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RACP Written Exam > Haematology > Flashcards

Haematology Flashcards

1
Q

Immunophenotypic markers typical of CLL:

A

Co-expression of B-cell and T-cell markers is characteristic:

B-cell: CD19, CD20, CD23
* If CD23 absent, need to rule out mantle cell lymphoma

T-cell: CD5

Kappa light chain restriction on scattergram.

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2
Q

Symptoms of lymphoproliferative disorders:

A

Often none - detected incidentally on blood test

Lymphadenopathy
Fatigue
Weight loss
Night sweats (common in HL; uncommon in high grade or indolent lymphomas)

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3
Q

Signs of lymphoproliferative disorders:

A

Often none

Palpable lymphadenopathy
Splenomegaly
Hepatomegaly (rarely)
Signs of anaemia (if present), jaundice (if haemolytic), or bleeding (if thrombocytopaenic)
Lymphatic obstruction (almost never)
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4
Q

CLL vs MBL (Monoclonal B-cell Lymphocytosis):

A

Arbitrary cut off of 5000/uL B-cells of CLL/SLL (small lymphocytic lymphoma) type.

MBL =
5000, but develop symptoms or signs).

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5
Q

Differentials for CLL (to rule out):

A
  1. Mantle cell lymphoma - suspect of CD23 absent –> oncogene bcl-1 (cyclin D1) usually positive in MCL, negative in CLL.
  2. Hairy cell leukaemia - hairy cells (cytoplasmic projections) or immunophenotype differentiates: CD5 and CD21 negative, and positive for CD25, CD11c, and CD103.
  3. Prolymphocytic leukaemia - usually differentiated on blood film morphology (prolymphocytes occur in CLL but are abundant in PLL); PLL is CD5 negative.

PLL - >55% circulating cells in peripheral blood are prolymphocytes (immature-appearing cells - approx. twice the size of normal lymphocyte, abundant cytoplasm, round

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6
Q

CLL staging system:

A

Rai (US) vs Binnet (Europe)

Binnet: number of nodal sites and presence of cytopaenias.

Rai and median survival:

  • Low risk - Stage 0 - lymphocytosis - 12.5yrs
  • Intermediate risk: lymphadenopthy / organomegaly

> Stage I - lymphadenopathy - 5-8yrs
Stage II - splenomegaly or hepatomegaly

  • High risk: cytopaenias - Stage III - anaemia (Hb Stage IV - thrombocytopaenia (<100)
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7
Q

Prognostic features in CLL:

A

Age

Stage

Short lymphocyte Doubling-time (<12 months)

Serum markers: Beta2 microglobulin concentration

Surface marker expression (worse prognosis): ZAP70, CD38

Genetic risk factors (FISH): 17p deletion, 11q deletion, p53 mutation.
[Note: Trisomy 12q or normal karyotype or 13q deletion have better prognosis]

IgVH gene: unmutated = worse prognosis; mutated = better prognosis

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8
Q

Complications of CLL:

A

> Autoimmune - eg. haemolytic anaemia or ITP - not sign of progression
(need to differentiate ITP from BM involvement or splenic sequestration)

> Hypogammaglobulinaemia, with recurrent infections requiring hospitalisation

> Transformation ( to PLL, or Richter’s - usually to large cell lymphoma)

> Other malignancies (especially GU, GI, cutaneous; but also head & neck, Kaposi, lung, brain).

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9
Q

Treatment of CLL:

A

Observe at least 6 months, unless: symptomatic, advanced stage, autoimmune complications.

Standard of care:

  • Fludarabine
  • Cyclophosphamide
  • Rituximab

Lomger-term rituximab improves survival.

Usually not STC as older population.

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10
Q

CLL and SLL - defintions:

A

Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes, which are monoclonal in origin.

CLL is considered to be identical (ie, one disease at different stages) to the mature (peripheral) B cell neoplasm small lymphocytic lymphoma (SLL), one of the indolent non-Hodgkin lymphomas.

The term CLL is used when the disease manifests primarily in the bone marrow and blood, whereas the term SLL is used when involvement is primarily nodal.

While there is some difference to the treatment of early stage CLL and SLL, the treatment of advanced stage disease is the same.

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11
Q

Median survival in CLL:

A

10 years

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12
Q

Essential thrombocythaemia diagnostic criteria:

A
  1. Sustained platelet count >450 x 109/L
  2. Predominantly megakaryocytic hyperplasia in
    bone marrow
  3. NOT –
    CML (BCR/ABL negative),
    PV (Red cell mass measurement if Hct >40%)
    Primary Myelofibrosis
    Myelodysplastic Syndrome
    or other neoplasm
  4. JAK2V617F +ve or no evidence for reactive
    thrombocytosis (incl. normal ferritin levels)
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13
Q

Aplastic anaemia - definition:

A

The bone marrow fails to produce cells, leading to a hypocellular marrow and pancytopaenia.

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14
Q

Causes of aplastic anaemia:

A 
Congenital 15-20% - eg. Fanconi anaemia
Idiopathic
Drugs
Infection
Toxins
Radiation exposure
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15
Q

Fanconi anaemia is a congenital form of aplastic anaemia which is an AR, X-linked disorder. What are the other associated clinical features?

A 
Microcephaly
Short stature
Skin defects
Hypogonadism
Urogenital abnormalities
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16
Q

Investigations for pancytopaenia (when suspecting aplastic anaemia):

A
  • Blood count - note: aplastic anaemia usually shows pancytopaenia, but may have isolated cytopaenia.
  • Blood film: ?signs of myelodsyplasia
  • Bone marrow biopsy: hypocellular, increased fat content, decreased haematopoietic elements.
  • Cytogenetics for chromosomal abnormalities of bone marrow disorders eg. hypocellular MDS
  • B12, folate
  • LFTs
  • Viral serology: HIV, HBV, HCV
  • Chromosomal breakpoint analysis if suspect Fanconi anaemia (<50yo)
  • Flow cytometry to exclude paroxysmal nocturnal haemoglobinuria (deficiencies of CD55, CD59)
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17
Q

Presentation of paroxysmal nocturnal haemoglobinuria (PNH):

A
  • haemolytic anaemia: fatigue, lethargy, breathlessness, jaundice
  • haemoglobinuria (may be paroxysmal in a few patients)
  • pancytopaenia - bruising / bleeding, infections, anaemia (common even without a BM syndrome)
  • unprovoked atypical thrombosis: eg. mesenteric or cerebral infarction; Budd-chiari (hepatic vein). Cause unclear.

