Haematology

Question 1

Describe the volume and composition of blood

Answer 1

Blood:

• 5 L blood volume per adult (7% body weight)
• 40-50% increase in volume during pregnancy
• Composition of blood:
  
  • Erythrocytes
  • Thrombocytes
  • Leukocytes: neutrophils, eosinophils, basophils, lymphocytes, monocyte
  • Plasma: water, proteins, clotting factors, electrolytes, CO₂, O₂
• ​Haematocrit:
  
  • Volume percentage of red blood cells (47% M; 42% F)

Question 2

Describe haematopoeisis

Answer 2

Haematopoiesis – production of blood cells in bone marrow (BM):

• Multipotent hematopoietic stem cells (HSCs) are able to differentiate into both myeloid and lymphoid cell lines.
• Dysregulation may lead to deficiencies (e.g. anaemia, leukopenia, thrombocytopaenia) or over-production (e.g. haematological malignancies)

Question 3

Describe the regulation of haematopoeisis

Answer 3

Regulation depends on glycoprotein growth factors, which drive the proliferation and differentiation of progenitor cells:

• Erythropoietin (EPO)
• Thrombopoietin (TPO)
• Interleukins (e.g. IL-3, IL-6, IL-7, IL-11)
• Colony-stimulating factors (e.g. M-CSF, G-GSF)
• Negative regulators (e.g. TNF-alpha, TGF-beta)

Question 4

Recall the haematopoetic cell lineages

Answer 4

Question 5

Describe the pre-natal and post-natal haematopoetic niches (2 points)

Answer 5

Two key hematopoietic niches:

1. Prenatally: aorta-gonad-mesonephros (AGM) region and yolk sac, placenta, foetal liver, spleen, and bone marrow.
2. Postnatally: primary site is bone marrow (BM) but can shift to extramedullary sites in response to haematopoietic stress.

Bone marrow niches:

• Local tissue microenvironments that maintain and regulate HSC
• Perivascular
• Most commonly located near trabecular bone.

Question 6

Describe the maturation process of red blood cells (4 points)

Answer 6

Erythropoiesis – synthesis and maturation of red blood cells (erythrocytes):

1. HSCs differentiate into myeloid progenitor cell
2. Nucleated erythroblasts are committed to becoming mature erythrocytes
3. Extrusion of their nucleus (to increase space for Hb)
4. Reticulocytes – immature red blood cells that contain organelle remnants (enter circulation)

Question 7

Recall the erythopoeisis mechanism of action (4 points)

Answer 7

Regulation – negative feedback mechanism (4 points):

1. Low O₂ level in the blood (2° to hypoxia, hypotension, hypovolaemia)
2. Kidneys produce and secrete ertythropoetin (EPO)
3. EPO acts on committed, undifferentiated cells to stimulate maturation
4. Increased oxygen-carrying capacity of the blood results in return to original levels of EPO (negative feedback)

Question 8

Recall the breakdown of red blood cells in the recycling or iron and haem

Answer 8

Question 9

Recall the Schilling Test

Answer 9

Note:

IM injection of Vitamin B12 needed to fully saturate the transcobalamin proteins in blood. Once saturated, any remaing free (or later absorped vitamin B12) cannot be bound and so will just end up excreted in the urine – we want this to happen as part of the test.

The “later absorped” vitamin B12 in this case is the oral dose, and this is what is being tested to see if your GI tract can naturally absorb vitamin B12.

Any absorption of vitamin B12 into the blood (by either IM or p.o.) must result in excretion by the kidney.

To know if you are actually peeing out vitamin B12 which was taken orally and absorped via the terminal illeum, it is radiolabelled for detection.

Vitamin B12 in blood → “When it’s free, it will pee. When it’s bound, it is sound (i.e. cannot be peed out whilst still bound to transcobalomin protein).”

Question 10

Recall the metabolic pathway of vitamin B12 and folate

Answer 10

Question 11

Recall the lymphopoeisis pathway

Answer 11

Question 12

List 5 properties of an erythrocyte

Answer 12

Erythrocytes:

1. Biconcave shape
2. No nucleus
3. Rich in haemoglobin (iron-containing protein)
4. Primary function is gas exchange
5. Lifespan of ~120 days

Question 13

Recall the exchange of gases (O₂ and CO₂) in alveolar capillaries of lungs

Answer 13

Question 14

Describe haemoglobin (4 points)

Answer 14

Haemoglobin (Hb):

1. ~6 x 10⁹ Hb molecules per erythrocyte (i.e. inside each RBC)
2. Each Hb molecule made of 4 subunits:
   
   • 2 alpha globin chains
   • 2 beta globin chains
3. Each Hb can carry 4 oxygen molecules
4. Centre is ferric iron (Fe²⁺) – binding site for O₂.

