B7 Cell Bio FINAL

blood plasma

top layer of blood sample

buffy coat

middle layer of blood sample

RBCs

bottom fraction of blood sample

WBCs & platelets

components of the buffy coat

increases

how does hematocrit change with dehydration?

cytoskeleton that is anchored to the plasma membrane by glycophorin and the band 3 Cl-HCO3 exchanger

what helps maintain the shape of erythrocytes

-mainly hemoglobin

-also carbonic anhydrase, 2,3BPG, glutathione

what are the cytoplasmic components of erthrocytes

anaerobic glycolysis (90%)

pentose shunt (10%)

energy source of RBCs

12 weeks

at what week of gestation are RBCs start to be produced by spleen, lymphoid tissue, bone marrow

12 weeks

at _____ weeks gestation iron accumulates rapidly and is used for hemoglobin production and stored in liver

-this is important bc there is little iron in breast milk!

bone marrow of all bones

from the last month of gestation to 5 years old, where doe RBCs come from

bone marrow of vertabrae, sternum, ribs

beyond 5 years of age, where do RBCs come from?

Hematopoiesis

the process of generating all of the cell types present in blood

IL-3, low blood oxygen

growth inducers of hematopoietic stem cell growth

low blood oxygen, EPO

inducers of hematopoietic stem cell differentiation

Erythropoieten (EPO)

hormone essential for the differentation of burst forming erythroid cells to proerythroblasts

proerythroblasts

EPO helps differentiate cells to this RBC precursor which lacks hemoglobin

polychromatic erythroblasts

at what stage of erythropoiesis doe hemoglobin first appear?

reticulocyte

exocytosis of the nucleus results in what RBC precursor?

-proerythroblasts: light, spherical nucleus with thin rim of cytoplasm

-basophilic erythroblasats: fractured

-polychromatophilic: darkening, pools of grey

-orthochromaatophilic: dark, small nucleus

-reitculocytes: no nucleus and blue cytoplasm

-erythrocytes: no nucleus and red cytoplasm

name the stages of erythropoiesis and their histology (bottom to top)

-make sure adequate RBCs are available for O2 transport

-make sure excessive number of RBCs do not impede blood flow

regulation considerations of EPO

tissue oxygenation

most important regulator of RBC production

high HIF1a transcription factor is a hypoxia sensor that tells EPO in the kidney to turn up

how does hypoxia activate EPO

PGE2, adenosine, NE, thyroid hormone, androgens (estrogen inhibits)

stimuli of EPO production

-vitamin B12 and folic acid are essential for synthesis of DNA

vitamins essential for RBC maturation

-abnormal or diminished DNA resulting in failure of nuclear maturation

-macrocytes

-fragile RBCs

lack of vitamin B12 or folic acid causes maturation failure of RBCs due to:

globin

a polypeptide, either alpha chain or Beta chain

-synthesis begins in the proerythroblast

Orthochromatic erythroblast

by what stage of erythropoiesis has the cell synthesized all the hemoglobin it will ever carry?

glycine and succinyl coA

from what amino acids is heme formed?

condense via δ-ALA synthase

form δ-aminolevulinic acid

in the formation of heme, glycine and succinyl CoA condense via _______ to form _____

Vitamin B6 (pyridoxine)

what vitamin is required in the formation of heme?

-required for Succinyl-CoA and Gly condense via δ-ALA synthase to form δ-aminolevulinic acid

mitochrondria

first step of heme synthesis occurs in

cytosol

where in the cell are prophyrinogens formed during heme synthesis

-in the mitochondria

-iron (Fe2+) is incorporated into protoporphyrin IX in a reaction catalyzed by ferrochelatase (heme synthase)

-generating heme

describe the final step of heme synthesis

ALA-dehydrase (beginning)

ferrochelatase (final step)

what enzyme does lead poisoning inhibit in heme synthesis

-increased H+ (low pH)

-increased CO2

-increased temp

-increased DPG

causes of right shift in oxygen binding curve (decreased affinity)

2,3-diphosphoglycerate (2,3-DPG)

component of RBCs

-when bound to hemoglobin, it stabiilizes the T state conformation and decreases hemoglobin affinity for O2

HbF α2γ2

-quiclly replaced after birth with beta

Hb subunits in fetal development

α2δ2

hemoglobin type highly associated with thalassemias

sub valine for glutamate in the 6th amino acid of the β-globulin gene

genetic substitution associated with sickle cells anemia (HbS)

-makes the Hb less soluble resulting in its polymerization and precipitation

sub lysine for glutamic acid in the 6th position of the β-globulin chain

genetic substitution associated with HbC (mild form of sickle cell, cliniclaly silent)

thalassemia major (cooley's anemia)

homozygous B-thalassemia that results in severe hemolysis, ineffective erythropoiesis, transfusion dependency, iron overload

Hemoglobin H (alpha thalassemia)

thalassemia associated with mild hemolysis; not transfusion dependent

Hemoglobin is broken down into heme, which is converted to biliverdin, and finally into unconjugated bilirubin (which is not water-soluble).

