Haem2

Question 1

Which one of the following is the most important component in the pathogenesis of β thalassaemia?

A. Iron overload.

B. α/β globin chain imbalance.

C. Ineffective erythropoiesis.

D. Dysfunctional β globin.

E. Haemolytic anaemia.

Answer 1

**B. α/β globin chain imbalance.

Excess alpha chains are unstable and precipitate - RBC membrane damage (target cell)

Results in:

• Intramedullary and peripheral haemolysis
• Erythroid hyperplasia,
• Ineffective erythropoeisis due to intramedullary destruction of erythroid cells.**

Question 2

1. What are the three different kinds of haemoglobin?
2. Which forms the majority of adult Hb?
3. On what genes are haemoglobin alpha and beta located?

Answer 2

HBA (A₂B₂)- a tetramer of two alpha and two beta chains

HBA2 (a₂δ₂) tetramer forms - 1-2% adult Hb

HBF - a₂γ₂ tetramer forms - fetal Hb but <1% of adult Hb

2. 98% adult Hb primarily HBa

2 alpha-globin genes - Cr16, w/ no substitutes.

B-globin gene - Cr11, adjacent to B-like glob in genes delta δ and gamma γ

Question 3

In the context of thalassaemia, define the following terms:

1. Trait
2. Intermedia
3. Major

Answer 3

1. Trait - lab features, no clinical impact
2. Intermedia - occastional transfusion requirement
3. Major - life threatening or transfusion dependent - most die of iron overload.

Question 4

Describe the pathogenesis of alpha-thalassaemia

Answer 4

Alpha thalassaemia - Cr16 x 2

• due to gene deletions —> reduced a-globin chain synthesis
• each gene produces 1/4 of total alpha-globin quantity
• all adult Hb are alpha containing, so there will never be any change in percentage distribution of it on Hb EPG.
• Severe forms: excess B chains will form B2B2 tetramer (H bodies), or HbH which are highly unstable.

Question 5

Describe the clinical features of alpha thalassaemia

Answer 5

Southeast Asians and Chinese

• aa/a- : silent carrier
• aa/— or a-/a- : Clinically normal, mild microcytic anaemia
• a-/— : HbH disease - chronic haemolytic anaemia of variable severity (minor or intermedia) with pallor and splenomegaly. Intermittent transfusions only (infection / stress or by RBC production shutdown (aplastic crisis) by certain viruses (i.e. parvovirus).)
• —/— : Hydrops fetalis (no normal Hb is produced only Bart’s y4) - fetus is stillborn

Question 6

Describe the lab findings for alpha-thalassaemia trait and HbH disease.

Answer 6

Trait - MCV (60-75)

• normal or increased RBC count
• smear: microcytes, hypochromia, occ target cells, acanthocytes.
• retic and iron counts normal
• Hb EPG: no change in percent HbA2/F/or HbH
• dx of exclusion

HbH disease

• marked anaemia HCT 22-32%
• very low MCV 60-70
• smear: hypochromia, microcytosis, target cells, poikilocytosis (annoying term that means ‘varied’!)
• elevated retics, elevated/normal RBC count
• Hb EPG: fast migrating haemoglobin (HbH) accounting for 10-40% of the Hb.
• Can stain smear with supra vital dye to show HbH

Question 7

Describe the pathogenesis of beta-thalassaemia

Answer 7

Beta thalassamia - Cr 11 point mutation

• little to no B-Hb –> more HBA2 & HbF on EPG
• excess alpha chains precipitate –> RBC membrane damage
• intramedullary and peripheral haemolysis, erythroid hyperplasia

Absent b-chains: B0

Reduced b-chains: B+ (variable severity)

Severe disease

• marrow expansion –> bone deformities, osteopaenia, path fractures

Question 8

Describe the clinical manifestations of all forms of beta-thalassaemia

Answer 8

Homozygotes (B0/B0 or B+/B+)

• thal major
• normal @ birth, severe tfusion dependence at 6/12 (HbF–>HbA)
• Stunted growth
• Bony deformities (frontal bossing, chipmunk facies, path fractures)
• Hepatosplenomegaly
• Cirrhosis, jaundice (due to gallstones), thrombophilia
• Iron overload (due to transfusion) –> heart failure & arrythmias, cirrhosis, endocrinopathies, pseudoxanthoma elasticum - calcification of epithelial cells of skin, retina, CVS) due to inability to excrete iron. Poor survival.

Homozygosity for milder B+/B+: chronic haemolytic anaemia, transfusions only during aplastic crises. May still develop iron overload, hepatosplenomegaly and bony deformities but survive into adulthood.

Heterozygosity for B/B0 or B/B+ : thalassaemia minor, clinically insignificant microcytic anaemia

Question 9

What are the lab findings for beta-thal major and minor?

Answer 9

B-thal minor:

• Modest anaemia - HCT 28-40%, MCV 55-75
• RBC count normal or increased
• Retic count - normal or slightly elevated
• Smear: Hypochromia, microcytosis, target cells, basophilic stippling
• Hb EPG: Increased HBA2 to 4-8%, occ increased HbF - 1-5%

B-thal major:

• severe anaemia - HCT to
• smear: severe poikilocytosis, hypochromia, microcytosis, target cells, basophilic stiplling, nucleated RBCs.
• HbEPG - little to no HbA, variable amt HBa2, major Hb present is HbF

Question 10

How do you differentiate thalassaemia from iron deficiency anaemia?

How is the diagnosis of b-thal and a-thal made?

Answer 10

Compared to Fe+ deficiency anaemia

• lower MCV
• normal or elevated RBC count
• more abnormal smear at modest lvld anaemia
• normal or elevated transferrin sat/ferritin (or both)

Dx of b-thal made with above plus HbEPG showing elevated HbA2 and F (assuming iron replete)

Dx of a-thal is one of exclusion since HbEPG levels of a-globin remains the same.

Other microcytic anaemia with normal or elevated RBC count is Fe+ deficiency + PCV

Question 11

Describe the treatment for all forms of thalassaemia

Answer 11

Treatment

Mild a or b - no treatment but need identification so they don’t keep getting investigated for Fe deficiency anaemia!

HbH - Folic acid, avoid medicinal iron and oxidative drugs (sulphonamides)

Severe thalassaemia - regular transfusion, folic acid and iron chelation.

Allogeneic SCT - treatment of choice for B-thal major, only cure, and in kids w/o Fe+ overload or chronic organ toxicity - long term survival of >80%.

Question 12

Which one of the following occurs most frequently in the α thalassaemia syndromes?

A. Mental retardation.

B. Reduced mean corpuscular volume.

C. Gene deletions.

D. Haemoglobin H inclusion bodies.

E. Reduced haemoglobin.

Answer 12

C. Gene deletions.

Question 13

AMP 1999 Question 30

In which one of the following conditions has initial therapy with imatinib been shown to cause the best improvement in survival?

A. Multiple myeloma.

B. Low grade non-Hodgkin’s lymphoma.

C. Chronic myeloid leukaemia.

D. Chronic lymphocytic leukaemia.

E. T-cell acute lymphocytic leukaemia.

Answer 13

C. CML

TKIs (Imatinib, Dasatinib, Nilotinib, Ponatinib) • specific competitive binders in the ATP-pocket of BCR-ABL tyrosine kinase. Associated with >80% progression free at 8 years.

Question 14

What is the pathogenesis of CML?

Answer 14

Chromosomal abnormality

Reciprocal translocation of Cr9 to 22

Cr9q Abl protoncogene fused to BCR on Cr22q

then

Molecular abnormality

Fusion gene deregulates abl tyrosine kinase activity —> autophosphyrlation, altered adhesion, inhibition of apoptosis

then

Myeloid proliferation

Question 15

What are the clinical findings of CML?

Answer 15

• Middle aged, more men
• May be asymptomatic - discovered incidentally on an FBC with elevated WCC

• Hyper metabolic sx; night sweats, low-grade fever caused by overproduction of white cells

• May have splenomegaly and or sternal tenderness from marrow overexpansion
• Rarely; leukostasis: blurred vision, resp distress, priapism (usually w/ very high white cell counts
• Acceleration: Fever in absence of infection, bone pain and splenomegaly.

Question 16

What are the lab findings in CML?

Answer 16

• Early CML: normal BM function, normal WBCs, normal neutrophils
• Untreated: accelerated then acute blast phase - indistinguishable from acute leukaemia
• Median WBC count >150
• Blood film: Left-shifted (immature cells present) with cells present in proportion to their degree of maturation (i.e. blasts <5%), normal RBC morphology, normal or elevated platelets (abnormal megakaryocytes)
• Basophilia and eosinophilia of granulocytes is pathognomic
• Peripheral blood PCR (required for diagnosis): Increased levels of BCR-ABL gene.
• BM: Hypercellular w/ left shift myelopoesis

Question 17

What is the diagnostic criteria for CML?

Answer 17

• Peripheral blood: bcr/able gene present on PCR - hallmark of the disease – this is diagnostic criterai
• BMB is NOT necessary for dx but useful for prognosis and detecting additional chromosomal abnormalities

Question 18

How is the blast phase of CML defined?

What is it associated with?

Answer 18

One or more of:

o Blasts composing >20% of nucleated bone marrow cells.

o Extramedullary blast proliferation

o Large foci or clusters of blasts in the bone marrow biopsy

Evolution to a blast cell crisis in CML associated w/:

o Non-random secondary chromosomal changes

o Mutations or deletions of tumour suppressor genes

Question 19

How do you differentiate CML from infection and other blood disorders?

Answer 19

• Infection - no splenomegaly, WBC <50, no bcr/abl gene
• Other blood disorders - normal RBCs, no nucleated RBCs, definitive finding of bcr/abl gene

Question 20

Define the types and goals of therapy in CML

Answer 20

Treatment

• Untreated progresses from chronic phase (3-5 years) to blast crisis
• Chronic-phase CML: TKI aiming for complete remission w/ normalisation of blood count and splenomegaly within 3 months initiation. Aim for MAJOR molecular response in 1 year.
• Blast/accelerated phase: ASCT + myelosuppressive therapy
• Hyperleukocytosis (priapism, respiratory distress, visual blurring, altered mental state): emergency leukapheresis + myelosuppressive therapy.

Question 21

What do the terms major molecular response, and complete molecular response refer to in the context of CML?

Answer 21

Major molecular response

• 3-log reduction of bcr/abl transcript on PCR within a year (corresponds to bcr/abl RATIO (compared to alb) of <0.01).
• Goal is to achieve MMR within a year
• excellent prognosis - up to 100% progression-free at 8 years.

Complete MR = >4.5 log reduction ie undetectable

Question 22

What is the mechanism of action of tyrosine kinase inhibitors?

What are the side effects?

Answer 22

Tyrosine Kinase Inhibitors

• specific competitive binders in the ATP-pocket of BCR-ABL tyrosine kinase
• Imatinib: first line, MMR @ 30% at 1 year in chronic phase. SEs: NV, chronic diarrhea, intolerable fatigue
• Dasatinib: pleural effusions esp. in the elderly, pneumonitis, pulmonary hypertension, bleeding, possibly increased infection risk
• Nilotinib: cardiac SEs: esp IHD, CVA, PAD (inc limb ischaemia, claudication), also increases cholesterol and LDL
• 3rd gen agents may be more effective - can salvage 90% of patients who do not respond to imatinib. Are now approved as first line agents.

Question 23

What is the mechanism of tyrosine kinase inhibitor resistance?

How is it managed in CML?

Answer 23

• Due to:

• drug influx/efflux due to low OCT-1 expression
• amplification and over expression of BCR-ABL
• Mutations of BCR-ABL kinase domain (found in 50-90% w/ secondary resistance)
• can increase dose with variable response (depends on mutation
• or use alternative TKIs

Question 24

How is disease progression in CML monitored?

Answer 24

Peripheral blood PCR, if it increases on therapy check compliance, check for a new abl mutation, may be able to get away with increased dose of Imatinib, otherwise switch to a new inhibitor.

Question 25

What is the course and prognosis of CML?

Answer 25

Course & Prognosis * 80% w/o progression at 9 years w/ TKIs * essentially 100% survival at 9 years if good molecular response * Complete (undetectable bcr/abl) response lasting \> 2years may be able to cease therapy all together. * Untreated progresses from chronic phase (3-5 years) to blast crisis

Question 26

What is the pathogenesis of CLL?

Answer 26

Pathogenesis * B Cell lymphocytosis w/ coexpression of **_CD19, CD5_** (pathognomic: aberrant T-cell marker) on lymphocytes. * indolent, long lived small (unactivated) lymphocytes * immunoincompetent, poorly antigenic responsive * immunosuppression, * BM failure * organ infiltration with lymphocytes * inadequate antibody production * damage due to direct tissue introduction

Question 27

What is the epidemiology of CLL?

Answer 27

Epidemiology - 25% of all leukemias (2.7/100,000) , increasing - Unknown aetiology - Increased other malig (SCC) - Only leukemia NOT linked to radiation - M:F=2:1, less in Asian’s - Disease of old age - median at presentation is age 70

Question 28

What are the clinical findings in CLL?

Answer 28

Clinical Findings * incidental: lymphocytosis - usually indolent * symptomatic: fatigue or _lymphadenopathy_ * 80% will have lymphadenopathy, 50% _splenomegaly_ * subtype prolymphocytic leukaemia (larger and more immature cells) is more aggressive but rare * maybe complicated by _AIHA_ or autoimmune thrombocytopaenia * 5% of systemic cases may have an isolated lymph node transform into an aggressive large cell lymphoma (_Richter syndrome_)

Question 29

What is the Rai staging system used for? Can you describe it?

Answer 29

Used to stage CLL Staging - Rai Stage 0 - lymphocytosis (low-risk) Stage II - organomegaly (low risk) Stage III - anaemia (high risk) Stage IV - thrombocytopaenia (high risk)

Question 30

What is the diagnostic criteria for CLL?

Answer 30

Diagnostic criteria _Peripheral absolute B lymphocyte count_ \> 5 x 109/L w/ mainly morphologically mature lymphocytes _Flow cytometry_: clonality of circulating B-lymphocytes w/ low levels of SmIg and either kappa or lambda (not both) and expression of B-cell antigens (CD19, 20, 23), and expression of T-Cell associated antigen CD5.

Question 31

Name the investigations you would do when working up CLL

Answer 31

Ix * FBE,differential; lymphocytosis,cytopenias * Flowcytometry: CD19/5,Ig(weak),CD23 * Coombes test * LDH, B2 microglobulin * Uric acid, calcium * BMBx – cytopenias– ‘assessment’ pre-treatment – cytogenetics * +/-CTscan

Question 32

Describe the lab findings in CLL for the FBC Smear BMBx Cytogenetics.

Answer 32

Lab Findings * hallmark: isolated lymphocytosis * WBC \>20k, \>75% small and mature lymphocytes, normal HCT and platelets. * may have cytopaenias inc neutropaenia. * smear: normal-looking small lymphocytes predominate with reduced numbers of larger activated lymphocytes, **SMUDGE CELLS** * BMBx: Infiltrated w/ small lymphocytes Immunophenotype (Flow): **Coexpression of CD19 with T-lymphocyte marker CD5 - ONLY found in CLL** and mantle-cell lymphoma (Not mantle cell lymphoma if: expression of CD23, low expression of surface Ig and CD20, absence of cyclin D1) Cytogenetics (BMBx) * Associated mutation of Ig (Vh) gene = more indolent disease * Genomic changes assessed by flow cytometry or FISH o Chromosome **17p (p53) deletion or 11q (ATM) = POOR prognosis** o Isolated **13q deletion = favourable prognosis** (in Myeloma, it’s BAD!) • 50% have hypogammaglobulinaemia, more common with advanced disease, may have a small amt of IgM paraprotein.