Question 15

Recall the oxygen-haemoglobin dissociation curve

Answer 15

Question 16

List 4 key erythrocyte (red blood cell) diseases

Answer 16

Key erythrocyte diseases (4 points):

1. Anaemia
2. Polycythaemia
3. Haemochromatosis
4. Haemolysis

Question 17

Define anaemia

Answer 17

Anaemia – decreased number of RBCs, haemoglobin or ability to carry oxygen in blood

Basic causes of anaemia (3 points):

1. Blood loss
2. Impaired RBC production
3. Increased RBC destruction

Classified by size (MCV):

• Hb < 130 g/L (M); < 120 g/L (F)

Question 18

List 3 key basic causes of anaemia

Answer 18

Basic causes of anaemia (3 points):

• Blood loss
• Impaired RBC production
• Increased RBC destruction

Question 19

List the 3 classifications of anaemia

Answer 19

Classifcations of anaemia:

1. Microcyitc anaemia (MCV < 80 fL)
2. Normocyctic anaemia (MCV 80–100 fL)
3. Macrocytic anaemia (MCV > 100 fL)

Reference Hb levels by gender:

• Hb < 130 g/L (M)
• Hb < 120 g/L (F)

Question 20

Describe 2 key underlying causes of normocytic anaemia

Answer 20

Anaemia (MCV 80–100 fL) – normocytic anaemia:

• Total Hb and haematocrit reduced, RBC size remains normal.

Reticulocyte (immature RBC) count low – hypoproliferative (< 2%):

1. Anaemia of chronic disease (e.g. cancer, autoimmunity) related to infalmmation-mediated reduction in RBC count
2. Aplastic anaemia (bone marrow failure – haematopoietic stem cells damaged → pancytopenia)

Question 21

Recall anaemia of chronic disease with respect to inflammation-mediated reduction in RBC count

Answer 21

Question 22

Define microcytic anaemia and list 2 main types

Answer 22

Anaemia (MCV < 80) – microcytic anaemia:

• Main types (2 points):
  
  1. Iron deficiency anaemia
  2. Thalassaemia (haemoglobin deficiency)

Question 23

Describe the aetiology of iron deficiency anaemia and list 8 risk factors

Answer 23

Main causes of iron deficiency anaemia (3 key points):

1. Blood loss – principal cause, GI bleed (e.g. NSAID-associated peptic ulceration), menorrhagia
2. Decreased dietary intake – inadequate diet/impaired absorption of iron
3. Increased demand – pregnancy, lactation, growth

Prevalence of iron deficiency aneamia – 3% (M); 8% (F) in UK:

More common in premenopausal and third trimester women (i.e. menstruation/postpartum hemorrhage)

Infants and adolescents increased risk during growth spurt

Prevalence decreasing due to fortification of foods (e.g. cereals)

Risk factors for iron deficiency anaemia:

1. Black women
2. Pregnancy
3. Vegan diet
4. Menorrhagia
5. Haemodialysis
6. Gastrectomy
7. NSAID use
8. Obesity

Question 24

List 5 key signs and symptoms of iron-deficiency anaemia

Answer 24

Signs and symptoms:

1. Fatigue
2. Koilonychia (‘spoon nail’ convexity)
3. Alopecia
4. Glossitis
5. Angular stomatitis

Question 25

Describe the treatment options for iron-deficiency anaemia

Answer 25

Treatment of iron deficiency anaemia – where dietary changes insufficient:

• Oral supplementation – ferrous sulfate 2-3 mg/kg/day divided doses
• Red cell transplantation – symptomatic at rest with dyspnoea, chest pain or pre-syncope

Question 26

Describe the aetiology of thalassaemia (4 points)

Answer 26

Thalassaemia aetiology:

1. Inherited erythropoiesis disorder – abnormal Hb production
2. Type depends on which globin chain is abnormal:
   
   • Alpha
   • Beta
3. Inherited in recessive fashion
   
   • Parents diagnosed with thalassaemia minor have a 50% of passing on the disorder to their offspring
4. Most common in Italian, Greek, Middle Eastern, South Asian, and African ethnicity

Question 27

Describe thalassaemia pathophysiology (5 points)

Answer 27

Thalassaemia pathophysiology:

1. Globin chain production is deficient/absent
2. Imbalance between alpha and beta chains
3. Precipitation of excess chains in erythroid precursors and maturing red cells
4. Results in membrane damage and cell destruction → anaemia
5. Extramedullary haematopoiesis in the liver and spleen, resulting in organomegaly.

