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Chapter 3 Blood Physiology
• Blood composition and properties
• Blood cells
–
–
–
–
Hematopoiesis
RBC: function, anemia.
WBC
Platelet: function, coagulation and fibrinolysis.
• Blood grouping and transfusion
Introduction
• Blood volume: 7~8% (70-80ml/kg B.W)
– Plasma (60%) and cells (40%).
• Types of blood cells:
– RBC (Erythrocytes), WBC (Leukocytes) and Platelets (Thrombocytes)
• Main function:
– Maintain homeostasis
• Buffering pH
• Humoral regulation
• Body temperature regulation
– Transportation:
• Gases, nutrients, hormones, and so on.
– Host defense:
• Immune reaction, coagulation.
Section 1 Components and Characteristic
Water: 93-95%
Plasma: 50-60%
Whole
blood
Solutes: 5-7% Proteins:
Nutrients
Products
Electrolytes:
Others: urea, gases.
WBC, Platelet: 1%
RBC: 40-50% (male)
37-48% (female)
Blood Components
• Water:
– 93~95% (plasma); 65~68% (RBC); 81~86% (whole blood).
– Solvent, humoral balance, osmotic pressure.
• Electrolytes:
– Na+, K+, Mg2+, Cl-, HCO3-, etc. Cell shape, pH.
• Proteins:
– Albumin: 40-48g/L. Colloidal osmotic pressure; carrier;
buffer pH.
– Globulin: 15-30g/L. Immune reaction: antibody; carrier.
– Fibrinogen: 2-4g/L. Blood coagulation.
– Hemoglobin (Hb):
• 120-160g/L (male), 110-150g/L (female)
• Function: carry gases.
• Others:
– carbohydrates, lipids, amino acid, pigments,
hormones, gas (O2, CO2), and others like urea, uric
acid.
Physical and chemical properties
• Blood pH:
– Normal interval: 7.35~7.45.
• Regulated by lung and kidney.
• Viscosity:
– Friction of molecules and cells in blood.
– Relative viscosity:
• Whole blood: 4~5 times to water (RBC).
• Plasma: 1.6~2.4 times to water (Proteins).
• Anemia or body fluid loss.
• Osmotic pressure
– Definition:
• An ability of a liquid to attract and retain water. It
drives osmosis. 300mmol/L
– Composition and roles:
• Crystal osmotic pressure: 298.7 mmol/L.
– Maintain shape and size of cells.
• Colloid osmotic pressure: 1.3 mmol/L.
– Retain blood volume
– Decide distribution of water between blood and
interstitial fluid.
Section 2 Blood Cells
• Red blood cell
• White blood cell
• Platelet
Hemopoiesis
• The process of blood generation.
Cell Lineage
Lifespan
Daily Production Rate
RBC
120 days
2.5  109/L
Neutrophil
7 hours
0.85  109/L
Platelet
10 days
2. 5  109/L
• Ontogeny of Hematopoiesis
– Prenatal stages:
• First month: yolk sac.(During fetal development, hematopoiesis
occurs in multiple waves throughout the developing embryo and fetus,
including extraembryonic yolk sac (YS), the para-aortic region of the
embryo, fetal liver, and placenta before eventually homing to the bone
marrow where it occurs just before birth)
• Third month: liver
• Fourth month: bone marrow
– Postnatal stages:
• Bone marrow of almost any bone, predominantly by
flat bones and long bones.
100
100
Hemopoitic
activity (%)
Yolk Sac
Bone morrow
Liver
Lymph nodes
Spleen
0
1
2
3
4
5
6
7
8
9
Prenatal age (months)
Proportion of Red
Morrow (%)
100
birth
100
Vertebrate
Tibia
Sternum
Femur
10
20
30
Ribs
40
50
Postnatal age (years)
60
70
80
90
– Stage 1, hemopoietic stem cells: pluripotent uncommitted
stem cells.
– Stage 2, committed progenitor cell: unipotent committed
stem cells. Includes:
•
•
•
•
Erythrocytic progenitor cell
Megakaryocytic progenitor cell
Granulocytic progenitor cell
Lymphocytic progenitor cell
– Stage 3, precursors (cell): immature cells, differentiate
functional cells. Including:
• Ery. progenitor erythrocytes.
