1.1 Haematopoiesis and its regulation

Question 1

What are the characteristics of haematopoietic stem cells?

Answer 1

Perpetual 
Extensive proliferation 
Self renewal 
Pluripotency 
Quiescence

Question 2

What are the characteristics of progenitor cells?

Answer 2

Non perpetual 
Limited proliferative capacity 
Diminished or no self renewal 
Lineage commitment 
Mor actively cycling

Question 3

What will you see for Haematopoietic Stem Cells on flow cytometery?

Answer 3

CD34+ CD45 RA -/low

Question 4

Where does haemopoiesis occur at different stages of gestation?

Answer 4

Aorta Gonad Mesonephros (4-5 weeks)

Yolk sac (4-6 weeks)

Fetal liver (6-22 weeks)

Bone marrow (16 weeks onwards)

Question 5

In what adult bones does haempoiesis occur?

Answer 5

pelvis, ribs, spine, skull and proximal parts of arm/leg bones

Question 6

What types of blood cells arise from the CLP?

Answer 6

B, T and NK cells

Question 7

What types of blood cells arise from the CMP?

Answer 7

platelets, RBC, mast cells, basophils, neutrophiles, eosinophils, monocytes

Question 8

Describe the process of erythropoiesis

Answer 8

The kidneys detect low levels of circulating oxygen and this stimulates the production of EPO. EPO will travel to the bone marrow and stimulate precursors to make RBCs and increase the oxygen carrying capacity of the blood. This will feedback to the kidneys to stop further production of EPO

Question 9

Describe the mechanism of the JAK/STAT pathway

Answer 9

A cytokine will bind to the cytokine receptor and activate the JAK protein. This causes phosphroylation of the STAT transcription factors. This results in their dimerization and translocation to teh cell nucleus. Here the STAT dimers activate transcription of specific genes

Question 10

Describe the mechanism of the JAK/STAT pathway

Answer 10

A cytokine will bind to the cytokine receptor and activate the JAK protein. This causes phosphroylation of the STAT transcription factors. This results in their dimerization and translocation to teh cell nucleus. Here the STAT dimers activate transcription of specific genes

Question 11

What regulates erythropoiesis?

Answer 11

Erythropoietin.

Question 12

What is the role of erythroferrone?

Answer 12

Erythroferrone is released in response to increased EPO levels. This will supress the hepcidin production by the liver allowing an increased availability of iron to be used for oxygen transport

Question 13

Describe the breakdown of RBCs

Answer 13

Macrophages in the bone marrow and spleen break down the RBCs into heme and then bilirubin. The bilirubin travels linked to albumin to the liver. Here the bilirubin is conjugated and secreted in the bile. In the small intestine the conjugated bilirubin is converted back into bilirubin and into urobilinogen. If it remains in the colon it is converted into stercobilin and excreted in teh feces, if it enters the plasma and is filtered by the kidney it is converted to urobilin and excreted in the urine.

Question 14

What is the structure of the red cell membrane?

Answer 14

Phosopholipid bilayer with membrane proteins and a membrane skeleton

Question 15

What forms the red cell membrane skeleton?

Answer 15

alpha and beta spectrin, ankyrin, protein 4.1 and actin

Question 16

What are the two pathways for RBC energy production?

Answer 16

Glycolysis and antioxidant production

Question 17

What is the pathway of granulocyte production called and what are the blood cells formed?

Answer 17

Granulopoiesis - neutrophils, eosinophils, monocytes, macrophages, basophils/mast cells

Question 18

What is the role of GCSF?

Answer 18

stimulate the production of neutrophils - can be given therapeutically

Question 19

What is the role of IL-6 in grabulopoiesis?

Answer 19

Stimulates emergency white cell production. The production of IL6 indicates an infection which will sitmulate macrophages into making an enzyme ADAM which will go to teh surface of immature immune cells and macrophages cleaving off teh IL6 receptor. This receptor wil form a complex which will travel to the bone marrow to stimulate emergency granulopoiesis

Question 20

Describe the production of platelet formation and what is this process called?