Question 33

Describe the chromosomal abnormalities that are associated with good and poor prognoses in CLL

Answer 33

o Chromosome 17p (p53) deletion or 11q (ATM) = POOR prognosis o Isolated 13q deletion = GOOD prognosis (in Myeloma, it’s BAD!)

Question 34

DDx of CLL?

Answer 34

DDx * Exclude viral infections that cause lymphocytosis (i.e. Pertussis) * Fever in CLL may be concomitant bacterial infection * Other B-Cellopathies are distinguished on morphology and immunophenotype. * Monoclonal B-cell lymphocytosis (\<5x109) is a precursor to B-CLL

Question 35

Describe the treatment approaches and what you would use for each of the following groups in CLL: Comorbid elderly Robust older patient Younger patient

Answer 35

Comorbid elderly - symptom control, QOL —\> observe or ‘gently oral CTx with chlorambucil or cyclophosphmade Robust older pt - QOL, bulk reduction, deepest achievable response —\> observe is asymptomatic, otherwise multi drug CTx, ritux + fludarabine for prolonged remission. Younger pt - as above, possible allogeneic BMTc

Question 36

What prophylaxis should you use when giving fludarabine or alemtuzumab in CLL?

Answer 36

Prophylaxis * Fludarabine or alemtuzumab —\> PJP pneumonia, HSV, HZV and fungal prophylaxis. * Alemtuzumab - monitor for CMV reactivation * Lower strength ‘nonmyeloablative’ transplant + drugs good for older people.

Question 37

What are the prognostic features of CLL?

Answer 37

Prognostic features Stage 0-1: 10-15 years, Stage 3-4: \>90% at 2 years w/ fludarabine High risk disease: Allogeneic transplant may lead to long term disease control. Serum LDH and B2-microglobulin Unmutated IgH (adverse) vs mutated * ZAP 70 (zeta chain associated protein) (bad if positive) , CD38 + (bad if +) * Cytogenetic translocations (not trisomies or deletions) * ~5% terminally  "Richter's syndrome"; consider if: B-Sx, painful, rapidly enlarging mass rapid unexpected rise in LDH

Question 38

What is Richters Syndrome?

Answer 38

Transformation of CLL 5-10% of CLL patients B-Sx, painful, rapidly enlarging nodal mass and rapid unexpected rise in LDH fast-growing diffuse large B cell lymphoma BAD prognosis

Question 39

What is alemtuzumab and when is it used?

Answer 39

Alemtuzumab (mAb to mature lymphocyte CD52), but immunosuppression, severe and fatal infections. Used in CLL

Question 40

What is Ibrutinib and when is it used? What is a Bruton's tyrosine kinase?

Answer 40

Used in CLL Ibrutinib (PCI-02765) a Bruton’s TKI. Bruton's tyrosine kinase (BTK) BTK is a kinase that plays a crucial role in B-cell development

Question 41

How do you treat AIHA in CLL?

Answer 41

AIHA: rituximab, prednisone or splenectomy - AVOID fludarabine as may exacerbate (but concurrent rituximab reduces this risk)

Question 42

What is the pathogenesis of multiple myeloma?

Answer 42

Monoclonal proliferation (kappa/lambda light chain restriction) of plasma cells in the BM (any percentage) or as a tumor (plasmacytoma) resulting in: End-organ damage: C - Hypercalcaemia R - Renal failure A - Anaemia B - Bone disease Recurrent infections w/ encapsulated organisms (due to b-cell deficiency) Plasmacytomas Hyperviscosity syndrome

Question 43

Who is most susceptible to overwhelming infection with encapsulated organisms?