Other symptoms (related to NO deficiency as bound by free Hb): oesophageal spasm, abdominal pain, erectile dysfunction.

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18
Q

Paroxysmal nocturnal haemoglobinuria - findings on flow cytometry:

A

Deficiency of CD55 and CD59 on surface of peripheral erythrocytes or leucocytes

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19
Q

When to anticoagulate in paroxysmal nocturnal haemoglobinuria:

A

Acute thrombotic event
OR
Consider if >50% cells are CD55 or CD59 deficient (but no thrombosis)

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20
Q

Median survival in paroxysmal nocturnal haemoglobinuria; usual causes of death:

A

10-15 years

Thrombosis or progressive pancytpaenia

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21
Q

Pathogenesis of PNH:

A

Acquired abnormality of PIG-A gene due to somatic mutation
–>
Populations of abnormal RBCs (“PNH cells”) that are deficient in terminal complement inhibitors (GPI-linked proteins on red and white cell surfaces - see below)
–>
PNH RBCs sensitive to persistent terminal complement-mediated destruction
–>
Intravascular haemolysis.

Genetic mutation in PNH leads to a partial or complete absence of GPI-linked proteins on red & white cell surfaces, eg:

  • CD59 (membrane inhibitor of reactive lysis)
  • CD55 (decay accelerating factor)

Note: The proportion of affected cells and degree of deficiency relates to haemolysis rate / presentation.

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22
Q

Treatment:

A
  • Treat IDA (iron can number of deficient clones –> precipitate haemolysis)
  • Transfusion
  • Eculizumab: humanised mab which binds c5 and prevents terminal complement activation (hence need for 3-5yrly meningococcal vaccination - but still 0.5%/yr risk)
  • Possibly high-dose EPO; G-CSF
  • Anticoagulation when indicated (thrombosis / >50% deficient clones)
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23
Q

Level of blasts on BM aspirate required for AML diagnosis?

A

> 20%

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24
Q

What are auer rods?

A

structures seen in myeloid cells on microscopy that are indicative of AML

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25
Q

Chromosomal abnormality classic for promyelocytic leukaemia?

A

Translocation: t15:17

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26
Q

Inheritance pattern of haemophilia A and B

A

X-linked recessive disorders

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27
Q

Sideroblastic anaemia diagnosis:

A
  • microcytosis
  • ring sideroblasts in BM
  • evidence of iron overload
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28
Q

Why are ABO antigens important?

A

Antibodies to ABO antigens are IgM, activate complement, and cause immediate intravascular haemolysis.

Blood of adults contain antibodies to ABO antigens (anti-A, anti-B or anti-A,B). First detectable at 3-6months of age.

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29
Q

Why are Rhesus D (RhD) antigens important?

A

Antibody to RhD (called anti-D) is produced by RhD negative individuals when exposed to RhD positive red blood cells.
Anti-D causes severe haemolysis (acute and delayed).
Antibodies can cross the placenta.
Commonest cause of severe haemolytic disease of the foetus / newborn.
15% caucasians are RhD negative.

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30
Q

How important is blood group in platelet transfusion?

A

Platelet transfusion contains plasma.
Therefore, if not exact match:
- ABO compatible but plasma incompatible: +ve DAT / possible haemolysis

  • ABO incompatible but plasma compatible: decreased platelet lifespan
  • RhD+ platelets to RhD- patients –> Anti-D Abs (doesn’t affect pt, but may have implications for women who become pregnant)
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31
Q

Universal RBC donor?

A

Group O

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32
Q

Universal plasma (FFP, cryo) donor?

A

Group AB

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33
Q

Criteria for Transfusion Associates Lung Injury:

A

TRALI:

  1. ALI:
    - acute onset
    - hypoxaemia (sats<300)
    - CXR bilateral infiltrates
    - no e/o LA hypertension
  2. ≤6 hrs from transfusion
  3. No ALI prior to transfusion
  4. no alternative risk factor for ALI
    (If there is but others satisfied = POSSIBLE TRALI)
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34
Q

Which blood products are highest risk for contamination and transfusion-associated sepsis?

A

Platelets - because stored at room temperature.
(1/25,000 –> sepsis events)

RBCs - refridgerated 2-6 degrees (1/250,000 units –> sepsis events)

FFP, Cryo - frozen / refridgerated

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35
Q

Pre-storage leucodepletion of all red cells and platelet products has which benefits?

A
  • ↓ FNHTR (febrile non-haemolytic transfusion reactions)
  • ↓alloimmunisation (platelet refractoriness, organ transplant donor matches)
  • ↓ risk of CMV
  • Possible: ↓ transfusion-associated GVHD (TaGVHD), ↓prions (vCJD), ↓ transfusion related immune modulation (TRIM)
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36
Q

Three pillars of patient blood management:

A
  1. PRE-OP: optimise Hb pre-operatively (reversible causes?)
  2. INTRA-OP: minimise blood loss (identify bleeding risks, surgical technique, cell salvage)
  3. POST-OP: optimise patient’s tolerance of anaemia (optimise oxygen delivery - cardiorespiratory reserves ; restrictive transfusion policy)
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37
Q

Definition of massive transfusion:

A

≥10 units RBCs in 24hrs.

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38
Q

Recommended ratio of blood products in massive transfusion:

A

1 : 1 : 1
RBCs : Plts : Plasma

However, no prospective studies to confirm yet.