Answer 20

Thrombopoiesis

TPO will go to the bone marrow causing stimulation of megakaryocytes to make platelets

Question 21

Describe the production of platelet formation and what is this process called?

Answer 21

Thrombopoiesis

TPO will go to the bone marrow causing stimulation of megakaryocytes to make platelets

Question 22

What are the processes involved in platelets forming clots?

Answer 22

Adhesion, activation, aggregation and formation of a haemostatic plug

Question 23

Describe adhesions of platelets

Answer 23

Glycoproten Ib binds to von willebrand factor leading to the adhesion to teh subendothelium

Question 24

Describe activation of plateleys

Answer 24

Adhesion triggers glycoprotein IIb/IIa activation causing irreversible binding

Question 25

Describe aggregation of platelets

Answer 25

Activated GP IIb/IIa mediates aggregation of fibrinogen and VW factor

Question 26

What do you need for stem cells to survive?

Answer 26

the haemopoietic microenvironment including glial cells, neurons, MSC, endothelial cells, CEMP cells and adipocytes

Question 27

What are the disorders of too much, too little and poor quality RBCs?

Answer 27

too much: polycythaemia Too little: anaemia Poor quality: haemaglobinopathy, RC enzymopathy, RC membrane defects

Question 28

What are the disorders of too much, too little and poor quality white cells?

Answer 28

Too much: leucocytosis, leukaemia, lymphoma Too little: leucopenia, lymphopenia Poor quality: chronic granuloma disease

Question 29

What are the disorders of too much, too little and poor quality platelets?

Answer 29

Too much: thrombocytosis/cythaemia Too little: thrombocytopaenia Poor quality: functional platelet disease, storage pool disease

Question 30

What are the primary and secondary causes of polycythaemia?

Answer 30

Primary: bone marrow diseases secondary: EPO mediated (bone marrow told to make too much)

Question 31

What are the causes of true polycythaemia?

Answer 31

``` Sensitization of EPO receptor JAK-2/CAL-R mutation in stem cell progenitor cells Defective EPO receptor Reduced O2 carrying capacity Polycystic kidney disease post transplant erythrocytosis any hypoxic conditions ```

Question 32

What are the causes of anaemia?

Answer 32

``` Defective EPO receptor congenital conditions B12/folate deficiency Marrow damage (drugs, radiation) Anaemia of chronic disease Blood loss premature mechanical or immune destruction of RBC chronic kidney disease Immune deficiency of EPO ```

Question 33

What are the causes of anaemia?

Answer 33

``` Defective EPO receptor congenital conditions B12/folate deficiency Marrow damage (drugs, radiation) Anaemia of chronic disease Blood loss premature mechanical or immune destruction of RBC chronic kidney disease Immune deficiency of EPO ```

Question 34

What is leukaemia?

Answer 34

disruption of the normal processes that regulate differentiation and development characterised by the accumulation of malignant haemopoietic precursors

Question 35

What are the causes of reduced granulopoiesis?

Answer 35

``` Acquired mutations stromal cell damage increased destruction (immune, splenic) Immunosuppressive drugs Increased magrination B12/folate deficiency Infection Drugs Immune insult Defective GCSF receptor Genetic abnormalities (Downs) ```

Question 36

What causes increased thrombopoiesis?

Answer 36

Infection and inflammation | Acquired mutations in JAK2, CALR, bcr-abl and TPOR

Question 37

What causes reduced thrombopoiesis?

Answer 37

``` Liver diease B12/folate deficiency Acsuired muattions in MDS Congenital syndromes: TARS Immune insult Drugs Marrow insults (radiation) Increased destruction (immune, mechanical, spleen) ```

Question 38

What causes reduced thrombopoiesis?

Answer 38

``` Liver disease B12/folate deficiency Acquired mutations in MDS Congenital syndromes: TARS Immune insult Drugs Marrow insults (radiation) Increased destruction (immune, mechanical, spleen) ```