Haemopoiesis

Question 1

Where are haemopoietic stem cells found? [1]

Answer 1

in the inner cell mass of bones (i.e. the bone marrow)

Question 2

What are the sites of haemopoiesis in the foetus at:

a. 0-2 months [1]
b. 2-7 months [2]
c. 5-9 months [1]

Answer 2

a. yolk sac
b. liver and spleen (which will continue producing blood cells until 2 weeks after birth)
c. bone marrow

Question 3

What is the site of haemopoiesis in infants? [2]

Answer 3

bone marrow in all bones

• nearly all bones are haemopoietic in infants but there’s a progressive replacement of marrow by fat in the long bones

Question 4

What is the site of haemopoiesis in adults? [2]

Answer 4

bone marrow in the central skeleton (vertebrae, ribs, sterum, skull, sacrum, pelvis) and ends of femurs

• around 30% of bone marrow is still haemopoietically active

Question 5

What are the characteristics of haemopoietic stem cells? [5]

Answer 5

self-renewal capacity

unspecialised

ability to differentiate and mature

rare

quiescent (not undergoing cell cycle, in G0) - only undergoes occasional cell division

Question 6

Where are haemopoietic stem cells found? [3]

Answer 6

bone marrow

peripheral blood after treatment with G-CSF

umbilical cord blood

Question 7

What is G-CSF? [1]

Answer 7

glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream

Question 8

Why are HSCs referred to as having multipotent properties? [1]

Answer 8

due to the fact they produce several different cell types

Question 9

Name the 3 types of stem cell division and explain the different effects that each has on stem cell numbers

Answer 9

1. Symmetrical Division leading to contraction of stem cell numbers
2. Symmetrical Division leading to expansion of stem cell numbers
3. Asymmetrical Division leading to maintenance of stem cell numbers

Question 10

What is the bone marrow microenvironment composed of? [2]

Answer 10

stromal cells

microvascular network (ECM)

Question 11

Give 5 examples of stromal cells [5]

Answer 11

Macrophages

Fibroblasts

Endothelial cells

Fat cells

Reticulum cells

Question 12

What do stromal cells secrete? [6]

Answer 12

Secrete extracellular molecules including growth factors and adhesion molecules, all of which are essential for stem cells to grow, divide and differentiate into mature blood cells

molecules: e.g.

• laminin
• proteoglycans
• collagen
• haemonectin
• fibronectin

Question 13

What are the 2 types of bone marrow and what are each composed of? [4]

Answer 13

Red - due to erythrocytes

Yellow - due to fat cells

Question 14

Name the hereditary conditions that impair bone marrow function [8]

Answer 14

1. Thalassaemia
2. Sickle cell anaemia
3. Fanconi anaemia
4. Dyskeratosis congentia
5. Schwachman-Diamond syndrome
6. Diamond-Blackfan anaemia
7. Thrombocytopenia with absent radii
8. Hereditary leukaemia (very rare)

Question 15

Name the acquired conditions impairing bone marrow function [10]

Answer 15

1. aplastic anaemia
2. leukaemia
3. myelodysplasia
4. myeloproliferative disorders
5. myelofibrosis
6. metastatic malignancy (e.g. breast, prostate)
7. infections (e.g. TB/HIV)
8. drugs and toxins
9. chemotherapy
10. haematinic deficiency

Question 16

Describe the principles/pathogenesis of leukaemogenesis [4]

Answer 16

it’s a multistep process

the neoplastic cell is either a haemopoietic stem cell, lymphoid cell or an early myeloid cell

1. dysregulation of cell growth & differentiation occurs (often associated with mutations)
2. proliferation of the leukaemic clone with differentiation blocked at an early stage

Question 17

Define clonal haemopoietic stem cell disorders [1]

Answer 17

haematological malignancies and pre-malignant conditions that arise from a single ancestral cell

Question 18

What are the 3 criteria needed for evidence of clonality in haemopoietic stem cell disorder? [3]

Answer 18

1. almost all lymphoproliferative disorders and some AMLs carry a unique rearrangement of either an immunoglobin or TcR gene
2. X-chromosome inactivation studies in women with leukaemia show that the clonal proliferation carries either an active maternal or paternal X-chromosome
3. acquired cytogenetic or molecular changes that arise during the development of a malignancy

AML: acute myeloid leukaemia/CML: chronic myeloid leukaemia

Question 19

Define myeloproliferative disorders [1]

Answer 19

clonal disorders of haemopoiesis leading to increased numbers of one or more mature blood progeny

Question 20

Give examples of myeloproliferative disorders [6]

Answer 20

1. polycytaemia rubra vera
2. essential thrombocytosis
3. myelofibrosis
4. mastocytosis
5. clonal hypereosinophilic syndromes
6. chronic neutrophilic leukaemia

Question 21

What is the main risk associated with myeloproliferative disorders?