Answer 43

``` Asplenic patients B-cell deficient patients Complement deficiency (esp C3 and C5+ (MAC complex) ``` Children 6/12 - 1 year

Question 44

Name the encapsulated organisms. Why are they important?

Answer 44

_Streptococcus pneumoniae_ _Haemophilus influenzae type B (B polysaccharide)_ _Neisseria meningitidis_ Klebsiella pneumoniae Salmonella typhi Pseudomonas aeruginosa Cryptococcus neoformans only encapsulated fungal pathogen Other encapsulated bacteria Anti-phagocytic - susceptible to antibody (B-Cells) and not cell mediated responses. People w/ B-cell deficiencies are highly susceptible.

Question 45

What is the mechanism and outcome of hyperviscosity syndrome in multiple myeloma?

Answer 45

Excess paraprotein production (monoclonal Igs) in addition to excess plasma cells —\> hyperviscosity —\> spont.bleeding, retinopathy/vision disturb, vertigo, nausea, seizures, coma

Question 46

What is the mechanism of renal failure in multiple myeloma?

Answer 46

**Cast nephropathy:** Tumour mass expansion —\> FLC serum concentration exceeds renal absorptive capacity →excess light chains—\> direct damage to PCT—\> casts at distal tubules (containing BJP and tamm-horsfall proteins) —\> FLC in urine, positive BJP **Monoclonal Ig deposition disease (usually light chains)**—\> glomerular disease, proteinuria Hypercalcaemia —\>nephrocalcinosis Cryoglobulins, Fanconi syndrome (type2 RTA, phosphaturia, glycosuria, uricosuria & osteomalacia), hyperuricemia

Question 47

What is the mechanism of recurrent infection in multiple myeloma?

Answer 47

Underproduction of normal Ig + neutropenia + CTx immunosuppression —\> recurrent infections esp encapsulated organisms.

Question 48

What are the clinical findings of multiple myeloma and who does it affect?

Answer 48

Older adults - i.e. 65 y old Pallor, bone tenderness, soft tissue masses Bone tenderness/pain: hips, back, ribs, path # esp fem neck, vertebrae Neurologic signs: neuropathy, SC compression (plasmacytoma) Primary amyloid —\> enlarged tongue, peripheral/autonomic neuropathy, CHF, hepatomegaly NO splenomegaly unless amyloidosis NO fever unless infection

Question 49

What are the lab findings of multiple myeloma? What is the predominant paraprotein?

Answer 49

FBE: _Rouleaux_ (high protein), cytopenias, macrocytosis ESR elevated _Normal urine_ ‘dip-stick’ (i.e BJP): may be + if nephrotic (albumin) Electrolytes: Renal function, calcium, _ALP normal_ Low B12 Protein EPG (serum or urine) - detects a clonal protein - Monoclonal spike in b or gamma globulin region, known as _‘M-protein’_ IEPG - identifies the clonal protein - Paraprotein estimation: Serum/urine: _IgG(70%)_ \>_IgA(20%)_ \>IgD(5%) \>LCD(5%) \>NS(2.5) \>\>IgM - no paraprotein = nonsecretory myeloma = BAD _Elevated B₂ microglobulin_ (prognostic test)

Question 50

What are free light chains and what is the role of the serum free light chain test?

Answer 50

Free Light Chains - Ig are heavy chains – the light chains (kappa or lambda) produced separately - kappa and lambda bound to heavy chains, but free light chains produced in healthy people when there are more light chains than heavy chains - bound and free light chains are structurally identical - Free light chains reach a threshold before detectable in urine - need for serum FLC. - 15% will have no paraprotein due to free light chain only disease which pass freely into the urine. Serum FLC (free light chains) Will pick up light chains in non-secretory myeloma (too low to be detected in urine) - use at _dx of all types of myeloma inc MGUS, plasmacytoma and AL amyloidosis_ - use in combo with EPG/IEPG - sufficient to screen for all except AL amyloid (which needs more serum tests and urine IEPG)

Question 51

When would you do a bone marrow in multiple myeloma? What would it show? How do you differentiate it from reactive (benign) plasmacytosis?

Answer 51

Bone marrow (only for symptomatic - i.e. paraprotein plus end organ damage) Morphologically abnormal plasma cells Skewing of kappa to lambda light chain ratio May have reactive (benign) plasmacytosis - but atypical cells, LC restriction and effacement of normal BM = myeloma

Question 52

In multiple myeloma, when would you do a: Skeletal survey Nuclear bone scan MRI/PET? and what would they show?

Answer 52

Symptomatic myeloma: Skeletal survey (whole body x-ray) - lytic lesions of axial skeleton; skull, spine, prix long bones, ribs - OR general OP only Wouldn't - Nuclear bone scan - unuseful, no osteoblastic component MRI - severe back pain, suspected vertebral compression, isolated plasmacytoma - really good but expensive, pick up lesions that x-ray doesn’t PET - pre CTx

Question 53

What is the differential diagnosis of a positive paraprotein on EPG?

Answer 53

CLL Waldenstrom NHL primary amyloid cryoglubinaemia MGUS

Question 54

What is the definition and risk factors for progression of MGUS to MM?

Answer 54

_BM_ monoclonal plasma cells \<10% or _serum_ M-protein \<30g/L) _No end organ damage or other B-cell disorder_ 1/4 progresses to malignant disease in 10 years (1%/year) Must be distinguished from reactive (benign) polyclonal hypergammaglobulinaemia _Risk factors for progression_ Size of M-band (best predictor of risk) IgM or IgA monoclonal protein Eleveated serum FLC

Question 55

What is the definition of smoldering myeloma?

Answer 55

_BM_ monoclonal plasma cells \>10% or _serum_ M-protein \>30g/L No end-organ damage

Question 56

What is the treatment for MGUS and smoldering myeloma?

Answer 56

Observe

Question 57

What is the role of auto-sct and thalidomide in multiple myeloma?

Answer 57

Auto-SCT - prolongs duration of remission and overall survival, long treatment-free intervals - thalido/lenalidomide prolong remission and survival as post-transplant maintenance therapy

Question 58

What is the treatment of symptomatic myeloma in the non-transplant candidate?

Answer 58

Non-transplant candidate: Melphalan + Pred + Thalidomide \> Melphalan, Pred, bortezomib

Question 59

What is the treatment of symptomatic multiple myeloma in an eligible candidate?

Answer 59

–Auto-Transplant ‘candidate’ (\<76) » Induction therapy: chemotherapy +/- thalidomide, bortezomib, lenalidomide » Melphalan (alkylator) stem cell transplant [tandem v single] » Maintenance: steroids, thalidomide

Question 60

What is bortezomib, when is it used and it's side effects?

Answer 60

Bortezomib (proteosome inhibitor) Relapsed MM /poor prognosis --\> rapid response. SE: neuropathy (peripheral/autonomic), less if given SC (instead of IV)

Question 61

What is thalidomide/lenalidomide, when is it used and it's side effects?

Answer 61

Inhibits angiogenesis Used for multiple myeloma and leprosy Thalidomide/Lenalidomide SEs * Somnolence * Thalidomide neuropathy – painful neuropathy, reduced sens nerve AP (AP) * Constipation, tremor, skin rash and oedema * Thrombosis * Myelosuppression

Question 62

Define the international staging system - what is it used for?

Answer 62

International Staging System B2 microglobulin (both stages) and albumin (stage 1) Stage 1 - low B2 (\<3.5mg/L), normal albumin - survival \>5 years Stage 2 – not stage 1 or 3 Stage 3 - High B2 (\>5.5mg/L), survival \<2 years] Multiple Myeloma

Question 63

What are the cytogenetics of multiple myeloma and the associated prognoses?

Answer 63

Cytogenetics: Chrom 13 del (bad but good in CLL!), Hypodiploidy (bad), 17p del (bad) FISH: T(4:14) T(14;16)(bad) – by FISH only T(11;14) ‘good’

Question 64

Describe the sites of mutations and cell heritage for the following What do they all have in common? Chronic lymphocytic leukaemia Acute lymphocytic leukaemia Follicular lymphoma Diffuse large b-cell lymphoma Multiple myeloma

Answer 64

Chronic lymphocytic leukaemia- lymphoid tissue, mature naive b-cell Acute lymphocytic leukaemia - bone marrow, pre-b-cell Follicular lymphoma - lymphoid tissue, germinal centre b-cell Diffuse large b-cell lymphoma - lymphoid tissue, germinal centre be cell Multiple myeloma - plasma cell Hodgkin lymphoma - lymphoid tissue, germinal centre b-cell ![]()

Question 65

What are the unfavourable classifications of Hodgkin's lymphoma?

Answer 65

Unfavorable Early Stage (B-Sx, age \>50, ESR \>50, bulky, 3+ areas) Advanced Stage (III-IV)

Question 66

What does ABVD stand for in the treatment of _Hodgkin_ lymphoma? What are the side effects?

Answer 66

Adriamycin Bleomycin Vinblastine Dacarbazine SEs * Hair loss * Neutropenia * Cardiotoxicity from adriamycin * Lung toxicity from bleomycin * _Low_ risk of infertility

Question 67

What does BEACOPP stand for in the treatment of Hodgkins lymphoma? When is it used? What are the drawbacks?

Answer 67

Bleomycin, Etoposide, Adriamycin, Cyclophosphomide, O-Vincristine, Procarbazine, Prednisone Used for advanced Hodgkins or unfavourable stage More risk of infertility and late-stage cancers

Question 68

Why is low dose RTx used (where necessary) in Hodgkin's lymphoma?

Answer 68

Reduces risk of late breast cancer in young women

Question 69

What are the adverse prognostic factors in Hodgkin's lymphoma? (Hasenclever Index) What is the difference between having 1 or 5 or more of these?

Answer 69

Serum albumin \< 40 g/L Haemoglobin \< 10.5 g/dL Male gender Stage IV disease Total WCC \> 15 Lymphocytes \< 0.6, or \< 8% of total WCC Age \> 45 years Survival drops cumulatively - \>5 = \<50% PFS

Question 70

Which chemotherapy drugs are associated with secondary CML?

Answer 70

Alkylators and etoposide

Question 71

Aside from CML and breast cancer, what are the other cancers associated with Hodgkin's treatment? Which treatment do they stem from?

Answer 71

Thyroid, lung, bone - mainly XRT Brain - unknown cause

Question 72

What is the mechanism of secondary cardiovascular disease due to Hodgkins lymphoma treatment?

Answer 72

XRT

Question 73

What are the survivorship issues in long term survivors of Hodgkin's lymphoma?

Answer 73

Infertility - worse in men, worse if older Second cancers - breast, lung, colon, leukaemia Organ damage - heart (coronary disease), lung, thyroid

Question 74

What is the significan of PET positive and PET negative disease in Hodgkin's lymphoma?

Answer 74

FAR worse survival if PET positive

Question 75

What is nodular lymphocyte predominant Hodgkin's lymphoma? Why is a misnomer? How is it treated?

Answer 75

Unusual form of B-cell lympoma (Reed-Steenberg cells express CD20) A misnomer due to the CD20 expression - it is a non-hodgkin's lymphoma May progress to DLBCL Long survival if localised (surg +/- RTx) Responds to anti-CD20 agent Rituximab - long survival interspersed with relapses

Question 76

What are the commonest types of Non-Hodgkin lymphoma? What are the other main types?

Answer 76

Follicular lymphoma Diffuse large b-cell lymphoma Others Burkitt SLL/CLL MALT Mantle cell

Question 77

What are the cytogenetics of follicular non-Hodgkin lymphoma?

Answer 77

t(14;18) and bcl-2 rearrangement in \> 85% Follicular - t(14;18) —\> overexpresson of BCL-2 —\> failure of apoptosis (the usual mechanism of B-Cell death)

Question 78

What is the epidemiology of follicular non-hodgkin lymphoma?

Answer 78

Median age at dx 60-65y Male = Female Western countries

Question 79

What are the clinical features of follicular non-hodgkin lymphoma?

Answer 79

Generalised lymphadenopathy w/ BM involvement +/- splenomegaly or hepatomegaly Indolent clinical course Cumulative risk of histologic transformation around 25% B-symptoms in 10%

Question 80

Should indolent stage IV non-hodgkin lymphoma be observed or treated? Why?

Answer 80

Treated with anti-CD20 antibodies (Rituximab) Much better survival

Question 81

What are the prognostic factors of follicular lymphoma? (Follicular lymphoma international prognostic index - FLIPI)

Answer 81

Age \>60 Ann Arbor stage III/IV Hb \<120 LDH \> ULN (Upper limit of normal) \>4 involved nodal sites

Question 82

What is CHOP and R-CHOP? When is it used?

Answer 82

Cyclophosphamide, H -Doxorubicin (Adriamycin), O-Vincristine, Prednisone R- Rituximab Used for Non-Hodgkin Lymphoma

Question 83

What is the role of rituximab-maintenance therapy in NHL?

Answer 83

Improves event-free rate in comparison to observation alone. Given for 2 years.

Question 84

What is the potential role of lenalidomide in follicular lymphoma?

Answer 84

Augments rituximab, improves PFS - may replace CHOP in future.

Question 85

What are the cytogenetics of DLBCL?

Answer 85

t(14;18) and bcl-2 rearrangement in \< 30%

Question 86

What is the epidemiology of DLBCL?

Answer 86

Median age at dx 55-60 Male \>female Minimal geographic variation Around 50% disseminated at dx

Question 87

What are the clinical features of DLBCL?

Answer 87

Usually - localised lymphadenopathy - BM involvement uncommon - B-sx in 30-40% - Aggressive but curable around 60% of cases - Risk of CNS involvement around 5%

Question 88

When is the international prognostic index used? What are it's factors?

Answer 88

Predicts survival in NHL. Performance status \> 2 Age \> 60 years Ann Arbor stage III or IV LDH above normal 2 extranodal sites of disease

Question 89

Describe the ECOG score

Answer 89

0 – Asymptomatic 1 – Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory. ie light housework, office work) 2 – Symptomatic, \<50% in bed during the day (Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours) 3 – Symptomatic, \>50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours) 4 – Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed _or chair_) 5 – Death

Question 90

What two prognostic subgroups have been identified by DNA microarray analysis in DLBCL? Which one has better survival?

Answer 90

Germinal-center B-Cell like (better survival) Type 3 (worse) Activated B-cell like (worst)

Question 91

What is first line therapy for DLBCL?

Answer 91

R-CHOP

Question 92

What are the most significant risk factors for CNS disease in lymphoma? What are the independent risk factors?

Answer 92

- testicular involvement - clinical stage - IPI score Independent - elevated LDH - \>1 extranodal disease site - ECOG \>2

Question 93

When is intrathethecal methotrexate used? Why is concurrent IV used? What is the role of rituximab?

Answer 93

Used in DLBCL if risk factors for CNS disease present (extranodal site + 1 other risk factor i.e. LDG, ecog, testicular) Intrathecal does not get into brain parenchyma, high dose MTx crosses the BBB. Reduces CNS disease in patients with IPI of 0 or 1

Question 94

What is a 'double hit' lymphoma? What is it's relevance?

Answer 94

Dual positivity for BCL-2 + C-MYC portends a poor prognosis, either de novo or with t-FL No standard treatment Rituximab-containing therapy provides a benefit but is still inadequate

Question 95

What are the cytogenetics of Burkitt's NHL?

Answer 95

Burkitt’s NHL: t(8;14) & c-myc, highly aggressive, curable - t(8;14) —\> overexpreesion of c-myc —\> malignant transformation through excess b-cell proliferation - associated with abdominal pain/fullness as disease prefers abdomen

Question 96

What is associated with primary cerebral NHL? What is the standard treatment?

Answer 96

HIV-related or sporadic Standard is high dost MTx and XRT

Question 97

What viruses are associated with HIV-related NHL?

Answer 97

HHV-8, EBV, also related to CD4 count Often extra-nodal, aggressive.

Question 98

What are the cytogenetics and location of disease in mantle-cell NHL?

Answer 98

- t(11;14) and bcl-1 translocation (cyclin D1) - frequent GI involvement (lymphomatous polyposis) - aggressive clinical behaviour, treatment difficult

Question 99

What genetic mutation is associated with 100% of hairy-cell leukaemias?

Answer 99

B-RAF

Question 100

What does overexpression of BCL-2 result in, in the context of lymphoma?

Answer 100

resistance to apoptosis

Question 101

What is Bruton's tyrosine kinase? When is an anti-BTK drug useful?

Answer 101

BTK is a kinase that plays a crucial role in B-cell development. Ibrutinib Is Highly Effective in Relapsed /Refractory CLL

Question 102

What are the marginal zone lymphomas?

Answer 102

MALT type Nodal type Splenic type

Question 103

Name the indolent lymphomas

Answer 103

- follicular, marginal zone, SLL/CLL

Question 104

What is the treatment for MALT lymphoma?

Answer 104

MALT - H-pylori and PPIs w/ frequent endoscopy, or whole-stomach XRT

Question 105

Name the aggressive lymphomas

Answer 105

DLBCL, Mantle cell lymphoma, primary CNS lymphoma, T-Cell lymphoma, high grade (Burkitt or lymphoblastic)

Question 106

What is the treatment for DLBCL and mantle-cell lymphoma?

Answer 106

R-CHOP Maybe Auto-SCT

Question 107

What is the treatment for primary CNS lymphoma?

Answer 107

Repetitive cycles of high-dose intravenous methotrexate with rituximab early in the treatment course produce better results than whole brain radiotherapy and with less cogni- tive impairment.

Question 108

What is the treatment for high grade lymphomas? (Burkitt or Lymphoblastic)

Answer 108

Intense, cyclic chemotherapy in the hospital similar to that given for ALL, and they also require intrathecal chemotherapy as central nervous system prophylaxis.

Question 109

How do peripheral t-cell lymphomas fare compared to B-cell disease?

Answer 109

Peripheral T-cell lymphomas usually have advanced stage nodal and extranodal disease and typically have inferior response rates to therapy compared to patients with aggressive B-cell disease

Question 110

What is the prognosis of indolent non-hodgkin lymphoma?

Answer 110

10–15 years. These diseases ultimately become refractory to chemotherapy.

Question 111

What is the likelihood of survival after relapse of non-hodgkins lymphoma?

Answer 111

Depends on whether the lymphoma is still responsive to chemotherapy. If the lymphoma remains responsive to chemotherapy, autologous hematopoietic stem cell transplantation offers a 50% chance of long-term lymphoma-free survival.

Question 112

Describe the Ann-Arbor staging system. What is it used for?

Answer 112

