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Haematology Flashcards

1
Q

B12 and folate deficiency markers

A

B12 will have elevated homocysteine AND MMA
Folate will be only homocysteine

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2
Q

B12 deficiency - features, film, cause, abs

A

Macrocytic anaemia, glossitis, stomatitis, sub-acute combined degeneration

Additional features on film: oval microcytes, hyper-segmented neutrophils, low reticulocyte count

Most common:
Pernicious anaemia
- autoimmune destruction of gastric mucosa/ parietal cells
- intrinsic factor antibodies are specific
- parietal cell antibodies are sensitive

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3
Q

Causes of hemolysis

A

Intravascular = fragmentation (MAHA, DIC, mechanical), PNH, PCH

Extravascular = immune mediated, RBC membrane, RBC enzymes, metabolic defects, infections

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4
Q

Thrombotic thrombocytopenic purpura (TTP) - features, gene, management

A

– haemolysis with red cell fragmentation
– thrombocytopenia
– fever
– neurological changes
– renal impairment

ADAMTS13
- deficiency (<5%) due to acquired antibodies
- usually cleaves vWF&raquo_space; nets formed that use up plt and shear RBCs

Management:
- PLEX (removes ab + vWF while replacing ADAMTS13)
- FFP will replace ADAMTS13
- steroids + rituximab
- Caplacizumab (prevents platelet interaction with vWF)

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5
Q

Eculizumab

A

Anti-C5 humanized chimeric monoclonal antibody
* Targets the terminal component of the complement cascade (reducing haemolysis)
* Vulnerability to infection by encapsulated organisms

Clinicaluses:
– Atypical haemolytic uraemic syndrome
– Paroxysmal nocturnal haemoglobinuria

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6
Q

PNH diagnosis and

A

Defective PIG-A

Diagnosis: current gold standard is flow cytometry
– loss of CD55 and CD59 on red cells and neutrophils
– FLAER: fluoroscein-labelled pro-aerolysin which binds selectively
to GPI-anchor

Management
– Transfusions; supportive care; SCT
– Thrombosis management: life long after first thrombosis
– Eculizumab: fewer transfusions and cessation of haemoglobinuria

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7
Q

Paroxysmal cold haemoglobinuria

A

Rare form of AIHA with acute intravascular haemolysis after exposure to cold

Causes
– Idiopathic, syphilis, viral infections (kids)
– Biphasic IgG anti-P antibody (Donath-Landsteiner Antibody): binds RBC at low temperatures and upon warming complement- mediated lysis occurs

Findings
– Blood film shows red cell agglutination
– Intra-vascular haemolysis
– anti-P antibody

Management
– Cold avoidance, supportive care
– Similar to AIHA discussed later
– Splenectomy not useful (haemolysis mainly intra-vascular)

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8
Q

Warm AIHA

A

DAT: IgG +/- complement components (C3d) - cleared by reticuloendothelial system

Anaemia, haemolysis, spherocytes, splenomegaly

Causes: Idiopathic
- SLE/autoimmune disease
– Lymphoproliferative disease: CLL/lymphoma
– Infection: Hep C, CMV
– Drugs: methyldopa, antibiotics
– Evan’s syndrome

Management
- transfusion as needed (can continue to lyse)
- prednisolone 1mg/kg
- IVIg
- splenectomy, rituximab, other immunosuppression

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9
Q

Cold AIHA

A

DAT: C3d only- most typically IgM antibody react with RBCs <37°C

Causes are secondary:
- lymphoproliferative disorder
- mycoplasma
- EBV
- autoimmune disease
- Rarely is “Primary cold agglutinin disease”

Management:
- cold avoidance, chlorambucil (underlying LPD), rituximab
(Does not respond to steroids or splenectomy)
- Inhibition of Complement C1s with Sutimlimab appears promising at increase hb, reducing fatigue, halting haemolysis

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10
Q

Hereditary spherocytosis

A

Most common inherited haemolytic anaemia
- Autosomal dominant
- Haemolysis of varying intensity – worsened by illness
- jaundice, cholelithiasis, splenomegaly