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39
Q

Why not use MTP ratios of blood products in all patients with high transfusion requirement (but not MT)?

A

Increased exposure to plasma (blood components) appear to outweigh benefits

→ ↑ risk of TRALI, TACO, anaphylaxis, MODS, ARDS

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40
Q

Red cell storage lesions (5):

A
  1. Loss of 2,3-DPG → ↓oxygen delivery as ↑ affinity of Hb
  2. Loss of ATP, ADP, AMP → RBC shape change
    20-25% not viable
  3. Na+/K+ pump paralaysed at 2-6’ → Na+ enters and K+ leaves RBCs
  4. Microvesiculation –> loss of membrane –> tendency to haemolysis, change in deformality, osmotic fragility
  5. Accumulation of free Hb in supernatant
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41
Q

Most common underlying cause of FNHTRs in platelet transfusions?

A

Donor cytokines released by donor white cells during storage.

Therefore pre-storage leucodepletion particularly effective.

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42
Q

Most common underlying cause of FNHTRs in RBC transfusions?

A

Donor leucocytes (reaction of recipient Abs to donor leucocytes).

Leucodepletion by pre-storage and by bedside-filter both effective.

Approx 1% (episodes/units transfused) pre-universal leucodepletion. Now closer to 0.1%.

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43
Q

Purpose of irradiation of blood products?

A

Inactivate WBCs and decrease risk of TaGVHD in immunodeficient patients.

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44
Q

Relative frequency of transfusion reactions (10):

A
  1. Allergic reaction 1-3%
  2. TACO (transfusion-assoc. cardiac overload) ≤1%
  3. FNHTR (febrile non-haemolytic) 0.1-1%
  4. TRALI
  5. DHTR (delayed haemolytic)
  6. Acute haemolytic
  7. Anaphylaxis
  8. Sepsis (platelets)
  9. HBV
  10. HIV, HCV
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45
Q

Relative mortality rates of transfusion reactions:

A
  1. TRALI
  2. HTR (haemolytic)
  3. sepsis
  4. TACO
  5. Anaphylaxis
  6. Ta-GVHD
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46
Q

Classic coagulation pathway is still useful, but what is the current thinking about the three main steps of invivo coagulation?

A
  1. Injury at site exposes TF –> activates Factor VII –> Activates Factor X –> Prothrombin to Thrombin
  2. Amplification phase: Thrombin –> activation of Factor VIII and V + activation of platelets
  3. Coagulation occurs at platelets surfaces, within fibrin clot formation and cross-linking to form stable clot.
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47
Q

When will thrombin time be prolonged?

A

Heparin

Dysfibrinogenaemia

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48
Q

Prolonged aPTT normalises with mixing study. Cause?

A

Mixing study: add normal plasma to patient’s (1 : 1) and test aPTT.

aPTT normalises if Factor deficiency is the cause

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49
Q

Prolonged aPTT normalises with mixing study. Cause?

A

Mixing study: add normal plasma to patient’s (1 : 1) and test aPTT.

aPTT does not normalise if an inhibitor is present (eg. acquired Factor VIII inhibitor or Lupus Anticoagulant).

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50
Q

Is mucosal bleeding / petechiae more typical for platelet disorder or coagulation factor deficiency?

A

Platelet disorder

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51
Q

Are haemarthroses and large ecchymoses more typical of platelet disorder or coagulation factor deficiency?

A

Coagulation factor deficiency.

Eg. haemophilia;
Acquired factor VIII inhibitor; Warfarin

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52
Q

D-dimer looks for ____?

A

Fibrin degradation products.

High if large clot, DIC (many other causes).

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53
Q

Ecarin time:

A

?? Liver disease vs Vit K deficiency

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54
Q

Factor XII deficiency and contact factor deficiency are associated with which clinical picture?

A

Prolonged aPTT (other coag studies normal) but no increased bleeding or thrombosis.

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55
Q

Normal first-line coag studies but abnormal bleeding - DDx?

A 
Platelet dysfunction
Factor XIII deficiency (child)
Mild factor deficiency
vWD
Normal
56
Q

Dabigatran - mechanism; coag study results:

A

Mechanism: Anti-IIa inhibitor
(Direct thrombin inhibitor)

  • Ecarin clotting time: QUANTITATIVE (but not widely avail?)
  • Thrombin time: prolonged (may need dilution as very sensitive)
  • aPTT > PT

Anti-Xa levels not useful

57
Q

Rivaroxaban and Apixaban - mechanism; coag study results:

A

Mechanism: Anti-Xa inhibitors
(have an ‘X’ in their names)

  • Anti-Xa levels: QUANTITATIVE
  • PT > aPTT

TT, Ecarin CT: not useful

58
Q

Acquired bleeding disorder in liver disease - multiple mechanisms:

A
  • ↓Synthesis: measure Factors V & VII
  • ↓Breakdown: activated factors and activated fibrinolytic factors
  • ↓vitamin K absorption: due to biliary tree obstruction
  • thrombocytopaenia with hypersplenism
  • DIC in ACUTE liver disease
59
Q

What is DIC?

A

Disseminated intravascular coagulation:

  • acquired
  • intravascular activation of coagulation
  • loss of localisation, many causes
  • microvascular damage (can arise from or can subsequently cuase) –> organ dysfunction.
  • acute or chronic (malignancy, vascular malformations)
60
Q

Clinical presentation of DIC:

A
  1. Bleeding
  2. 5-10% microthrombotic lesions –> ARF, gangrene
  3. MAHA (microangioathic haemolytic anaemia) - schistocytes, low platelets
61
Q

Schistocytes

A

Red cell fragments
“Helmet cells”

Seen in: MAHA - DIC, TTP, severe vasculitis, valve abnormalities (AS), disseminated cancer.

