CVS: Red blood cell production and survival Flashcards
What is the first recognisable cell in the erythroid series?
Proerythroblast - Large cell with loose, lacy chromatine + clearly visible nuclei. Cytoplasm = basophilic (this means it leans to a more alkali pH, so is attracted to basic (pH higher than 7) substances)
What are the intermediate cells from stem cell to mature RBC?
Hemocytoblast (stem cell) → Proerythroblast → Early erythroblast → Late erythroblast → Normoblast → Reticulocyte → Erythrocyte
- Both erythroblasts are basophilic, with a strongly basophilic cytoplasm and a condense nucleus that has no visible nucleolus. The basophilia is caused by large number of polyribosomes involved in synthesis of Hb
How is RBC production regulated?
EPO feedback loop:
Number of RBC inversely related to ambient O2 pressure.
If there are normal blood oxygen levels, there is no need to produce more RBCs. However, if there is an imbalance (e.g. hypoxia, decreased Hb content, decreases O2 availability), then:
- If there’s reduced O2 in blood:
- Kidney + liver (to smaller extent) release erythrpoietin
- This hormone stimulated red bone marrow to produce red blood cells
- Enhanced erythropoiesis increases RBC count
- Increases O2 carrying ability of blood
- Brings O2 blood levels back up to normal
What are HIFs and what do they do?
HIFs = Hypoxia-inducible transcription factors
HIF determines EPO gene expression in kidneys, also enhances expression of iron-absorbing genes. Iron absorbing proteins = feeroportin. Iron is an important substrate, and is regulated by hepicidin
HIF hydroxylated by PHD (prolyl hydroxylase domain) enzyme for degradation when O2 levels are sufficient
What stressors are there for RBCs?
- RBCs circulate for approx 120 days without nuclei or cytoplasmic organelles
- They travel 300 miles through microcirculation
- 7.8 micron diameter
- Capillaries as small as 3.5 microns
What are sources of iron, how is it absorbed and what is its role in the body?
Sources:
- Meat
- Eggs
- Veg
- Dairy
Absorption:
- Normal western diet provides 15mg daily
- 5-10% absorbed (1mg) principally in duodenum and jejenum
- Gastric secretion (HCL) and ascorbic acid help in absorption
- DMT-1 and ferroportin regulate
Role:
- Forms centre of porphyrin ring in Hb
- Binds to O2
What are sources of B12 & folate, how are they absorbed and what are their roles in the body?
Sources:
- B12 found in liver, meat, fish, dairy
- Folate found in fruit + vegetables
Absorption:
- Absorbed in ileum bound to intrinsic factor (IF).
- Folate is absorbed in duodenum and jejenum in form of MTHF
Roles:
- Both essential for DNA synthesis and RBC maturation
- Both needed for formation of thymidine triphosphate (essential building block of DNA)
- B12 is coenzyme for methionine synthases in methylation of homocysteine to methionine
What are causes of iron deficiency? What can iron deficiency lead to?
- Poor diet
- Inadequate intake
- Malabsorption
- Increased demand for iron
- Pregnancy
- Growth spurt
- Chronic blood loss
- GI bleed
- Excess loss in menses
- Malabsorption
- Coeliac dx
- Gastritis
Iron deficiencies lead to anaemia
What are causes of vitamin B12 deficiency?
- Inadequate intake
- Vegan diet
- Absorption defect
- Tropical sprue
- Coeliac dx
- Intrinsic factor deficiency
- Pernicious anaemia = Most common cause of B12 deficiency due to autoimmune gastric atrophy resulting in loss of IF production required for B12 absorption
- Crohn’s
- Gastrectomy
What are causes of folate deficiency?
- Inadequate intake
- Poor nutrition
- Absorption defect
- Coeliac disease
- Crohn’s
- Tropical sprue
- Increase demand/losses
- Pregnancy
- Haemolysis
- Cancer
- Drugs
- Anticonvulsants
What can B12 and folate deficiency lead to?
Failure of nuclear maturation
Folate deficiency causes magaloblastic anaemia by inhibiting thymidylate synthesis, a rate limiting step for DNA synthesis
What are the clinical effects of anaemia?
- Fatigue + weakness
- Shortness of breath
- Dizziness, light-headedness
- Cold hands + feet
- Headaches
If left unteated:
- Severe tiredness - unable to complete daily tasks
- Pregnancy complications, such as premature birth
- Heart problems, irregular HB (arrhythmia), enlarged heart, heart failure
How do RBCs survive for 120 days?
- RBCs are capable of limited metabolic activity
- The metabolic pathways provide energy to accomplish its function and survival
- Function does not require the consumption of much energy
- Metabolic processes include:
- Glycolytic (Embden-Meyerhof) pathway
- Hexose Monophase Shunt Or Pentose phosphate pathway
Describe the glycolytic pathway
Glucose converted into G6P (this can enter the hexose monophase shunt)
G6P converted into F6P, this yields NADPH
F6P converted into 1,3 DPG
1,3 DPG converted into 3PG
3PG converted into pyurvate, mediated by pyruvate kinase enzyme, ADP converted into ATP, generates NADH
RBCs cannot undergo aerobic respiration, therefore the pyruvate is converted into lactate
This pathway generates ATP to:
- Maintain red cell shape, deformability and flexibility
- Regulate intracellular cation concentration via cation pumps (Na/K pump)
What happens if there is a pyruvate kinase deficiency?
ATP is depleted:
- Cells lose large amount of potassium and water, becoming dehydrated and rigid
- Causes chronic non-spherocytic haemolytic anaemia