Investigations:
– Film: polychromasia, prominent spherocytes
– FBC: increased MCHC, RDW, reticulocytes
– Biochemical evidence of haemolysis
– DAT: negative
– Flow cytometry: eosin-5-maleimide (EMA) binding (Sensitive to HS, SEAO, congenital dyserythropoietic anaemia)

Management:
- folate supplementation
– Splenectomy

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11
Q

G6PD deficiency

A
  • Most common RBC metabolic defect
  • X-linked
  • Required for NADPH and oxidation of G6P
  • Benefit in survival with malaria
  • Oxidative hemolyitic crisis&raquo_space; bite cells
  • Precipitants: primaquine, dapsone, bactrim, aspirin, Vitamin K analogues, moth balls, lava beans, amyl nitrite
  • Management: avoid/stop precipitant, transfusion if severe
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12
Q

α-thalassaemia

A

α-thal trait: normal HPLC and electrophoresis; requires molecular studies to diagnose

HbH Disease (–/-α): chronic haemolysis, splenomegaly; HbH inclusions; HbH on HPLC; confirmation by genetic studies

Hydrops foetalis (–/–): incompatible with extra-uterine life; Hb Barts (γ4) only

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13
Q

β-thalassaemia

A

Minor
- Reduced Hb A (α2β2)&raquo_space; compensatory increase in Hb A2 (α2δ2) and in 25% Hb F (α2γ2)
- Poikilocytosis, basophilic stippling, target cells

Major
- transfusion dependent (>90)
- Erythroid marrow expansion, haemolysis, extra-medullary haemopoiesis
- Developmental delay, skeletal abnormalities: secondary to both chronic anaemia and iron overload
- Iron overload major cause of morbidity/mortality: deferoxamine (<1000)
- features as above but more severe (Hb A may be absent)

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14
Q

Sickle cell disease

A

Autosomal recessive
β-globin gene - GAG to GTG > Valine to Glutamate
Polymerises leading to hemolysis
Hyposplenism

Management
- hydroxyurea (induces Hb F)
- transfusion
- Voxeletor = polymerisation inhibitor

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15
Q

Chemotherapy associated with AML/MDS (2)

A

Alkylating agents ( 5-10 years)
* Cyclophosphamide
* Melphalan
* Busulfan

Topoisomerase II inhibitors (1-5 years)
* Etoposide
* Mitoxantrone

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16
Q

Oncogenic viruses (3)

A

EBV (aka HHV4) in immunocompromised individuals
* Strong association with B cell lymphomas
* Burkitt lymphoma, Classical Hodgkin lymphoma, DLBCL, PCNSL, plasmablastic lymphoma
* Post transplant lymphoproliferative disorder (PTLD)

HTLV-1 - adult T-cell leukaemia/ lymphoma

HHV8 - kaposi sarcoma

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17
Q

Flow cytometry: lymphoma vs leukemia

A

Lymphoma
* Aberrant B-cell, T-cell, NK-cell antigens
* Clonality analysis in B-cell NHL: neoplastic cells exhibit monotypia (over expression of either kappa or lambda); TRBC1 for T cell clonality

Leukaemia
* CD45 (human leucocyte antigen) to gate blast population
* Lineage differentiation (ALL vs AML), and maturation stages

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18
Q

Cytogenetics and fish

A

Cytogenetics
- Grow cells in culture and arrest in metaphase
- Good for large gains, losses and translocations

FISH confirms abnormalities with specific probes

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19
Q

Risks to fertility with haematology treatments (5)

A
  • Increasing age
  • Pelvic radiotherapy increases risk of uterine rupture
  • Alkylating agents
  • Platinum based treatments
  • Anthracyclines and anti metabolites – lower risk
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20
Q

Essential thrombocythemia - genes, features, management

A

Driver genes
* JAK2 (V617F) in 60%-65%
* CALR exon 9 indels in 20%-25%
* MPL exon 10 ~5%
* About 10% of patients do not carry any of the above (the so-called triple-negative cases)