62
Q

Dx DIC:

A
  1. Must have underlying disorder associated with DIC
  2. Scoring system based on results of coag studies:
    - ↓ platelet count
    - ↑ fibrin marker (d-dimer = fibrin degradation product)
    - ↑PT
    - ↓Fibrinogen
63
Q

Conditions associated with DIC:

A
  • Sepsis / severe infection
  • Trauma
  • Organ destruction (eg. pancreatitis)
  • Malignancy (solid tumour, leukaemia)
  • Obstetric
    (PET, placental abruption, amniotic fluid embolism)
  • Severe liver failure
  • Vascular abnormalities
    (aneurysm, large haemangiomata)
  • Toxic / immunol insults:
    ABO transfusion incompatibility, transplant rejection, snake bites, recreational drugs
64
Q

Management of DIC:

A

TREAT UNDERLYING CAUSES

Support with appropriate blood products

  • platelets / FFP / Cryo
  • aFVII and aPCC have been tried
65
Q

“Triad of Death” in Coagulopathy of Trauma & Shock:

A

Acidosis –> Hypothermia –> Coagulopathy (cycle)

Not just dilutional with massive transfusion.

66
Q

Acquired disorders of platelets:

A
  1. Medications
  2. Herbal / foods
  3. Renal failure
  4. CPB / extracorporeal membrane oxygenation
  5. MPDs
  6. MDS
  7. Paraproteinaemia
  8. Platelet antibody-induced (can occur in ITP).
67
Q

Medications that interfere with platelet function

A
  • COX-1 inhibitors (aspiring, NSAIDs)
  • ADP P2Y12 Rc inhibitors (clopidogrel, prasugrel, ticagrelor)
  • GPIIb/IIIa inhibitors (tirofiban, abciximab)
  • dipridamole
  • beta lactam ABs
  • SSRIs
  • Alcohol
68
Q

Diagnostic algorithm for suspected acquired platelet dysfunction:

A
  1. Hx
  2. Coags: abnormal –> evaluate coagulopathy
  3. Renal function: abnormal –> correct renal failure, correct anaemia (EPO, transfusion), DDAVP
  4. FBC:

(A) Normal:

  • drugs
  • supplements
  • paraproteins
  • acquired VWD (hypothytroidism, paraprotein, high shear in AS, drugs)

(B) Isolated plt abnormality:

  • drugs, supplements
  • ITP
  • MDS
  • MPD

(C) Abnormal Plts + WCC or Hb:

  • Leukaemia
  • MDS
  • MPD
  • paraproteinaemia
69
Q

Functions of von Willebrand Factor:

A
  1. plasma VWF carries FVIII (secondary haemostasis)
    - -> if VWF low then factor VIII may also be slightly low
  2. plt-plt and plt-vessel wall adhesion at sites of damage - interacts with collagen (primary haemostasis)

[high molecular weight multimers particularly important for 2].

70
Q

Female members with low Factor VIII?

A

Consider VWD Type 2N

71
Q

Mild haemophilia: factor level and presentation

A

5-49% factor level

  • Easy bruising / epistaxis
  • Surgical bleeding / post-dental extraction
72
Q

Moderate haemophilia: factor level and presentation

A

1-5% factor level

  • present <2yo usually
  • joint and muscle bleeds after minor trauma
  • easy bruising & epistaxis
  • post-surgical bleeding
73
Q

Severe haemophilia: factor level and presentation

A

<1% factor activity

  • Bleeding within first year
  • Spontaneous joint and muscle bleeds
  • CNS bleeding
74
Q

Treatment of clotting factor deficiencies (haemophilias, VWD):

A 
P = replacement
R = rest
I = ice
C = compression
E = elevation

** delay full assessment until after replacement therapy given! It is the priority!

Replacement therapy: on demand vs. prophylaxis (eg. multiple times per week in severe haemophilia)

Replacement: factors, DDAVP, anti-fibrinolytics (rarely fresh blood components when necessary)

75
Q

Mechanism if DDAVP in decreasing bleeding in VWD and mild haemophilia A:

A

DDAVP causes acute release of VWF and FVIII from endothelial cells.

76
Q

Recombinant factor concentrates are used for replacement in haemophilia A & B, but we still need to use plasma-derived concentrates in:

A

VWD (when replacing FVIII)

FXI deficiency

77
Q

Clotting factor inhibitors: low titre vs high titre levels?

A

5 Bethesda units = HIGH titre

Most common in severe haemphilia A.

78
Q

Inherited platelet disorders:

A

FAR less common than acquired.

May have co-existing coagulation disorders.

79
Q

What is Glanzmann thrombasthenia?

A

Severe inherited platelet disorder.

Deficiency of plt Integrin Rc (GPIIb/IIIa).

Presents early, requires plt transfusions.

80
Q

Small platelets with thrombocytopaenia in a male:

A

Wiskott-Aldrich syndrome (or variant)

  • x-linked recessive
  • assoc. eczema, immunodefic
  • AI disorders and malignancy at young age
81
Q

What is the significance of the platelet GP Ib-IX-V receptor?

A

Primary site of binding of vWF to platelets during platelet adhesion / aggregation.

Deficient in Bernard-Soulier syndrome (rare, AR, coagulopathy).

82
Q

What are plasma cell dyscrasias?

A

Clonal proliferations of immunoglobulin-secreting differentiated B lymphocytes and plasma cells.