Used for Hodgkin's lymphoma. Ann Arbor I - one LN II - 2 or more on one side of diaphragm III - Both sides of diaphragm IV - disseminated w/ extranodal involvement A - no constitutinal sx B - 10% wt loss of six months, fever, drenching night sweats (one or more)

Question 113

What are the clinical findings of Hodgkin Lymphoma?

Answer 113

Bimodal - age 20s and then age 50s Painless mass, commonly in the neck Constitutional symptoms Pain in lymph node following alcohol ingestion Starts in one lymph node then spreads contiguously

Question 114

What is the treatment for Hodgkin lymphoma?

Answer 114

Treatment - RTx for stage 1A with high cervical LN and low ESR Otherwise - ABVD (BEACOPP if bad but toxic + infertility and no definite survival advantage) Stage I-II - usually short course ABVD +/- RTx - full course if bulky disease II-IV - full course ABVD w/ no RTx Must watch for bleomycin plum toxicity. Relapse may still be curable with CTx - high dose + auto SCT - 35-50% chance of cure.

Question 115

What is the prognosis of Hodgkin lymphoma?

Answer 115

Prognosis Factors: Stage, age, gender, Hb, alb, abc and lymphocyte count Cure rate 75% if zero to two factors present, excess of 90% if Ia or IIa disease.

Question 116

What is the pathogenesis of non hodgkin lymphoma?

Answer 116

Oncogene juxtaposed next to a either an Ig-gene (B-cell lymphoma) or t-cell receptor or related gene (t-cell lymphoma) —\> painless lymphadenopathy —\> indolent to rapidly progressive.

Question 117

What are the prominent non-hodgkin lymphomas?

Answer 117

85% of NHL are B-cell, mainly DLBCL and follicular

Question 118

What are the lab findings in non-hodgkin's lymphoma?

Answer 118

Normal peripheral blood, no circulating lymphoma cells Elevated LDH (prognostic) BMB - paratrabecular monoclonal lymphoid aggregates LP - (high grade) - meningeal involvement w/ malignant cytology CXR - mediastinal mass

Question 119

How do you make the diagnosis of non-hodgkin's lymphoma?

Answer 119

Tissue bx (LN or extra nodal tissue) for dx and classification

Question 120

What is the treatment for the indolent non-hodgkin lymphomas?

Answer 120

Indolent (follicular, marginal zone, SLL/CLL) Limited disease (1-2 contiguous LNs) —\> XRT for cure Most are disseminated though. - R-CHOP or R-CVP - allo-SCT if aggressive and low grade MALT - H-pylori and PPIs w/ frequent endoscopy, or whole-stomach XRT

Question 121

What is the treatment for the aggressive non-hodgkin lymphomas?

Answer 121

DLBCL - RCHOP +/-Auto SCT if responsive to chemo Mantle cell - as above Primary CNS - high dose IV MTx + rituximab High grade lymphoma (Burkitt/Lymphoblastic) - intense CTx plus intrathecal CTx as prophylaxis Peripheral T-cell lymphomas - poor response, usually disseminated disease.

Question 122

What is the prognosis for the indolent lymphomas?

Answer 122

Indolent - 10-15 years, ultimately becomes refractory and progresses

Question 123

What is the IPI (International Prognostic Index) used for in regards to non-hodgkin lymphoma? What are the factors?

Answer 123

IPI (International Prognostic Index) stratifies risk of those with intermediate grade lymphoma factors: Age \>60, elevated LDH, Stage III, or IV disease. 80% chance of complete response rate with no or one risk factors

Question 124

What are the two critical histopathological features of Hodgkin lymphoma?

Answer 124

_Reed-Sternberg cells_ in an appropriately _reactive (inflammatory) cellular background_

Question 125

What are the clinical findings of Hodgkin lymphoma?

Answer 125

Bimodal - age 20s and then age 50s Painless mass, commonly in the neck Constitutional symptoms Pain in lymph node following alcohol ingestion Starts in one lymph node then spreads contiguously

Question 126

What are the prognostic factors for Hodgkin lymphoma?

Answer 126

Prognosis Factors: Stage, age, gender, Hb, alb, WBC and lymphocyte count Cure rate 75% if zero to two factors present, excess of 90% if Ia or IIa disease.

Question 127

What is the aetiology of the acute leukaemias?

Answer 127

Aetiology - AML: adult disease around 60, increased incidence with age - ALL: 20% of adult acute leukaemia’s - no clear cause - radiation, benzene - prior Ctx - cyclophos, melphalan, other alkylators, etoposide - after toxins/CTx —\> MDS w/ Cr 5 & 7 abnormalities; etoposide Cr 11q23

Question 128

What is APL? Why does it differ from the other acute leukaemias?

Answer 128

APL (Acute promyelocytic leukaemia) - t(15;17) —\> PML-RARa fusion gene -\> interacts w/ retinoid acid receptor causing differentiation block. - can give ATRA —\> differentiated into neutrophils occur —\> neutrophils apoptose within minutes —\> cure!

Question 129

What are the favourable cytogenetics in AML?

Answer 129

Favourable - ‘core binding factors’ 15% of cases - t(8;21) - inv(16) - p(13;q22)

Question 130

What are the unfavourable cytogenetics in AML?

Answer 130

Unfavourable - poor prognosis -5, -7, del(5q), Abnormal 3q, Complex cytogenetics 2 or more monosomy’s 3 or more separate cytogenetic abnormalities

Question 131

What is the significance of the intermediate-risk subgroup of AML?

Answer 131

- normal cytogenetics or abnormalities w/o strong prognostic significance - new molecular markers - FLT3-ITD (internal tandem duplication) - 30% of CN-AML (cytogenetically normal AML) - very poor prognosis - NPM1 (nucleophospmin 1) - favorable prognosis

Question 132

What are the molecular markers of AML and what are their prognoses?

Answer 132

- FLT3-ITD (internal tandem duplication) - 30% of CN-AML (cytogenetically normal AML) - very poor prognosis - NPM1 (nucleophospmin 1) - favorable prognosis

Question 133

What are the cytogenetics of ALL?

Answer 133

- Common, early B, or T-cell Hyperdiploidy has a better prognosis but is in kids Unfavourable: Philadelphia chromosome and t(4;11) which has fusion genes involving the MLL gene at 11q23

Question 134

What are the clinical findings of ALL?

Answer 134

Clinical findings - presentation of days to weeks - bleeding of skin and mucosal surfaces due to thrombocytopaenia - DIC (APL and monocytic leukaemia) - Infection due to neutropaenia; gram negative bacteria (e.coli, Klebsiella, pseudomonas), or fungi (candida, aspergillus —\> cellulitis, pneumonia, perirectal infections. - Gum hypertrophy, bone and joint pain - Hyperleukocytosis - impaired circulation —\> headache, confusion, dyspnoea, need urgent leukopheresis and chemotherapy - 40% mortality

Question 135

What are the examination findings in ALL?

Answer 135

Pale, purpura, petechiae Stomatits, gum hypertrophy and rectal fissues in monocytic leukaemia Hepatosplengomegaly, lymphadenopathy Bone tenderness: sternum, tibia, femur

Question 136

What are the lab findings in ALL?

Answer 136

Hallmark: Pancytopaenia with circulating blasts Bone marrow: Hypercellular, \>20% blasts Hyperuricaemia DIC: low fibrinogen, fibrin degradations products _ALL: Mediastinal mass on CXR_ Meningeal leukaemia: Blasts in spinal fluid - 5% of cases, mainly monocytic AML Myeloperoxidase stain: Auer rod - eosinophilic needle-like inclusion in the cytoplasm = pathognomonic of AML (but has been superceded by flow cytometry) (Not in ALL because peroxidase is only in myeloid cells)

Question 137

Describe the flow cytometry findings of AML and ALL.

Answer 137

Flow cytometry: AML - CD13 or CD33 (myeloid antigens) ALL - B-lineage: CD19 (all B-Cells), and CD10 (common ALL antigen) T-lineage - CD2, 5, and 7 (some combo of), but NOT mature t-cell markers, i.e. 3, 4, or 8, and not surface iG. Almost all ALL cells express terminal deoxynucleotidyl transferase (TdT) (but not Burkitt type ALL)

Question 138

What is the treatment of AML?

Answer 138

- Anthracycline (daunorubicin or idarubicin) plus cytarabine - complete remission in 80-90% under 60, 50-60% older patients - Intermediate risk - cure rates ascend from 35-40% w/ CTx to 50-60% with allo-transplant - Positive core binding factor cytogenetics have a more favourable prognosis with CTx, while CTx alone is not helpful if unfavourable profile. - FLT3 inhibitors are in trial. Unfavourable - allo-transplant but poor cure rates 20-30%, worse if over 60 even if in first remission - may be a role for reduced intensity allo-transplant. - Prognosis drops with recurrence after first remission.

Question 139

What is the treatment of APL?

Answer 139

- Anthracycline plus ATRA - 90-95% CR - High risk (higher WBC count) - added arsenic improves outcomes - Arsenic can produce second remission in 90% of cases if required.

Question 140

What is the treatment of ALL? What if they are Ph+?

Answer 140

- Vincristine, Daunorubicin, Asparaginase, PreD (VDAC) - CR in 90% - Ph+ needs TKI in addition to standard CTx as T315i (resistant to all 3 TKIs) mutation much more common than in CML, unless older - 90% can achieve remission - Need CNS prophylaxis to avoid meningeal sequestration of leukaemia cells. - Low risk: 70% chance of cure with - Intermediate: 30-50% chance - High risk (adverse cytogenetics or poor response to CTx) —\> Allo-BMT

Question 141

What is the prognosis in AML?

Answer 141

AML: High dose post remission CTx —\> cure in 35-40%, high dose cytarabine superior Allo BMT curative in 50-60% of cases Cure rates for older patients very low even with remission

Question 142

How is complete remission (CR) in AML defined?

Answer 142

\<5% blasts on bmbx

Question 143

Which leukaemia is a widened mediastinum a hallmark of?

Answer 143

ALL

Question 144

Question 5 In females under 20 years of age treated successfully with radiotherapy for Hodgkin's disease, which one of the following is the most frequent second tumour occurring after 10 years? A. Acute leukaemia. B. Thyroid cancer. C. Non-Hodgkin's lymphoma. D. Breast cancer. E. Ovarian carcinoma.

Answer 144

D

Question 145

A 32-year-old man presents with weight loss, splenomegaly 20 cm below the left costal margin and a white cell count of 480 x 109/L [3.5-9.5]. Bone marrow examination confirms the diagnosis of an accelerated phase myeloid leukaemia in chronic phase. Which treatment option offers this man the best chance of long-term disease-free survival? A. Imatinib. B. Interferon and cytarabine. C. Hydroxyurea. D. Autologous bone marrow transplantation. E. Allogenic stem cell transplantation.

Answer 145

A. Patients with advanced-stage disease (accelerated phase or myeloid/lymphoid blast crisis) should be treated with a tyrosine kinase inhibitor alone or in combination with myelosuppressive chemotherapy. The doses of tyrosine kinase inhibitors in that setting are usually higher than those appropriate for chronic-phase disease. Since the duration of response to tyrosine kinase inhibitors in this setting is limited, these patients should ultimately be con- sidered for allogeneic stem cell transplantation.

Question 146

A 62-year-old woman underwent an elective cholecystectomy. Routine full blood examination revealed: ![]() Physical examination revealed no lymphadenopathy and no hepatosplenomegaly. The woman was asymptomatic. Flow cytometry revealed that the lymphocytosis marked as CD5+, CD19+ and CD23+. What is the most appropriate management of this patient? A. Observation alone. B. Prednis(ol)one. C. Chlorambucil. D. Combination chemotherapy. E. Autologous bone marrow transplantation.

Answer 146

Answer - A Treatment Early stage - observation Indications for tx: progressive fatigue, symptomatic lymphadenopathy, anaemia or thrombocytopaenia (either symptomatic and progressive Rai II, or stage III/IV disease) Staging - Rai Stage 0 - lymphocytosis (low-risk) Stage II - organomegaly (low risk) Stage III - anaemia (high risk) Stage IV - thrombocytopaenia (high risk)

Question 147

Question 53 A patient bleeds during low molecular weight heparin treatment. Which one of the following best indicates whether the heparin is contributing to bleeding? A. The activated partial thromboplastin time. B. The thrombin clotting time. C. The antifactor Xa activity. D. The prothrombin time. E. The tissue factor inhibitor assay.

Answer 147

Answer: C

Question 148

Describe the second test you would do after confirming a prolonged APTT and the meaning of it's results.

Answer 148

Mixing study: 50% pooled:50% pt plasma Imm/Incubated Correction = factor deficiency Imm/Incubated delay: Inhibitor (heparin) Immediate correction/Incubated delay = delayed inhibitor present Inhibitors: Heparin, Lupus AC (in vivo), acquired factor inhibitors (commonly VIII) Deficiencies: VIII (a), IX (b), VWF (VIII carrier)

Question 149

Which cytotoxics cause peripheral neuropathy?

Answer 149

Platins Vincristine

Question 150

What are the indications, MOA, and main side effect of hydroxyurea?

Answer 150

Polycythaemia vera and essential thrombocytosis Inhibits ribonucleotide reductase, decreasing DNA synthesis Myelosuppression

Question 151

What side effect does the antimetabolite drugs all have in common?

Answer 151

Myelosuppression

Question 152

What is Haemophilia A? What are it's clinical findings? How is it diagnosed? How is it treated?

Answer 152

Hamophilia A (VIII Deficiency) - X-linked recessive (men get, women carry) - 30% are spontaneously ACQUIRED - less common than B, more severe - mild \>5% (no bleed) /mod 1-5% (variable) / severe \<1% (VIII deficiency) - Once bleeding, all phenotypes bleed the same - _Haemarthroses_ (knee\>elbow\>ankle) 70-80% - _CNS bleeds_ in severe phenotype - Tx: prophylaxis in severe (aim to reduce to mod), early tx of bleeds with factor replacement (at home if simple), avoid antiplatelets, regular exercise, replace factors (plasma/recombinant, cry in developing world), DDAVP (increases VIII and VWB levels, transexamic acid (antifibrinolytics) to stop clot breakdown

Question 153

What is vonWillebrands disease?

Answer 153

VWB (deficiency or dysfunction - multimeric protein, plasma & endothelial cells (Weibel-palade bodies) - Expressed on activated endothelial cells, released from alpha granules of activated platelets - synthesized in megakaryocytes - T ½ = 12 hours - binds plt at injury site, _carries VIII_ - _decreased plt adhesion, decreased VIII_ → bleeding - Increased by: age, African, non O blood, inotropes (aderenaline), inflammation, hormones (OCP, pregnancy, periods) - Type 1: _partial_ quantitative deficiency, decreased VWF levels, likely gene mutation, significant bleeding and FHx of. - Type 3: Rare, _near complete deficiency_ Tx: DDAVP (increases VIII and VWB levels), human derived VWF with VIII, antifibrinolytics (transexamic acid)

Question 154

Which is more common, haemophilia A or B?

Answer 154

B. Factor 9 deficiency

Question 155

What are the causes of a prolonged APTT and INR?

Answer 155

Global dysfunction (APTT & INR) DIC = plus low fibrinogen and high d-dimer Liver disease → synthetic ftn (check albumin), TV factors Direct thrombin inhibitors / Xa inhibitors (dabigatran and rivaroxaban) Common pathway deficiency (rare)

Question 156

What are the lab findings in DIC?

Answer 156

DIC = Low APTT and INR plus low fibrinogen and high d-dimer

Question 157

What does the INR/PT look at in terms of the coagulation cascade? What prolongs it?

Answer 157

INR/PT (Extrinsic/Tissue factor pathway) Fibrinogen, prothrombin, V, VII, & X Particularly sensitive to VII Prolonged by Vit-K antagonism (Warfarin), deficiency (ETOH/malabsorption), undx VII deficiency Relationship to factor-level is non-linear (still have 30% of factors if level is 2, low bleeding risk) Curve plateaus at 3 and beyond so bleeding risk same between 3-14 This is the main pathway activated by endothelial damage

Question 158

Which coagulation pathway is activated by endothelial damage?

Answer 158

Extrinsic pathway

Question 159

What does the anti-Xa level test?

Answer 159

Anti-Xa assay Measures heparin effect Can use to titrate dose down

Question 160

What is the Thrombin Clotting Time (TCT) test used for?

Answer 160

Thrombin Clotting Time (TCT) Used when mixing study not corrected - looks for an inhibitor Increased by heparin (reptilase normal), faulty fibrinogen, increased fibrin degradation products, and dabigatran

Question 161

What to protein C & S do?

Answer 161

Protein C & S (anticoagulants) Activated by thrombin to form a negative feedback loop. Forms the APC (activated protein C) complex with protein S, which then degrades Factor V and VIIIa (so blocks the common pathway and last step of the intrinsic pathway respectively

Question 162

What does the reptilase test do?

Answer 162

Reptilase test - looks for an acquired inhibitor that isn't heparin Reptilase splits fibrinogen →fibrin Not prolonged by heparin

Question 163

Which factors belong to the intrinsic coagulation pathway?

Answer 163

12, 11, 9, and 8

Question 164

Which factors belong to the extrinsic coagulation pathway?

Answer 164

7 and tissue factor

Question 165

Which factors belong to the common coagulation pathway?

Answer 165

Factors 10, 5, 2 (prothrombin), and 1 (fibrinogen)

Question 166

What does factor 12 do?

Answer 166

Starts the intrinsic pathway coagulation cascade

Question 167

What does factor VII do?

Answer 167

The main role of factor VII (FVII) is to initiate the process of coagulation in conjunction with tissue factor (TF/factor III). Tissue factor is found on the outside of blood vessels - normally not exposed to the bloodstream.

Question 168

What does factor VIII do?

Answer 168

In response to injury, coagulation factor VIII is activated and separates from von Willebrand factor.

Question 169

What is the main role of the extrinsic pathway?

Answer 169

The main role of the tissue factor pathway is to generate a "thrombin burst", a process by which thrombin, the most important constituent of the coagulation cascade in terms of its feedback activation roles, is released very rapidly.

Question 170

What is the role of factor V?

Answer 170