Clinical features
* Platelet count ≥450
* Pseudohyperkalemia with marked thrombocytosis - in vitro phenomenon
* Normocellular bone marrow with proliferation of enlarged megakaryocytes

Clinical outcome
* risk of venous and arterial thrombosis (triple negative have low incidence)
* Leukemic transformation <1% at 10 years

Management (risk dependent - IPSET score)
- observation
- aspirin (<60yo and JAK2 V617F)
- aspirin + hydroxyurea (>60yo and JAK2 wild-type)
- systemic anticoagulation + hydroxyurea (>60 and JAK2 V617F OR previous thrombosis)

21
Q

Polycythemia Vera - genes, features, management

A
  • JAK2 (V617F) ~ 96%
  • JAK2 exon12 ~ 4%
  • Wild-type JAK2 extremely rare

Clinical features
* Hb >16.5g/dL in men, Hb >16.0g/dL in women or hematocrit >49% in men or > 48% in women
* Erythrocytosis frequently combined with thrombocytosis and/or leukocytosis
* Bone marrow hypercellularity for age with trilineage growth (panmyelosis)
* Supressed EPO

Clinical outcome
* risk of venous and arterial thrombosis
* Leukemic transformation 3% at 10years

Management
* Risk stratification (BSH guidelines 2018)
Low risk: Age <65, No hx PV associated arterial or venous thrombosis.
High risk: Age ≥65, hx of prior PV associated arterial or venous thrombosis.

  • Low dose aspirin for all
  • HCT target <0.45
  • Venesection
  • Addition of cytoreductive therapy (hydroxyurea or interferon) in high risk patients
22
Q

Primary Myelofibrosis - genes, features, management

A

Driver genes
* JAK2 (V617F) in 60%-65%
* CALR exon 9 indels in 25%-30%
* MPL exon 10 mutations 5%
* About 5%-10% of patients do not carry any of the above somatic mutations (triple-negative
cases)

Clinical features
* Pre fibrotic phase
* Anaemia, leucocytosis, raised LDH, splenomegaly

Clinical outcome
* DIPSS score
* Risk of leukaemic transformation

Management
* Supportive
* Disease modifying – JAK2 inhibitor
* Allogeneic stem cell transplant for younger patients

23
Q

Chronic myeloid leukaemia - genes, features, management

A

Driver genes
- Philadelphia chromosome (Ph) - reciprocal translocation between 9 and 22 [t(9;22]
- Gives rise to a BCR-ABL1 fusion gene
- deregulated tyrosine
kinase activity (p210)

Clinical features
- Chronic phase – 90% of patients at diagnosis
- Blast phase - myeloid or lymphoid

Management
* Risk stratification – Sokal, Hasford or EUTOS scores
* TKIs – three generation, IRIS trial – imatinib vs IFN/cytarabine, imatinib demonstrated superior safety and efficacy with 11 year PFS>90%
* Major and deep responses are achieved faster and more frequently with second-
generation TKIs
* PFS only marginally improved
* OS same irrespective of which TKI is used first-line

24
Q

Mastocytosis

A

Increased accumulation of abnormal mast cells in various organs or tissues - spectrum to mast cell leukaemia

Classification
* Cutaneous
* Systemic
* Localised mast cell tumours

Activation mutation of the KIT receptor >80% D816

25
Q

Chronic myelomonocytic leukaemia - features and treatment

A

MPN features
* Leucocytosis , monocytosis >1 x 109/L for longer than 3 months (excluded a
reactive cause)
* Splenomegaly
* Circulating immature myeloid cells
* Absence of MPN driver mutations (JAK2 / BCR-ABL1)
* Somatic mutations commonly encountered – TET2 , SRSF2, ASXL1

MDS features
* Dysplasia of myeloid lineages

Treatment
* Supportive
* Cytoreductive agents if proliferative – hydroxyurea
* Hypomethylating agents – azacitidine