  • MM
  • MGUS
  • AL amyloidosis (immunoglobulin light chain)
  • Waldenstrom macroglobulinaemia
83
Q

Diagnosis of MM:

A
  1. Monoclonal plasma cells in BM (>10%) or plasmacytoma (biopsy)
  2. Monoclonal protein in serum or urine
  3. Myeloma-related organ dysfunction (≥1):
    (a) hypercalcaemia
    (b) renal insufficiency (Cr>155)
    (c) Anaemia ( active observation)
84
Q

Staging parameters for MM:

A
  • Beta2-microglobulin levels

- serum albumin

85
Q

Diagnosis of MGUS:

A
  1. serum monoclonal protein >30g/L
  2. bone marrow plasma cells <10%
  3. absence of features of MM (lytic bone lesions, hypercalcaemia, anaemia, renal insufficiency related to plasma cell proliferative process) or related B-cell lymphoproliferative disorder
    [ie. Dx of exclusion]
86
Q

Progression of MGUS (rate, Dx)

A

1 - 1.5% / year

IgG or IgA MGUS –> MM or AL amyloidosis

IgM MGUS –> Lymphoproliferative disorder (NHL, CLL, Waldenstrom MG)

87
Q

Risk factors for progression of MGUS:

A
  1. high serum M protein level (≥1.5g/dL)
  2. non-IgG MGUS
  3. abnormal serum free light-chain ratio

Should monitor 6-12 monthly for progression. No treatment to prevent. Early Dx and Tx favourably affect outcome.

88
Q

MGUS can be associated with which medical problems?

A
  1. Skin disease (scleroderma, pyoderma gangrenosum)
  2. Liver disease (cirrhosis, PBC, hepatitis)
  3. Rheum disease (RA, polymyositis, PMR)
  4. HIV infection
89
Q

DDx for massive splenomegaly?

A 
Myelofibrosis
Lymphoma
CML
CLL
Hairy cell leukaemia
Polycythaemia
Sarcoid
Autoimmune haemolytic anaemia
Malaria
90
Q

Does chronic haemolytic anaemia result in iron deficiency or iron overload?

A

Chronic intravasclar haemolysis –> persistent haemoglobinuria –> iron loss requiring replacement.

Chronic extravascular haemolysis can –> iron overload (especially if frequent blood transfusions required) –> secondary haemochromatosis.

91
Q

Which infection classically causes compensated haemolysis to become decompensated?

A

Parvovirus B19 can lead to an “aplastic crisis” with a precipitous fall in Hb in a person with haemolysis (much more marked effect than in people without underlying haemolysis).

92
Q

Increased MHCH (mean corpuscular Hb concentration) is pathognomic of which haemolytic anaemia?

A

Hereditary spherocytosis.

This is almost the only condition in which increased MHCH is seen.

93
Q

What is the pathology underlying hereditary spherocytosis?

A

Abnormalities in any of the components of the membrane-cytoskeleton complex causes structural failure and results in haemolysis (extravascular - as decreased deformability through spleen) –> lifelong excessive breakdown of Hb.

It is a heterogenous condition, caused by many different gene defects.

Inheritance is usually AD.
Some severe forms are AR, and it can arise de novo.

94
Q

What are the clinical findings in hereditary spherocytosis?

A

Broad spectrum of severity.
May present early in life or in adulthood.
- anaemia
- jaundice
- splenomegaly
- gallstones (pigment GS, due to excessive bilirubin)

May or may not have a family Hx

95
Q

Investigations for hereditary spherocytosis?

A

Normocytic anaemia
Raised MHCH
Red cell morphology: Spherocytes (smaller, denser, sphere-shaped)

Confirm with flow cytometry.

Osmotic fragility test: measures erythrocyte resistance to hemolysis while being exposed to varying levels of dilution of a saline solution. Positive if decreased membrane to cytoplasm ratio. Not used much anymore.

May perform gene testing (usually not needed).

96
Q

Treatment for hereditary spherocytosis?

A

Splenectomy - as spleen is main site of destruction, and also increases spherocytosis.

97
Q

What is the mode of inheritance of G6PD deficiency?

A

X-linked.
Usually missense mutation of coding region of G6PD gene.
Highly variable expression in female heterozygotes due to X-chromosome inactivation (Lyonisation) - can be as severe as hemizygous males.

98
Q

What are the 3 main triggers of acute haemolysis in G6PD deficiency?

A

Oxidative stress:

  1. Fava bean ingestion (“Favism”)
  2. Infections
  3. Drugs
    - Antimalarials, esp. primaquine, dapsone
    - Sulphonamides, esp. sulphamethoxazole in cotrimoxazole
    - Antibiotics, esp. cotrimoxazole, nitrofurantoin
    - Many others
99
Q

What are Heinz Bodies on a blood film? What do they suggest?

A

Heinz bodies = precipitates of denatured Hb.
Signature of oxidative damage to RBCs (DDx: unstable Hb - rare), as in G6PD.

This staining is now rarely carried out.
Semi-quantitative and quantitative testing can now identify most cases of G6PD deficiency.
Note: testing during an acute episode can yield false neg results in some phenotypes.

[Think “Beans means Heinz” - can’t eat Fava beans in G6PD deficiency].

100
Q

What are Howell-Jolly bodies on blood film?
What are they indicative of?
What other features may be seen in this setting?

A

Howell-Jolly bodies: nuclear remnants which are present in some normal red cells in the bone marrow but are usually removed or ‘pitted’ by the spleen during the first few hours the cells spend in the circulation.

Seen on peripheral film POST-SPLENECTOMY.

Also - target cells, spherocytes (older RBCs), odd cells, lymphocytosis, thrombocytosis (due to lack of sequestration)

101
Q

Spherocytes are seen on blood film in…

A
  1. Autoimmune Haemolytic Anaemia
  2. Hereditary Spherocytosis
  3. Post-splenectomy (older RBCs)
102
Q

Rouleaux are seen on the blood film when…

A
  • High globulins / fibrinogen
  • Chronic infection / inflammation
  • Monoclonal proteins
103
Q

What happens to the ESR in polycythaemia rubra vera?

A

Characteristically LOW ESR for complex reasons.

Cf. inflammatory conditions where ESR is raised.

104
Q

Atypical lymphocytes on the blood film may suggest…

They represent…..

A
  • EBV
  • CMV
  • Acute HIV
  • Toxoplasmosis
  • Sometimes other viral infections

They represent CD8+ cytotoxic T cells.

105
Q

In which situations could you see haemolysis without a reticulocyte count?