Bony changes in the skull due to the marked erythroid hyperplasia:

Question 28

Outline the thalassaemia history and examination

Answer 28

Thalassaemia Hx and examination:

1. Lethargy
2. Hepatosplenomegaly
3. Jaundice
4. Spinal deformity
5. Large head
6. Chipmunk facies
7. Misaligned teeth
8. Failure to thrive

Question 29

List the treatment options for thalassaemia and the disease complications

Answer 29

Thalassaemia treatment options:

• Genetic counselling
• Transfusion if symptomatic
• Iron chelation
• Splenectomy
• Stem cell transplant is only cure

Thalassaemia complications:

• Thrombotic complications
• Arthropathy (Fe²⁺ related)
• Osteopaenia
• Skin pigmentation
• Anterior pituitary dysfunction
• Transfusion complication
• Cord compression
• CVS complications

Question 30

Define macrocytic anaemia and describe 2 main types

Answer 30

Anaemia (MCV > 100) – macrocytic anaemia:

• Inhibition of DNA synthesis during erythropoiesis → cell therefore has prolonged growth phase of cell cycle → large (macro-) cell (-cyte)

Main types of macrocytic anaemia (2 points):

1. Megaloblastic
2. Non-megaloblastic

Question 31

List three basic causes of macrocytic anaemia (3 points)

Answer 31

Main causes of macrocytic anaemia:

1. Vitamin B₁₂/folate deficiency (resulting in megaloblastic anaemia)
2. Alcoholism (resulting in non-megaloblastic anaemia)
3. Hypothyroidism (resulting in non-megaloblastic anaemia)

Question 32

Define megaloblastic anaemia and list 2 main causes

Answer 32

Megaloblastic anaemia – results from inhibition of DNA synthesis:

• Megalocytes and hypersegmented neutrophils are present on peripheral smear.

Main causes of inhibition of DNA synthesis (which leads to megaloblastic anaemia):

1. Vitamin B_12­ deficiency (e.g. pernicious anaemia due to lack of intrinsic factor produced by stomach)
2. Folate deficiency (e.g. dietary insufficiency; absorption insufficiency

Both vitamin B12 and folate mutually depend on each other for metabolism:

Question 33

Define non-megaloblastic anaemia and list 4 main causes

Answer 33

Non-megaloblastic anaemia – megalocytes and segmented neutrophils are not present on peripheral smear.

Therefore, unlikely to be due to inhibition of DNA synthesis.

Main causes of non-megaloblastic anaemia

• Alcohol abuse (resulting in liver disease)
• Hypothyroidism
• Reticulocytosis (i.e. BM is highly active in an attempt to replace RBC loss in haemolytic anaemia)
• Myelodysplastic syndrome

Question 34

Describe the aetiology of sickle cell anaemia (4 points)

Answer 34

Sickle cell anaemia is caused by an autosomal-recessive gene defect in the beta chain of Hb (HbA – ‘adult’) which results in production of sickle cell haemoglobin (HbS – ‘sickle’).

HbS causes the red blood cell to assume a sickle cell shape which is more easily destroyed (resulting in anaemia)

Question 35

Describe the epidemiology of sicle cell anaemia (5 points)

Answer 35

Sickle cell anaemia epidemiology:

1. SCA – 1 in 2000 live births in UK
2. 8% of black people carry the sickle cell gene
3. 10% - 30% in sub-Saharan Africa
4. Associated with African, Arab, Indian subcontinent, SE Asia and Mediterranean ethnicities
5. Gives some resistance to Malaria

Question 36

Describe the pathophysiology of sickle cell anaemia (6 points)

Answer 36

SCA pathophysiology:

1. Deformed cells cause vaso-occlusion in the small vessels or adhere to vascular endothelium, resulting in intimal hyperplasia in larger vessels and slowing blood flow
2. Inflammatory state
3. Precipitating factors: acidosis, dehydration, cold temperatures, extreme exercise, stress and infection
4. High blood cardiac output to compensate for anemia may result in cardiomegaly.
5. Splenic sequestration or temporary bone marrow aplasia can cause circulatory failure and become life-threatening in children
6. Splenic dysfunction increases vulnerability to serious infections

Question 37

List 9 history and examination findings of SCA

Answer 37

SCA Hx and examination:

1. Painful crises
2. Maxillary hypertrophy with overbite
3. Dactylitis
4. Fever
5. Pneumonia-like symptom
6. Bone pain
7. Visual floaters
8. Failure to thrive
9. Pallor
10. Jaundice
11. Tachycardia

Question 38

List the treatment options for sickle cell anaemia (SCA) and the disease complications

Answer 38

SCA treatment:

• Analgesia
• Antihistamine
• Correction of trigger
• Hydration
• Antibiotics
• Blood transfusion
• Hydroxyurea
• Bone marrow transplant

Question 39

Define haemostasis ( 2 points)

Answer 39

Haemostasis is the physiological process that stops bleeding at the site of an injury while maintaining normal blood flow elsewhere in the circulation

Question 40

List 3 basic components of haemostasis (3 points)

Answer 40

Components of haemostasis:

1. Vascular reaction
2. Platelet aggregation – primary haemostasis
3. Coagulation cascade – secondary haemostasis

Question 41

Describe the vascular reaction of haemostasis

Answer 41

Vascular reaction:

1. Vascular endothelial cells produce both pro- and anti-coagulating factors
2. In the absence of injury anti-coagulation factors are released
3. Pro-coagulant factors are contained in subendothelial tissue and so are only exposed during vessel injury (e.g. von Willebrand factor, vWF)