26
Q

Myelodysplastic syndrome (MDS)

A

Heterogeneous group of clonal haematopoietic stem cell malignancies Significant morbidity
> 60 years of age

Associated with :
1. Bone marrow failure
2. Peripheral cytopenia(s)
3. Propensity for progression to acute myeloid leukaemia

Diagnosis
- Blood film: microcytic anaemia, dysplasia
- BM biopsy: cellularity, morphology, blasts, cytogenetics

27
Q

Factors for MDS prognosis (5)

A

Cytogenetics
Blast %
Hemoglobin
Platelets
ANC

28
Q

Treatment of MDS

A

Supportive
- transfusions Hb<80g/L, Platelets <10 or <20 if febrile
- EPO, G-CSF

Low risk
- Luspatercept or sotatercept = fusion protein blocking TGF B thus allowing effective erythropoiesis through maturation

High risk
- Azacitidine = hypomethylating agent decreases inhibition of tumor supressor genes&raquo_space; decreases transformation to AML and improves survival

29
Q

Acute myeloid leukaemia diagnosis (2)

A
  1. FBE and blood film
    * Pancytopenia
    * Blasts in peripheral blood
    * Morphology
  2. BM aspirate and trephine
    * percentage of blasts in the bone marrow
    * >20% of leucocytes
    * Blasts with Auer rods = myeloid leukaemia
    * Immunophenotyping of the blasts
30
Q

AML curative treatment, targeted therapy, and definition of relapse

A

Curative
- 3 days of an anthracycline and 7 days of cytarabine&raquo_space; allogenic stem cell
- Unfit >70yo&raquo_space; azacitidine an dvenetoclax (70% response, similar to 7+3)

Targeted
- Midosaturin = FLT3 inhibitor
- Gilteritinib = more potent and specific FLT3 inhibitor for relapsed/ refractory

Measurable residual disease defines response and outcomes

Relapse = one of:
1. >5% blasts in BM
2. Reappearance of blasts in peripheral blood
3. Development of new extra medullary disease

31
Q

Acute Promyelocytic Leukaemia - path, features, treatment

A

Balanced chromosomal translocation t(15;17)(q24;q21)&raquo_space; fusion of promyelocytic leukaemia (PML) and the retinoic acid receptor alpha (RARA) genes&raquo_space; impairs myeloid differentiation

High risk due to coagulopathy and DIC risk

Treatment
* Standard-risk vs High-risk (WBC ≥10)
* all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) +/-
chemotherapy (anthracycline), CR 96%
* Differentiation syndrome is a potentially life-threatening complication of treatment

32
Q

Acute Lymphoblastic Leukaemia diagnosis and prognosis (5)

A

Diagnosis
- film: pancytopenia + blasts
- biopsy: >20% blasts with lymphoid antigens
- extra medullary involvement common in B cell, T cell will have mediastinal mass

Prognosis
- excellent in children, worsens with age
- Poor risk
1. BCR-ABL1 (9;22)
2. Ph-like
3. Early thymocyte precursor (ETP) phenotype
4. 11q23
5. Ikaros deletion

33
Q

ALL treatment

A
  • Induction chemotherapy with a number of different regimens – ongoing trials
  • BCR-ABL inhibitor if Ph+ALL (e.g. imatinib, dasatinib)
  • Maintenance chemotherapy (up to 2 years)

Allogeneic BMT - graft versus leukemia
* Ph+ ALL in CR1
* MRD+
* Relapsed disease

Targeted therapy
- Bispecific t-cell engaging (BiTE) abs promote elimination of lymphoblasts by cytotoxic T cells
- Bilnatumomab (CD19/CD3)
- relapsed/ refractory
- SE - neurotoxicity (ICANS), and cytokine release syndrome

34
Q

Chronic Lymphocytic Leukaemia diagnosis (2) and staging via Rai and Binet

A

FBE and blood film
* Isolated lymphocytosis , > 5 x 109/L clonal B
lymphocytes > 3 months
* Cytopenias