A
  1. Primary marrow disorder - eg. PNH
  2. Folate deficiency –> megaloblastic crisis
  3. Autoimmune destruction of erythroid precursors (as well as peripheral RBCs)
  4. Aplastic crisis - parvovirus
  5. Sudden onset / acute (too early)
106
Q

Causes of low haptoglobin?

A
  • Haemolysis
  • Post-transfusion (as non-viable cells in transfusion –> free Hb)
  • Megaloblastosis (due to ineefective erythropoiesis)

Remember - haptoglobin’s job is to “mop up” free Hb in plasma, which would otherwise be nephrotoxic.

Note: normal haptoglobin does not exclude haemolysis.
Haptoglobin is an acute phase reactant. It is increased in pregnancy, malignant and inflammatory processes, OCP.

107
Q

What causes haemosiderinuria? Why and how would you test for it?

A

Detectable on Prussian Blue Stain on urinary sediment.
Hb-containing tubular cells shed in urine.

Positive one week after acute intravascular haemolysis or with chronic intravascular haemolysis.

Persists for several weeks after a haemolytic episode.

108
Q

Which test would you perform if you suspected PNH?

A

Flow cytometry for PIG anchored proteins.

109
Q

Differences in treatment of cold and warm antibody haemolytic anaemia?

A

Cold antibody haemolysis tends to respond poorly to glucocorticoids. Splenectomy is not part of the treatment.
- Warm the patient
- AVOID transfusion (transfused RBCs prone to lysis as not coated with c3d)
- Rituximab has a modest response rate and fewer side effects than alkylating agents.
Alkylating agents: chlorambucil / cyclophosphamide considered, but poor response rate.

Warm antibody haemolysis:
- 1st line: glucocorticoids (90% initially respond)
- 2nd line: splenectomy
- 3 rd line: rituximab.
Then azathioprine or cyclophosphamide.
- Avoid over-transfusion (suppresses endogenous erythropoiesis).

Need to treat underlying cause whether warm or cold Ab.

110
Q

Why do you use FFP as fluid replacement in plasmapheresis for TTP?

A

Mechanism of TTP: high molecular weight multimer of vWF, due to deficiency of vWF cleaving protease (ADAMTS13).

Plasmapheresis removes large multimers. Then need to replace with normal vWF multimers in FFP.

When plamapheresis is used in other disorders (MG, GBS, CIDP, Waldenstrom’s MG), FFP is not required (ie. use saline or albumin).

111
Q

Serum ferritin >100. Is this helpful when there is chronic disease?

A

If IDA unlikely that serum ferritin will be >100.

Even in chronic disease, if iron deficient ferritin most often <100.

112
Q

Warm antibody haemolytic anaemia can be associated with…?

A

80-90% AIHA is mediated by warm-active autoantibodies (37 degrees C).

May be primary or secondary – need to rule out an underlying disorder:

  • Lymphoproliferative disorders eg. NHL, CLL
  • AI disorders, eg. SLE
  • Non-lymphoid neoplasma eg. ovarian tumours
  • Chronic inflammatory diseases, eg. UC
  • Drugs, eg. methyldopa
113
Q

Treatment of warm antibody AIHA?

A

Transfusion – only for severe / symptomatic anaemia

  • may be impossible to find truly seropos donor
  • important to exclude concomitant ALLOantibody if prior transfusion or pregnancy
  • don’t over-transfuse to avoid suppression of endogenous erythropoiesis
  1. Glucocorticoids (prednisone 1-2mg/kg and wean over 3-4 months)
    - 90% respond initially
    - early action: suppress sequestration of opsonised RBCs by splenic macrophages
    - late: reduction in autoAb production
    - relapse common – then need to consider other options
  2. Splenectomy – laparoscopically if possible (+/- cholecystectomy)
    - 60-70% have partial or complete remission, but significant relapse rate
  3. Immunosuppressive / Cytotoxic agents: if failed 1st and 2nd line, or poor surgical candidate
    - Azathioprine, cyclophosphamide, cyclosporine, MMF, rituximab, alemtuzumab, IVIG, PEx, danazol.
114
Q

Prognosis of warm antibody AIHA?

A

Secondary: relates to underlying disease.
Primary: unpredictable. Approx. 73% alive at 10 years. Die of PE, infection, severe anaemia. 18% develop NHL.

115
Q

What are the types of cold-antibody AIHA and their associations?

A

Cold-antibody AIHA ~ 15% AIHA.

  1. Cold Agglutinin Disease (CAD): usually IgM antibodies
    - acute: mycoplasma, EBV
    - chronic: NHL, can be idiopathic
  2. Paroxysmal Cold Haemoglobinuria (PCH): cold reactive IgA b (usually polycolonal)
    - Post-infection (viral, syphilis)
    - Autoimmune
116
Q

Treatment of Cold Agglutinin Disease (AIHA)?

A

Acute CAD is usually self-limited.
Chronic CAD often has a benign course.
Management:
- Keep warm (consider moving place of residence)
- NOT responsive to steroids or splenectomy
- avoid transfusion if possible (use blood warmer if necessary)
- Consider alkylating agents : chlorambucil /cyclophosphamide
- Rituximab: response rate 54%
- Sometimes used: Plasmapheresis, IFN

117
Q

MAHA – blood film features?

A
  • anaemia
  • schistocytes, microspherocytes
  • polychromasia (ie. reticulocytosis)

Pathogenesis: RBC fragmentation as pass through platelet-fibrin mesh of microthrombi.

118
Q

Causes of TTP/HUS (ie. DDx)?

A

Primary ~ 1/3 cases

Secondary:

  • HTN: hypertensive crisis, pregnancy-related (preeclampsia, HELLP syndrome)
  • Immunologic – SLE, acute GN, PAN, scleroderma
  • Malignancy
  • Drugs – cyclosporine, mitomycin, OCP
  • Radiation
  • BMT
  • Surgery
  • Diffuse DIC – infection, snake bite, placental abruption
  • Cavernous haemangioma
119
Q

What is the classic clinical pentad of TTP/HUS?

