RBC physiology Flashcards
1
Q
RBC metabolism
A
- RBCs use glc (enters via facilitated diffusion, does not require GLUT/ins for uptake) and metabolizes it to lactate via glycolysis/LA fermentation
- Only 5-10% of glc is not metabolized via glycolysis, instead it enters the PPP (AKA hexose monophosphate pathway) to generate NADPH
- 2 moles of ATP/glc via LA fermentation
- Glycolysis in RBCs also generates 2,3-BPG from 1,3-BPG (normal intermediate in glycolysis)
- 2,3-BPG used to stabilize deoxyHb
2
Q
Functions of ATP in RBC
A
- ATP is used mostly for Na/K-ATPase, to maintain high K and low Na inside the cell
- ATP is also used to maintain low concentration of intracellular Ca, by efflux of Ca through the Ca-ATPase
- If Ca-ATPase activity is reduced (such as in SCD or low glc), there is an accumulation of Ca in the cell (membrane-associated Ca)
- This leads to increased rigidity (decreased deformability) and hemolysis of RBCs
- Increased intracellular Ca in SCD RBCs causes opening of K-channels, resulting in efflux of K (known as Gardos effect)
- Therefore, SCD RBCs will have increased intracellular Ca, decreased intracellular K, and are dehydrated (leads to hemolysis in capillaries)
3
Q
Functions of NADH on Hb
A
- NADH is generated in conversion of glyceraldehyde-3-P to 1,3-Bisphosphoglycerate
- NADH converts metHb to Hb via cytochrome B5 reductase
- MetHb is created by oxidizing Hb, from ROS (super oxide anion)
- Patients w/ partial deficiency (heterozygous) for NADH-cytochrome B5 reductase will develop methemoglobinemia in response to oxidant drugs (malaria prophylactic agents: chloroquine)
4
Q
Pyruvate kinase deficiency
A
- Most common nz abnormality in glycolytic pathway, causing life-long hemolytic anemia (5-25% of normal PK activity)
- Rate of glycolysis is decreased, resulting in less ATP
- Cell cannot maintain structural integrity of membrane, leading to hemolysis
5
Q
Functions of NADPH
A
- The 5-10% of glc utilized by PPP yields NADPH, which is used to regenerate reduced glutathione (GSH)
- GSH is oxidized to GSSG during reactions to eliminate ROS (like H2O2 generated during infections), or reduce oxidized sulfur bridges cross-linking membrane proteins
- GSSG must be reduced back to GSH via glutathione reductase, using NADPH as an electron donor
6
Q
Glucose-6-P dehydrogenase deficiency
A
- Deficiency in G-6-PD (inherited) leads to a lack of NADPH in RBCs
- Decreased NADPH levels leads to the inability to reduce ROS’s and cross-links, since GSSG can’t be recycled to GSH
- Both of these lead to hemolytic anemia, due to rigidity of RBCs (most common cause of hemolytic anemia)
- Hemolytic anemia in these patients can be acute due to infection or taking oxidant drugs, resulting in increased ROS and cross-liking
- Life span of these patients is somewhat shortened
- Positive effect: female carriers become resistant to malarial falciparum
7
Q
ROS effects in RBCs
A
- Oxidizes Hb to metHb
- Accumulation of metHb leads to formation of heinz bodies at membrane (increases permeability of ions and fragility of RBC)
- Causes cross-linking of membrane proteins, increasing rigidity
8
Q
Distribution of phospholipids
A
- There is an asymmetric distribution of phospholipids (PLs) in the RBC membrane
- The inner membrane contains phosphatidyl ethanolamine (PE) and phosphatidylserine (PS)
- The outer membrane contains phosphatidylecholine (PC) and sphingomyelin (SM)
- During PL synthesis in reticulocytes, PLs are distributed randomly throughout the bilayer
- An ATP-dependent aminophospholipid translocase (Flipase) moves both PE and PS to the inner membrane of the bilayer
- Presence of PS in external membrane is harmful as it can initiate coagulation cascade
- In SCD a small amount of PS is found in the outer membrane (due to decreased ATP), which contributes to clot formation and vasoocclusion
9
Q
Cytoskeleton and maintaining deformability
A
- Cytoskeleton underlies membrane but is intimately attached to it
- Cytoskeleton consists mostly of spectrin, ankyrin, actin, and protein 4.1
- They maintain shape and deformability of RBC, and alterations results in susceptibility to hemolysis
10
Q
Spectrin and inherited defects
A
- 2 large peptides (a and b) that self-assemble into tetramers (a2b2), which binds to actin and protein 4.1 to maintain shape and deformability
- Hereditary spherocytosis: reduced spectrin content, resulting in spherocytes and mild anemia
- Hereditary elliptocytosis: spectrin fails to form tetramer resulting in weakened skeleton, ellipocytes, and mild anemia
11
Q
Acanthocytosis
A
- Inherited autosomal recessive
- Increase in cholesterol and sphingomyelin
- Causes rounded RBCs with thorny projections (of cholesterol), RBCs called spur cells (increased rigidity)
- Occurs in chronic alcoholic liver disease
12
Q
Factors that increase rigidity of RBCs
A
- Decreased ATP (LOF of ion transport)
- Decreased GSH/NADPH (cross-liking of membrane proteins, metHb and heinz bodies)
- Cytoskeletal protein defects
- Increased cholesterol
13
Q
SCD
A
- Production of HbS (Glu6->Val mutation in B globin chain)
- At low O2 tension HbS polymerizes leading to insoluble long fibers, causing change in shape and deformability of RBCs
- Hydrophobicity of val leads to nucleation of HbS and crystallization of RBC
- Sickle-shaped RBCs occlude small capillaries and lyse (vaso-occlusive crisis)
- SC RBCs also adhere to endothelial cells via binding of integrins on RBC to VCAM on endothelial cells, furthering vasoocclusion
- Hypoxia-induced hemolysis leads to generation of ROS, pro-inflammatory cytokines, and HIF1a activation
14
Q
Clinical manifestation of SCD
A
- Chronic hemolytic anemia and hypoxia
- Vaso-occlusive crisis
- Frequent infection, increased leukocytes
- Pulmonary hypertension (due to PLGF-induced expression of endothelium-1 on RBC, getting them stuck in lungs, or reduced NO levels)
- Asthma and reactive airways (due to PLGF-induced expression of leukotrienes, causing inflammation)
- Increased EPO production due to HIF1a expression, EPO leads to increased levels of PLGF (placental growth factor)
- Rx of SCD: just controlling it, using hydroxyurea (increasing expression of HbF and reducing expression of HbS), lowering temp and increasing pH (high temp and low pH increase HbS polymerization)
