wk 11, lec 2 Flashcards
what are red blood cells aka
erythrocytes
what do RBCs contain
- Carry O2
- Contain hemoglobin bind O2 in lungs and release in tissues (for gas transport and exchange)
- Remove CO2 (bring back to lungs for exhalation)
where are RBCs made
- Made in bone marrow
o Erythron= proliferating marrow erythroid precursors + circulating RBCs
RBC lifecycle
120 days
where are RBC recycled
where are made in fetus
- Recycled in liver and spleen
o Made in spleen and liver in fetus
shape of RBC
- Biconcave shape; maximize SA for gas exchange and to move through vessels
when will hemoglobin bind and dissociate at low and high [ ]
o Hemoglobin binds oxygen at high [ ]
o Oxygen dissociates from Hb at low [ ]
o Healthy O2 saturation in Hb is 95-99%
when will Hb bind Co2
o HB binds CO2 with low affinity
what do RBCs have to convert CO2 in bicarbonate HCO3-
carbonic anhydrase
what do RBC lack
nuclei
o Cant synthesize protein and limit lifespan
what are RBC derived from
from myeloid progenitor (pronormoblast)
steps to form RBC
- RBCs derived from myeloid progenitor (pronormoblast)
o Stimulated to divide by GM-CSF and erythropotein (EPO)
o Before nucleus extruded; RBC accumulate Hb and proteins
o The late normoblast because anucleate
o Reticulocyte has remnants of golgi, ER, ribosomes which get extruded to become mature RBC
what 2 things stimulate myeloid progensit to divide and get closer to being RBC
GM-CSF and erythropoietin (EPO)
how many times does pronormoblast divide to make RBC and via stimulation of what
- Pronormoblast divides to make 16-32 mature RBCs via EPO stimulation
where is EPO erythropoietin made
kidneys by epithelial cells
- EPO made in kidney by epithelial cells ; what happens in high vs low oxygen conditions
o High oxygen conditions= hypoxia inducible factor (HIF) is ubiquinated and degraded by proteasomes
o Low oxygen conditions= HIF binds proteins, is translocated to the nucleus and stimulates EPO production (make more RBCs)
high or low oxygen to make EPO
low oxygen
generation of RBC depends on
EPO, bone marrow, adequate iron and amino acids for HB production
which energy pathway for RBC to get ATP
- RBC need glycolysis for ATP (no oxidative metabolism bc no mitochondria)
what antioxidant to RBC have
- RBC have glutathione stores when in high oxygen and cant make new proteins need to be able to combat free radical production
cytoskeleton in RBC - if absent what disorder does it cause
- Cytoskeletal proteins help RBC maintain shape –> disorder = loss of red cell mass (anemia)
subunits in hemoglobin
2 alpha and 2 other chains
what does each subunit in hemoglobin contain
o Each subunit has heme moiety containing iron to bind oxygen
what is the majority type of hemoglobin and what is less
- 97% is HbA (2 alpha, 2 beta chains)
o 2% is HbA2 (2 alpha, 2 delta chains)
fetal hemoglobin
o Fetal Hb (2 alpha, 2 gamma) – very high affinity for oxygen bc cant bind 2,3 DPG well
what has a higher affinity for hemoglobin that oxygen
- Carbon monoxide has 200x higher affinity for Hb than oxygen
o Forms carboxyhemoglobin
how is heme made
- Heme is made through reactions with glycine and succinyl-CoA precursors
what is the hemoglobin dissociation curve
what 4 things decrease hemoglobin affinity for oxygen**
- increase temp
- increase DPG
- increase PCO2
- decrease pH
where are RBCs eliminated
by macrophages in spleen red pulp
how is hemoglobin metabolized
where does the iron go? where does the heme go? where does the globin go?
o Iron recycled and sent back to bone marrow
o Heme eliminated in bile and stool as bilirubin
o Globin is recycled into its component amino acids
what happens to senescent (old) erythrocytes/ RBCs
- Senescent (old) erythrocytes are phagocytosed by macrophages and heme degraded into biliverdin then bilirubin and released into blood
what is heme degraded into
degraded into biliverdin then bilirubin and released into blood
o Unconjugated bilirubin carried to liver bound by albumin
what is unconjugated bilirubin carrier to the liver by
albumin
where is bilirubin conjugated and how
in the liver
o Add 1-2 residues of glucuronic acid
o Catalyzed by uridine diphosphate glucanosyltransferase (UDG)
how is conjugated bilirubin excreted
- Bilirubin glucuronide excreted into bile
where is iron absorbed
duodenum
what is better absorbed fe2+ or fe3+
fe2+
how is iron transported
o Transported through divalent metal transporter (DMT)
what prevents iron overload
hepcidin
hepcidien function
o Excess iron can damage cells so liver transport iron from enterocytes into bloodstream via hepcidin
Hepcidin prevents iron overload
what does hepcidin block
ferroportin transporter
what is hepcidin stimulated by
inflammation IL-6
what is hepcidin inhibited by
reduced iron stores and erythroferrone (released by developing erythroblasts)
what does transferrin transporter accept iron from
- Transferrin transporter transport iron though blood
o Accepts iron from ferroportin
cells with transferring receptors do what
- Cells with transferrin receptors can endocytose transferrin and store it in ferritin protein complex
where is iron stored
- Store iron in hepatocytes, spleen, and bone marrow
storage form of ferritin is
hemosiderin
what % of anemia is iron deficiency anemia
50%
causes of iron deficiency anemia
- Lack of iron in diet, parasites stealing iron, increased iron requirements in childhood or pregnancy, menstruation, trauma, GI bleed
iron requirements for male and female
- Male: 15 mg/d with 6% absorption
- Female: 11 mg/d with 12% absorption
what increases the absorptionn of iron and what decreases it
- If iron deficient can increase absorption by 20% if meat, but 5-10% if vegetarian
o Vegetarians; phytates and phosphates reduce iron absorption by 50%
symptoms of iron deficiency
fatigue, dyspnea, exercise intolerance
o Blood loss: metorrhagia, hematochenzia, melena, hematuria
signs of iron deficiency
pallor (conjunctiva), tachycardia, flow murmur
labs for iron deficiency anemia
o labs: abnormal CBC
Low CBC count, reduced Hb [ ], reduced reticulocytes, microcytic and hypochromic RBC, increased red cell distribution width
- Severe: size (anisocytosis) and shape (poikocytosis) changes in microcytic and hypochromic RBC
- Labs: iron
o Decreased ferritin and serum iron, increased total iron binding capacity
morphology in iron deficiency anemia
microcytic and hypochromic
what’s impacted in early iron store depletion
marrow iron stores, serum ferritin, total iron binding capacity (TIBC)
progression of iron deficiency
- Initially: ferritin drops, TIBC increases
- Then: serum iron and transferrin saturation drop
- Late: CBC abnormal; hypochromic, microcytic anemia
- Blood Hb [ ] drop
alsolute iron deficiency vs functional iron deficiency
Absolute iron deficiency: Reduction of total body iron stores, which may progress to IDA
Functional iron deficiency: Iron is inadequately mobilized from stores to the circulation and erythropoietic tissue.
causes of absolute iron deficiency
-increased demands
-decreased intake
-decreased absorption
-chronic blood loss
causes of functional iron deficiency
-chronic inflammation and elevated hepcidin levels (i.e. IBD, kidney disease, autoimmune, infection)
-increased erythropoiesis (ESA therapy or endogenous response to anemia)
iron stores in functional iron defieincy
could be normal or high