Question 42

Recall the basic components of endothelial cells and subendothelial connective tissue in relation to blood

Answer 42

Question 43

List 4 properties of a thromboyctes (platelets)

Answer 43

Thrombocytes (4 points):

1. Anuclear
2. Derived from megakaryocytes of myloid cell lineage (fragments of cytoplasm)
3. Circulating lifespan ~10 days
4. Without injury – do not adhere to each other or to endothelium

Question 44

Recall the platelete adhesion and aggregation pathway of primary haemostasis

Answer 44

Platelet adhesion and aggregation pathway:

1. Vessel injury
2. Platelets adhere to exposed subendothelial materials e.g. collagen and von Willebrand factor (vWF)
3. vWF in endothelium binds to platelet glycoprotein GP Ib
4. vWF binding exposes GPIIb/IIIa sites (activation of GP IIb/IIIa)
5. GP IIb and GP IIIa link with counterparts on other platelets via vWF
6. Primary haemostatic plug → stable haemostatic plug

Question 45

Recall the primary haemostasis pathway

Answer 45

Question 46

List the stages of primary haemostasis

Answer 46

Primary haemostasis mechanism – primary haemostatic plug formation:

1. Platelets adhere to exposed vWF and collagen, and partially activate
   
   • _​_Full activation of platelets via paralell secondary haemostasis pathway
2. Platelets degranulate releasing adenosine diphosphate (ADP), serotonin and thromboxane A2.
   
   • ADP recruits more platelets
   • Serotonin is a vasoconstrictor
   • Thromboxane A2 stimulates platelet aggregation and further activation
3. Platelet plug generated at site of vessel injury (needs to be stabilized)

Stabilization of haemostatic plug → via secondary haemostasis pathway

Question 47

Recall the secondary haemostasis pathway

Answer 47

Question 48

List the secondary haemostasis mechanism

Answer 48

Secondary haemostasis mechanism – cogulation cascade

Coagulation cascade overview:

1. Three pathways:
   
   • Intrinsic pathway and extrinsic pathway result in a common pathway
2. Stepwise progression
3. Most components are serine proteases (about 30 proteins involved overall)
4. Activated components act as enzyme for next step (i.e. cascade)
5. Results in generation of fibrin clot (i.e. stable haemostatic plug)

Question 49

Describe the intrinsic pathway of the coagulation cascade (5 points)

Answer 49

Intrinsic pathway:

1. Activated by endothelial injury (exposure to subendothelial connective tissue)
2. Takes minutes to activate
3. Otherwise known as “contact pathway”
4. Cascade: (XII→XIIa) ⇒ (XI→XIa) ⇒ (IX→IXa) ⇒ (VIII→VIIIa)
5. Results in formation of factor Xa
   
   • Factor XIIIa and Ca²⁺ converts factor X to Xa

Question 50

Describe the extrinsic pathway of the coagulation cascade (5 points)

Answer 50

Extrinsic pathway (5 points):

1. Activated by endothelial injury (exposure to subendothelial connective tissue)
2. Immediate activation
3. Otherwise known as “tissue factor pathway”
4. Tissue factors released converts factor VII to VIIa
5. Results in formation of factor Xa
   
   • Factor VIIa and Ca²⁺ converts factor X to Xa

Question 51

Describe the common pathway of the coagulation cogaulation cascade (3 points)

Answer 51

Common pathway:

1. Factor Xa converts prothrombin to thrombin
2. Thrombin converts soluble fibrinogen to insoluble fibrin
3. Factor XIIIa helps crosslinking of fibrin to stabilize clot (form stable haemostatic plug)

Question 52

List 2 clotting co-factors essential for normal haemostasis

Answer 52

Clotting co-factors (2 points):

1. Calcium – binds to the phospholipids of endothelial cells to provide a surface for local assembly of coagulation factors
2. Vitamin K – required for carboxylation of factors II, VII, IV, and X in the liver:
   
   • Vitamin K is given to newborns to prevent neonatal haemorrhagic disease.

Question 53

Recall the pathways for clot stabilzation and clot breakdown (fibrinolysis)

Answer 53

Question 54

List 2 antiplatelet drugs and describe their role in treatment and prevent of blood clots

Answer 54

Antiplatelet drugs:

1. Aspirin
2. Clopidogrel

Role in treatment and prevention of blood clots:

• Decrease platelet aggregation (inhibit thrombus formation)
• Effective in arterial circulation
• Used in prevention (and management) of small vessel disease
• Indications: secondary prevention of stroke/MI

Question 55

List 2 key anticoagulant drugs

Answer 55

Anticoagulant drugs:

1. Warfarin
2. Heparin (and low molecular weight heparin, LMWH)

Other drugs include directly acting oral anticoagulants (DOACs) and fondaparinux

Role in the treatment and prevention of blood clots:

• Inhibit the coagulation cascade (targets clotting factors)
• Prevent and treat thrombus e.g. in DVT/PE/AF

