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~ LSM3212 ~
A/Prof Wong Chong Thim
Department of Physiology
MD9, #03-08
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BLOOD
Composition of blood: plasma and
ce u ar e emen s o oo
Functions of BloodBlood Cells and their Production
Hemostasis: revention of blood loss
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Blood Cells & Plasma
Components
Plasma the liquid component of the blood
Cells
Some blood arameters Hematocrit
Hemoglobin concentration
Red blood cell (rbc, erythrocyte) count
White blood cell (wbc, leukocyte) count
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Differential wbc count
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. , .
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p e s p s
Protein concentrations:Total 6.0-8.0 g/dL
Albumin 3.1-4.3 g/dL
o u ns . - . g
Fibrinogen 200-450 mg/dL
Transferrin 3.0-6.5 mg/dL
All the plasma proteins are
immunoglobulins, from B-
lymphocytes.
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Components of formed elements
thrombocytes
reticulocytes
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#14
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Main blood cell parameters of normal healthy adults
Cells/L (average) Approx. range Percentage of Total White Cells
Erythrocytes
MalesFemales
5.4 x 106
4.8 x 1064.4 5.8 x 10
6
4.1 5.2 x 106
,
Granulocytes
Neutrophils 5400 3000 6000 50 70
Eosinophils
Basophils35
150 300
10 - 100
1 4
0.4
Lymphocytes 2750 1500 4000 20 - 40
Monocytes 540 300 600 2 - 8
Platelets 300,000 200,000 500,000
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Main blood parameters
Test Measures Elevated Depressed
va ues va ues
Hematocrit (Hct) Percentage of formed
elements in whole blood.
Polycythemia Anemia
Reticulocyte count(retic) Circulating percentage ofreticulocytes Reticulocytosis
concentration (Hb)
hemoglobin in blood
RBC count Number of RBCs per l of Erythrocytosis/ Anemia
Male Female
Hematocrit (%) 40 to 54 37 to 47
Hemoglobin conc
( /dL)
14 to 17 12 to 16
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Reticulocyte count ~0.8%
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Functions
Transport/Distribution
Metabolic wastes Various substances (eg. minerals, vitamins, etc)
Homeostasis/Regulation
Body temperature p
Fluid volume
Against blood loss (Hemostasis)
Against infection (Immunology) *
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Immune system
Leukocytes are the mobile units of the bodys immune
outside the blood.
They defend against the invasion of pathogens.
They identify cancer cells. They remove the bodys litter by phagocytosis.
They can leave the circulation and go to the sites of.
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#09mmuno ogy
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15
Fig. 13-26, p. 487
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Exchange of oxygen and carbon dioxide at tissue level
Diffusion
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Hb = hemoglobin
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Transport of oxygen
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1 Hb molecule = 4 Hb chains
1 Hb chain = 1 heme + 1 globin
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abm3s6a.mov
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Oxygen carrying capacity of blood
In hemoglobin
~ 15 g Hb/dL blood
~ 1.34 ml oxygen/g Hb (fully saturated)
~ 20 ml oxygen/dl blood
In plasma ~ 0.003 ml oxygen/dL blood/mm Hg oxygen (partial
pressure of oxygen)
Systemic arteries = 100 mmHg
S stemic veins = 40 mm H
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Transport of carbon dioxide
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Transport of carbon dioxide
[carbaminoHb]
(~7%) (~23%)
(~70%)
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Blood Cell Production
An erythrocyte in the circulation cannot reproduce, as it lacks anucleus. Erythropoiesis (erythrocyte production) is the productionof new red cells, replacing the functionally worn-out cells in thecirculation. This occurs in the bone marrow in the adult.
Pluripotent stem cells in the red marrow differentiate into all thedifferent types of blood cells that we find in the circulation.
Regulatory factors act on hemopoietic (blood-producing) redmarrow to govern the type and number of cells produced and
discharged into the circulation. The average life span of an erythrocyte is 120 days. The final
demise of old erythrocytes is mainly in the spleen.
The number of erythrocytes normally remains constant.
Cell production = cell death.
However, a low level of oxygen delivery to the tissues stimulates
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controlled by erythropoietin, a hormone produced by the kidneys.