A
  1. Fever
  2. MAHA (ie. schistocytes, microspherocytes)
  3. Thrombocytopaenia
  4. Neurological dysfunction
  5. Renal dysfunction

Neuro symptoms: TTP > HUS
Renal dysfunction: HUS > TTP

**Dx of TTP only requires MAHA (with no apparent cause) + Thrombocytopaenia

120
Q

Treatment of TTP?

A

TTP Treatment:

  1. PLASMA EXCHANGE:
    - Has improved prognosis so significantly that it should be commenced early, even if awaiting confirmation of Dx / ruling out other Dx
    - Note: fluid replacement should be with FFP during PEx for TTP, to replace abrnormal vWF multimers (removed by PEx) with normal multimers (in FFP)
    - duration depends on cause
  2. Corticosteroids: idiopathic TTP or in conjunction to PEx if poor response
  3. Vincristine
  4. Splenectomy: variable response; used in refractory / relapse
  5. Rituximab
  6. Antiplatelet agents: role uncertain, no value as maintenance therapy.
121
Q

PNH – clinical features?

A

An ACQUIRED disorder (somatic mutation in PIG-A gene):

  • nocturnal ahemoglobinuria (only a few patients)
  • chronic haemolysis
  • iron deficiency (urinary iron loss as Hb / haemosiderin)
  • aplastic anaemia (15% at 8 years)
  • thrombosis eg. Budd-Chiari Syndrome – mechanism unclear
  • Bleeding – thrombocytopaenic

Course is variable

Can get secondary myelodysplasia / acute leukaemia

Median survival 14.6 years (pre-eculizumab studies)

122
Q

Treatment of PNH?

A

Supportive care:

  • transfusion: packed RBCs ok, no need for washed.
  • antibiotics
  • iron therapy if deficient
  • anticoagulants – no proven benefit for prophylactic use

Allogeneic BMT – may be curative in selective patients

ECULIZUMAB – improves haemolysis, decreases transfusion, improves QOL and decreases thrombosis risk.
- Humanised mAb that binds c5 and inhibits terminal complement complex activation

123
Q

What is the mechanism of Eculizumab?

A

Mechanism of Eculizumab:

Humanised mAb that binds c5 and inhibits cleavage to c5a and c5b → inhibits generation of terminal complement complex (MAC).

Uses:

  • PNH: inhibits terminal complement-mediated intravascular haemolysis
  • aHUS: inhibits complement-mediated thrombotic microangiopathy (TMA)
124
Q

What is the presentation of G6PD deficiency?

A

Can be abrupt onset.
Malaise, weakness, abdo pain, lumbar pain.
Jaundice and haemoglobinuria (after hours - 3 days).
May develop ARF.

Moderate to severe anaemia: normocytic, normochromic.

As intravascular component: haemoglobinaemia, haemoglobinuria, high LDH, low / absent haptoglobin.
Also elevated unconjugated bilirubin (extravascular haemolyis).

Blood film:

  • normocytic, normochromic anaemia
  • Anisocytosis, polychromasia, spherocytes, poikilocytes
  • HEINZ BODIES: intracellular inclusions (damaged Hb)
  • BITE CELLS: due to removal of damaged Hb by splenic macrophages.
125
Q

In which forms of haemolysis do Bite cells and/or Heinz bodies occur?

A

Bite cells and Heinz bodies inply oxidative injury (eg. G6PD deficiency) rather than other causes of haemolysis.
They do not occur in other forms of haemolysis.

126
Q

Interpretation of Direct Antiglobulin Test (Direct Coomb’s Test) in suspected AIHA?

A

97-99% have a positive DAT.
Negative DAT does not completely exclude coating globulins (eg. if low level).

IgG +ve: more likely warm-Ab than cold-Ab, as cold-Abs are usually IgM or IgA
(but cold-Ab AIHA can occasionally be due to IgG)

Cd3 +ve: more likely cold-Ab AIHA, but can be warm-Ab AIHA.

IgM is much more efficient at initiating fixation of complement as only one molecule of Ab is required, thus Cd3 more common in cold-Ab AIHA.

IgG Abs require two molecules to initiate complement sequence, thus direct lysis of RBCs by complement is a less common mechanism for IgG-associated AIHA (typically warm).

127
Q

Pathogenesis of TTP vs HUS?

A

Systemic endothelial damage is the central phenomenon.

TTP:

  • Non-familial: due to inhibitor (Ig) of vWF-cleaving protease (ADAMTS13)
  • Familial: constitutional deficiency of vWF-cleaving protease ADAMTS13.

HUS:
Not related to protease deficiency
- “Typical”, Infection-Induced Secondary HUS: pathogenesis unclear, but related to bacterial proteins / toxins
- “Aypical”, Primary, Complement-mediated HUS: mutations in genes for complement proteins (c3, CD46) and complement factors (H, B, I) leads to impaired regulation of complement activity and uncontrolled terminal complement activation → plt activation, endothelial cell damage and thrombotic microangiopathy.

128
Q

Haemoglobin C disease - pathophysiology and presentation?

A

Haemoglobinopathy that results from mutation in beta chain gene. HbC is less soluble than HbA.

Abnromal hexagonal crystallisation (unlike long polymers in HbS).

Causes RBC dehydration –> raised MCHC.

HbC trait (heterozygous, ie. HbAC) phenotypically normal.
HbC Disease (homozygous, ie HbCC): with mild haemolysis, mild anaemia, mild splenomegaly.

Blood film abnormal: crystals, target cells, microcytosis.

Iron studies usually normal.

Occurs in people of West African and Central / South American descent.

Relevant to genetic counselling as heterozygotes for both HbC and sickle cell (ie. HbSC) have more severe phenotype than HbCC.

129
Q

What are the clinical features of Fanconi’s anaemia?

How do you test for it?

A

Fanconi’s Anaemia:

Rare, AR or X-linked disorder.
Most common congenital form of aplastic anaemia.

