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CH. 32 RBC's, Anemia, Polycythemia
pg 413-422
RBC's
---"Erythrocytes"
---Main function is to x-port Hemoglobin, which carries O2 from lungs to tissues.
---Hgb in free form (in some animals) leaks through capillary membranes, so it must be bound by RBC.
---Acid-Base Buffer Function: Use of Carbonic Anhydrase to x-fer CO2 out of the body as Carbonate. Does
most of the acid-base buffering.
---Shape: Biconcave discs that is highly deformable to squeeze through capillaries.
---b/c of excess membrane vs intracellular proteins; deformation does not rupture cell.
Quantity Hgb in Cells
---For most. Percent Hgb in cells is at it's max
---Metabolic limits how much Hgb can be in a RBC, thus it can only be less than the max/normal lvls.
Production of RBC
---Synth Sites during development: Yolk Sac (Early embryonic)----> Liver/Spleen/Lymph Nodes (Middle tri
gestation)----> Bone Marrow (Last of gestation, into birth)
---Bone produces RBC's until ~5 y.o.
---Marrow in Long bones (except Proximal Humeri and Tibiae) become fatty; no RBC synth @ age 20.
---Beyond age 20, synth in membranous bone (Vertebrae, Sternum, Ribs, Ilia), but synth here still
decreases w/ age.
Blood Cell Synth
---All stem from Pluripotential Hematopoietic Stem Cells in the bone marrow.
---As these cells reproduce, small amounts remain exactly the same as pluripotent cells and stay in
marrow for backup stores. (these numbers diminish w/ age).
---Committed Stem Cells: Intermediate stage of developement that are very much like Pluripotent cells,
but are Committed to a specific line of cells.
---Colony-Forming Unit-Erythrocyte ("CFU-E"): Committed stem cell that will make an RBC
---CFU-GM - "granculocytes" CFU-B "blast" CFU-M "megakaryoctye" LSC "Lymphoid stem cell"
---Synth controlled by Growth Inducers that enhance growth, NOT maturation.
 ie - Interleukin-3: Promotes growth and reproduction of most all types of committed cells.
---Growth Differentiation Inducers; promote differentiation of committed cells multiple steps along
path.
---Both Inducers are controlled by factors outside bone marrow.
Stages of Differentiation
---Proerythroblast: First cell that can be identified as RBC along synth path.
 SIDE NOTE: in the biochem bk, it says Normoblasts are the first.
---Basophil Erythrblasts: First division of proeryth., which can begin to build a little Hgb.
y.o. - Years old
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---Reticulocyte: the next division, where nucleus and most organelles extruded, but still has some.
 At this stage they pass into capillaries by Diapedesis (squeezing through pores of capillaries).
 Once in circulation: continues to make heme for 1-2 days.
---Mature Erythrocyte: Reticulocyte loses Nuclues and other organelles.
Regulation of RBC Synth and Erythopoietin
---RBC synth regulated by:
1. Adequate RBC available to x-port enough O2 from lungs to tissues
2. Cells do not become numerous enough to impede blood flow.
Tissue oxygenation Is Important
---Any condition (anemia, hemmorage, Cardiac Failure, Lung Disease) that causes O2 x-port to tissues to
decrease, will stimulate RBC synth.
---Hyperplasia of intact bone marrow may occur.
---At high altitudes: Less atmospheric O2 = higher Hct%.
---Most result in increased Hct% and Total Blood volume.
Erythropeitin
---Principle stiumulus of RBC synth.
---In absence, the body does not respond to hypoxia, or alike states by increasing RBC synth.
The Role Of Kidneys
---90% of Erythropoietin is produced in Kidneys, remainder in Liver.
---Hypoxia-Inducible Factor 1 (HIF-1): X-scription factor for many hypoxia inducible genes (like erythrop.)
---Hypoxia Response Element: Resides in erythrop gene which binds to mRNA and pushes synth when
HIF-1 binds to it.