Factor V: Procoagulant that amplifies thrombin production. Small amount of thrombin at a wound activates factor V via limited proteolysis, which in turn becomes a cofactor in the prothrombinase complex, cleaving prothrombin to generate more thrombin in a positive feedback loop. Thrombin then generates a negative feedback loop by converted protein C to activated protein C.

Question 171

What is the role of protein C in the coagulation cascade?

Answer 171

Activated protein C (APC): natural anticoagulant, cleaves and inactivates activated factor V and VIII which then reduces thrombin production. APC affects both factor V and factor Va (activated V) to increase clotting risk. 1. When APC cleaves factor V (the inactive version), it (factor V) becomes a cofactor in further degration of Va and VIIIa. With the point mutation at position 506 on Factor V, APC can't cleave the factor, it becomes less effective as a cofactor and the degradation 2. APC performs a series of sequential cleavages on Factor Va, the first of which is the position 506 point. With this site removed, sequential cleavage cannot happen, resulting in 20x slower degration of the factor (factor V Leiden). With the activated factor unable to be cleaved, more thrombin continues to be generated. These effects contribute equally to thrombosis and explain the stronger presentation in homozygotes.

Question 172

What is leucodepletion? Why is it important?

Answer 172

Leucodepletion is the removal of white blood cells from a blood component. In Australia, this applies to whole blood, red cells and platelets. The potential benefits of leucodepletion for patients include: - Reduction in platelet refractoriness 
- Reduction in febrile non-haemolytic transfusion reactions. (FNHTR) 
- Reduction in CMV transmission risk 
- Improved chance of finding an organ transplant match if required 
- Reduction in storage lesion effect


Question 173

Which of the following transfusion reactions is leucodepletion most effective in preventing? A. Febrile non-haemolytic transfusion reaction. 
 B. Transfusion associated graft versus host disease. 
 C. Anaphylaxis. 
D. Transfusion related acute lung injury. 
 E. Delayed haemolytic transfusion reaction.

Answer 173

Answer: A

Question 174

What is a febrile non-haemolytic transfusion reaction? What causes it?

Answer 174

1. Unexpected temperature rise (≥38ºC or ≥1ºC above baseline, if baseline ≥37ºC) during or shortly after transfusion. Usually an isolated finding. 2. Caused by leucocyte antigen-antibody reaction and by cytokine accumulation produced by leucocytes in transfused blood. Formation of cytokines can be avoided if the leucocytes can be removed immediately (leucodepletion) FNHTR is also caused by the presence of recipient antibodies (raised as a result of previous transfusions or pregnancies) reacting to donor human leucocyte antigens (HLA) or other antigens. These antigens are present on donor lymphocytes, granulocytes, or platelets.

Question 175

With regards to blood products, what is a storage lesion? How can you reduce it?

Answer 175

The changes occurring in storage of RBCs including increased ammonium, free Hb, and potassium, and decreased ATP, 2,3DPG, labile proteins (complement, coagulation factors, fibronectin), sodium, and pH. Leucocyte degradation during storage results in cell fragments which may not be removed by post-storage filtration - can provoke HLA or platelet alloimmunisation. In leucodepleted blood - there is a lower incidence of alloimmunisation and (possibly) diminished immunomodulation that may result from the transfusion of membrane fragments.

Question 176

What is the most common cause of transfusion-related fatalities? What are the symptoms, timeframe, and incidence?

Answer 176

TRALI
 Symptoms: Acute onset of fever, chills, dyspnoea, tachypnoea, tachycardia, hypotension, hypoxaemia and noncardiogenic bilateral pulmonary oedema leading to respiratory failure during or within 6 hours of transfusion. Implicated in transfusion of unfractionated plasma-containing components. 
Incidence: 1:10,000 most commonly reported.

Question 177

With regard to transfusion, what constitiutes a delayed haemolytic transfusion reaction? Which blood groups are associated with it? How do you treat it?

Answer 177


Patients may present with unexplained fever and anaemia usually 2 to 14 days after transfusion of a red cell component. Unexplained fever and anaemia 2-14 days after transfusion of red-cell component. May also have jaundice, high bilirubin, high LDH, reticulocytosis, spherocytosis, positive antibody screen and a positive Direct Antiglobulin Test (DAT). Causes: After transfusion, transplantation or pregnancy, a patient may make an antibody to a red cell antigen that they lack. If the patient is later exposed to a red cell transfusion which expresses this antigen a DHTR may occur. DHTRs may also occur with transfusion transmitted malaria and babesiosis. Blood group antibodies associated with DHTRs include those of the Kidd, Duffy, Kell and MNS systems, in order of decreasing frequency. Most delayed haemolytic reactions have a benign course and require no treatment, however life-threatening haemolysis with severe anaemia and renal failure may occur. If an antibody is identified, you may request for antigen-negative blood if further transfusion is needed.

Question 178

Name the thrombin inhibitors

Answer 178

Dabigatran Argotroban Bivalriduin Lepirudin

Question 179

Name the XA inhibitors)

Answer 179

Xa Inhibitors Rivaroxaban Apixaban Fondaparinux (via AT Danaprinoid

Question 180

Name the combined Xa & thrombin inhibitors

Answer 180

Heparin

Question 181

Name the vitamin K antagonist and what it inhibits

Answer 181

Warfarin (Thrombin (II), VII, IX and X) via impaired hepatic synthesis.

Question 182

What is the mechanism of action, clearance and indications for Rivaroxaban? What blood tests does it affect?

Answer 182

Factor Xa inhibitor T ½ = 12-17h Peak 1-3h Renally excreted Minimally protein bound Irreversible Monitor: dilute thrombin time (special) Prolongs APTT & INR Does not affect fibrinogen level Indicated for stroke prevention (non-valvular AF), thromboprophylaxis post hip and knee replacement

Question 183

How do you manage bleeding associated with dabigatran and rivaroxaban?

Answer 183

Dabigatran or Rivaroxaban Bleeding Coag screen, G&H, usual bloods, stop drug Mild: compression, antifibrinolytics (tranexamic acid) QID, delay further oral anticoagulation Mod/Severe: Antifibrinolytics, as for usual bleeding, transfuse, consider charcoal if \<2h for dabigatran, \<8h for rivaroxaban Consider HD for dabigatran

Question 184

How does dabigatran work? What blood tests does it affect? Indications? How do you manage bleeding?

Answer 184

Direct thrombin (IIa) inhibitor T ½ = 7-11h Peak 1-3h 50% renally excreted Highly protein bound Irreversible Prolongs APTT & INR, TCT Does not affect fibrinogen level Indicated for stroke prevention (non-valvular AF), thromboprophylaxis post hip and knee replacement, treatment of DVT Bleeding: INR, APTT,TCT, Fibrinogen, check renal ftn, if TCT normal then low dabigatran level, supportive, tranexamic acid, charcoal, dialysis

Question 185

What test would you do to see if the dabigatran level was low?

Answer 185

Thrombin clotting time. It will be normal if the dabigatran level is low.

Question 186

How does heparin work?

Answer 186

Heparin binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop. The activated AT then inactivates thrombin and other proteases involved in blood clotting, most notably factor Xa.

Question 187

What is tranexamic acid? How does it work? When is it useful?

Answer 187

It is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin, by binding to specific sites of both plasminogen and plasmin, a molecule responsible for the degradation of fibrin, a protein that forms the framework of blood clots. Useful where bleeding is going to be a problem, i.e dental extraction, certain surgeries.

Question 188

Describe factor V leiden disease: - mechanism - epidemiology - clinical findings - when to test

Answer 188

Factor V Leiden - mutant Factor V, can’t be switched off by APC so clotting continues. - most common hereditary hyper coagulability disorder among caucasians. - restricted to veins (so DVT and PE, not strokes or heart attaches) - happens in 30% of unprovoked DVT/PE - risk increases in pregnancy or oestrogen containing drugs. - suspect in any DVT patient under the age of 45

Question 189

How do you test for factor V leiden disease?

Answer 189

Most laboratories screen 'at risk' patients with either a snake venom (e.g. dilute Russell's viper venom time) based test or an aPTT based test. In both methods, the time it takes for blood to clot is decreased in the presence of the factor V Leiden mutation. This is done by running two tests simultaneously; one test is run in the presence of activated protein C (APC) and the other, in the absence. A ratio is determined based on the two tests and the results signify to the laboratory whether APC is working or not. These are quick, three minute, automated tests that most hospital laboratories can easily perform.

Question 190

A 42-year-old previously healthy woman presents with an above-knee deep venous thrombosis of the right leg complicated by probable pulmonary thrombo-embolism. She has no clinical risk factors such as recent surgery or trauma. In the investigation of her thrombo-embolic disease, which one of the following is the most likely abnormality to be found? A. Lupus anticoagulant. B. Protein C deficiency. C. Protein S deficiency. D. Dysfibrinogenaemia. E. Factor V Leiden.

Answer 190

Answer E. The most common of the inherited disorders of DVT.

Question 191

What does the prothrombin time measure?

Answer 191

PROTHROMBIN TIME (PT) — The prothrombin time (PT) (figure 1) is used to assess the extrinsic pathway of clotting, which consists of tissue factor and factor VII, and coagulation factors in the common pathway (factors II [prothrombin], V, X, and fibrinogen).

Question 192

What does the aptt measure?

Answer 192

ACTIVATED PARTIAL THROMBOPLASTIN TIME (aPTT) — The activated partial thromboplastin time (aPTT or PTT) is used to assess the integrity of the intrinsic coagulation pathway (prekallikrein, high molecular weight kininogen, factors XII, XI, IX, VIII) and final common pathway (factors II, V, X, and fibrinogen), and to monitor therapy with unfractionated heparin.

Question 193

What does FFP contain and when is it used?

Answer 193

Fresh frozen plasma comprises the acellular component of blood and contains _**all of the coagulation factors**._ It is used in patients with coagulopathy who are bleeding, or at risk of bleeding, when more specific therapy is not appropriate or available. Fresh frozen plasma is most commonly used in massive transfusion, cardiac bypass, liver disease or acute disseminated intravascular coagulopathy. It is essential as the exchange product in plasmapheresis for TTP

Question 194

What is in cryoprecipitate and when is it used?

Answer 194

Mainly used in DIC to replace fibrinogen. Sometimes to correct platelet dysfunction in CKD. Derived from FFP. Cryoprecipitate contains most of the factor VIII, factor XIII, von Willebrand factor, and fibrinogen. Cryodepleted plasma can be used in plasma exchange for thrombotic thrombocytopenic purpura.

Question 195

What does Factor XIII do?

Answer 195

Factor XIII or fibrin stabilizing factor is an enzyme (EC 2.3.2.13) of the blood coagulation system that crosslinks fibrin. Upon activation by thrombin, factor XIIIa acts on fibrin to form γ-glutamyl-Є-lysyl amide cross links between fibrin molecules to form an insoluble clot.

Question 196

Transfusion transmitted infections are now most likely to occur in Australasia following the infusion of which one of the following: A. red blood cells. B. platelets. C. factor VIII concentrate. D. fresh frozen plasma. E. anti D immunoglobulin.

Answer 196

B. Bacterial contamination of blood products, especially in platelets that are stored at room temperature, is the most common infectious risk of blood transfusion, occurring in approximately 1 of 2000-3000 platelet transfusions. Transfusion–transmitted sepsis, while less common, can cause severe illness and death.

Question 197

Why don't pregnant patients with Von Willebrands disease need treating?

Answer 197

Pregnant patients with vWD usually do not require treatment because of the natural physiologic increase in vWF levels

Question 198

Which drug is useful in the treatment of mild von Willebrands disease?

Answer 198

DDAVP is useful in the treatment of mild bleeding in most cases of type 1

Question 199

What are the lab findings in Von Willebrands disease?

Answer 199

vWF activity (by ristocetin co-factor assay) and Ag are mildly depressed, whereas the vWF multimer pattern is normal. Except in the more severe forms of vWD that feature a significantly decreased factor VIII activity, the aPTT and PT in vWD are usually normal.

Question 200

What are the clinical findings of vonWillebrand disease?

Answer 200

Type 1 vWD usually have mild or moderate platelet-type bleeding (especially involving the integument and mucous membranes).

Question 201

What is the main type of vonWillebrands disease? What proportion does it make up?

Answer 201

Between 75% and 80% of patients with vWD have type 1. It is a quantitative abnormality of the vWF molecule that usually does not feature an identifiable causal mutation in the vWF gene.

Question 202

What is von Willebrand factor? What does it do?

Answer 202

vWF is an unusually large multimeric glycoprotein that binds to its receptor, platelet glycoprotein Ib, bridging platelets together and tethering them to the subendothe- lial matrix at the site of vascular injury. vWF also has a binding site for factor VIII, prolonging its half-life in the circulation.

Question 203

What is the most common inherited bleeding disorder? What does the factor do normally?

Answer 203

The most common inherited bleeding disorder. von Willebrand factor aggregates platelets and prolongs the half-life of factor VIII.

Question 204

What is the significance of the lupus anticoagulant other than it's presence in connective tissue disease? Which test confirms it's presence?

Answer 204

May occur with increased frequency in individuals with underlying infection, inflammation, or malignancy, and they also can occur in asymptomatic individuals in the general population. A prolongation in the aPTT is observed that does not correct completely on mixing. Russell Viper Venom test.

Question 205

How does uremia cause bleeding?

Answer 205

Damages platelets via --\> Increased Nitric oxide; decreased release of granules

Question 206

How do salicylates cause bleeding?

Answer 206

Irreversible inhibition of platelet cyclooxygenase

Question 207

How do NSAIDS cause bleeding?

Answer 207

Reversible inhibition of platelet cyclooxygenase

Question 208

How do SSRIs induce bleeding?

Answer 208

Decreases serotonin in dense granules in platelets

Question 209

What is a Heinz body? In what condition would you see them?

Answer 209

Heinz bodies appear as small round inclusions within the red cell body and are formed by damage to the hemoglobin component molecules, usually through oxidant damage, or from an inherited mutation (i.e. change of an internal amino acid residue). In the spleen, macrophages attempt to remove these, leaving bite cells. Found in G6PD deficiency Alpha thalassaemia NADPH deficiency Liver disease.

Question 210

What is HbH?

Answer 210

The excess β chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves. The excess γ chains form tetramers which are poor carriers of O2 since their affinity for O2 is too high so it is not dissociated in the periphery.

Question 211

What are Howell-Jolly bodies?

Answer 211

Howell–Jolly bodies are histopathological findings of basophilic nuclear remnants (clusters of DNA) in circulating erythrocytes. During maturation in the bone marrow late erythroblasts normally expel their nuclei, but in some cases a small portion of DNA remains. Its presence usually signifies a damaged or absent spleen.

Question 212

What is autoagglutination?

Answer 212

Autoagglutination represents clumping of an individual's red blood cells (RBCs or erythrocytes) by his or her own serum due to the RBCs being coated on their surface by antibodies. Happens in COLD haemagglutinin disease.

Question 213

Which haematological malignancy is AIHA most commonly associated with?

Answer 213

CLL

Question 214

What is a schistocyte? What causes it?

Answer 214

Fragmented red blood cell Also known as 'helmet cell' Associated with microangiopathy Most commonly mechanical valves or AS HUS TTP DIC

Question 215

What is the general pathogenesis of thrombotic microangiopathy? TTP? HUS?

Answer 215

Thrombotic microangiopathy Pathogenesis Platelet aggregation due to either endothelial damage (HUS) or protease insufficiency (ADAMST-13, TTP) —\> shearing of circulating erythrocytes —\> thrombocytopaenia and haemolytic anaemia. TTP —\> Autoantibodies against ADAMST-13, a protease that cleaves ultra-large vWF multimers —\> accumulation of uncleaved multimers —\> TTP (Congenital TTP is a gene mutation resulting in decreased levels of Adamst-13) Adults HUS —\> damage to endothelial cells (E.coli, cancer, stem cell transplant, HIV, drugs) —\> platelet aggregation. Kids

Question 216

What are the clinical findings in TTP and HUS? What is required for diagnosis?

Answer 216

For diagnosis: Microangiopathic haemolytic anaemia Thrombocytopaenia Pentad (not req for dx) Microangiopathyc haemolytic anaemia Thrombocytopaenia Fever Renal insufficiency Neurological abnormalities Recent diarrhoeal illness (HUS)

Question 217

What are the lab findings in TTP and HUS?

Answer 217

Haemolysis: elevated LDH, bili, low haptoglobin, reitculocytosis, negative DAT, schistocytes on blood smear) Thrombocytopaenia ARF (usually HUS) Positive stool culture for E.coli or shiga-toxin Coagulation studies are normal

Question 218

What is the treatment for TTP and HUS?

Answer 218