-unconjugated bilirubin binds to albumin and takin to the liver to become conjugated and ultimately excreted

breakdown of hemoglobin into bilirubin

megaloblastic anemia

anemia associated with incomplete maturation of RBC precursor cells

microcytic, hypochromic anemia

anemia associated with aberrant O2 carrying capacity of RBCs

-more RBCs being made by bone marrow

-high altitude

high values of reticulocyte count indicate

1. aplastic anemia

2. iron deficiency anemia

3. radiation

4. chronic infection

causes of low reticulocyte count

reticulocyte count

marker of effective erythropoiesis

hematocrit

percentage of whole blood volume composed of erythrocytes

1. hemoconcentration (burns, dehydration, vomiting)

2. polycythemia

3. extreme physical exercise

increased hematocrit indicates

Macrocytic, microcytic, and normocytic anemia

decreased hematocrit indicates:

Mean Corpuscular Volume (MCV)

average volume of red cells

Liver disease, alcohol abuse, hemochromatosis, vitamin B12 deficiency, reticulocytosis, chemotherapy

increasaed MCV indicates

Iron deficiency, polycythemia vera, thalassemia, sideroblastic anemia, lead poisoning

decreased MCV indicates

mean corpuscular hemoglobin concentration

the average hemoglobin concentration in the RBCs

1. Hypochromic anemia (iron deficiency, thalassemia, lead poisoning)

2. sideroblastic anemia

3. anemia of chronic disease – various forms of microcytic anemia

decreased MCHC indicates

1. increase in the mass of red blood cells (absolute polycythemia)

2. problem with plasma (relative polycythemia)

main two causes of polycythemia

Blood becomes more viscous, slows its flow through the body

-inc risk of a thrombotic event and related symptoms (clots that lead to stroke or MI or DVTs, blurred vision etc.)

what is the main problem of polycythemia

Reduced plasma volume (hemoconcentration) due to dehydration (diarrhea and severe vomiting) or diuretics

cause of relative polycythemia

absolute polycythemia

primary polycythemia in presence of low erythropoietin

activating mutation in JAK2

mutation associated with polycythemia vera

-increase in mast cells---> itching after hot shower

-erythromelagia--> redness in hands and feet

weird symptoms of polycythemia vera

natural or artificial increases in EPO

-ex: steroids, testesterone, tumors, renal disorders, elevated carboxyhemoglobin

secondary polycythemia is induced by

<65mmHg

PO2 criteria threshold for development of secondary polycythemia

relative polycythemia

plasma volume has decreased by BVC mass has not changed

-normal EPO and no hypoxia

secondary polycythemia

high red blood cell mass due to high EPO

primary polycythemia

erythrocytosis due to neoplastic growth of RBCs even when unstimulated (EPO is low)

mutation of JAK2 associated with EPO receptor---> erythroid lineage cells in bone marrow become hypersensitive to EPO

what causes polycythemia vera?

erythroblastosis fetalis

Hemolytic disease of the new born due to Rh-incompatibility between the mother and the fetus

-antibodies cause baby RBC to be destroyed--> anemia

-compensatae anemia by releasing erythroblsts from bone marrow and liver

-overproduction of erythrroblasts--> liver and spleen enlargement--> rupture

-bilirubiin accumulates---> kernicterus

manifestations of erythroblastosis fetalais

• iron deficiency

• anemia of chronic disease

• thalassemia

• sideroblastic anemia

name the microcytic anemias

• folate deficiency

• vitamin B12 deficiency

name the macrocytic anemias

microcytosis and hypochromia

hallmarks of microcytic anemia

-iron deficiency

-sideroblastic anemia

-lead poisoning

-anemia of chronic disease or inflammation

microcytic anemias secondary to defects in heme synthesis

Sideroblastic anemia

microcytic anemia marked by genetic defects in heme synthesis pathway causing failure to synthesize porphyrin ring

lead poisoning

blocks incorporation of iron into heme----> microcytic anemia

microcytic anemia

in chronic disease, secretion of inflammatory markers impair RBC synthesis by interfering with iron absorption and erythropoietin function--->

thalassemias

example of microcytic anemia caused by failure of globin synthesis

-peptic ulcer

-celiac disease

-gasterctomy

-infections (hookworm)

causes of impaired iron absorption

cytochrome B and vitamin C

non heme ferric (Fe3+) reduced by ferrous (Fe2+) by

vitamin C

vitamin to help absorb Fe2+

DMT1

non-heme iron is taken up into enterocyte via

HCP1

heme iron is taken up into enterocyte by

Plants

non-heme iron comes from

meat

heme iron in diet comes from

hephaestion

-converts ferrous iron into ferric iron after absorption by enterocytes

-ferric (Fe3+)iron is then transported into blood by ferroportiin

ferroportin

ferric iron is transported in blood via

Transferrin

ferritin is transported to tissues via

high ferritin--> iron overload

defect in ferroportin leads to

hepcidin

central regulator of iron homeostasis, found in liver parenchymal cells and induced by inflammation

ferroportin

hepcidin interracts with _______ to iinhibit iron absorption

-Internalized and degraded thus decreasing intestinal iron absorption and inhibiting release of iron from enterocytes and macrophages

HFE gene

protein that inhibits release of Fe from the cytoplasm to mitochhondria

-defect causes hemochromatosis

serum iron

ferric (Fe3+) iron bound to serum transferrin

increases

transferrin _____ in iron deficiency to maximize the utilization of availaable iron

• chronic infections

• hemochromatosis

• protein deficiency

transferrin is decreased in:

iron deficiency anemia, pregnancy

transferrin is increased in

direct

relationship of TIBC and transferrin

iron deficiency anemia

low serum iron

low ferritin

low transferrin saturation

high TIBC

high transferrin

hemochromatosis

high serum iron

high ferritin

high transferrin saturation

low TIBC

low transfferrin