Immunophenotyping peripheral blood
* CD5 + CD19 + clonal B cells

Rai and Binet classification
Low-risk
* Stage 0 - lymphocytosis only

Intermediate risk
* Stage I - lymphocytosis
* Stage II – lymphadenopathy at any site , hepatosplenomegaly

High risk
* Stage III – anaemia Hb < 10g/dL
* Stage IV – thrombocytopenia
* These cytopenias are non immune and due to bone marrow replacement

35
Q

CLL good (2) and poor prognosis (4)

A

Good
- 13 q deletion
- IGHV gene mutation

Poor
- 11q deletion
- 17p deletion
- unmate

36
Q

CLL treatment - when (4) and immunotherapy (3)

A

When
1. Autoimmune complications
2. Bone marrow failure – cytopenias
3. Lymphocyte doubling time–>50% 2 months OR doubled in<6months
4. Disease related symptoms

Immunotherapy
1. Venetoclax
* Inhibits BCL‐2, an anti‐apoptotic protein. BCL‐2 is over-expressed in CLL mediates tumour cell survival and has been associated with resistance to chemotherapeutics
*can be combined with obinutuzumab
2. Ibrutinib
* B-cell–receptor signaling has emerged as a driving factor for CLL tumor-cell survival
* Downstream of the B-cell receptor and of critical importance to its function is a member of the Tec
family of kinases, Bruton’s tyrosine kinase (BTK)
* Monotherapy in relapsed/refractory disease
3. Acalabrutinib

37
Q

Plasma Cell Dyscrasias (5)

A
  1. MGUS
    - protein <30, plasma cells <10%, no end-organ
  2. Plasmacytomas
    - bone or soft tissue lesion with clonal plasma cells, none in bone marrow, and no end-organ
  3. POEMS
    - polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes
  4. Systemic AL amyloidosis
    - MGUS + deposition
    - Kidney, cardiac, GI, skin
    - Congo stain
    - Bortezomib based or autologous transplant
  5. MM (detailed in another card)
38
Q

Multiple myeloma diagnosis, prognosis and treatment

A

Diagnosis = >10% plasma cells and one of the following:
1. Hypercalcemia
2. Renal insufficiency
3. Anaemia
4. Bone lesions
5. >60% plasma cells
6. Ratio >100
7. 2 or more lesions on MRI at least 5mm

Prognosis - stage 2 = B2 micro globulin 3.5-5.5 and albumin <35

Treatment
- autologous stem cell
- induction/ alone for frail: dexamethasone + bortezomib + lenalidomide (VRD)
- daratumumba + lenalidomide = gold standard

39
Q

Diffuse large B cell lymphoma (DLBCL) - presentation, prognosis, treatment

A

Rapidly enlarging mass - single or multiple sites&raquo_space; diagnose via biopsy (excisional)

Risk
1. Age >60yo
2. Ann arbor stage III or IV (extensive)
3. ECOG >2
4. Serum LDH
5. Extra nodal sites

Treatment
- R-CHOP +/- radiotherapy
- refractory > high dose chemo + autologous stem cell transplant

40
Q

Burkitt lymphoma - presentation, histology, translocations (3), treatment

A

Doubling time of 25hrs - very aggressive
Endemic to Africa + PNG

Histology
- atypical lymphoid cells with high proliferation and apoptosis
- starry-sky = large histiocytes with ingested apoptotic tumor cells on a background of basophilic tumor cells

Diagnosis = translocation involving myc
1. Ig heavy chain 8;14
2. Kappa light chain 2;8
3. Lambda light chain 8;22

Multiagent chemo

41
Q

Follicular Lymphoma - diagnosis, prognosis (5), and treatment

A

Indolent

Diagnosis
- follicles composed of centrocytes and centroblasts
- BCL2 overexpression
- t(14;18) - IGH and BCL2

Prognosis
1. >4 nodal groups
2. LDH
3. Age >60
4. Extensive stage III/IV
5. Hb <120