Plasma exchange and replace w/ FFP —\> essential, 95% mortality without it Supportive only if diarrhoea-HUS Continue to exchange for two days until platelet count and LDH are normal for at least 2 days. Give FFP if no plasma available Platelet transfusions are CONTRAINDICATED as may make it worse Dialyse if significant renal failure Relapse —\> Plasma exchange

Question 219

What the main differences between TTP and HUS?

Answer 219

TTP —\> autoantibody to ADAMST-13 Usually has fever and neurological defects HUS —\> Endothelial damage - usually due to e.coli Usually has renal failure, no fever or neurological defects Recent history of diarrhoea

Question 220

What is the pathogenesis of hereditary spherocytosis?

Answer 220

Familial defect of red cell membrane due to an abnormality in spectrin, actin or other proteins. Scaffolding defect results in decrease surface to volume ratio and loss of central pallor of the RBC —\> less deformability —\> trapping of RBCs in the spleen —\> removal by splenic macrophages.

Question 221

What are the clinical findings in hereditary spherocytosis?

Answer 221

Autosomal dominant Variable anaemia May have aplastic crisis due to infection (Parvo B19) or folate deficiency Gallstones from a young age Jaundice Icterus Palpable spleen

Question 222

What are the lab finding in hereditary spherocytosis?

Answer 222

Smear: Reticulocytosis always, large amount of spherocytes on the blood film, microcytosis Increased MCHC Negative coombs Increased osmotic fragility (abnormal vulnerability to swelling induced by hypotonic media)

Question 223

What is the treatment of hereditary spherocytosis?

Answer 223

Daily folic acid Splenectomy (if severe) cures it (stops destruction, doesn’t cure abnormal RBCs)

Question 224

What is the pathogenesis of paroxysmal nocturnal haemoglobinuria?

Answer 224

Pathogenesis Acquired defect in PIG-A (phosphatidylinositol class A) gene —\> deficient GPI anchor for cell membrane protein —\> deficient complement regulating proteins CD55 and CD59 —\> unregulated formation of MAC attack complex on RBC membranes —\> intravascular haemolysis. Free haemoglobin is released into the blood —\> scavenges nitric oxide —\> oesophageal spasm, erectile dysfunction, renal damage, thrombosis (primary cause of death) In short - abnormal sensitivity of the RBC membrane to complement.

Question 225

What are the clinical findings in PNH?

Answer 225

Episodic haemoglobinuria on first morning urine (pH drops at night —\> haemolysis) Thrombosis (mesenteric and hepatic veins, CNS veins (sagittal), skin vessels (painful nodules) May arise on it’s own or in setting of aplastic anaemia with progression to myelodysplasia or AML

Question 226

What are the lab findings in PNH?

Answer 226

Variable anaemia May or may not have reticulocytosis Smear is non diagnostic - may have macro-ovalocytes and polychromasia Urine haemosiderin (chronic haemolysis) Iron deficiency due to haemoglobinuria Flow cytometry: Deficiency of CD55 and 59 Low WBC and PLT, esp if aplastic anaemia

Question 227

What is the treatment of PNH?

Answer 227

Mild - do nothing Severe or thrombosis —\> Eculizumab Aplastic anaemia or MDS —\> allo STC Replace iron Corticosteroids can be useful

Question 228

What is eculizumab and what are the benefits?

Answer 228

Anti-terminal complement protein C5 (initiator of MAC) - used for PNH. Improves QOL, reduces haemolysis, transfusion requirements and thrombosis risk

Question 229

What is the pathogenesis of G6PD deficiency?

Answer 229

Hereditary enzyme (G6PD) defect (deficiency) —\> excess oxidised glutathione —\> haemoglobin denatures —\> precipitates Heinz bodies causing RBC membrane damage —\> premature removal of RBCs by spleen (extravascular haemolysis)

Question 230

What are the clinical findings in G6PD deficiency?

Answer 230

X-linked Found in Africans (milder), and Mediterraneans (severe), and Ashkenazi Jews. Episodic haemolysis in response to oxidative stress on RBCs (infection, exposure to certain drugs

Question 231

Why is the haemolysis in G6PD deficiency often self limiting?

Answer 231

Self limited haemolysis because old RBCs w/ low enzyme activity are removed and replaced with young RBCs (reticulocytes) which are G6PD replete. Severe deficiency (Mediterranean variant) —\> chronic haemolytic anaemia.

Question 232

What are the lab findings in G6PD deficiency?

Answer 232

Between episodes —\> normal blood During —\> Hb rarely drops below 80, reticulocytosis, increased bill Smear: Bite/blister cells (pitting of Hb aggregates by the spleen). Heinz bodies on cresyl violet stain Low G6PD levels BETWEEN episodes (false normal during or shortly after due to replete retics), check weeks later. Severe disease - permanently low enzyme levels

Question 233

What is the treatment of G6PD defiency?

Answer 233

Avoid oxidant drugs

Question 234

What drugs should you avoid in G6PD deficiency and why?

Answer 234

They are oxidant drugs causing oxidant stress --\> haemolysis. Drugs to avoid: Dapsone (leprosy), methylene blue, phenazopyridine, primaquine (malaria, PCP), rasburicase (gout, tumor lysis syndrome), toluidine blue, nitrofurantoin

Question 235

What is the pathogenesis of sickle cell anaemia?

Answer 235

Autosomal recessive disorder —\> DNA base change of valine for glutamine on the B-globin change —\> Bs —\> A2BS2 —\> HbS —\> unstable, polymerises under stress (dehydration, acidosis, hypoxia) —\> sickled RBCs —\> splenic sequestration —\> haemolytic crises & eventual splenic infarction \* HbF cannot polymerise —\> retards sickling when present

Question 236

What are the clinical findings in sickle cell anaemia?

Answer 236

Onset in 1st year of life (HbF levels fall due to y-globin switching to B-globin Chronic haemolytic anaemia —\> jaundice, pigment gallstones (young) splenomegaly (young), poorly healing ulcers over lower tibia Life threatening severe anaemia during haemolytic or aplastic crises (viral or other infections, folic acid deficiency) Acute painful episodes due to acute vaso-occlusion Delayed puberty, increased incidence of infection due to hyposlenism Chronically ill, jaundice, hepatomegaly but no splenomegaly Cardiac enlargement with hyper dynamic and systolic murmurs Nonhealing lower leg ulcers

Question 237

What are the features of the vaso-occlusive disease in sickle-cell anaemia?

Answer 237

Acute painful episodes due to acute vaso-occlusion from clusters of sickled cells (spontaneous, infection, dehydration, hyopxia) Pain —\> back and long bones, chest, lasts hours to days Acute vaso occlusion —\> sagital sinus thrombosis (strokes), priapism, organ and bone necrosis, renal medullary papillae infarcts —\> gross haemoturia (more in trait), retinopathy, plum HT Not assoc w/ increased haemolysis Ischaemic necrosis of bone due to vascular occlusion —\> salmonella osteomyeletis

Question 238

What are the lab findings of sickle cell anaemia?

Answer 238

Lab findings Chronic haemolytic anaemia Smear: Irreversibly sickled cells, nucleated RBCs, hyposplenism: Howell-Jolly bodies and target cells Elevated WBC and reactive thrombocytosis Elevated indirect bili Hb EPG (diagnostic): HbS comprises 85-98% of the haeoglbonin Homozygous - no HbA present, elevated HbF (high = better prognosis)

Question 239

What is the treatment of sickle-cell anaemia?

Answer 239

Allo SCT is curative \>80% of kids Hydroxyurea increases HbF levels epigenetically, reduces painful crises and overall survival Supportive care is mainstay - folic acid, transfuse in aplastic or haemolytic crises, pneumovax. Hydrate and oxygenate through acute painful episodes. Acute vaso-occlusive crises (pain, acute chest, priapism, stroke) —\> exchange transfusion

Question 240

What is the clinical significant of sickle-cell trait?

Answer 240

Heterozygotes —\> may be positive on screening test, HbS 40% on EPG Haematologically normal May experience sudden cardiac death and rhabdo during vigorous exercise esp at high altitude Increased risk of VTE May have renal medullary disease as it’s acidotic —\> microscopic and gross haematuria. No treatment.

Question 241

What is the mechanism of autoimmune haemolytic anaemia?

Answer 241

Acquired IgG autoantibody binds RBC at body temp —\> Antibody directed at basic component of Rh system present on most human RBCs —\> splenic macrophage recognises Fc portion of antibody —\> removal of RBC membrane by macrophage —\> spherocyte formed —\> decreased deformability -\> trapped in splenic red pulp —\> haemolysis

Question 242

What is the second mechanism of haemolysis in autoimmune haemolytic anaemia?

Answer 242

If large amounts of IgG —\> fixation of complement —\> presence of C3b on RBC —\> destruction of RBC by hepatic Kupffer cells (Direct complement driven lysis anywhere else is rare).

Question 243

What is the aetiology of autoimmune haemolytic anaemia?

Answer 243

50% idiopathic Rest: SLE, CLL, or lymphoma Drug induced: Antibody is against membrane-drug complex. (Penicillim ceftriaxone, piperacllin, cefotetan, and fludarabine (immunosuppresson —\>defective immune surveillance)

Question 244

What are the clinical findings in autoimmune haemolytic anaemia?

Answer 244

Rapid onset haemolytic anaemia Fatigue and dyspnoea Angine or cognitive heart failure Jaundice and splenomegaly

Question 245

What are the lab findings in autoimmune haemolytic anaemia?

Answer 245

Variable anaemia, may be v severe Reticulocytosis and spherocytosis on smear, nucleated RBCs if severe Indirect hyperbilirubinaemia 10% have concurrent immune thrombocytopaenia (Evans syndrome) DAT positive for IgG +/- C3b

Question 246

What is Evans syndrome?

Answer 246

AIHA + concurrent immune thrombocytopaenia

Question 247

What is the difference between the direct antiglobulin test (Coombs) and indirect?

Answer 247

DAT: rabbit IgM antibody against Human iG or complement —\> agglutination = presence of antibody on RBC surface Indirect: patient SERUM mixed with type O RBCs —\> agglutination = presence of free antibody Positive IDAT = large amount of autoantibody that has saturated RBC binding sites, winding up in the serum.

Question 248

What is the treatment of AIHA?

Answer 248

Autoantibody makes it difficult to get a compatible cross-match Pred 1mg-2mg/kg Transfused RBCs will survive similarly to the patient’s own Splenectomy potentially curable Rapid + severe —\> therapeutic plasmapheresis Rituximab may be effective

Question 249

What is the prognosis for AIHA like?

Answer 249

The long-term prognosis for patients with this disorder is good, especially if there is no underlying autoimmune disorder or lymphoma.

Question 250

What is the pathogenesis of cold agglutinin disease?

Answer 250

IgM autoantibody (cold agglutinin) against I antigen on RBCs —\> binds and fixes complement at peripheries (cool areas) —\> RBC returns to warmer circulation —\> IgM dissociates —\> only complement (C3b) left behind —\> recognised by hepatic Kupffer cells —\> RBC sequestration and destruction, sometimes MAC attack

Question 251

What is the aetiology of cold agglutinin disease?

Answer 251

Idiopathic Waldenstrom or CLL due monoclonal iGm paraprotein Infectious: Mycoplasma pneumonia, mono, measles, mumps

Question 252

What are the clinical findings of cold agglutinin disease?

Answer 252

Mottled or numb fingers or toes Episodic low back pain Dark coloured urine one exposure to cold Haemolytic anaemia is rarely severe

Question 253

What are the lab findings in cold agglutinin disease?

Answer 253

Mild anaemia w/ reticulocytes Agglutinated RBCs on smear at room temp DAT + for C3b only Serum cold agglutinin titer semi-quantitative

Question 254

What is the treatment of cold agglutinin disease?

Answer 254

Avoid cold! Splenectomy and pred ineffective unless underlying lymphoproliferative disease (haemolysis takes place in liver and blood) Rituximab is treatment of choice, relapse is effectively retreated May need to use alkylators in severe disease May be difficult to find compatible blood TRANSFUSE THROUGH A BLOOD WARMER

Question 255

What is the hallmark of microangiopathic haemolytic anaemia?

Answer 255

The finding of fragmented red blood cells (schistocytes, helmet cells) on the peripheral blood smear. The anemia is intravascular, producing hemoglobinemia, hemoglobinuria and, in severe cases, methemalbu-minemia

Question 256

Is the anaemia of cold-agglutinin disease intravascular or extravascular?

Answer 256

Mainly extravascular --\> liver Intravascular due to fixation of complement

Question 257

What is the mechanism of iron deficiency in chronic microangiopathic haemolytic anaemia?

Answer 257

Continuous low-grade haemoglobinuria

Question 258

Question 66 A 45-year-old woman presents with progressive lethargy over 10 days. There is no history suggestive of infection. There has been no previous medication. Initial investigations show: ![]() Which one of the following is most likely to be present on the blood film? A. Plasma cells. B. Red cell autoagglutination. C. Red cell fragmentation. D. Hypersegmented neutrophils. E. Target cells.

Answer 258

Answer: B - cold agglutinin disease is DAT positive of complement only

Question 259

Question 69 A 38-year-old woman presents with a one-week history of dyspnoea on exertion. She has had no previous medical problems and is taking no medications. Physical examination is unremarkable apart from mild pallor and a palpable splenic tip. Initial investigations are as follows: ![]() The blood film is shown below. ![]() Which one of the following conditions is the most likely cause of these findings? A. Hereditary spherocytosis. B. Systemic lupus erythematosus. C. Infectious mononucleosis. D. Mycoplasma infection. E. Cold haemagglutinin disease.

Answer 259

Answer: B This is autoimmune haemolytic anemia - there are minimal spherocytes on the film so it's not A - and C, D, and E all cause cold agglutinin disease and are only positive for C3 on the DAT as the Ig hs dissociated (it's IgM anyway)

Question 260

A 69-year-old woman commences a chronic transfusion program for anaemia secondary to myelodysplasia. She experiences a non-haemolytic febrile transfusion reaction during each of two red cell transfusions administered four weeks apart. Which one of the following reasons best explains the benefit of using filtered blood to prevent further reaction? Reduced exposure to: A. donor leucocytes. B. donor cytokines. C. bacterial antigen. D. cytomegalovirus (CMV). E. donor isohaemagglutinins.

Answer 260

A. donor leucocytes.

Question 261

A 62-year-old woman underwent an elective cholecystectomy. Routine full blood examination revealed: ![]() Physical examination revealed no lymphadenopathy and no hepatosplenomegaly. The woman was asymptomatic. Flow cytometry revealed that the lymphocytosis marked as CD5+, CD19+ and CD23+. Which one of the following is the most appropriate management option? A. Observation alone. B. Prednis(ol)one therapy. C. Chlorambucil therapy. D. Combination chemotherapy. E. Autologous bone marrow transplantation.

Answer 261

Answer - A, this is asymptomatic CLL.

Question 262

A 65-year-old man with a history of osteoarthritis and mild chronic obstructive pulmonary disease presents with several days of nausea and vomiting and is now confused, febrile and icteric. He has extensive bruising and some oral mucosal bleeding. His medications are intermittent piroxicam and a salbutamol inhaler. His full blood count shows: ![]() ![]() Blood film as shown in the photograph below. ![]() The most likely diagnosis is: A. gram-negative sepsis. B. leptospirosis. C. disseminated intravascular coagulation. D. thrombotic thrombocytopenic purpura. E. piroxicam toxicity.

Answer 262

Answer: D This is TTP - there is fragmented red cells (hallmark) and thrombocytopaenia due to platelets clumping. The absence of a recent diarrhoeal infection and presence of neurological symptoms makes it more likely to be TTP over HUS (if that were an option).

Question 263

What is the hematocrit?

Answer 263

Percentage of red blood cells in the full blood count. It is usually 45% for men and 40% for women.

Question 264

What is anisocytosis?

Answer 264

Variations in red blood cell size

Question 265

What is poikilocytosis?

Answer 265

Variations in red blood cell shape

Question 266

What is the difference between horse and rabbit ATG?

Answer 266

Horse is twice as effective, rabbit is not used in Australia.

Question 267

Which drug causes a delayed neutropaenia of around 2-3 months?

Answer 267

Rituximab

Question 268

What are the central causes of pancytopaenia?

Answer 268

Drugs B12/folate deficiency • AA MDS Haem malignancy Myelofibrosis Non-haem infiltration – Solid tumour – Storage disorders Haemophagocytic Syndrome

Question 269

What are the peripheral causes of pancytopaenia?

Answer 269

Peripheral Destruction * Hypersplenism * Dilutional (pregnancy) * Severe sepsis

Question 270

Which is the only cause of pancytopaenia that does not result in a hypercellular bone marrow?

Answer 270

Aplastic anaemia (any cause)

Question 271

What is the epidemiology of aplastic anaemia?

Answer 271

* RARE – 1-2/million) * 3 peaks – 2-5 yrs (inherited) – 20-25 yrs – \>55 yrs (acquired)

Question 272

What is the clinical presentation of aplastic anaemia?

Answer 272

– Bleeding – Fatigue & pallor – Fevers/mouth ulcers/bacterial infections

Question 273

What is the basic pathogenesis of aplastic anaemia?

Answer 273

Stem cell failure – inherited or acquired

Question 274

What are the causes of childhood aplastic anaemia?

Answer 274

* 75% inherited * Fanconi Anaemia (FA) * Dyskeratosis Congenita (DC) * Congenital Amegakaryocytic Thrombocytopenia (CAMT) • Schwachmann-Diamond Syndrome (will be discussed under neutropenia)

Question 275

What are the pathogenesis and features of Fanconi's anaemia?

Answer 275

