Red Cell Function and Metabolism Flashcards
Where does hematopoiesis take place thru life?
- Yolk sac for 3 mo after fertilization –> liver and spleen until 3 mo after birth –> long bones –> by 30 yo switches to axial/proximal skeleton
- Radiation to axial skeleton in older patients can affect bone marrow (both suppression and ablation)
Extra-Medullary Hematopoiesis
- RBC production shifts back to spleen, liver, lymph nodes (enlarged spleen and liver)
- Causes …
- Myelofibrosis - excess fibroblast proliferation in bone marrow
- Cancer infiltration marrow, hepatocellular injury, chronic hemolysis, growth factor treatment, marrow regeneration injury, autoimmune assaults, idiopathic
3 Steps of Hematopoiesis
- 1- HSCs tethered to adhesion molecules on marrow accessory cells
- Ex) CXCR4 is chemokine receptor on HSC which binds SDF-1 on stromal cells of bone marrow
- 2- Stimulated by growth factors
- 3- Proliferation and development
2 Drugs to Free HSCs for Harvesting
- G-CSF growth factor –> neutrophil proliferation and MMP secretion –> MMPs then break CXCR4-SDF1 bond
- Plerixafer - competes w/ SDF1 for CXCR4 which releases bond
Aplastic Anemia
- Hypocellular bone marrow
- can be due to damage to microenvironment, damage to HSCs or dysregulation of development (all lead to pancytopenia)
Epo Production (location and influences)
- Stimulated by hypoxia (dec O2 in atmosphere, dec blood flow to kidney, dec O2 release by Hb)
- If oxygen + iron … then HIF1alpha is ubiquinated and degraded by proteasome
- If hypoxia … then HIF1alpha complexes w/ HIF1beta –> stimulates DNA to produce various proteins including Epo
- Made in peritubular interstitial cells of kidney (90%) and perisinusoidal cells of liver (10%)
What is the specific role of Epo?
- Late growth factor that mainly works on CFU-E (BFU-E –> CFU-E part of RBC development) then iron needed for rest (erythroblast –> reticulocyte –> RBC)
- Binds Epo receptors –> JAK2 monomors dimerization, activation and auto-phosphorylation –> downstream phosphorylation including STAT5 –> translocates to nucleus –> inc proliferation
What is heme + how is it made?
- Heme = protoporphyrin ring w/ Fe atom in center
1- Glycine + succinylcholine –> ALA in mito
2- ALA –> porphobilinogen –> uroporphorinogen –> coproporphyrynogen –> protoporphyrin in cytoplasm
3- Add iron in cytoplasm (via ferrochelatase enzyme - if deficiency get protoporphyrin build up - photosensitive)
Types of globin, chromosomes, where are they made?
MADE IN CYTOPLASM
- 2 alpha (from chromosome 16)
- 2 beta (from chromosome 11)
- or + 2 gamma in fetal Hb (also chromosome 11)
- Mom can have up to 10% HbF in pregnancy
- HbF > HbA in oxygen affinity - lower P50 and curve shifted L
- or + 2 delta in minor HbA (also chromosome 11)
When does Hb switching occur?
- starting at birth and complete at 6 mo
- **So alpha globin problems detected right away while beta globin problems not detected until 6 mo
Cooperative Binding
- When O2 binds that iron atom is shifted to center of ring –> histidine helix pulled toward ring –> strain in histidine helix transferred to all 4 histidine helices –> makes easier for other chains to reach O2
Hb Dissociation Curve Shifts
- Inc 2,3 DPG, inc acid (dec pH), inc CO2 and inc temp = R shift (lower affinity)
- 2,3 DPG restructures globin chains to make it harder for O2 to reach heme
- Methemoglobin and fetal hemoglobin have higher affinity so L shifted curve in comparison
What 4 Paths do RBCs depend on? (important enzymes of ea)
1- Glycolysis - for ATP (fragile w/o it)
- Affected by pyruvate kinase deficiency
2- Luebering-Rapaport Path - 2,3 BPG production
- PFK and DPG dismutase deficiencies –> hemolysis
3- Pentose Phos Shunt - NADPH generation (needed to reduce glutathione - reduced glutathione protects RBC wall from oxidants)
- Ex) oxidizing agents - anti-malarials, sulfonamides, fava beans - Affected by G6PD deficiency
4- Methemoglobin reductase path - uses NADH to maintain iron in ferrous form
- Mutations in path - ferric state
Methemoglobinemia
- Caused by mutation in methemoglobin path OR acquired from drugs/chemicals –> cyanosis, fatigue, shock, seizures, death and chocolate blood
- Tx - stop drug and use methylene blue (acts as electron acceptor in hexose monophosphate shunt to reduction of ferric to ferrous)
Iron Metabolism
- Iron absorbed and from broken down RBCs travels via transferrin –> marrow and liver where it binds transferrin receptor –> endocytosed and iron released / transferrin returned to circulation
- Ferroportin is transport protein - transports iron out of enterocytes and out of RES/macrophages
- Hepcidin (made by liver) regulated ferroportin (inc hepcidin blocks ferroportin activity so iron trapped in enterocytes and macrophages)
