5mm
Hyper Ca2+
Renal failure
Anaemia
Lytic lesions

68
Q

Management of MM

A

Chemotherapy based regimens
- Bortezomib + cyclophohsphamide + dex (VCD)
- Bortezomib + doxo + dex (PAD)
- Vincristine + doxo + dex (VAD)

Non-chemotherapy regimens:
- Thalidomide/lenalidomide and dex
- Carflizomib/bortezomib
-Daratumumab

Autologous stem cell transplant

69
Q

APML genetics + treatment

A

t(15:17)(q22:a12)
ATRA + arsenic

70
Q

Indications for treatment of follicular lymphoma?

A

GELF criteria/FLIPI:
Nodes >7cm
>3 nodes >3cm each
B symptoms
Splenomegaly >16cm
Compression of vital organs
Serous effusions
Lymphocytes >5
Cytopenias

71
Q

What is SLiM criteria for MM?

A

S - sixty, >60% clonal plasma cells in bone marrow
Li - Light chains, SFLC >100
M - MRI, more than 1 5mm or greater lesion

72
Q

Blood film for lead poisoning?

A

Microcytic anaemia
Basophilic stippling

73
Q

Where is vWF secreted from?

A

Endothelial cells (Weibel-Palade bodies), secreted in ultra-large form

Then cleaved by ADAMTS13

74
Q

What can affect VWF levels?

A

Blood type O - lower levels
Exercise/stress - increases levels

75
Q

Heyde syndrome?

A

Aortic stenosis + GI bleeding (2’ AVMs) + acquired VWF

76
Q

Classification criteria for antiphospholipid syndrome?

A

Persistent presence of antiphospholipid antibodies, measured by at least 1 of 3 tests:

(1) Lupus anticoagulant (e.g. APTT, dilute Russell viper venom time)
(2) Immunoassay for anti-beta2 glycoprotein antibodies (IgG/IgM)
(3) Immunoassay for anticardiolipin antibodies (IgG/IgM)

76
Q

Classification criteria for antiphospholipid syndrome?

A

Persistent presence of antiphospholipid antibodies, measured by at least 1 of 3 tests:

(1) Lupus anticoagulant (e.g. APTT, dilute Russell viper venom time)
(2) Immunoassay for anti-beta2 glycoprotein antibodies (IgG/IgM)
(3) Immunoassay for anticardiolipin antibodies (IgG/IgM)

Positivity correlates with increased risk of thrombosis

77
Q

What factors are involved in extrinsic pathway (PT)?

A

Factor III (tissue factor)
Factor VII

78
Q

What factors are involved in intrinsic pathway (APTT)?

A

Factor XII
Factor XI
Factor IX
Factor VIII

79
Q

What is the common pathway in clotting cascade?

A

Factor Va and Factor Xa
(+ calcium)

Activates prothrombin (II) to thrombin (IIa)

Thrombin then activates fibrinogen (I) to fibrin (Ia)

Factor XIIIa helps stabilise fibrin network

80
Q

What does activated Protein C and Protein S inhibit?

A

Activated protein C and protein S form activated Protein-C complex which inhibits factors Va and VIIIa

81
Q

What is Factor V Leiden?

A

DNA point mutation (guanine for adenine)

Leads to APC (activated Protein C complex) resistance therefore Factor V remains active

82
Q

What does antithrombin do?

A

Degrades thrombin and factors IXa and Xa.

Activates tissue plasminogen activator.

82
Q

What does antithrombin do?

A

Degrades thrombin and factors IXa and Xa.

Activates tissue plasminogen activator.

83
Q

Factor V Ledein - mechanism of inheritance?

A

Autosomal dominant

84
Q

Pathophysiology behind heparin induced thrombophilia?

A

Antibodies against platelet-factor-4 (PF-4) therefore increased activation of platelets and thus depletion

85
Q

Cell surface markers for CLL?

A

CD5, CD19, CD20 and CD23

86
Q

Most common genetic variant in hereditary haemochromatosis?

A

C282Y (1)
- Esp. common in white people of European ancestry

H63D (2) - less common

87
Q

Role of hepcidin?

A

Controls iron absorption in intestine and iron release from macrophages via its binding to ferroportin

Low hepcidin levels = increased iron absorption and release from macrophages

High serum hepcidin = inflammation, CKD
Low serum hepcidin = iron deficiency anaemia

Primary site of synthesis - liver
Excreted by kidney and reabsorbed in proximal tubules

FRACP Written Exam 2023 (20 decks)

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