Question 56

Recall the mechanism of action of warfarin

Answer 56

Warfarin – Vitamin K antagonist (inhibits vitamin K reductase, VKORC1):

• Reduces availability of functional factor II, VII, IX, X → inhibits coagulation cascade

Question 57

Recall the mechanism of action of heparin

Answer 57

Heparin:

• Binds to and activates antithrombin → inactivates thrombin and factor Xa → prevents formation of fibrin → destabilizes blood clot

Question 58

Describe 3 pro-coagluant drugs

Answer 58

Pro-coagulant drugs (3 points):

1. Tranexamic acid – antifibrinolytic:
   
   • Stabilization of fibrin clot (commonly used in trauma, XLA, PPH)
2. Prothrombin complex
   
   • Contains factors II, VII, IV and X (reverses effects of warfarin)
3. Vitamin K (e.g. phytomenadione)
   
   • Inhibits action of warfarin by replacing vitamin K

Question 59

List 5 key blood clotting disorders

Answer 59

Bleeding disorders – coagulopathies:

“Vampires Do Have Long Teeth”

1. Von Willebrand disease (most common hereditary coagulopathy):
   
   • Autosomal dominant
   • Deficiency in vWF
   • Easy bruising, nosebleeds and bleeding gums
   • Tx with desmopressin prior to dental procedure.
2. Disseminated intravascular coagulation:
   
   • Widespread clotting throughout body
   • Occlusion of small vessels
   • Clotting factors and platelets “used up”
   • Widespread bleeding and organ failure – high mortality
   • Key causes of disseminated intravascular coagulation (3 points):
     
     • Cancers
     • Massive tissue injury
     • Sepsis.
3. Haemophilia A and B:
   
   • X-linked recessive inheritance
   • Type A – reduced factor VIII; type B – reduced factor IX
   • Spontaneous bleeding (commonly intra-articular)
   • Heavy bleeding in dental treatment/surgery.
4. Liver failure:
   
   • Impaired clotting factor synthesis – jaundice, ascites, bleeding gums
5. Thrombocytopaenia:
   
   • Low levels of platelets
   • Inherited or acquired condition (e.g. heparin-induced thrombocytopaenia)
   • Purpura of arms and petechiae in feet, legs, and mucous membranes.

Question 60

Recall the triad of death

Answer 60

Trauma and severe blood loss → triad of death:

“Cuts Are Hazardous”

1. Coagulopathy (decreased coagulation)
2. Acidosis (incrased acid in blood)
3. Hypothermia (decreased heart performance)

Question 61

Define leukaemia

Answer 61

Leukaemia (‘leuk-’ – white; ‘-aemia’ – blood):

• Uncontrolled proliferation of partially developed white blood cells (i.e. blast cells) – build up in blood
• Although leukaemia specifically means cancer of white blood cells, it may refer to cancer of any of the blood cells (including erythrocytes, thrombocytes, and lymphocytes)

Question 62

Describe 4 key haematological malginancias

Answer 62

Hamatological malignancies (4 points):

1. Acute myeloid leukaemia (AML)
2. Chronic myeloid leukaemia (CML)
3. Acute lymphoid leukaemia (ALL)
4. Chronic lymphoid leukaemia (CLL)

Both myeloid and lymphoid progrenitors are susceptiple to haematological malgnancy

Question 63

Recall the genetic aetiology of leaukamia with reference to clonal expansion (5 points)

Answer 63

Genetic factors – clonal expansion:

“Somatic Mutation Allows Leukaemia Commencement”

1. Single cell somatic mutation – alteration of DNA that happens after conception
2. Mutation can occur at stem cell or progenitor cell stages during development
3. Acquisition of growth advantage
4. Leukaemic stem cells (LSCs) then undergo clonal expansion → bulk leukaemia
5. Clonal expansion exhibits pre-clinical and eventually clinical manifestations

Question 64

List 4 environmental factors associated with leukamogenesis

Answer 64

Environmental factors (4 points):

“Carcinogens Do Increase Risk”

1. Carcinogens (e.g. alkylating agents, oxidising agents, DNA)
2. Drugs (e.g. nitrosourea)
3. Infections (e.g. EBV, H pylori)
4. Radiation (e.g. X-ray, UV)

Question 65

Describe the pathophysiology of acute myeloid leukaemia (5 points)

Answer 65

AML pathophysiology:

1. Differentiation “freeze” occurs in myeloid progenitor cell (myeloblast)
2. Myeloblasts do not mature/differentiate
3. Disruption in control of proliferation leads to uncontrolled clone of immature myeloid cells
4. Immature myeloblasts secrete inhibitory substances into BM
5. Development of healthy blood cells in marrow disrupted → “ANT”:
   
   • Anaemia
   • Neutropenia
   • Thrombocytopenia.

