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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
Consequences of hereditary spherocytosis?
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
26
Blood film changes suggestive of G6PD deficiency?
Bite cells, keratocytes X-linked
27
Role of G6PD and consequences
Precipitates of Hb (Heinz bodies) results in bite cells Heinz bodies = Heinz beans = beans = G6PD def
28
Drugs that cause drug-induced oxidative haemolysis?
Sulphonamides Dapsone Antimalarials Cotrimoxazole Naphthalene Etc.
29
Causes of rouleaux?
High globulins/fibrinogen - Chronic infection/inflammation - Monoclonal proteins
30
Causes of reactive lymphocytes?
EBV CMV Toxoplasmosis Reactive lymphocytes = reactive CD8+ T cells
31
Causes of cold agglutinins?
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.
32
Fragile cells, smear/smudge cells, basket cells - cause?
CLL
33
Hairy cells on blood film?
Hairy cell leukaemia
34
Hairy cells on blood film?
Hairy cell leukaemia
35
Clefted, cerebriform cells of Sezary syndrome
T cell lymphoma
36
Granular lymphocytes of large granular lymphocyte leukaemia
Associated with neutropenia/RA Felty Syndrome
37
Reed-Sternberg Cell
Hodgkin Lymphoma
38
B cell surface markers
CD19, CD20 Kappa, lambda
39
T cell surface markers
CD3, CD4 CD5, CD8
40
Granulocyte surface markers
CD33, CD13, CD15
41
Most common cause of TTP (thrombotic thrombocytopenic purpura)?
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
Characteristic presentation of TTP?
All have thrombocytopenia and microangiopathic haemolytic anaemia. Most common: non specific, abdo pain, nausea, vomiting and weakness Microthrombi everywhere - esp. brain, kidneys
43
Treatment of TTP?
Plasma exchange to replace ADAMTS13 and to remove antibodies Mortality: 90> 20%
44
Abnormalities of VWF?
45
What is HUS (haemolytic uraemic syndrome)?
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
What is type 1/2/3 Von Willbrand Disease?
Reduction in VWF/function Type 1 - reduced level Type 2 - reduced function Type 3 - very very low levels (both alleles affected)
47
What are 4 functional tests of VWF?
(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
Causes of acquired von Willbrand syndrome?
(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
Mixing studies - Results for deficiency + inhibitor?
Factor deficiency - haemophilia, warfarin, liver disease > Mixing study will show correction Inhibitor - heparin, antiphospholipid etc. > Mixing study will not correct completely
50
Management of triple positive (lupus anticoagulant, anti-cardiolipin, anti-beta2glycoprotein1)?
Needs wafarin rather than DOACs
51
4T scoring system for HIT (heparin induced thrombocytopenia)?
Typical onset for HIT is 5-10 days post exposure If re-exposed within 30 days, platelet count will drop within 1 day
52
Most common mutation in haemophilia A?
Inversions of intron 22 (in 40-45% of severe patients) >2000 defects in F8 Point mutations 67% Small insertions/deletions 25%
53
Management of Haemophilia 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
What is haemophilia B?
Deficiency in factor IX "Christmas disease" Factor IX on X chromosome X-linked recessive
55
If on warfarin, INR ≥1.5 and life threatening bleeding:
IV Vitamin K 5-10mg Prothrombinex +/- FFP
56
Effect on DOACs on coagulation tests?
Not reliably... But can be helpful...
57
Definition of febrile neutropenia
Fever >38 + neutrophils <0.5
58
Tumour lysis syndrome - manifestations?
Increased uric acid Hyperkalaemia Hyperphosphataemia Hypocalcaemia Oedema, fluid overload, seizures, muscle cramps (Phosphate binds to the calcium)
59
Diseases at high, intermediate and low risk for TLS?
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
Indications for CAR-T cells
Relapsed refractory ALL Relapsed/refractory DLBCL after failure of ≥2 lines of therapy Relapsed/refractory mantle cell lymphoma after failure of BTK inhibitor
61
Complications of CAR-T cells
Cytokine release syndrome - Fevers, chills, dyspnoea, nausea, headaches, tachycardia etc. Neurotoxicity - Headache, confusion/agitation, seizures
62
Management of CRS/neurotoxiciity 2' CAR-T cells
Symptomatic management - antibiotics, fluids, paracetamol Tocilizumab (8mg/kg) Dexamethasone 10-20mg
63
DLBCL
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
DLBCL - standard therapy?
R-CHOP Rituximab Doxorubicin Vincristine Prednisone
65
Indications for treatment for CLL?
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
Investigations for MM?
FBE - anaemia, thrombocytopenia EUC - check renal function Calcium Skeletal survey Protein electrophoresis SFLC BM biopsy - >10% plasma cells
67
Indications for MM treatment?
CRAB or SliM criteria >60% plasma cells SFLC >100 MRI lesions >5mm Hyper Ca2+ Renal failure Anaemia Lytic lesions
68
Management of MM
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
APML genetics + treatment
t(15:17)(q22:a12) ATRA + arsenic
70
Indications for treatment of follicular lymphoma?
GELF criteria/FLIPI: Nodes >7cm >3 nodes >3cm each B symptoms Splenomegaly >16cm Compression of vital organs Serous effusions Lymphocytes >5 Cytopenias
71
What is SLiM criteria for MM?
S - sixty, >60% clonal plasma cells in bone marrow Li - Light chains, SFLC >100 M - MRI, more than 1 5mm or greater lesion
72
Blood film for lead poisoning?
Microcytic anaemia Basophilic stippling
73
Where is vWF secreted from?
Endothelial cells (Weibel-Palade bodies), secreted in ultra-large form Then cleaved by ADAMTS13
74
What can affect VWF levels?
Blood type O - lower levels Exercise/stress - increases levels
75
Heyde syndrome?
Aortic stenosis + GI bleeding (2' AVMs) + acquired VWF
76
Classification criteria for antiphospholipid syndrome?
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
Classification criteria for antiphospholipid syndrome?
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
What factors are involved in extrinsic pathway (PT)?
Factor III (tissue factor) Factor VII
78
What factors are involved in intrinsic pathway (APTT)?
Factor XII Factor XI Factor IX Factor VIII
79
What is the common pathway in clotting cascade?
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
What does activated Protein C and Protein S inhibit?
Activated protein C and protein S form activated Protein-C complex which inhibits factors Va and VIIIa
81
What is Factor V Leiden?
DNA point mutation (guanine for adenine) Leads to APC (activated Protein C complex) resistance therefore Factor V remains active
82
What does antithrombin do?
Degrades thrombin and factors IXa and Xa. Activates tissue plasminogen activator.
82
What does antithrombin do?
Degrades thrombin and factors IXa and Xa. Activates tissue plasminogen activator.
83
Factor V Ledein - mechanism of inheritance?
Autosomal dominant
84
Pathophysiology behind heparin induced thrombophilia?
Antibodies against platelet-factor-4 (PF-4) therefore increased activation of platelets and thus depletion
85
Cell surface markers for CLL?
CD5, CD19, CD20 and CD23
86
Most common genetic variant in hereditary haemochromatosis?
C282Y (1) - Esp. common in white people of European ancestry H63D (2) - less common
87
Role of hepcidin?
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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