• Mega. progenitor  platelets.
• Gran. progenitor  granulocytes and monocytes.
• Lym. progenitor  T and B lymphocytes.
• Hematopoietic growth factor and related molecules
– Necessary for proliferation and differentation of
hematopoietic cells in the marrow.
– Colony-stimulating factors (CSF): see a table in next slide.
– Cytokines:
• IL-1, stem cell factor (CSF), etc.
– Extracellular matrix proteins:
• Sulfated glycosamimoglycans and heparin sulfate, may
concentrate hematopoitic growth factors in local micro
environment;
• Fibronectin and hemonectin, mediate adhension of
cells, and may serve a growth promoting function.
Hematopoietic growth factors
Growth Factors
Function: stimulate progenitor
of the followings:
GM-CSF (granulocytemacrophage CSF)
Granulocyte-monocyte
G-CSF (granulocyte CSF)
Granulocyte
M-CSF (macrophage CSF)
Monocyte
EPO (Erythropoietin)
Erythrocyte
IL-1,3,6 (Interleukin-3, 1, 6)
Myeloid lineage
TPO (Thrombopoietin)
Platelet
Red blood cells (erythrocytes)
• Circular, biconcave discs without nuclei. 7~8m,
thickness 1~2.5 m.
• Cell count and volume:
– Hematocrit: Percentage of blood volume occupied by
packed cell volume.
– Volume:
• 4.5~5.51012/L, average 5.01012/L (male).
• 3.8~4.61012/L, average 4.21012/L (female).
• Physical properties
– Permeability:
– Deformation:
– Fragility and hemolysis:
• Isosmotic solution and lower osmotic solution
– Suspension stability:
• The erythrocytes are very stable in suspension.
• Cause: repelling force of same charge and bigger
surface area.
• Erythrocytes Sedimentation Rate (ESR):
Sedimentated distance of RBC after one hour.
– 0~15 mm/h (male), 0~20 mm/h (female).
– Ratio of Surface area/Volume of RBC.
– Albumin, globulin, fibrinogen, and cholesterol.
– Rouleaux: RBC aggregate.
• Function of RBC:
– The main constituent of RBC is hemoglobin.
– To deliver O2 to tissues by hemoglobin.
Hemoglobin (HB)
• HB is made up of two
polypeptide  chains
and  chains.
• Each polypeptide has
alpha helical segments
folded and bent into a
globular configuration,
with a heme ring
within a pocket where
the iron molecule can
interact with oxygen.
• Hb formation materials:
– Protein: enough intake from food.
– Iron: 3-4g/person. Mainly in Hb (70%).
• Degrading Hb: 95%.
• Absorbed from small intestine: 1mg/d, 5%.
• Microcytic hypochromic anemia: Lack of iron.
• RBC Maturation factors:
– Vitamin B12:
• Cobalamine, 2~5g/d.
• Produced by gut bacteria (esp. in ruminants). Good sources
include meat, liver, fish, eggs and milk.
• Absorbed in terminal ileum with intrinsic factor’ help.
• Function: Improve utilization of FA.
– Folic acid:
•
•
•
•
FA is essential for the synthesis DNA.
Synthesized by microorganisms and higher plants.
Good sources are green leafy vegetables, yeast and organ meats.
Absorbed in the proximal jejunum.
– Lack of folic acid and vitb12: give rise to immature
cells due to DNA synthesis derangement.
– Megaloblast anemia.
•Regulation of erythropoiesis: Hypoxia:  EPO RBC
Hemopoitic stem cell (uncommitted progenitor)

Erythrocytic progenitor (committed progenitor)

EPO
Pronormblast (precursor)

Normoblast, Reticulocyte

Mature RBC (without nucleus)
• Erythropoietin (EPO):
– A glycoprotein, 34kd. Produced in interstitial cells in cortical
kidney such as fibroblast, endothelial cells.
– Roles:
• Erythrocytic progenitor proliferate and differentiate to
precursor.
• Accelerate precursor proliferation and differentiation.
• Promote bone marrow release reticulocytes.
• Renal type anemia: EPO production decrease
• Other hormones:
– Androgen, thyroid hormone, parathyroid hormone,etc.