Question 66

List the genetic changes which lead to AML

Answer 66

Genetic changes which lead to AML (3 points):

1. Reciprocal chromosomal translocations:
   
   • Rearrangement of chromosomes leads to gene fusion – most commonly (t8;21)(q22;q22)
2. Point mutations of the p53 tumour suppressor gene
3. Specific genetic mutations:
   
   • Class I mutations spontaneous mutations:
     
     • JAK2, FLT3, cFMS, cKIT, or downstream signalling pathways (KRAS, NRAS/BRAF, or PTPN11)
   • Class II mutations – DNA damage
     
     • In genes encoding for transcription factors important in haematopoietic differentiation

Normal karyotype:

• 23 pairs of autsomal chromosomes and 1 pair of sex chromosomes

Question 67

Recall the French-American-British (FAB) classification of AML

Answer 67

Question 68

List 8 clinical presentations of AML

Answer 68

AML clinical presentations:​

1. Mucosal bleeding
2. Bruising/petechiae
3. Gingival enlargement
4. Recurrent infections (dental, nasopharyngeal, chest, perianal)​
5. Hepatosplenomegaly
6. Sweet’s syndrome (neutrophilic infiltrates in skin)
7. Bone pain
8. Non-specific signs and symptoms:
   
   • pallor, fatigue, fever, dyspnoea, lymphadenopathy, abdominal pain, palpitations

Question 69

List the diagnostic investigations for AML (5 points)

Answer 69

AML diagnosis and investigations:

1. Full blood count – neutropaenia, thrombocytopaenia, anaemia
2. Peripheral blood smear – immature blast cells, Auer rods
3. Coagulation screen
4. Electrolytes – increased uric acid, hypercalcaemia
5. Bone marrow biopsy – provides definitive diagnosis (blast cells in ≥ 20%)

Question 70

List 3 treatment options for AML and 5 disease complications

Answer 70

AML treatment options (3 points):

1. Supportive care
   
   • Hydroxycarbamide (i.e. hydroxyurea) to increase Hb
   • Hydration therapy
   • Blood transfusions
   • Anti-infectives
2. Chemotherapy
3. Stem cell transplant

AML complications and prognosis (5 points):

1. Tumour lysis syndrome
2. Pancytopenia
3. Disseminated intravascular coagulation (DIC)
4. Neutropenic sepsis
5. Leukostasis (extremely elevated blast cell count and symptoms of decreased tissue perfusion)

Prognosis – 5-year survival rate 25%; poorer prognosis in patients aged > 60 years.

Question 71

Describe the pathophysiology of chronic myeloid leukaemia (CML)

Answer 71

CML pathophysiology:

1. Reciprocal chromosomal translocation between chromosomes 9 and 22
   
   • Results in an abnormal chromosome 22 → Philadelphia chromosome
2. BCR gene on Ch 22 is fused to ABL gene on Ch 9,
   
   • Results in a BCR-ABL fusion oncogene → p210 BCR-ABL protein
3. p210 BCR-ABL protein is an active tyrosine kinase that alters activity of downstream signal transduction proteins (via phosphorylation of a tyrosine residue of the target substrate) → transforming normal haematopoietic stem cells into malignant cells.

Question 72

Recall the genetic changes which lead to CML

Answer 72

Question 73

List the 3 clinical presentation phases of chronic myeloid leukaemia (CML)

Answer 73

CML clinical presentation phases (3 points):

1. Chronic phase (< 5% blasts)
2. Accelerated phase (10–30% blasts)
3. Blast crisis (> 30% blasts)

Question 74

List 2 treatment options for CML

Answer 74

Treatment options for CML:

1. Imatinib – tyrosine kinase inhibitor
2. Stem cell transplant plus high dose chemotherapy

Question 75

Define myeoloproliferative disorders

Answer 75

Myeloproliferative disorders – group of disorders characterised by overproduction of myeloid cells lines in BM

Question 76

List the 5 WHO classified myeloproliferative disorders

Answer 76

Myeloproliferative disorders – group of disorders characterised by overproduction of myeloid cells lines in BM

WHO classified myeloproliferative disorders (5 points):

“Chronic Cell Proliferation Provokes Emergencies”

1. Chronic neutrophilic leukaemia
2. Chronic eosinophilic leukaemia
3. Primary myelofibrosis
4. Polycythaemia vera
5. Essential thrombocythemia

Includes also chronic myelogenous leukaemia and mastocytosis

Question 77

Describe chronic neutrophilic leukaemia

Answer 77

Chronic neutrophilic leukaemia:

• Rare
• Hepatosplenomegaly (accumulation in liver and spleen)
• Progressive neutrophilia (≥ 25×10⁹/L)
• Absence of Philadelphia chromosome is diagnostic criteria
• Transformation to AML (median time 21 months)
• Survival 6 m – 20 yrs

Question 78

Describe polycythaemia vera

Answer 78

Polycythaemia vera:

• Primarily erythrocytosis; often thrombocytosis and leukocytosis
• JAK2 V617F somatic mutation → activates EPO receptor signalling
• Increased RBC mass and/or haematocrit → hyperviscosity → increased clotting risk
• Increased risk of thrombosis (arterial and venous)
• ‘Red face’ due to excess blood volume
• Tx – phlebotomy (bloodletting) and aspirin (to prevent clotting)

