1.1 Haematopoiesis and its regulation Flashcards
What are the characteristics of haematopoietic stem cells?
Perpetual Extensive proliferation Self renewal Pluripotency Quiescence
What are the characteristics of progenitor cells?
Non perpetual Limited proliferative capacity Diminished or no self renewal Lineage commitment Mor actively cycling
What will you see for Haematopoietic Stem Cells on flow cytometery?
CD34+ CD45 RA -/low
Where does haemopoiesis occur at different stages of gestation?
Aorta Gonad Mesonephros (4-5 weeks)
Yolk sac (4-6 weeks)
Fetal liver (6-22 weeks)
Bone marrow (16 weeks onwards)
In what adult bones does haempoiesis occur?
pelvis, ribs, spine, skull and proximal parts of arm/leg bones
What types of blood cells arise from the CLP?
B, T and NK cells
What types of blood cells arise from the CMP?
platelets, RBC, mast cells, basophils, neutrophiles, eosinophils, monocytes
Describe the process of erythropoiesis
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
Describe the mechanism of the JAK/STAT pathway
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
Describe the mechanism of the JAK/STAT pathway
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
What regulates erythropoiesis?
Erythropoietin.
What is the role of erythroferrone?
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
Describe the breakdown of RBCs
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.
What is the structure of the red cell membrane?
Phosopholipid bilayer with membrane proteins and a membrane skeleton
What forms the red cell membrane skeleton?
alpha and beta spectrin, ankyrin, protein 4.1 and actin
What are the two pathways for RBC energy production?
Glycolysis and antioxidant production
What is the pathway of granulocyte production called and what are the blood cells formed?
Granulopoiesis - neutrophils, eosinophils, monocytes, macrophages, basophils/mast cells
What is the role of GCSF?
stimulate the production of neutrophils - can be given therapeutically
What is the role of IL-6 in grabulopoiesis?
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
Describe the production of platelet formation and what is this process called?
Thrombopoiesis
TPO will go to the bone marrow causing stimulation of megakaryocytes to make platelets
Describe the production of platelet formation and what is this process called?
Thrombopoiesis
TPO will go to the bone marrow causing stimulation of megakaryocytes to make platelets
What are the processes involved in platelets forming clots?
Adhesion, activation, aggregation and formation of a haemostatic plug
Describe adhesions of platelets
Glycoproten Ib binds to von willebrand factor leading to the adhesion to teh subendothelium
Describe activation of plateleys
Adhesion triggers glycoprotein IIb/IIa activation causing irreversible binding
Describe aggregation of platelets
Activated GP IIb/IIa mediates aggregation of fibrinogen and VW factor
What do you need for stem cells to survive?
the haemopoietic microenvironment including glial cells, neurons, MSC, endothelial cells, CEMP cells and adipocytes
What are the disorders of too much, too little and poor quality RBCs?
too much: polycythaemia
Too little: anaemia
Poor quality: haemaglobinopathy, RC enzymopathy, RC membrane defects
What are the disorders of too much, too little and poor quality white cells?
Too much: leucocytosis, leukaemia, lymphoma
Too little: leucopenia, lymphopenia
Poor quality: chronic granuloma disease
What are the disorders of too much, too little and poor quality platelets?
Too much: thrombocytosis/cythaemia
Too little: thrombocytopaenia
Poor quality: functional platelet disease, storage pool disease
What are the primary and secondary causes of polycythaemia?
Primary: bone marrow diseases
secondary: EPO mediated (bone marrow told to make too much)
What are the causes of true polycythaemia?
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
What are the causes of anaemia?
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
What are the causes of anaemia?
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
What is leukaemia?
disruption of the normal processes that regulate differentiation and development characterised by the accumulation of malignant haemopoietic precursors
What are the causes of reduced granulopoiesis?
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)
What causes increased thrombopoiesis?
Infection and inflammation
Acquired mutations in JAK2, CALR, bcr-abl and TPOR
What causes reduced thrombopoiesis?
Liver diease B12/folate deficiency Acsuired muattions in MDS Congenital syndromes: TARS Immune insult Drugs Marrow insults (radiation) Increased destruction (immune, mechanical, spleen)
What causes reduced thrombopoiesis?
Liver disease B12/folate deficiency Acquired mutations in MDS Congenital syndromes: TARS Immune insult Drugs Marrow insults (radiation) Increased destruction (immune, mechanical, spleen)