Watch and wait unless symptomatic/ end-organ
- obinutuzumab = glycoengineered anti CD20, greater B cell killing then rituximab
+ bendamustine or CHOP

42
Q

Waldenstrom Macroglobulinemia / Lymphoplasmacytic Lymphoma - pathophys (6) and diagnosis

A

Symptoms related to IgM
1. Acts an autoantibody – peripheral neuropathy
2. May precipitate out of the serum in cold temperatures – cryoglobulinemia
3. Pentamer – hyperviscosity syndrome
4. Can deposit as amorphous extracellular material in GIT – malabsorption

Infiltration of haematopoietic tissue by neoplastic B cells
5. Cytopenias
6. Hepatosplenomegaly

Diagnosis
- IgM paraprotein + >10% small lymphocyte infiltrate in BM
- MYD88 L256P in >90% of patients

Plasma exchange for hyper viscosity syndrome

43
Q

Hairy cell leukaemia - mutation and treatment

A

BRAF V600E
Cladribine

44
Q

Post-transplant lymphoproliferative disorders

A

95% b-cell lineage > CD20+
Associated with EBV

Decrease immunosupression
Rituximab followed by chemotherapy

45
Q

Hodgkin lymphoma identifying feature and treatments

A

multinucleated Reed-Sternberg cells
CD30+

Early stage - non bulky&raquo_space; ABVD + RT

Advanced stage - IIB-IV, bulky, B symptoms&raquo_space; ABVD +/- IFRT or escalated BEACOPP

Refractory
- salvage chemo
- brentuximab (anti CD30) vedotin (anti-tubulin)
- PD-1 inhibitors - Nivolumab

46
Q

Hereditary hemorrhagic talengectasia diagnosis

A

Autosomal dominant

Definite requires 3:
1. Epistaxis
2. Telangiectases: multiple at characteristic sites (lips, oral cavity, fingers, nose)
3. visceral lesions: for example gastrointestinal telangiectasia, pulmonary, hepatic, cerebral or spinal AVM
4. first-degree relative

47
Q

A 27 year old patient is being prepared for an urgent splenectomy in the next week. What pneumococcal vaccine regime should be given?
A. Conjugate vaccine (PCV13) before polysaccharide vaccine (PPSV23) 8 weeks apart
B. Give both PCV13 and PPSV23 vaccines at same time
C. Polysaccharide vaccine (PPSV23) before conjugate vaccine (PCV13) 8 weeks apart
D. Give 2 polysaccharide vaccine (PPSV23) 8 weeks apart

A

Answer = A

For emergency/urgent splenectomy give the vaccine series 14 days after splenectomy

  1. A pneumococcal protein‐conjugate vaccine (PCV13; Prevnar 13) that includes capsular polysaccharide antigens covalently linked to a nontoxic protein that is nearly identical to diphtheria toxin.
  2. A pneumococcal polysaccharide vaccine (PPSV23; Pneumovax 23, Pnu‐Immune) that includes 23 purified capsular polysaccharide antigens

The recommendation is to give the PCV13 first followed by the PPSV23 8 weeks later.

If this is for an elective/planned splenectomy this can be completed 10‐12 weeks prior to surgery so that the last vaccination is given at least 14 days prior to the operation.

48
Q

Stem cells are recognised by the presence of which cluster of differentiation?
A. CD45
B. CD34
C. CD4
D. CD24

A

Answer = B

Stem cells are recognised by CD34+. CD45 is found on all leukocyte groups. CD4 on monocytes and T helper cells, and CD24 on B lymphocytes and granulocytes.

49
Q

Three-drug regimens are common as the first line management of multiple myeloma. Which of the following medications used to treat multiple myeloma is most likely to cause peripheral neuropathy as a side effect?
A. Lenalidomide
B. Bortezomib
C. Cyclophosphamide
D. Dexamethasone

A

B. Bortezomib

Major side effect = painful glove-and-stocking neuropathy, usually after the first few cycles of therapy

CLS (13 decks)

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