Question 79

Describe primary myelofibrosis

Answer 79

Primary myelofibrosis:

• Abnormal HSC clone proliferation results in fibrosis/scarring/replacement of BM
• Unknown aetiology – associated with JAK2 mutation
• Abnormalities in RBC, WBC, and platelet production (cytopenias)
• Leukoerythroblastosis and splenomegaly are the clinical hallmarks

Question 80

Describe essential thrombocythemia

Answer 80

Essential thrombocythemia:

• Dysregulated megakaryocyte proliferation → increased platelet no./size
• Thrombosis and bleeding
• Half of patients are asymptomatic
• Diagnosis of exclusion
• High-risk patients treat with aspirin and hydroxycarbamide

Question 81

Describe chronic eosinophilic leukaemia

Answer 81

Chronic eosinophilic leukaemia:

• Very rare myeloproliferative disease
• Overproduction of eosinophils
• Chronic disease that may progress to AML
• Overactivation of the oncogene or translocation
• Can be treated with Imatinib

Question 82

Describe the pathophysiology of acute lymphoid leukaemia (ALL)

Answer 82

ALL pathophysiology:

• Genetic alteration of lymphoid progenitor through somatic changes → uncontrolled proliferation and clonal expansion
• Leukaemic blasts infiltrate the BM and other organs
• Leukaemic blast cells duplicate most normal lymphoid progenitor cells
• Genetic abnormalities:
  
  • Chromosomal translocations or aneuploidy are found in 75% of ALL cases
  • Philadelphia chromosome
  • Philadelphia-like ALL (poor prognostic factor)

Question 83

List the ALL classification (2 points)

Answer 83

ALL classification:

1. B-lymphocytic leukaemia
2. T-lymphocytic anaemia

Question 84

List 9 clinical presentations of ALL

Answer 84

ALL clinical presentations:

1. Hepatosplenomegaly
2. Bruising/petechiae
3. Epistaxis
4. Menorrhagia
5. CNS infiltration – papilledema (optic disc swelling due to ↑ICP), meningism, focal neurological signs
6. Unilateral testicular enlargement
7. Renal enlargement
8. Skin infiltration
9. Non-specific – fever, lymphadenopathy, symptoms of anaemia, body pain

Question 85

List the diagnostic investigations for ALL (6 points)

Answer 85

ALL diagnosis and investigations:

1. FBC – normocytic normochromic anaemia, leukocytosis (WBC >50 x 10^9), thrombocytopaenia, neutropaenia
2. Blood smear – lymphoblasts
3. Bone marrow biopsy – lymphoblasts, hypercellularity
4. Lumbar puncture – if evidence of CNS infiltration
5. CT/MRI brain
6. CT thorax/abo/pelvis

Question 86

List 5 treatment options for ALL and 8 disease complications

Answer 86

ALL treatment (5 points):

1. Chemotherapy
2. Tyrosine kinase inhibitor
3. Prophylactic antibiotics +/- antifungals
4. Blood transfusions
5. Stem cell transplant

ALL complications (8 points):

1. Opportunistic infections
2. Febrile neutropenia
3. Tumour lysis syndrome
4. Tx-related alopecia
5. Tx-related coagulopathy
6. Multiorgan failure
7. CNS toxicity
8. Infertility

Question 87

Describe the pathophysiology of chronic lymphoid leukaemia (3 points)​

Answer 87

CLL pathophysiology:

1. Accumulation of multiple genetic events affecting oncogenes and tumour suppressor genes of lymphocytes
2. CLL cells infiltrate lymphatic system and haematopoietic organs such as liver, spleen, and BM
3. CLL cells also involved in initiating autoantibody production by normal B cells, leading to autoimmune reactions such as autoimmune haemolytic anaemia.

Question 88

Describe the genetic changes which lead to CML

Answer 88

CLL genetics:

1. Exact cause unclear → accumulation of multiple genetic events affecting oncogenes and tumour suppressor genes (e.g. TP53, NOTCH1, SF3B1, ATM, and BIRC3), leading to increased cell survival and resistance to apoptosis
2. Molecular markers e.g. mutated immunoglobulin heavy chain (IgHV)

Question 89

Recall the clinical presentation of CLL

Answer 89

CLL clinical presentation:

1. Non-specific: fever, chills, night sweats, symptoms of anaemia, lymphadenopathy, brusing
2. Splenomegaly
3. Recurrent infections

Question 90

List 3 treatment options for chronic lymphoid leukaemia (CLL) and 5 disease complications

Answer 90

CLL treatment options:

1. Observation only in early stages
2. Chemoimmunotherapy
3. Stem cell transplant

CLL complications:

1. Hypogammaglobulinaemia – deficient in IgG, IgA or IgM
2. Autoimmune haemolytic anaemia
3. Immune thrombocytopaenic purpura
4. Secondary malignancy
5. Richter transformation (15%)