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Blood cell production in boneTwo important properties of
stem cells:
. ep cat on2. Differentiation
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Ifoxygen delivery to the tissues,and kidneys, is decreased, the
kidneys detect this and increase theoutput oferythropoietin. The rate oferythropoiesis increases.
An increase in the rate of
erythropoiesis increases the number-carrying capacity to the tissues.
Once the oxygen delivery to the
tissues, and kidneys, is sufficient,the kidneys detect this. Theydecrease their output oferythropoietin.
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[Negative feedback system]
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Hemoglobin is a molecule consisting of two parts.
The heme part is nonprotein.
Each of its four iron atoms is
bound to one of the
polypeptides and cancombine with one molecule
o oxygen gas. s mo ecu e
is bright red when combined
with oxygen. e g o n s our, o e
polypeptide chains.
Hemoglobin can also
com ne w t car on ox e,hydrogen ions, carbon
monoxide, and nitric oxide.
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emog o n can u er p y
binding with hydrogen ions.
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Type of globin chain determines
.Each consist of a tetramer of
globin polypeptide chains., each
with an attached heme.
-like chains 141 aa long
-like chains 146 aa long
HbF (), fetal Hb
HbA (), adult HbHbA2 ( ), adu t Hb, norma
variant, very small %.
-
HbE () abn aa26 glu-lys
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Iron metabolism
Iron absorption occurs predominantly in the duodenum and upper jejunum.
Iron must traverse both the apical and basolateral membranes of absorptive
.
the oxidation state of iron.
Iron that is present in food (particularly in red meat, pulses (legumes) and dairy
roducts rimaril occurs as Fe III or as heme. There is evidence that heme
may be transported into the intestine by a specific carrier (heme carrier protein 1;
HCP1) although the nature of the carrier is unknown. Iron from heme is better
absorbed compared to non-heme iron.
Iron that is exported from cells into plasma by ferroportin becomes bound to
- - -,
iron-binding domains that is synthesized in the liver, retina, testis and brain.At the neutral pH of blood, transferrin can bind two atoms of Fe(III) with a
dissociation constant Kd of 1023 M. Fe III binds transferrin onl in the
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presence of an anion, usually carbonate, that bridges iron and transferrin.
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Iron transport across the enterocyte
of the intestines).
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Amount of available iron is de endent on
(1)Amount of iron in food we ingest main source is meat
(2)Form of iron present in the food
Ferric iron (Fe(III)) in the diet is
converted to ferrous iron (Fe(II))by a ferroreductase (DCYTB,
duodenal cytochrome B) that is
located on the apical surface of
enterocytes of the duodenal mucosa.
Amount of iron absorbed is well controlled by feedback system(many hypotheses, no complete agreement), absorbing enough to
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.
Liver stores a ready supply of iron.
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iron, transferrin and the
transferrin receptor.
The plasma protein transferrin
(Tf) binds Fe(III) with high
affinity. At the neutral pH (7.2)in plasma, TfFe(III) binds to
the cell surface from where it is
internalized by receptor-
mediated endocytosis throughclathrin-coated pits.
The internalized vesicle (an endosome) becomes acidified (pH 5.5) by the action of
an H+ ATPase not shown . As the H of the endosome decreases the structure of the
TfTfR complex changes and Fe(III) is released from TfFe(III). Fe(III) is converted toFe(II) by the endosomal reductase STEAP3 (six-transmembrane epithelial antigen of the
prostate 3) and is then transported out of the endosome into the cytosol by divalent metal
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ranspor er- . e can e s ore n err n n nonery ro ce s or ncorpora e
into haemoglobin in erythroid cells. The TfTfR complex is exocytosed by a recycling
endosome.
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In liver
A/Prof CT Wong LSM3212 Blood 32In maturing rbc
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Synthesis of Porphobilinogen and Heme
1* ALA synthase; 2 PBG synthase/ALA dehydratase; 3 PBG deaminase/Uroporphyrinogen
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III synthase; 4 Uroporphyrinogen decarboxylase; 5 coproporphyrinogen III oxidase;
6 protoporphyrinogen IX oxidase; 7 Ferrochelatase (Addition of iron occurs at this step)
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The largest repository of heme in the human
body is in red blood cells, which have a lifeHeme Catabolismspan o a out ays. ere s t us aturnover of about 6 g/day of hemoglobin,
which presents 2 problems. Breakdown of rbc
system, mainly in the spleen and liver (Kupffercells).