• RBC destruction:
– Life span of RBC is about 120 days. Older cells
White blood cells (leucocyte)
• WBC:
– 4~10109/L, average is 7109/L.
– Include:
• neutrophil, eosinophil, basophil
• monocyte, lymphocyte.
– Protection, execute specific and non-specific immune
reaction.
• Physical and chemical properties
– Chemotaxis: attracted by chemical substances released
by bacteria and foreign substances.
– Movement: Move to chemotaxic source
– Phagocytosis: engulf and digest
Composition and functions
• Neutrophil:
– 10~12m, 2.0~7.0109/L, 60-70%.
– Function:
• Phagocytosis: older cells, becteria, dead tissues, and
other foreign substances.
• To execute non-specific immune activity in first front.
• Monocytes:
– 15~30m, 0.12 ~ 0.8109/L, 3 ~ 8%.
– Monocytes-macrophages system:
• Monocytes (in blood) wander into tissues and become macrophages
(50 ~ 80 m). Stronger phagocytosis.
• Contain many kinds of cytokines such as CSF, ILs, TNF, INF-a,b.
– Roles:
• Engulf and clear: bacteria, vermins, older, necrotic tissues, dead
neutrophils, dead cells and fragments.
• Activate lymphocytes to execute specific immune response.
• Recognize and kill cancer cells.
• Produce CSF, Ils, TNF, INF-, , regulate growth of granulocytes.
• Lymphocytes:
– 0.8~4.0109/L, 20 ~ 40%.
– Development of lymphocyte:
• T lymphocyte:
– lymphocytic stem cells  T lymphocytes (thymus gland).
• B lymphocyte:
– lymphocytic stem cells  B lymphocytes (lymphoid tissue).
– Functions:
• T lymphocytes: cellular type of immunity
• B lymphocytes: humoral immunity
• Eosinophils
– 0.02~0.5 109/L, 0.5~5%.
– Functions:
• Inhibit allergic reaction induced by basophils:
– Produce PGE to inhibit secretion of basophils;
– Engulf substances secreted by basophils;
– Secrete matters to hydrolyze histamine and 5-HT.
• Phagocytic action to some worms.
• Basophils
– 0.0~1.0  109/L, 0~1%.
– Large cytoplastmic granules contain heparin, 5hydroxytryptamine and histamine.
– Function:
• Secrete heparin blood to prevent coagulation.
• Wander into tissue and become mast cell.
• Induce allergy.
Platelet
• Hemostasis:
– The process of blood clotting and then the subsequent
dissolution of the clot.
Platelet  activation  adhension  aggregation  clot  thrombus  FDP
thrombin
vWF
ADP and TXA2
fibrin
plasmin
fibrinogen
Blood Coagulation
Fibrinolysis
• Anatomic physiology of platelet:
– 2~4 m, thickness 1m.
Fibrinogen
GP IIb/III a
Phospholipid
Va
Ca2+
Receptor
X
GPI
vWF
– Membrane:
• Receptor: For adhension, aggregation and
coagulation.
• Phospholipid: provides the lipid cofactors needed for
coagulation reactions.
– Granules in platelet:
• -granules: coagulation factors, growth factors (e.g.
PDGF).
• -granules (dense bodies): Ca2+, ADP and serotonin.
– Volume: 100~300 109/L in adult.
• Thrombocytopenia: <50 109/L,  hemorrhage
• Thrombocytosis: >1000109/L,  Thrombosis
• Physical properties
– Adhesion:
• Mediated by von Willebrand factor (vWF).
• vWF is producted and stored in a-granules of
platelets. Also synthesized by megakaryocytes.
• Function of vWF:
– To act as a bridge between glycoprotein on the surface of
platelets (GPIb/IX) and collagen fibrils.
– Serves as a carrier protein for factor VIII.
• von Willebrand Disease (vWD): deficiency in vWF a
patient with long bleeding time, a low level of factor
vWF/VIII complex.
• Bernard-Soulier Syndrome:deficiency of glycoprotein
Ib/IX.
– Aggregation:
• Activated platelets aggregate together.
• Activation of platelets: induced by thrombin.
–
–
–
–
Thrombin + receptor  initiate signal cascade.
