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Why can't RBCs resynthesize damaged proteins?

- have no nuclei

- Erythrocytes lose nuclei before entering circulation
- mRNA disappears 1-2 days after release
- No protein synthesis = no replacement of damaged molecules


Intravascular Hemolysis

• Mechanical disruption
• Release of hemoglobin from RBCs
• Hemoglobinuria


Extravascular Hemolysis

- typically by spleen
• Removal of “stiff” RBCs
• Release of bilirubin from RBCs
• Possible Jaundice


Spherocytic anemia

due to cytoskeletal prob (mutated cytoskeletal protein) -> extravascular hemolysis


Non-Spherocytic anemia

due to metabolic prob (deficient glycolytic or PPP enzymes) -> intra- and extra-vascular hemolysis


purpose of RBC metabolism

to keep molecules reduced (oxidative defense; Fe, SH-groups),
maintain ion (k/Ca) gradients, and
maintain shape – requires NADH, NADPH, ATP


Regulated steps of glycolysis in RBCs

• Hexokinase
• Phosphofructokinase I


How is glycolysis in RBCs different from in muscles?

• Not responsive to insulin
--- Cannot switch to alternate energy source
- Energy Clutch (work-around from traditional glycolysis)


pH and RBC glycolysis

• Responsive to pH
--- Acidic pH inhibits glycolysis
-----> Temporarily shuts down while the RBC is passing through acidic tissues
--- less lactate production to raise pH


What is the energy clutch?

- glycolysis w/o ATP gain; Uncouples ATP/NADH production
--- Degrades glucose to lactate without any net E gain
--- Makes sense in RBCs b/c they want to make NADH

- bypass ADP-requiring step of glycolysis by making 2,3-BPG; no net ATP gain or ADP loss; subsequent lactate production yields NADH


2,3 Bisphosphoglycerate role in RBCs

• 1,3 bisphosphoglycerate (1,3 BPG) can be converted into 2,3 bisphosphoglycerate (2,3 BPG)
--- By diphosphoglyceromutase
--- 2,3 BPG can re-enter glycolysis by dephosphorylation to 3-phosphoglycerate. No ATP, just NADH gain from glycolysis.
-----> By DPG Phosphatase
--- This work-around from traditional glycolysis pathway makes one less ATP


2,3 Bisphosphoglycerate regulation in RBCs

• 2,3 BPG synthesis is inhibited at low pH (improves O2 Sat)
--- Bohr effect drives O2 off of Hb
--- Acidosis decreases 2,3-BPG -> ­increase Hb O2 affinity -> increases­ O2 saturation of blood
-----> note: Bohr effect in hypoxic tissues overcomes increased O2 affinity, and O2 released to tissues


Metabolic problems encountered with RBC metabolism

- Need NADH, but have plenty ATP (little ADP)
--- solution = E Clutch: bypass ADP-requiring step of glycolysis by making 2,3-BPG; no net ATP gain or ADP loss; subsequent lactate production yields NADH


What is PPP

- Starts with G6PD
- Series of transaldolase and transketolase reactions that rearrange Carbons for re-introduction into glycolysis


Goal of the Pentose phosphate pathway (PPP)

provides reduction equivalents in the form of NADPH.


Regulation of PPP

Low intracellular NADPH concentration activates glucose 6-phosphate dehydrogenase


Why are glutathione and NADPH important for RBC?

NADPH and Glutathione are imp for oxidative defense
--- RBC carry a lot of O2 – this puts them at risk for damage by ROS
----> ROS oxidize protein sulfhydryl groups → disulfide bridges form (changes protein conformation/fxn - structural proteins and enzymes denature); Hb may precipitate as Heinz bodies
------>> GSH protects by keeping sulfhydryl groups reduced
---->O2- (superoxide radical) converted to H2O2 by superoxide dismutase; glutathione peroxidase requires GSH and NADPH to convert H2O2 to water
--- e- needed for antioxidant defense come from glucose (make NADPH) and are used to reduce GSS to its usable form (GSH)


Presentation of RBC Enzymopathies

Enzymatic problems cause nonspherocytic anemia for different reasons:
--- G6 PD deficiency causes hemolytic anemia for lack of NADPH
--- Pyruvate kinase deficiency causes hemolytic anemia for lack of NADH/ATP


Glucose 6-phosphate dehydrogenase deficiency

- most common PPP defect
• X-linked recessive
• Prevalent in African/Mediterranean populations, mostly males
• Characteristic Heinz bodies and bite cells (by spleen trying to remove Heinz spot)
- lack of NADPH for antioxidant defense, renders RBC susceptible to oxidative damage


Response to Glucose 6-phosphate dehydrogenase deficiency

- Hematopoietic system compensates well for premature RBC loss under normal circumstances
- Hematopoietic system overwhelmed, and ROS-induced hemolytic crises triggered by:
--- Infections
--- Drugs producing ROS (H2O2)
--- Fava beans
- Overwhelmed hematopoietic system → > than normal RBC destruction → splenomegaly, jaundice, kernicterus (potential brain damage in children)
--- *G6PD is a preventable form of mental retardation


Most common RBC glycolysis defect

pyruvate kinase deficiency (still rare though)


pyruvate kinase deficiency

- lack of NADH/ATP needed to maintain shape and ion gradients
- Hemolysis due to lack of ATP and subsequent degeneration (NOT by oxidative stress)
- RBC run out of ATP and degenerate; degraded in spleen → splenomegaly, jaundice, gallstones (insoluble bilirubin)
--- Hereditary, non-spherocytic hemolytic anemia
- see membrane blebbing


Defects in RBC cytoskeleton present as

hereditary spherocytosis (Spherocytic anemia)
--- PBS: round cells (spherocytes), loss of central pallor
--- Spherocytes removed by spleen – splenomegaly possible


RBC cytoskeletal proteins

(spectrin, ankyrin, band 3, glycophorin)
- imp to maintain RBC elasticity
- Spectrin and ankyrin form scaffold connecting to membrane glycoproteins (band 3, glycophorin)
- Defective cytoskeletal protein → ↓ PM elasticity → early destruction


Defects in GPI-anchored proteins present as ...

(Paroxysmal Nocturnal Hemoglobinuria – intravascular hemolytic anemia)


What causes Paroxysmal Nocturnal Hemoglobinuria ?

PIGA gene mutation → PNH: impaired GPI anchor → decay accelerating factor not held to RBC membrane → RBC susceptible to C’ attack → intravascular hemolysis

- PIGA gene is on X-chrom: mutations fully penetrant if they occur on active copy (progeny of mutate cell will have defect)


somatic mosaicism

- common feature of hematopoietic system genetic disorders (Ex/ PNH)
- Hematopoietic cells continue dividing after most somatic cells stop → ↑ risk mutations
- Stem cell mutations → somatic mosaicism
- Blood cells may show diff genotype than rest of pt


cancer cell metabolism vs RBC metabolism

very similar:
- Constantly consume glucose and don't adapt by switching to FA metabolism
--- Use as much glucose as they can, break it down, and make a lot of lactate (oxidized back to pyruvate and used for gluconeogenesis)
-----> tumors use glucose then make more glucose to use!
- E from anaerobic glycolysis
--- Express hypoxia-inducible factor 1a(HIF-1a) to support anaerobic metabolism
-----> ↑ glucose transporters and ↓ pyruvate decarboxylase complex
--- Allows tumor cells to live off glycolysis only