Answer 21

potential to transform to acute myeloid leukaemia (AML)

Question 22

Define essential thrombocytosis [1]

Answer 22

a primary myeloproliferative disorder with a platelet count (Plt) >600x10⁹/L persistently

Question 23

Describe the genetic basis (associated mutations) of essential thrombocytosis [2]

Answer 23

approx. 50% of cases carry JAK2V617F
approx. 50% of cases carry calreticulin mutation

Question 24

What are the clinical features of essential thrombocytosis? [6]

Answer 24

1. continuum with polycythaemia rubra vera (PRV)
2. thrombotic complications
3. haemorrhagic complications
4. splenomegaly
5. can transform into PRV or myelofibrosis
6. leukaemia transformation in about 3%

Question 25

Essential thrombocytosis can be stratified into risk groups to decide suitable management. Define each risk group [3] and state the suitable management plan for low and intermediate risk groups [2]

Answer 25

1. low risk = age \<40 with no high risk factors * give aspirin or anti-platelet agent 2. intermediate risk = aged 40-60 with no high risk factors * given aspirin +/- hydroxycarbamide 3. high risk = aged \>60 with 1 or more high risk factors

Question 26

What are the high risk factors associated with essential thrombocytosis? [4]

Answer 26

plt \> 1500x10⁹/L previous thrombosis thrombotic risk factors, e.g. diabetes and hypertension

Question 27

Name the drugs used for management of high risk essential thrombocytosis under the following headings: a. first line therapy [2] b. second line therapy [2] c. what is used during pregnancy? [1] d. name 3 other drugs used [3]

Answer 27

a. hydroxycarbamide + aspirin b. anagrelide + aspirin c. IFN-alpha d. the other drugs: * busulphan * ³²P * JAK2 inhibitors

Question 28

What are the 3 features of hydroxycarbamide? [3]

Answer 28

1. very gentle form of chemotherapy 2. can**not** be used during pregnancy as it is teratogenic 3. ribonucleotide reductase inhibitor resulting in reduced production of deoxyribonucleotides

Question 29

Describe the mechanism of action of anagrelide

Answer 29

inhibits megakaryocyte differentiation

Question 30

What is JAK2 and what is its normal function? [2]

Answer 30

JAK2 is a cytoplasmic tyrosine kinase Function = it transduces signals, especially those triggered by haemopoietic growth factors such as erythropoietin, in normal and neoplastic cells

Question 31

What does JAK mutations result in? [1]

Answer 31

continuous activation of the JAK receptor regardless of ligand binding

Question 32

JAK inhibitor: a. drug name? [1] b. used to treat what condition? [1] c. main side effect? [1]

Answer 32

a. ruxolitinib b. myelofibrosis c. thrombocytopenia

Question 33

Define thrombocytopenia [1]

Answer 33

an abnormal drop in blood platelet count

Question 34

Define myelodysplastic syndromes (MDS) [3]

Answer 34

group of acquired bone marrow disroders characterised by: * dysplasia [1] * ineffective haemopoiesis in 1 or more of the myeloid series (granulocytes/monocytes, red cells or platelets) [1] * may have increased myeloblasts [1]

Question 35

Who commonly gets MDS? [1]

Answer 35

elderly people

Question 36

How do myelodysplastic syndromes present? [3]

Answer 36

70-80% present with **fatigue due to anaemia** 20% present with **infections** or **bleeding** 20% incidental findings on full blood count

Question 37

Describe the 7 methods of management of myelodysplastic syndromes [7]

Answer 37

1. **supportive care** - blood and platelet transfusion (may need to consider iron chelation in younger patients) 2. **growth factors** - erythropoietin +/- granulocyte colony stimulating factor (G-CSF) 3. **immunosuppression** - anti-thymocyte globulin (ATG), which is partly successful in treating low-risk MDS 4. **lose dose chemotherapy** - e.g. hydroxycarbamide or low dose cytarabine 5. **demethylating agents** - e.g. azacytidine (an epigenetic therapy) 6. **intensive chemotherapy** - AML-type chemotherapy 7. **allogenic stem cell transplantation**

Question 38

Define Fanconi anaemia [1]

Answer 38

type of anaplastic anaemia that results in bone marrow failure which can present from birth into adulthood

Question 39

Define anaplastic anaemia [1]

Answer 39

autoimmune disease in which the body fails to produce blood cells in sufficient numbers

Question 40

How is Fanconi anaemia inherited? [1]

Answer 40

autosomal recessive

Question 41

List the characteristics of Fanconi anaemia [5]

Answer 41

1. causes somatic abnormalities 2. bone marrow failure 3. short telomeres (abnormal chromosomes) 4. malignancy (increased risk of skin cancer) 5. chromosome instability

Question 42

How does Fanconi anaemia typically present? [7]

Answer 42

1. microphthalmia 2. GU malformations 3. GI malformations 4. mental retardation 5. hearing loss 6. CNS abnormalities (e.g. hydrocephalus) 7. short stature

Question 43

Define microphthalmia

Answer 43

congenital reduction in eye size

Question 44

What is the golden standard therapy for Fanconi anaemia [1] and what are the other options? [3]

Answer 44

gold standard: **allogenic stem cell transplant** other options: * supportive care * corticosteroids * androgens (oxymethalone)

Question 45

Define autologous transplant

Answer 45

uses the patient's own blood stem cells

Question 46

Define allogeneic transplant

Answer 46

any transplant in which the stem cells come from a donor

Question 47

Name the 5 types of donors [5]

Answer 47

1. syngeneic transplant (between identical twins) 2. allogenic transplant (HLA identical) 3. haplotype identical (a half-matched family member: parent or sibling) 4. volunteer unrelated 5. umbilical cord blood