Usually Dx made in childhood but approx. 9% Dx >16yo.

  1. congenital development anomalies: short stature, cafe au lait spots, anomalies of thumb, radius, genitourinary tract, hypogonadism, microcephaly, developmental delay.
  2. progressive pancytopaenia
  3. increased malignancy risk, esp. MDS, AML, SCC of H&N or vulva.

Various underlying genetic defects.

The diagnosis is made by the presence of increased chromosomal breakage in lymphocytes cultured in the presence of DNA cross-linking agents such as mitomycin C.

130
Q

What would you see on a blood film in aplastic anaemia?

A

Typically PANCYTOPAENIA, though may have depression of fewer cell lines with later progression to pancytopaenia.

  • Large erythrocytes, increased MCV
  • Few/absent retics
  • Few platelets
  • Few granulocytes
  • Lymphocyte numbers normal or reduced

Findings that would suggest an alternative Dx:

  • immature myeloid forms (MDS or leukaemia)
  • nucleated RBCs (marrow fibrosis, tumour invasion)
  • Abnormal platelets (MDS or peripheral destruction)

Dx of aplastic anaemia usually requires a BMAT showing hypocellularity and fatty BM.

131
Q

Tell me about splenomegaly and lymphadenopathy in aplastic anaemia.

A

Splenomegaly and lymphadenopathy are highly atypical of aplastic anaemia and should prompt a search for another Dx.

(unless perhaps it occurs post-hepatitis or related to alcohol cirrhosis).

DDx / overlaps of aplastic anaemia include PNH, MDS, Pure red cell aplasia.

Causes / associations of aplastic anaemia?
Inherited, eg. Fanconi’s anaemia.

Secondary-
1. Radiation
2. Drugs / chemicals - regular effects (eg. chemotherapy) vs. idiosyncratic reactions.
Benzene exposure commonly associated.
3. Viruses: EBV, seronegative hepatitis, parvovirus B-19 (transient aplastic crisis or PRCA), HIV.
4. Immune diseases, including SLE and GVHD.
5. PNH
6. Pregnancy

Idiopathic

132
Q

Treatment of aplastic anaemia?

A

Prognosis related to: degree of hypocellularity of BM, retic count, ANC, age.

  • Cease exposure to any possible causative agents.
  • Allogeneic HCT: first-line in young ( ATG + cyclosporine
    > high dose cyclophosphamide
    > Addition of Alemtuzumab still being investigated, but increases infection risk.

Does NOT respond to glucocorticoids haematopoietic growth factors are of limited use.

133
Q

Management of Pure Red Cell Aplasia?

A

Rule out thymoma (radiographically)

  • Test for Parvovirus B19 (PCR for DNA) - persistent Parvovirus infection (which occurs in immunodeficiency such as AIDS) responds to IVIG, though frequently relapses.
  • Supportive care: red cell transfusion and iron chelation
  • Immunosuppression may be used: glucocorticoids, cyclosporine, ATG, azathioprine, cyclophosphamide
  • Daclizumab (mAb to high affinity IL-2 Rc), rituximab and alemtuzumab have all been used - no definitive data.

If associated with EPO therapy (rare, due to inhibitor) - treat with immunosuppression and withdraw EPO.

134
Q

Prognosis of MDS is based upon which factors?

A

Note: Variations between WHO classification of MDS and French-American-British. There are overlaps with myeloproliferative disorders (AML, CMML).

WHO classification: Currently based upon cell line affected, % blasts in peripheral blood and in BM, presence / absence of Auer rods.

PROGNOSTIC factors (from IPSS Score) are:
- % BM blasts.
- cytopaenias (#lineages affected).
- karyotype:
eg. 5q- syndrome or del(5q) good prognosis as responds to LENALIDOMIDE;
Whereas ≥3 abnormalities or chr7 abnormality = poor prognostic karyotype.

Marrow fibrosis is also a poor prognostic feature.

Prognosis varies from months to years. Most will die of complications of pancytopaenia rather than leukaemic transformation.

135
Q

Treatment options in Myelodysplastic Syndrome:

A

Treat once symptomatic (bleeding, infection, anaemia).
Treatment choice guided by IPSS Score of severity, which correlates with prognosis.

  1. Symptomatic / Supportive treatment: RBC transfusion + iron chelation; platelet transfusions; antibiotics early for infection, but not prophylactic.
  2. “Low intensity therapies”: Azacytadine or decitabine, immunosuppressants (ATG, cyclosporine), lenalinomide.
  3. “High intensity therapies”: chemotherapy and HCT, eg. daunorubicin, cytarabine.

Patients with 5q deletion have superior outcomes with LENALIDOMIDE.

Patients with CMML (Chronic Myelomonocytic Leukaemia) and particular gene mutations have superior outcomes with IMATINIB.

136
Q

What is the pathogenesis of primary myelofibrosis?

A

The primary disease process is a clonal hematopoietic stem cell disorder that results in chronic myeloproliferation and atypical megakaryocytic hyperplasia.

The secondary process of bone marrow fibrosis is the result of nonclonal fibroblastic proliferation and hyperactivity induced by growth factors abnormally shed from clonally expanded megakaryocytes.
BM fibrosis is the hallmark of Primary Myelofibrosis and contributes to the impaired hematopoiesis that leads to severe anemia.

In addition to BM fibrosis and anemia, patients with PMF suffer from marked SPLENOMEGALY, extramedullary hematopoiesis, and severe constitutional symptoms.

137
Q

What are some causes of secondary myelofibrosis (aka myelophthisis)?

A

Secondary fibrosis = response to:

  • invading metastatic tumour cells
  • haematological malignancies (CML, MM, lymphoma, hairy cell leukaemia).
  • mycobacterial infection (M. Tuberculosis or M. avium)
  • Disseminated fungal infection
  • HIV
  • Sarcoidosis
  • Gaucher’s disease (intracellular lipid deposition)
  • Radiation therapy (late consequence)

RACP Written Exam (7 decks)

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