First, the porphyrin ring is hydrophobic and
must be solubilized to be excreted.
Second, iron must be conserved for new heme
synthesis. Normally, senescent red blood cells
and heme from other sources are engulfed by
cells of the reticuloendothelial system. Theglobin is recycled or converted into amino
acids, which in turn are recycled or catabolized
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as requ re . ron s re ease n o e c rcu a on
for reuse by the body.
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eme s ox ze , w t t e eme r ng e ng opene y t e
endoplasmic reticulum enzyme, heme oxygenase. The oxidation step
requires heme as a substrate, and any hemin (Fe3+) is reduced to heme
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.
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bridging methylene (between
rings III and IV) is reduced by
biliverdin reductase roducin
bilirubin.
Bilirubin is released into the
circulation. It is transported in theplasma bound to albumin. This is
the free or unconjugated
bilirubin, and it is quite insoluble.
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Albumin bound bilirubin is
transport to hepatocytes, where
UDP glucuronyl transferase adds 2
equivalents of glucuronic acid to
bilirubin to produce the more
water soluble, bilirubindiglucuronide derivative.
The increased water so ubi ity of
the tetrapyrrole facilitates its
excretion with the remainder of the.
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Destruction of rbc and reutilization of breakdown products
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Destruction of rbc and reutilization of breakdown products
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Jaundice
,
bacteria to produce the final porphyrin products, urobilinogensand urobilins, that are found in the feces.
Bilirubin and its catabolic products are collectively known as
the bile pigments.
In individuals with abnormall hi h red cell l sis or liverdamage or obstruction of the bile duct, the bilirubin and its
precursors accumulate in the circulation; the result is
,
pigmentation known asjaundice.
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Anemia
Anemia is a reduction below the normal capacity in the blood to carry
oxygen. ere are many n s o anem a.
Nutritional anemia is caused by a dietary deficiency of a factor neededfor erythropoiesis (eg. iron, vitamins).
Aplastic anemia is due to the failure of the bone marrow to make
adequate numbers of RBCs.
Renal anemia is due to kidney disease; lack of Epo. Hemorrhagic anemia is due to the loss of significant amounts of blood
(and production cannot keep up with loss).
Hemolytic anemia is due to the rupture of many RBCs. Sickle cell
disease can make red cells fragile and vulnerable to hemolysis.
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PRODUCTION vs LOSS/DESTRUCTION
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Polycythemia
Polycythemia is an excess in circulating erythrocytes.
.
Primary polycythemia is caused by an tumor-like condition in the bone
marrow.
-
mechanism to improve the oxygen-carrying capacity in the blood.
Relative (spurious) polycythemia: Other conditions can elevate the
, .
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PRODUCTION vs LOSS/DESTRUCTION
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Leukocytes are produced at varying rates.
Their rates change depending on the changing defense needsof the body.
They are produced from pluripotent stem cells in the bonemarrow. These cells can differentiate and proliferate into
different cell lines, producing the different kinds of white bloodce s.
Granulocytes and monocytes are produced only in the bonemarrow.
Lymphocytes are originally produced from precursor cells in thebone marrow. Most new ones are produced from lymphocytesin lymphoid tissue (eg lymph nodes).
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Hemostasis Primary hemostasis
Vesse wa s
Platelets
Coagulation factors
Extrinsic pathway Intrinsic pathway
Common pathway
ontro o emostas s Anticoagulants
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e s s s p eve s ss evessels.
The first two steps to stop escaping blood from a vessel
are: vascular spasm - This reduces blood flow through a damaged
vessel.
platelet plugging - An aggregation of platelets forms a plug.Platelets aggregate on contact with exposed collagen in thedama ed wall of a vessel. The latelet lu seals a break in avessel.
Platelets releases numerous substances when activated.Some of these substances will enhance the aggregation
process. Among t ese are ADP, t rom oxane A2, ca ciumions. Other substances from the endothelium of a bloodvessel inhibit platelet aggregation, keeping the process
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.
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Normal and damaged vessel wall
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No a a d da aged vesse wa
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factors. They lead to the final conversion of fibrinogen into fibrin.
e c o ng ac ors serve as pro eo y c enzymes n a ser es o
reactions, the clotting sequence. One factor in the sequence isactivated which in turn activates another factor and so on. This
.