---Synth stimulation signals can also come from outside the kidneys, espeicially in forms of
Norepinephrine and Epinephrine.
---Kidneys Removed/Destroyed: People become Anemic, other erythrop site can't compensate.
Erythrop effects on Erythrogenesis
---In Low O2 ATM: Erythrop forms w/in minutes to hours and reaces max production in 24 hours.
---But, no new RBC appear in blood until 5 days after.
---Studies showed that the effects are:
1. Increase synth of Proerythroblasts
2. Increase maturation/division rates of them
---This sate remains until O2 needs are met.
---NO Erythrop: few RBC formed by bone marrow.
Maturation of RBC (B12, Folic Acid)
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---RBC synth affected greatly by nutrition.
---Vit B12 and Folic acid are both essential for DNA synth.
---Lack of either will eventually make Macrocytes (large RBC), from what is called Maturation Failure.
 Pernicious Anemia: Atrophic gastric mucosa w/ failure to absorb B12 in small intestine.
---Intrinsic Factor: Binds to vitamin, which both protects it from digestion and allows passage into
mucosal cells. Lack of factor ----> B12 deficiency.
 Sprue: GI absoprtion abnorm for both Folic acid and Vitamin B12.
---Macrocytes: Can carry normal lvls of O2, but have weak membranes and will rupture easily.
---Vit x-ported into blood by pinocytosis along w/ intrinsic factor.
--- Most B12 stored in liver, then released as needed for bone marrow.
---Excessive stores of vitamin allow for 3-4 yrs of defective absorption before problems arise.
Hgb Formation
---Starts in Proerythroblasts and cont'd into reticulocyte stage.
---STEPS:
1. Succinyl CoA + Glycine -----> Pyrrole Molecule ("delta-ALA"; biochem note).
2. Four pyrroles combine to form Protoporphyrin IX.
3. Each heme molecule cobines w/ Globin forming a Hemoglobin Chain (hemoglobin subunit).
---Slight differences in each hgb subunit, based on Alpha, Beta, Gamme, or Delta, chain designation.
---Most Common: HgbA alpha2 beta2
---Structure:
 Four Iron atoms per Hgb molecule
 1 O2 per Fe. = 4 molecules O2 per Hgb molecule.
---Types of Hgb chains determine O2 affinity and defects can alter this affinity.
 Sickle Cell Anemia: valine AA switched for Glutamic Acid
---Exposure to low O2 formes long crystals inside RBC and make deformation impossible, thus they
rupture.
Hgb Combining w/ O2
---The most important feature is that the binding is Loose & Reversible.
---O2 binds loosely w/ the Coordination Bonds of iron, not the two positive bonds.
 This is the bond that is Loose and Reversible.
 Binds as Molecular Oxygen (O2), not ionic Oxygen. Makes it user ready.
Iron Metabolism
---65% in form of Hgb
---1% in various heme cpd's.
---15-30% stored in liver for later use (form of Ferritin).
Transport and Storage of Iron
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---(in small intestine) Fe bind to Apotransferrin (from liver) forming Transferrin absorbed and passed
mostly into liver to be stored as Ferritin (Fe + Apoferritin). This is Iron Storage
 Absorption is very slow, thus even large quantities ingested can only lead to small absorption.
 Total body iron regulated by altering absorption.
---Excess Iron: Stored as very insoluble Hemosiderin.
 These form clusters and are large compared to Ferritin which is small.
---Iron x-ported to cells as Transferrin and binds to receptors on membranes
 Endocytosis: how iron enters cells.
 Hypochromic Anemia: Result of failure to x-port iron to erythroblasts.
Daily Iron Loss
---Women lose more than men, having menses and childbearing and whatnots.
 Personal Note: Thank you ladies.
