eric niederhoffer siu-som
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A 4-year-old African boy is brought in by his adoptive parents who say that he has pain in his limbs and does not want to walk. What affects the normal functions of an erythrocyte?. Eric Niederhoffer SIU-SOM. RBC structure size, spectrin , channels Metabolism - PowerPoint PPT PresentationTRANSCRIPT
Eric NiederhofferSIU-SOM
What affects the normal functions of an erythrocyte?
A 4-year-old African boy is brought in by his adoptive parents who say that he has pain in his limbs and
does not want to walk
Red Blood Cell: Biochemistry and Sickle Cell Disease
• RBC structuresize, spectrin, channels
• Metabolismglycolysis (2,3-BPG), pentose phosphate pathway (G6PDH, NADPH), glutathione
• Hemoglobingenes, heme, Mb/Hb (normal), HbS (defect), fibers (sickling and inflammation),
thalassemia
An Erythrocyte (RBC)
Reference RangesRBCs, male 4.3-5.9 x 106/µL female 3.5-5.5 x 106/µLHb, male 13.5-17.5 g/dL female 12.0-16.0 g/dLHct, male 41-53% female 36-46%MCV 80-100 fLMCH 25.4-34.6 pgMCHC 31-36 %RDW 11-14.5 %
Practical Values65% of Fe in Hb1 g Hb = 3.46 mg Fe1 mL blood at 15 g/dL Hb = 0.5 mg FeRBC x 3 = HbHb x 3 = HctMicrocytic < 80 fLMacrocytic > 100 fL
Erythrocyte Membrane Composition
http://www.ruf.rice.edu/~bioslabs/studies/sds-page/rbcmembrane.html
RBC Metabolic Pathways
2,3-BPG
BPG mutase
2,3-BPG phosphatase
PPP
NADPH
6PG
3-7 C metabolites(R5P, F6P, G3P)
G6PDHlactonase6PGDH
CO2
NADP+ + H+
GSH
GSSGGR
GP
H2O2 H2O
Glc
Pyr
G6P
1,3-BPG
3PG
HK
PGI
PK
F6P
G3P
PFK
aldolaseF16BP
DHAP
2PG
PEP
PGK
PGM
enolase
G3PDH
Glycolysis
LactateNo O2
LDH
Hemoglobin Genes and Gene Products
http://www.mun.ca/biology/desmid/brian/BIOL3530/DB_Ch09/fig9_24.jpg
Hemoglobin Gene Product Production
Mehta, A. B., and A. V. Hoffbrand. 2000. Haematology at a glance, Blackwell Science, Malden, Mass.
HbF: 2α and 2γHbA1: 2α and 2β
HbA2: 2α and 2δHbE: 2ζ and 2ε
Yolk sac Liver Spleen Bone marrow
Myoglobin and Hemoglobin Structure
deoxyHbdeoxyMb
oxyHb (HbO2)
O2
O2
O2
O2
Glu6→Val6
Glu6→Val6
oxyMb (MbO2)
O2
Hemoglobin Structure Changes
http://www.mfi.ku.dk/PPaulev/chapter8/images/8-3.jpg
Sickle Cell Disease
http://www.emedicine.com/ped/TOPIC2096.HTM
Rare combinations of HbS with HbD Los Angeles, HbO Arab, G-Philadelphia, among others
(>6 major genotypes)at least 1 sickle gene, hemoglobin S (HbS) ≥ 50% Hb present.
homozygotic HbSS (sickle cell anemia) - HbS = 100% Hb present
HbSbeta-0 thalassemia - Severe double heterozygote for HbS and beta-0 thalassemia; almost indistinguishable from sickle cell anemia phenotypically (MCV low)
HbSC disease - Double heterozygote for HbS and HbC, with intermediate clinical severity
HbS/hereditary persistence of fetal hemoglobin (S/HPHP) - Mild form or symptom free
HbS/HbE syndrome - Rare and generally mild clinical course
Hemoglobin Electrophoresis
http://themedicalbiochemistrypage.org/hemoglobin-myoglobin.html
Homozygous HbS
Normal neonate
Normal adult
HbSC
Heterozygous HbS
Relative protein charge
Start (samples applied here)
Anode (+)
Cathode (-)
Molecular Changes of HbS
http://www.sicklecellinfo.net/fiberformation.htm.Daniel J. Harrington, D. J., K. Adachi, and W. E. Royer, Jr. 1997. J. Mol. Biol. 272(3):398-407
Heme
Val
Molecular and Cellular Changes of HbS
http://www.emedicine.com/ped/TOPIC2096.HTM
Decreased PO2
Permanent damage to RBC
Cell endothelium interactions⟺
Effects of Therapy with Hydroxyurea
http://www.emedicine.com/ped/TOPIC2096.HTM
★ ★ ★
Thalassemiasα-thalassemia
β-thalassemia
HbH (β4)
Hb Barts (γ4)
Review Questions
• What proteins compose the membrane of erythrocytes?• What metabolic pathways are used in erythrocytes?• What is hemoglobin; what changes with sickle cell
disease?• What clinical observations would you make concerning
patients with SCD?• What are the thalassemias?