The last two steps in the cascade are:
prothrombin is converted to thrombin
fibrinogen is converted to fibrin
intrinsic pathway - This uses the sequence of factors in the cascade.
extrinsic pathway - This requires only four steps and requires
contact with tissue factors external to the blood.
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Fig. 11-13, p. 408
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Coagulation factors
I FibrinogenII Prothrombin
III Thromboplastin/tissue factor*
V Proacclerin, labile factor, accelerator globulin
VII Proconvertin, SPCA, stable factorVIII Antihemophilic factor (AHF), antihemophilic factor A,
*
anti emop ilic glo ulin (AHG)
IX Plasma thromboplastic component (PTC), Christmas factor,
antihemophilic factor B
X Stuart-Prower factor
*
*XI Plasma thromboplastin antecedent (PTA), antihemophilic
factor C
XII Hageman factor, glass factor
- - ,
HMW-K High-molecular-weight kininogen, Fitzgerald factorPre-K Prekallikrein, Fletcher factor
Ka Kallikrein
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PL Platelet p osp olipi
* Vitamin K dependent coagulation factors
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Vitamin K acts as a cofactor
in the formation of g-
carboxyglutamyl residues
(gla components) fromlutam l residues lu
components) in the
coagulation factors listed.
in the formation ofcalcium
binding sites. The next slide
show the events that will
lead to the conversion of
rothrombin to thrombin.
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Coagulation cascade
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Coagulation cascade
Common pathway
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Fig. 11-14, p. 409
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Prothrombin activator
The figure on the left is the situation at the start of the common pathway.
Factor Xas gla components are attracted to the ionised Ca that are in contact
with latelet factor 3 also called latelet hos holi ids . These lateletphospholipids have negative charges that attract the Ca in the plasma. This
builds up the concentration of Xa in the damaged area. Prothrombin, which
also possesses gla components are also attracted by the Ca present. This thus
increases its concentration and also brings it in close proximity with Xa (seefigure on right). Xa then can act on the prothrombin and convert it to thrombin.
Same sort of reaction occurs in the activation of factor X by IXa (intrinsic
52
pathway) or VIIa (extrinsic). Next 2 slides show how inactive coagulation
factors are activated mainly by loss of part of the protein molecule, change in
3D structure, exposure of active sites in the molecule.
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(Either VIIa com lex or IXa com lex)
(active site)
Figure on left is the normal circulating inactive factor X. Removal of part of
the molecule by either IXa (intrinsic pathway) or VIIa complexes (extrinsic
pathway) allows for changes in 3D conformation, leading to exposure of
active site, converting it into an active enzyme. Similar events occur during
activation of IX, VII and conversion of prothrombin to thrombin.
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( = gla components)
A/Prof CT Wong
(Xa, V, Ca, PL)
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( = gla com onents)
(Thrombin removes part of the fibrinogen molecule,
which allows the fibrin monomer to bind to one
another)
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Anticoagulants
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Anticoagulants
Heparin/heparan
Heparin in plasma; heparan on endothelial surface
Functions as co-factor to anti-thrombin III
Normal constituent of plasma Anti-thrombin III
Plasma protein that binds to and inactivates thrombin,IXa, Xa
One of the many plasma proteins normally present inblood
Warfarin (coumarin) drugs
Drugs affecting vitamin K dependant coagulationfactors
Removal of calcium ions (in vitro)
Chelates/binds to calcium ions e . citrate, oxalate,
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EDTA)
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Additional notes on blood clottin :
1. Clot retraction occurs after the clot is formed.
2. Amplification occurs in the clotting process. One moleculecan activate one hundred molecules in the next step and soor .
3. Whether a clot will form or not is dependent on the balanceo e ac ors promo ng c o orma on an a o c odestruction (fibrinolysis)
http://www.mhhe.com/biosci/esp/2002_general/Esp/folder_str
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ucture/tr/m1/s7/trm1s7_3.htm
Balance between clot formation and destruction
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Aims & Objectives
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Aims & Objectives
1. Describe the composition of blood.
. .
3. Describe the process of normal erythropoiesis.
factors required for normal erythropoiesis.
. .involved in hemostasis.
Reference: Sherwood L 2010 Human Physiology. 7th ed
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Chapter 11