RBC Life Span
---~120 days
---Don't have organelles, but DO have enzymes that:
1. Can make ATP through Glycolysis
2. Maintain pliability of cell membrane
3. Maintain membrane x-port of ions
4. Keep iron in Ferrous (Fe2), not Ferric (Fe3).
5. Protect proteins from oxidative dmg.
---As these systems slow down w/ use, the cell becomes fragile ---> Filtered out by Spleen
---Splenectomy: Old abnormal RBC's build up in blood.
Destruction of Hgb
---Hgb is phagocytosed by Macrophages in Spleen, and bone marrow, and Kupffer cells in Liver.
 Macrophages release Iron which is passed back into blood for Transferrin to recycle into tissue.
---Bilirubin: Porphyrin portion of Hgb that was converted by Macrophages.
 Released into blood and later removed by secretion through Liver in Bile.
Anemia
Blood Loss Anemia
---Hemmorrhage: the body replaces fluid quickly, but RBC count is low (3-6 wks to recover).
---Chronic blood loss---->low MCHC-----> Microcytic, Hypochromic anemia.
Aplastic Anemia
---Bone Marrow Aplasia: Lack of functioning Bone marrow.
---Causes:
 Chemotherapy
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
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Toxic Chemicals
Autoimmune
Idiopathic Aplastic Anemia: Usually die if not treated w/ blood x-fusion
Megabloblastic Anemia
---Deficiency is Vitamin B12, Folic Acid, or Intrinsic Factor
---Reasons discussed earlier,
---Examples were Sprue, Pernicious Anemia, which lead to Megaloblasts.
Hemolytic Anemia
---Many Hereditarily acquired
---Abnormal RBC which make them fragile---> short lifespan
 Hereditary Spherocytosis: RBC are Spherical not biconcave and cannot w/stand compression
forces.
 Sicke Cell Anemia: HgS,; Mech discussed earlier. Long crystals build in low O2---->rupture.
---Sickle Cell Crisis: Low O2 tension in tissues causes sickling ----> RBC ruptures ----> further decrease in
O2 tension -----> more RBC's rupture ----> cycle continues.
 Erythroblastosis Fetalis: Rh-Positive RBC's of fetus are attacked by anit-b's of Rh-Negative
mother.
---Rapid RBC synth in babies can make up for the attack loss.
Effects of Anemia on Function and Circ System
---Viscosity of blood depends largely on RBC blood conc.
 Severe Anemia ---> low viscosity ----> Increased Vol returned to heart (venous return) ---->
Increased cardiac ouput.
 Hypoxia resulting from diminished x-port of O2 ---> vessel Dilation ---> Increased Venous Return ---> Even more Cardiac Output.
 THUS, Anemia greatly increases Cardiac output and Pumping workload of heart.
---Increased cardiac output can offset anemia/hypoxia when body is at rest.
---When exersizing: Heart can't take anymore ----> Acute Cardiac Failure may occur.
Polycythemia
---excess RBC's
Secondary Polycythemia
---Condition whenever tissues become hypoxic b/c of too little O2 in breathed aire (like high altitudes) or
failure of O2 delivery to tissues (cardiac failure), where the body responds by making a shit load
of RBC's.
 Most common: Physiologic Polycythemia: High altitude polycythemia
Polycythemia Vera (Erythemia)
---Huge increase in Hct%
y.o. - Years old
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---Cause: genetic aberration of hemocytoblast cells that won't stop synthesis.
---Total Blood volume also increases
 Entire vascular system becomes engorged, capillaries plugged by viscous blood.
Effect of polycythemia on Function and Circ System
---Blood flow becomes sluggish as Viscosity Increases ---> decreased Venous Return.
---Blood Volume Also Increases ----> Increased Venous Return.
---Thus, the two offset eachother to normal lvls.
---Arterial pressure often normal in Polycthemia patients.
 BP regulating mechanisms seem to adjust well enough to normalize BP.
---Skin: Deoxygenated RBC tend to overcome Oxygenated thus Bluish tint to skin.