AR or X linked All involved in DNA repair & stabilisation - 8 of these form complex in response to replicative stress, esp crosslinking and reactive O2 species All ethnic/racial groups (more in Ashkenazi) • congenital malformations in 60-70% – Café-au-lait spots & hypopigmentation – Abnormal thumbs – Microcephaly & short stature – Hypogonadism & delayed development - Bone marrow failure, MDS --\> AML (later)

Question 276

What is the natural history of fanconi's anaemia?

Answer 276

By age 40 progression to: * Complete BM failure 90% * Acute Leukaemia/MDS 33% * Solid CA 28% – SCC head & neck & vulva commonest • 80% mortality by age 40yrs

Question 277

What is the treatment of Fanconi's anaemia

Answer 277

Fanconi Anaemia - Treatment • Allogeneic Stem Cell Transplant – curative – problem of affected family donors (harder to find unaffected but HLA-matched donor) – May inc risk solid tumours • Androgens (oxymethalone) – If no transplant available – 50% respond – Anaemia responds best • Supportive care – transfusion, GCSF

Question 278

What are the features of dyskeratosis congenita?

Answer 278

Classic triad of ectodermal abnormalities - reticulated rash face/shoulders/trunk - mucosal leukoplakia - progressive nail dystrophy, small thin bed, longitudinal ridges, nails disappear with age 75% have one, 46% have all 3 at Diagnosis Childhood cause of aplastic anaemia

Question 279

How do drugs cause pancytopaenia?

Answer 279

Drugs as cause of pancytopenia • Direct toxic effect of drugs – eg chemotherapy or immunosuppression – commonest cause of pancytopenia – Recovery in days-weeks – G-CSF speeds recovery when some precursors present • Adverse interaction – Eg azathioprine + allopurinol – Eg Methotrexate in renal impairment

Question 280

What are the drugs that cause aplastic anaemia?

Answer 280

* Idiosyncratic effect of drugs * Rare effect * Cause unclear in most cases – Chloramphenicol 1:20,000 – Gold (dose-related \>200mg) – NSAIDs – Sulphonamides – Antiepileptics – Arsenics

Question 281

What are the non-drug causes of acquired aplastic anaemia?

Answer 281

– Irradiation – Viral – Parvo B19 (_more commonly causes PRCA_) , Hepatitis, HIV, EBV – Chemical – _benzene (rubber factories)_, lindane, glue vapours – Immune – eosinophilic fasciitis, SLE, GvHD – _PNH – 1/3 will develop AA_ – Pregnancy – usually resolves with delivery – Thymoma/thymic CA – But most adult cases are _IDIOPATHIC (80%)_

Question 282

What is the basis for aplastic anaemia having an underlying immune cause?

Answer 282

– Most respond to immunotherapy – Assoc w rare immune eosinophilic fasciitis – AA can develop in GvHD

Question 283

What are the outcomes in aplastic anaemia for allogeneic BMT vs Immunosuppression?

Answer 283

15 year surivival 69% for BMT vs 38% for immunosuppression Much less risk of malignancy with BMT, higher risk of MDS/AML with immunosuppression HOWEVER only 30% will have matched donor, risk goes up with age, and GvHD with BMT

Question 284

What is the prognosis in aplastic anaemia?

Answer 284

With immunosuppression: Best case around 50% in over 60s and 72% in under 50s Worst, 21% and 50% respectively

Question 285

Who do you give an allo-BMT to in aplastic anaemia?

Answer 285

20 years old if available, up to age 50 if no comorbidities Avoid pre-transfusion wherever possible.

Question 286

What is the treatment for relapsde and refractory aplastic anaemia?

Answer 286

Relapse – 50-60% respond to retreat with ATG (horse or rabbit), CAMPATH similar • Refractory – 30% respond to rabbit ATG, CAMPATH similar • OS in responders same as those with initial response but no relapse

Question 287

What is campath/alemtuzumab?

Answer 287

Monoclonal antibody that binds to CD52, (mature lymphocytes), but not stem cells.

Question 288

What is the septic risk in isolated neutropaenia?

Answer 288

Blood neuts = 3% total body neutrophil reserve =\> markers of reserve can indicate septic risk * Febrile, raised CRP, gingivitis, mucositis – poor reserve – high septic risk * Abscess formation – good reserve – lower septic risk

Question 289

When is septic risk greatest in neutropaenia?

Answer 289

Septic Risk relatively low down to around 0.5 x 10^9/L, then rises sharply • Risk is greater in context of: – a falling count (progressively decreasing availability) – lack of early precursors/empty BM rather than when maturation arrest) – prolonged length of neutropenia

Question 290

What is the most common fatal cause of transient neutropaenia?

Answer 290

Drug idiosyncratic V rare 1-10/million May be v severe Direct toxic effect on BM orimmune destruction

Question 291

What are the commonly implicated drugs in drug induced neutropaenia?

Answer 291

Carbimazole NSAIDS Sulphonamides Antiepileptics Captopril Dapsone PTU Rituximab

Question 292

When should you give G-CSF in neutropaenia?

Answer 292

When precursors appear in the bone marrow, without them, G-CSF will not work

Question 293

What is the mechanism of dialysis induced neutropaenia?

Answer 293

Haemodialysis – – Severe neutropenia on blood taken during dialysis – Complement activation on dialysis membrane causes attachment of neutrophils onto lung endothelium – Not true neutropenia - repeating the test off dialysis shows a normal neutrophil count

Question 294

Aside from drugs, what are the two very clinically relevant causes of transient acquired neutropaenia?

Answer 294

Bacterial Sepsis – - destruction exceeds production, - bad prognostic indicator - Commonest in neonates Neonatal Isoimmune – – transplacental passage of maternal Ab to paternal neutrophil Ag (cf Rh HDN). – Can be severe and prolonged (ie months after birth) – May respond to G-CSF

Question 295

What are the features of chronic benign neutropaenia?

Answer 295

Chronic Idiopathic Neutropenia/ Benign Chronic Neutropenia – Neutrophil equivalent to adult ITP – May be seen with SLE or other AI diseases Most are mild & never require Rx (Can do antibody testing but no one does)

Question 296

What is ‘Large Granular Lymphocyte’ Syndrome?

Answer 296

– Neutropenia associated with increased circulating LGLs (NK cells) – Total lymphocyte count often normal – Not malignant – May regress spontaneously One of the causes of acquired neutropaenia - it is a chronic condition

Question 297

What is Felty's Syndrome?

Answer 297

– Commonest mild-mod chronic neutropenia – Triad of seropositive RA, neutropenia and splenomegaly (but only 25% have splenomegaly) – about 1% RA patients – Probably AI basis (higher RF & ANA) – Can occur in ‘burnt-out’ RA – Often have "LGL’ syndrome

Question 298

What is Severe Congenital Neutropaenia?

Answer 298

– Life threatening neutropenia from birth – Neutrophils \< 0.5 – RARE - 2/million AR/AD -mixed bag of molecular defects found eg ELANE, HAX-1, 40% not known HAX-1 maintains mitochondrial membrane & prevents myeloid apoptosis @15yrs G-CSF– 10% death by sepsis, 22% AML HSCT curative

Question 299

What is Chediak-Higashi Syndrome?

Answer 299

Oculocutaneous albinism, Severe neutropenia & life-threatening pyogenic infections (most die by 7yr) Mild coagulopathy Progressive neurological deterioration – pp neuropathy (if don’t die of infection) Accelerated phase – lymphohistiocytosis usually fatal

Question 300

What is WHIM (lazy leucocyte syndrome?)

Answer 300

Warts, Hypogammaglobulins, Infections, Myelokathexis) – CXCR4 mutation – Abnormal apoptosis & migration (hypercellular BM) – Rarely fatal • Myelokathexis can also occur alone

Question 301

What is cyclic neutropaenia?

Answer 301

– Neuts cycle over 3 weeks (14-35d) –consistent within individual, lessens with age – 1-2/million – AD - Neutrophil elastase (ELANE) mutations (Chrom 19p13.3) – Usually mild but can be severe (death) – regular G-CSF reduces nadir and infections – NO somatic abnormalities, NO inc risk malignancy

Question 302

What are the acquired transient causes of neutropaenia?

Answer 302

– Drug – Viral – Bacterial – nutritional – Iso-immune

Question 303

What are the acquired chronic causes of neutropaenia?

Answer 303

– Benign chronic neutropenia – LGL syndrome – Felty’s syndrome

Question 304

What are the inherited causes of neutropaenia?

Answer 304

– Severe congenital neutropenia – Cyclical neutropenia

Question 305

What is the primary concern in febrile neutropaenia?

Answer 305

Enteric gram negative organisms

Question 306

What is the primary concern in prolonged neutropaenia? How should you treat it?

Answer 306

Fungal infections - candida or aspergillus Treat with azoles or echinocandins (the 'fungins' ie caspofungin)

Question 307

What are the clinical features of significant neutropaenia?

Answer 307

Stomatitis and in infections due to gram-positive or gram-negative aerobic bacteria or to fungi such as Candida or Aspergillus.

Question 308

What is the treatment for aplastic anaemia?

Answer 308

Mild —\> EPO, transfusions and antibiotics as necessary Severe —:\> ALLO BMT is curative Over 40/ or no HLA match —\> horse ETG plus cyclosporine or tac MUST give with pred to avoid serum sickness and infusion reactions Need to give ongoing cyclosporine for several years post ATG Androgens can be considered as may have some response.

Question 309

What are the two main proposed mechanisms behind aplastic anaemia?

Answer 309

Immunological Telomere length maintenance defects

Question 310

Which groups have lower limit of normal neutrophil count ranges but are healthy? Higher?

Answer 310

Lower --\> blacks and asians Higher --\> third tri pregnant women

Question 311

What is the pathophysiology of aplastic anaemia?

Answer 311

Haematopoetic stem cell injury (congenital: telomere length maintenance defect, acquired: autoimmune) —\> marrow hypoplasure —\> failure to produce all mature blood cells —\> pancytopaenia

Question 312

What are the factors that predict response to immunological treatment of aplastic anaemia ?

Answer 312

Age, Reticulocyte count, Lymphocyte count, Age-adjusted telomere length of leukocytes at the time of diagnosis.

Question 313

What is hemaphagocytic syndrome?

Answer 313

Severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages characterised by proliferation of morphologically benign lymphocytes and macrophages that secrete high amounts of inflammatory cytokines. It is classified as one of the cytokine storm syndromes.

Question 314

What are the clinical manifestations of haemophagocytic syndromes?

Answer 314

HLH clinically manifests with fever, hepatosplenomegaly, lymphadenopathy, jaundice and a rash.

Question 315

What are the lab findings of haemophagocytic syndrome?

Answer 315

The blood count typically shows pancytopenia — anemia, neutropenia and thrombocytopenia. The blood film may show hemophagocytosis. The liver function tests are usually elevated. Hypoalbuminemia is common. The serum C reactive protein, erythrocyte sedimentation rate and ferritin level are markedly elevated. The serum fibrinogen level is usually low and the D-dimer level is elevated. The sphingomyelinase is elevated.[4] BMB - histiocytosis

Question 316

What are the causes of secondary haemophagocytic syndrome?

Answer 316

Secondary haemophagocytic lymphohistiocytosis (acquired haemophagocytic lymphohistiocytosis) occurs after strong immunologic activation, such as that which can occur with systemic infection, immunodeficiency, or underlying malignancy. Both forms are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and haematologic alterations and death in the absence of treatment.

Question 317

What is the cause of primary haemophagocytic syndrome?

Answer 317

Autosomal recessive with 5 genetic subtypes.

Question 318

What are the most common infections associated with neutropaenia?

Answer 318

Most common infections: Sepsis, cellulitis, pneumonia, and fever

Question 319

Other than cytotoxic chemotherapy, which drugs can cause neutropaenia?

Answer 319

Sulfonamides, chlorpromazine, procainamide, penicillin, cephalosporins, cimetidine, methimazole, phenytoin, chlorprop- amide, antiretroviral medications, rituximab

Question 320

What's in prothrombinex and when is it used?

Answer 320

Provision of factors II, IX and X - bleeding and warfarinized - bleeding from factor deficiency - prophylaxis

Question 321

Question 52 A 58-year-old previously well man presents with a two-week history of spontaneous bruising and a large, painful left thigh haematoma following minimal trauma. He is on no medication and his blood count has been documented as normal 18 months earlier prior to elective surgery. There is no previous history of bleeding with trauma or with surgery and no family history of bleeding disorder. Physical examination is normal apart from scattered ecchymoses and the swollen, bruised left thigh. The haematoma is confirmed on ultrasound examination. Investigations show: ![]() The most likely diagnosis is: A. haemophilia A. B. haemophilia B. C. primary antiphospholipid antibody syndrome. D. von Willebrand’s disease. E. acquired factor VIIIc inhibitor.

Answer 321

Answer: E

Question 322

Question 96 A 62-year-old previously well woman is referred for evaluation of recurrent mouth ulceration and several bacterial skin and urinary tract infections over 12 months, with one episode requiring parenteral antibiotic therapy. She is on no medication apart from intermittent antibiotics. Physical examination shows some mouth ulcers and pustular skin lesions. Full blood count (as follows) is essentially unchanged compared with previous counts measured three times during the preceding few weeks. Investigations show: Antinuclear and rheumatoid factors are negative and a marrow examination is unremarkable except for left- shifted granulopoiesis. The most appropriate therapy is: A. granulocyte colony stimulating factor (G-CSF). B. lithium. C. intravenous gamma globulin. D. granulocyte transfusions from a family member. E. long-term prophylactic antibiotics.

Answer 322

A

Question 323

QUESTION 7 A 64-year-old man is taking oral prednis(ol)one (7.5 mg/day) for polymyalgia rheumatica. He reports progressive lethargy, shoulder girdle pain and stiffness and also recent indigestion. Full blood examination reveals: Blood film shows normocytic and microcytic red cells with mild hypochromasia and rouleaux, as well as neutrophilia, lymphopenia, monocytosis and thrombocytosis Iron studies reveal: ![]() What is the most likely cause of the patient’s anaemia? A. Chronic inflammation. B. Beta thalassaemia trait. C. Iron deficiency. D. Autoimmune haemolysis. E. Sideroblastosis.

Answer 323

Answer A

Question 324

QUESTION 28 A 26-year-old previously well woman presents with several weeks lethargy and the recent onset of pallor and dark urine. She is on no medication except an oral contraceptive. On examination she is afebrile, anaemic, slightly icteric and has mild splenomegaly. Full blood examination reveals: ![]() Her blood film is shown below. ![]() The most appropriate next investigation is: A. Heinz bodies preparation. B. glucose-6-phosphate dehydrogenase level. C. unconjugated bilirubin. D. direct antiglobulin (Coombs’) test. E. urinary haemosiderin.

Answer 324

Answer: D

Question 325

QUESTION 57 A 48-year-old previously well man is receiving a transfusion of four units of packed red cell concentrate via a peripheral intravenous line after presenting with melaena secondary to a bleeding duodenal ulcer. He has not been previously transfused. Admission biochemistry (including urea, electrolytes and creatinine) is normal and pre-transfusion blood counts are normal apart from anaemia (haemoglobin 64 g/L [135-170]). Less than five minutes after transfusion of the third unit of blood is commenced, he complains of feeling very unwell and abruptly develops fever, chills, rigors and profound hypotension. In the absence of ABO, Rhesus or minor blood group donor-recipient incompatibility, the most likely diagnosis is: A. bacterial contamination of the transfused blood. B. transfusion-associated graft-versus-host disease. C. electrolyte disturbance. D. citrate toxicity. E. reaction to plasticiser in infusion bag.

Answer 325

A

Question 326

QUESTION 8 A 65-year-old woman presents for inguinal hernia repair. She is otherwise well, apart from several years of hypertension, currently controlled by captopril. There is no history of excessive infection. Physical examination reveals borderline cervical lymphadenopathy. A preoperative full blood count shows: ![]() The blood film is shown in the photograph below. ![]() The most appropriate initial investigation for diagnosis is: A. a computed tomography (CT) scan of the neck, chest, abdomen and pelvis. B. Epstein-Barr virus serology. C. peripheral blood cytogenetic analysis. D. bone marrow examination. E. immunophenotypic analysis of peripheral blood mononuclear cells.

Answer 326

E

Question 327

QUESTION 33 A 70-year-old woman with chronic lymphocytic leukaemia and mild chronic airways disease presents for routine review. In the past eight months, she has been hospitalised twice for community-acquired pneumonia. ![]() Examination reveals minor cervical lymphadenopathy. There is no peripheral lymphadenopathy elsewhere and no hepatosplenomegaly. The most appropriate treatment is: A. prophylactic antibiotics. B. regular granulocyte colony-stimulating factor (G-CSF). C. oral corticosteroid. D. oral chlorambucil. E. regular immunoglobulin infusions.

Answer 327

E

Question 328

QUESTION 45 A 62-year-old man with a history of controlled hypertension presents with worsening lethargy over several months and more recently, weight loss, night sweats and easy bruising. Examination reveals anaemia, bruising and firm splenomegaly 12 cm below the left costal margin; no lymphadenopathy is evident. Full blood examination reveals: ![]() The blood film is shown below. ![]() The most likely diagnosis is: A. metastatic carcinoma. B. megaloblastosis. C. primary myelofibrosis. D. systemic lupus erythematosus. E. chronic myeloid leukaemia.

Answer 328

C

Question 329