Question 91

Define lymphoma

Answer 91

Lymphoma – malignant neoplasms of lymphatic tissue

Question 92

List the two main types of lymphoma

Answer 92

Two main types of lymphoma – Hodgkin’s lymphoma and Non-Hodgkin’s lymphoma:

• Hodgkin’s lymphoma:
  
  • 15% of all lymphomas
  • Presence of Reed-Sternberg cells
• Non-Hodgkin’s lymphoma:
  
  • 85% of all lymphomas (i.e. the remaining percentage that is not Hodgkin’s)

Question 93

Describe Hodgkin’s lymphoma (6 points)

Answer 93

Hodgkin’s Lymphoma (HL):

1. Uncommon haematological malignancy arising from mature B cells → Ig expression absent
2. Presence of Hodgkin’s cells and Reed-Sternberg cells
3. Can be EBV-related
4. PET-CT, essential to determine extent of disease
5. Biopsy necessary to confirm diagnosis
6. Treatment: chemotherapy plus radiotherapy

Question 94

Recall the clinical presentation of HL

Answer 94

HL clinical presentation:

• Most commonly presents with painless cervical and/or supraclavicular lymphadenopathy in a young adult
• Fevers, night sweats, and weight loss occur in 30%

Question 95

Recall the lymph nodes of the head and neck

Answer 95

Question 96

Describe Non-Hodgkin’s lymphoma (5 points)

Answer 96

Non-Hodgkin’s lymphoma (NHL):

1. NHL’s are a heterogeneous group (> 30) of solid malignancies of the lymphoid system
2. Malignant lymphoid cells retain qualities of normal counterparts (B cells to produce immunoglobulins; T cells to travel to extra-nodal sites such as skin and CNS)
3. Incidence increases with age
4. M > F
5. More common in Caucasians

Question 97

List the 4 stages of NHL progression

Answer 97

Stages of NHL progression (4 points):

1. Stage I – localized disease; single lymph node region or single organ
2. Stage II – two or more lymph node regions on same side of diaphragm
3. Stage III – two or more lymph node regions above and below diaphragm
4. Stage IV – widespread disease; multiple organs with or without lymph node involvement

Question 98

List 8 clinical presentations of NHL

Answer 98

NHL clinical presentation:

1. Non-specific – fever, fatigue/malaise, night sweats, lymphadenopathy, SOB, weight loss
2. Splenomegaly
3. Hepatomegaly
4. Focal neurological signs
5. Bone pain/back pain
6. Jaundice
7. Bruising
8. Skin lesions

Question 99

List 9 risk factors for NHL

Answer 99

NHL risk factors:

1. Age > 50 yrs
2. M > F
3. Immunocompromised host
4. EBV
5. Human T lymphocyte virus
6. Human herpes virus
7. H pylori
8. HIV
9. Organ transplantation

Question 100

List 8 diagnostic investigations for NHL

Answer 100

NHL diagnosis and investigations:

1. FBC
2. Blood smear
3. Lymph node biopsy
4. Skin biopsy
5. Bone marrow biopsy
6. HIV/hep virus
7. PET scan
8. Lumbar puncture

Question 101

What is the pharmacological treatment for NHL?

Answer 101

NHL treatment – ‘R-CHOP-21’

• R – rituximab
• C – cyclophosphamide
• H – doxorubicin (hydroxydaunomycin)
• O – vincristine (oncovin)
• P – prednisolone

Given for 21 days (tratment may require several 21-day cycles)

Question 102

Describe multiple myeloma (MM)

Answer 102

Multiple myeloma (MM):

Characterised by terminally differentiated plasma cells, infiltration of the bone marrow by plasma cells and the presence of a monoclonal Ig or Ig fragment in the serum/urine

Usually associated with osteolytic bone disease, anaemia and renal failure

Question 103

Recall the clinical presentation of MM (4 points)

Answer 103

Question 104

List the diagnostic investigations for MM (4 points)

Answer 104

MM diagnosis and investigations:

1. Serum/urine electrophoresis:
   
   • Paraprotein spike (IgG >35 g/L or IgA > 20 g/L and Bence-Jones proteins in urine)
2. Skeletal survey
3. Bone marrow aspirate
4. Full blood count.

Question 105

List 3 treatment options for MM and 2 disease complications

Answer 105

MM treatment:

1. Autologous HSC transplant if eligible
2. Bisphosphonates
3. Hydration therapy

MM complications:

• Death by infection
• Rrenal failure

Median survival ~3 years (remains incurable)

Question 106

Recall the oral manifestations of haematopoietic malignancies

Answer 106

Question 107

List 6 causes of localized and generalized lymphadenopathy

Answer 107

Localised and generalized causes of lymphadenopathy:

1. Infection (acute and chronic) e.g. HIV
2. Cancers
3. Benign tumours
4. Lymph obstruction
5. Trauma
6. Congenital defects