Heamatopoiesis and Anaemias Flashcards
What ancestral cell do all blood cells have?
Multipotent stem cell (MSC)
Outline HSCs
- Occur 1:5000 in bone marrow
- Have the capacity to give rise to non-self renewing populations that generate multiple terminally-differentiated cell types
- Contain efficient membrane pumps
State the two niches within bone marrow where stem cells renew and differentiate
Osteoblastic niche (endosteal surface)
Vascular niche (involving sinusoidal blood vessels)
What do each stem cell niche do?
Osteoblastic: maintains quiescence, harbours long term HSC
Vascular: Supports proliferation, differentation, mobalisation of short term HSC
What factors control haematopoiesis (blood component formation)?
Extrinsic factors (soluble growth factors)
Intrinsic factors (transcription factors)
State and outline some important transcription factors
- Runx1: required for normal haematopoiesis
- Ikaros: regulate immune system development
- Pax5, E2A, EBF
- Notch-1, GATA-3: T cell development
- GATA-1: essential for erythroid and platelet forming cells
State the key steps in erythropoiesis
- Proerythroblast (first committed RBC)
- Basophilic erythroblast (nucleus shrinks, cytoplasm beckmes more basophilic due to ribosome presence)
- Polychromatophilic erythroblast (produce more haemoglobin, cytoplasm takes up baso + eosin stains)
- Orthochromatohilic erythroblast (excludes nucleus)
- Reticulocyte (cytoplasm contains polyribosomes, enters circulation)
Where does erythropoiesis occur?
In early fetus: yolk sac, spleen, liver
After birth: bone marrow
State an example of an extrinsic factor.
Erythropoietin
Outline Erythropoietin
- Hormone, produced in fibroblast-like cells
- 165 animo acid glycoprotein
- 4 carbohydrate chains
- Anti-apoptotic (prevents apoptosis)
- Levels increase when haemoglobin levels decrease
How can erythropoietin levels help clinically?
- High levels indicate anemia (unless it is due to renal failure with a tumour)
- Low levels in renal disease or polycythemia vera
What family of proteins meditate the effect of growth factors?
Janus-associated kinase (JAK) proteins
Describe RBC characteristics
- Anucleate (increases flexsbility and O2 carrying capacity, but reduces life span)
- Highly flexible
- Biconcave discs
- 8μL diameter
- 80-100 fL volume
- Average 120 day lifespan
State 4 pathways involved in RBC metabolism
Pentose phosphate pathway
Methemoglobin reductase pathway
Luebering-Rapaport Bypass
Lactic acid fermentation
How do RBCs make ATP?
Embden Meyerhof pathway (glycolysis of glucose to pyruvate, forming ATP and NADH/lactic acid fermentation on pyruvate, forming ATP, NAD+, lactate)
Pentose phosphate pathway (important in generating NADPH, keeps haemoglobin in ferrous state)
What enzymes regulates pentose phosphate pathway to reduce oxidative stress?
glucose-6-phosphate dehydrogenase
How does anemia occur?
Lowered production of RBCs
Increased destruction/loss of RBCs
What can decrease RBC production?
- Disturbance of Hb synthesis
- Disturbance of DNA synthesis
- Unknown/multiple mechanisms
What can increase RBC loss/destruction?
Intrinsic (inherited) abnormality:
- Membrane defect
- Enzyme defect
- Globin abnormalities
Extrinsic (aquired) abnormality:
- Blood loss
- Mechanical
- Chemical/physical
- Infection
- Antibody mediated
- Hyperspleenism
How are anemias diagnosed?
Physical examination
Full blood count
Reticulocyte (immature RBCs) count
Bone marrow biopsy
What do MCV, MCH, and MCHC mean?
MCV: average volume of red cells-size
MCH: average content (mass, weight) of Hb/RBC
MCHC: average weight of haemoglobin per unit volume of red cell
State 4 types of anemia:
- Normocytic: normal sized RBCs, low in number
- Haemolytic: RBCs destroyed faster than synthesised
- Macrocytic: abnormally large cells, normal Hb
- Microcytic: smaller than usual due to reduced Hb
How is normocytic anemia classified?
- Reduced Hb and RBC counts
- MCV = normal (80-100 fL)
- Due to: internal/external bleeding or bone marrow faulure
Outline anemia due to hemorrhage
Acute (extrinsic):
- Hb normal immediately after blood loss
- Compensatory mechanisms kick in 24h later
- Fluid enters blood to restore blood volume, haemodilution causes anaemia
- Treat by stopping blood loss, transfusion
Chronic (extrinsic or intrinsic):
- Anaemia develops is normocytic and normochromic
- Iron stores depleted
- Treat by stopping bleeding and giving iron
- May need transfusion
Define normochromic and normocytic
Normochromic: RBCs have normal red colour
Normocytic: RBCs are normal size
Outline the types of aplastic anaemia
RBC aplasia:
- Reduced/increased erythroblasts
- Congenital
Acquired PRBCA:
- Primary or secondary cause
- E.g., infections like HIV
- Autoimmune disease
Outline macrocytic anaemia
- DNA synthesis disorder (incorrect division leads to larger cells)
- B12/folate deficiency
- Due to malabsorption or diet
- Reduced Hb, increased MCV
- normal + neurological symptoms
Outline polycythemia vera and erythemia
Polycythemia vera:
- increase in all blood cells
- unknown stem cell mutation
- JAK2 mutation
Erythemia:
- increase in RBCs
Outline haemolytic anaemia
- An increase in RBC destruction
- Normal life span shortened
- Removed by spleen
- Hyperspleenism
- Increased haemolysis, anaemia symptoms (doesn’t always lead to anaemia)
Compare intravascular and extravascular haemolysis
Intravascular:
- RBCs destroyed in circulation
- Hb release into plasma
- May be immune mediated
- Iron causes damage in blood
- Free Hb binds to haptoglobin, reducing levels
Extravascular:
- Premature RBC destruction in spleen/bone marrow
- RBC removed by macrophages
- Haem breakdown in macrophage generated bilirubin
- Bilirubin released, binds to albumin (liver) to excrete in bile
- Unconjugated bilirubin levels rise, leads to jaundice
How to diagnose increased haemolysis
- Morphology of RBCs
- Hb plasma levels
- Bilirubin levels
- Haptoglobin levels
- Hb in urine levels
- Increased erythropoiesis
Discuss RBC enzyme defects
- Glucose-6-Phosphate Dehydrogenase
- Causes increase in oxidative stress
- G6PD gene sex linked disorder (X)