QUESTION 58 A 72-year-old woman presents with confusion after a minor fall and is found to have a subdural haematoma on computed tomography (CT) scanning which requires urgent surgical drainage. She takes warfarin for atrial fibrillation and has been taking an antibiotic for urinary infection. Full blood examination reveals: ![]() In addition to parenteral vitamin K therapy, she should receive: A. fresh frozen plasma. B. cryoprecipitate. C. recombinant factor VIIIc. D. packed red cells. E. platelet concentrate.

Answer 329

Answer: A

Question 330

QUESTION 84 A 63-year-old woman is recovering from induction chemotherapy commenced 28 days previously for acute myeloblastic leukaemia. She is receiving granulocyte colony-stimulating factor (G-CSF) and is no longer neutropenic. A Hickman’s catheter is in situ. She remains intermittently febrile and Candida albicans continues to be cultured from samples obtained from the Hickman’s catheter and peripheral blood, despite therapy with intravenous amphotericin B (1 mg/kg/day) from day 20. The most appropriate course of action is to: A. increase the daily dose of amphotericin B. B. arrange granulocyte transfusion. C. change to liposomal amphotericin. D. exclude hepatosplenic candidiasis radiologically. E. remove the Hickman’s catheter.

Answer 330

E. remove the Hickman’s catheter.

Question 331

QUESTION 20 A 36-year-old previously well woman presents with lethargy of two to three weeks duration and gum bleeding over the previous week. Examination shows her to be afebrile and anaemic with scattered bruises and petechial haemorrhages. A chest X-ray is normal. ![]() A bone marrow aspirate shows that 90% of nucleated cells have the appearance as seen in the photograph below. ![]() The most appropriate initial therapy is: A. idarubicin. B. all-trans-retinoic acid. C. vincristine and prednis(ol)one. D. fludarabine. E. high-dose cyclophosphamide.

Answer 331

Answer B. The aspirate shows a hypergranular myelocyte which is characteristic of APML

Question 332

QUESTION 70 A 25-year-old previously well male student presents with recent exertional dyspnoea, epistaxis and bruising. There is no history of medication, toxic chemical exposure or infection. Examination reveals significant anaemia with scattered bruises and petechial haemorrhages. Full blood examination reveals: B12, folate and iron studies are normal. Hepatitis/human immunodeficiency virus (HIV) serology is negative. Attempted marrow aspiration results in a ‘blood tap’. A marrow trephine biopsy section is shown below. QUESTION 70 CONTINUED The therapy most likely to be associated with long-term remission is: A. granulocyte colony-stimulating factor (G-CSF) and erythropoietin. B. stem cell allograft from a human leucocyte antigen (HLA)-matched sibling. C. oxymetholone. D. antithymocyte globulin. E. high-dose cyclophosphamide.

Answer 332

Answer B

Question 333

Question 84 A 78-year-old man presents with progressive lethargy for several months and the recent onset of bruising, epistaxis, headaches and visual deterioration. Physical examination shows him to be anaemic with scattered ecchymoses; he has reduced visual acuity bilaterally and fundoscopy reveals retinal venous distension with numerous retinal haemorrhages. Investigations show: ![]() The most appropriate initial therapy is: A. melphalan and prednis(ol)one. B. platelet transfusion. C. plasma exchange. D. renal dialysis. E. intravenous gamma globulin.

Answer 333

E

Question 334

QUESTION 3 The predominant site of gastrointestinal absorption of dietary iron is the: A. proximal small intestine. B. gastric fundus. C. terminal ileum. D. pyloric antrum. E. colon.

Answer 334

A

Question 335

QUESTION 25 In a transfusion-dependent patient with idiopathic acquired sideroblastic anaemia, the most appropriate treatment for prevention of transfusional iron overload is: A. vitamin C. B. phlebotomy. C. desferrioxamine. D. ethylene-diamine tetra-acetic acid (EDTA). E. pyridoxine.

Answer 335

Answer: C

Question 336

QUESTION 35 Infusion of cryoprecipitate is principally indicated for the replacement of: A. factor IX. B. fibrinogen. C. immunoglobulin A (IgA). D. anti-thrombin. E. protein C.

Answer 336

Answer: B

Question 337

QUESTION 58 A 72-year-old woman presents with confusion after a minor fall and is found to have a subdural haematoma on computed tomography (CT) scanning which requires urgent surgical drainage. She takes warfarin for atrial fibrillation and has been taking an antibiotic for urinary infection. Full blood examination reveals: ![]() In addition to parenteral vitamin K therapy, she should receive: A. fresh frozen plasma. B. cryoprecipitate. C. recombinant factor VIIIc. D. packed red cells. E. platelet concentrate.

Answer 337

Answer: A

Question 338

QUESTION 51 A 48-year-old previously well man, currently smoking 10 to 20 cigarettes/day, presents with the progressive onset over several months of lethargy and headache. He takes no medications. Examination reveals him to be plethoric and hypertensive with no other significant findings. Which one of the following would most strongly support a diagnosis of polycythaemia vera? A. Raised serum vitamin B12 level. B. Elevated total red cell mass. C. Normal marrow karyotype. D. Elevated serum uric acid level. E. Lowered serum erythropoietin level.

Answer 338

Answer: E

Question 339

A 19-year-old woman presents with recent-onset right leg swelling and pleuritic chest pain and is found to have iliofemoral thrombosis on Doppler ultrasound examination. Results of a ventilation-perfusion lung scan indicate a high probability of pulmonary emboli. She had been taking the oral contraceptive pill for the last three years but has now ceased. She is a non-smoker. There is no significant medical history and no known family history of venous thromboembolism. The results of which one of the following investigations for an underlying hypercoagulable state are most likely to be affected by the presence of the extensive thrombosis? A. Anti-phospholipid antibody screen. B. Anti-thrombin level. C. Assessment of prothrombin and factor V genotypes. D. Activated partial thromboplastin time (APTT). E. Full blood count including blood film.

Answer 339

Answer: B

Question 340

QUESTION 10 A 25-year-old man presents with recent onset of lethargy, fever, bruising and abdominal pain. On examination, he is clinically anaemic and is noted to have scattered bruises, bilateral pleural effusions, an abdominal mass and cervical and axillary lymphadenopathy. Full blood examination shows: ![]() More than 90% of the nucleated cells in the bone marrow aspirate have the appearance shown below (examples indicated by arrows). ![]() Coagulation parameters are normal. The most likely marrow karyotypic abnormality is: A. monosomy 7. B. t (9;22). C. 5q minus. D. t (8;14). E. t (15;17).

Answer 340

Answer: D. Burkitt's lymphoma

Question 341

QUESTION 52 A 47-year-old man with severe haemophilia A and a high titre factor VIII inhibitor is scheduled for hip replacement surgery. The peri-operative replacement coagulation product of choice is: A. recombinant activated factor VII. B. recombinant factor VIII. C. recombinant factor IX. D. fresh frozen plasma. E. cryoprecipitate.

Answer 341

A

Question 342

QUESTION 65 A 36-year-old man presents in a post-ictal state after an observed generalised seizure. Full blood investigation shows: The blood film is shown below. ![]() The most likely cause of the peripheral blood macrocytosis is: A. β-thalassaemia trait. B. myelodysplasia. C. alcoholic liver disease. D. hereditary spherocytosis. E. myelofibrosis.

Answer 342

Answer: C

Question 343

A 24-year-old woman, who has recently arrived in Australia from Vietnam, presents for evaluation of abnormal menstrual bleeding. There are no abnormalities on examination. Results of investigations are listed below. ![]() The most likely diagnosis is: A. homozygous alpha+ thalassaemia (−α/−α). B. early iron deficiency. C. congenital sideroblastic anaemia. D. sickle cell anaemia. E. heterozygous beta thalassaemia.

Answer 343

A

Question 344

QUESTION 3 A 68-year-old man scheduled for herniorrhaphy presents for pre-anaesthetic assessment and is found to have non-tender cervical lymphadenopathy. Full blood examination shows: ![]() The blood film is shown below. ![]() With respect to the peripheral blood lymphoid cell immunophenotype, which of the following surface antigens is most likely to be co-expressed with CD19 (cluster of differentiation 19)? A. CD3. B. CD5. C. CD8. D. CD10. E. CD34.

Answer 344

B. This is CLL as there are smudge cells on the film along with the other findings.

Question 345

QUESTION 16 In a 50-year-old woman, which of the following isolated laboratory abnormalities would be associated with the highest level of blood viscosity? A. Serum immunoglobulin M (IgM) level of 40.0 g/L [0.5-3.0]. B. Peripheral blood leucocytosis of 25.0 x 109/L [3.9-12.7]. C. Haematocrit of 0.46 [0.32-0.42]. D. Serum immunoglobulin G (IgG) level of 40.0 g/L [7.5-15.6]. E. Peripheral blood thrombocytosis of 500 x 109/L [150-396].

Answer 345

A

Question 346

What is a Pelger-Huet anomaly? In which condition is it seen?

Answer 346

Dumbbell-shaped bilobed nuclei on peripheral blood film Myelodysplastic syndromes inc MDS, AML and CML

Question 347

QUESTION 44 A previously well 32-year-old man presents with progressive lethargy and no other symptoms. Physical examination shows him to have an enlarged spleen 6 cm below the left costal margin. There is no jaundice or lymphadenopathy and he is not clinically anaemic. The full blood examination shows: ![]() The blood film is shown below. ![]() The most likely marrow cytogenetic abnormality is: A. hyperdiploidy. B. t(9;22). C. t(15;17). D. 5q minus. E. trisomy 21.

Answer 347

**B**

Question 348

QUESTION 59 Megaloblastosis is least likely to be seen in which one of the following? A. Transcobalamin I deficiency. B. Pernicious anaemia. C. Strict veganism. D. Coeliac disease. E. Post-gastrectomy.

Answer 348

A

Question 349

QUESTION 62 The delay in the onset of the anticoagulant effects of warfarin is most dependent on the: A. loading dose of warfarin. B. rate of catabolism of clotting factors. C. rate of absorption of warfarin. D. clearance rate of the S-isomer of warfarin. E. clearance rate of the R-isomer of warfarin.

Answer 349

B

Question 350

QUESTION 22 A 75-year-old patient with chronic atrial fibrillation has been stable on warfarin 4 mg/day (international normalised ratio (INR) ranges from 2.1 to 2.5). The patient takes thyroxine 100 μg/day for hypothyroidism. Which one of the following actions is most likely to potentiate the risk of bleeding? A. Reducing the dose of thyroxine. B. Increasing dietary vegetable intake. C. Treatment with cholestyramine. D. Treatment with omeprazole. E. Treatment with amiodarone.

Answer 350

E

Question 351

QUESTION 33 A 72-year-old man with a history of chronic obstructive pulmonary disease (COPD) presents with an intercurrent lower respiratory tract infection. Apart from plethora and pulmonary signs associated with his respiratory disease, no other abnormalities are found. Full blood examination shows: ![]() The most likely cause of the elevated haematocrit is: A. dehydration. B. chronic hypoxaemia. C. polycythaemia vera. D. spurious polycythaemia. E. low affinity haemoglobin.

Answer 351

B

Question 352

A 35-year-old man who is receiving erythropoietin (EPO) therapy for anaemia associated with end stage renal disease presents with lethargy. There is no obvious source of bleeding. Blood investigations show: ![]() The most likely cause of his anaemia is: A. red cell aplasia. B. reduced iron stores. C. non-neutralising anti-EPO antibodies. D. aluminium toxicity. E. myelodysplasia.

Answer 352

A. Red cell aplasia. Due to NEUTRALISING EPO antbodies.

Question 353

QUESTION 46 Which of the following is most likely to prevent recurrent febrile non-haemolytic transfusion reactions in a patient requiring regular transfusion? A. Warm blood to 37°C. B. Leucodepletion. C. Gamma-irradiation. D. Cytomegalovirus (CMV)-negative donors. E. Slow transfusion time.

Answer 353

B

Question 354

QUESTION 48 A 68-year-old man is sent for a second opinion regarding recurrent iron deficiency anaemia requiring blood transfusion. Over the last three years, he has required an average of 4 units of packed cells every three months despite oral iron supplements. There is no history of melaena. Bone marrow examination is normal except for absent iron stores. Gastroscopy and colonoscopy have been negative on three separate occasions, the last being two months ago. Small bowel biopsy is normal. The patient had a barium meal and follow-through six months ago which was normal. General health is good and he is on no regular medications. Which of the following investigations is most likely to find the cause of his iron deficiency? A. Small bowel enema. B. Repeat gastroscopy and colonoscopy. C. Enteroscopy. D. Abdominal angiography. E. Labelled red cell scan.

Answer 354

C

Question 355

QUESTION 66 A 28-year-old man presents with a fractured ankle requiring surgical fixation. ![]() The most likely explanation for his anaemia is: A. β-thalassaemia trait. B. chronic blood loss. C. anaemia of ‘chronic disease’. D. congenital sideroblastosis. E. sickle cell trait.

Answer 355

A

Question 356

QUESTION 84 A previously well 46-year-old woman presents acutely unwell with right iliac fossa pain and fever. A laparotomy is planned. Which of the following is the most likely cause of the prolonged APTT? A. Disseminated intravascular coagulation. B. Heparin contamination. C. Lupus inhibitor. D. Factor XI deficiency. E. Haemophilia carrier.

Answer 356

C

Question 357

QUESTION 93 A 16-year-old adolescent male presents with lethargy and lower respiratory tract infection. Physical examination shows him to be febrile, icteric and pale in addition to respiratory findings. Full blood examination shows: ![]() The blood film is shown below. ![]() The most likely cause of the anaemia is: A. paroxysmal cold haemoglobinuria. B. glucose-6-phosphate dehydrogenase (G6PD) deficiency. C. red cell aplasia. D. cold agglutinin haemolysis. E. sickle cell anaemia.

Answer 357

B

Question 358

QUESTION 9 Which of the following transfusion-related events is most frequently reported (episodes/unit transfused) with transfusion of unmodified red cells? A. Acute haemolytic transfusion reaction. B. Febrile non-haemolytic transfusion reaction. C. Transmission of hepatitis B. D. Graft-versus-host disease. E. Transfusion-associated acute lung injury.

Answer 358

B

Question 359

QUESTION 18 A 67-year-old woman develops symptomatic anaemia and jaundice nine days after subtotal colectomy for adenocarcinoma of the colon, at the time of which she received a transfusion of 3 units of red cells. She is on therapy (which includes sulfasalazine) for ulcerative colitis. Review of the pre-operative antibody screen shows this to be negative for red cell alloantibodies. Her current full blood examination includes the following: haemoglobin 82 g/L [120-155] mean cell volume 99 fL [80-97] reticulocyte count 162 x 109/L [8-104] Her blood film is shown below. ![]() The most likely cause of her anaemia is: A. iron deficiency. B. peri-operative blood loss. C. red cell aplasia. D. delayed haemolytic transfusion reaction. E. megaloblastosis.

Answer 359

D

Question 360

QUESTION 41 During normal haemostasis, von Willebrand factor (vWF) plays a role in platelet adhesion/aggregation. During this process, which of the following is the primary binding site of vWF to platelets? A. Collagen receptor. B. Platelet glycoprotein Ib-IX-V. C. Adenosine diphosphate receptor. D. Platelet glycoprotein IIb-IIIa. E. Ristocetin.

Answer 360

B

Question 361

QUESTION 60 Intravenous infusion of which of the following blood components is most likely to be associated with a septic transfusion reaction? A. Red cell concentrate. B. Fresh frozen plasma. C. Pooled gammaglobulin. D. Platelet concentrate. E. Cryoprecipitate.

Answer 361

D

Question 362

What does antithrombin III do? What is it's clinical significance?

Answer 362

Deactivates factors 2 and 10, and thrombin. Heparin potentiates it as it has a very high affinity for the part that inactivates thrombin. LMWH has less of a charge and as a result, binds more to factor 10. As a result, the thrombin clotting time is only affected by heparin.

Question 363

QUESTION 20 A 65-year-old man presents to the emergency department with ischaemic chest pain. No abnormalities are noted on examination apart from mild hypotension. ![]() The most likely cause of the coagulation test abnormalities is: A. disseminated intravascular coagulation. B. administration of low-molecular weight heparin. C. administration of thrombolytic agent. D. lupus inhibitor. E. administration of unfractionated heparin.

Answer 363

E

Question 364

QUESTION 36 A 30-year-old man has previously undergone splenectomy (six months prior) for chronic idiopathic thrombocytopenic purpura (ITP). Apart from occasional bruising, there are no haemorrhagic symptoms. His full blood examination shows: ![]() Repeated autoimmune and viral serology remain negative. The most appropriate management of his thrombocytopenia is: A. danazol. B. immunoglobulin. C. prednis(ol)one. D. azathioprine. E. observation.

Answer 364

E

Question 365

QUESTION 47 A 36-year-old healthy male with no siblings is found incidentally to have mild anaemia. In addition to informing him of the diagnosis, which of the following is the most appropriate next step? A. Globin gene analysis. B. Provide information on partner screening. C. Commence iron therapy. D. Haemoglobinopathy screening for parents. E. Gastrointestinal endoscopy.

Answer 365

B

Question 366

QUESTION 51 A 35-year-old man who is receiving erythropoietin (EPO) therapy for anaemia associated with end stage renal disease presents with lethargy. There is no obvious source of bleeding. ![]() The most likely cause of his anaemia is: A. red cell aplasia. B. reduced iron stores. C. non-neutralising anti-EPO antibodies. D. aluminium toxicity. E. myelodysplasia.

Answer 366

A