G-protein, and phospholipase C(PLC-g).
PLC-g  IP3 and DAG formation.
IP3  Ca2+ , and DAG  PKC.
• Mechanisms:
– Ca2+  phospholipase A2 (PLA2) arachidonic acid 
thromboxane A2 (TXA2)
– PKC ADP  fibrinogen to adhere to two platelet surface
glycoproteins (GPIIb and GPIIIa)  fibrinogen-induced
platelet aggregation.
– Glanzmann-Thrombasthenia, deficiency of glycoprotein
IIb/IIIa.
• Contractile function:
– PLC-g  Ca2+  myosin light chain kinase (MLCK)
– MLCK  phosphorylation of light chain of myosin
– Myosin interacts with actin
– Platelet morphology, motility, and clot retraction.
• Roles of platelet:
– Platelet clot formation at the site of vessel injury
(primary hemostasis);
– Enhance activation of coagulation factors to solidify
platelet clot by interlacing with fibrin (secondary
hemostasis).
• Platelet function disorders:
– Disorders of platelet adhesion:
• Bernard-Soulier Syndrome: deficiency of glycoprotein Ib/IX.
– Disorders of platelet aggregation:
• Glanzmann-Thrombasthenia, deficiency of glycoprotein IIb/IIIa.
– Disorders of platelet secretion:
• Alpha or Dense Granules Deficiency.
– Disorders of platelet procoagulant activity:
• Platelets fail to promote activation of the blood clotting proteins.
– Acquired platelet function disorders:
• Drugs like aspirin, non-steroidal anti-inflammatory drugs like
indomethacin, ibuprofen.
Blood coagulation
• A process of blood from liquid to colloid. A serious of
enzymes reactions.
• Coagulation factors:
– Factors involved in the blood coagulation
– Attentions:
• FIII come from tissue, others from plasma.
• FIV is Ca2+, and others are proteins.
• FII, VII, IX, XII exist as proenzymes.
Factor
Trivial Name(s)
Pathwa
y
Prekallikrein
Fletcher factor
Intrinsi
c
High molecular weight
kininogen (HMWK)
contact activation cofactor; Fitzgerald, Flaujeac Williams factor
Intrinsi
c
Characteristic
I
Fibrinogen
Both
II
Prothrombin
Both
III
Tissue Factor
Extrins
ic
Contains N-term. gla
segment
-
IV
Calcium
Both
V
Proaccelerin, labile factor, accelerator (Ac-) globulin
Both
VI (Va)
Accelerin
VII
Proconvertin, serum prothrombin conversion accelerator (SPCA),
cothromboplastin
Extrins
ic
Endopeptidase with gla
residues
VIII
Antihemophiliac factor A, antihemophilic globulin (AHG)
Intrinsi
c
Protein cofactor
IX
Christmas Factor,
antihemophilic factor B,plasma thromboplastin component (PTC)
Intrinsi
c
Endopeptidase with gla
residues
X
Stuart-Prower Factor
Both
Endopeptidase with gla
residues
XI
Plasma thromboplastin antecedent (PTA)
Intrinsi
c
Endopeptidase
XII
Hageman Factor
Intrinsi
c
Endopeptidase
XIII
Protransglutaminase,
fibrin stabilizing factor (FSF), fibrinoligase
Both
Transpeptidase
Protein cofactor
This is Va, redundant to
Factor V
clotting cascade
Stage 1: Formation
of prothrombin
activator.
Stage 2:
Conversion of
prothrombin
to thrombin.
Stage 3: conversion of
fibrinogen to fibrin
• Difference of stage 1:
– Prothrombin-converting enzyme: Xa, Ca2+, V, PL.
– Difference of factor Xa:
• Intrinsic stage:
– Start from XII. The intrinsic pathway requires factors VIII,
IX, X, XI, and XII. Also required are the proteins
prekallikrein and high-molecular-weight kininogen, as well
as Ca2+ and phospholipids secreted from platelets.
• Extrinsic stage:
– Start from FIII (TF), is initiated at the site of injury in
response to the release of TF.
– TF is a cofactor in the factor VIIa
– Factor VIIa, cleaves factor X to factor Xa
Prevention of coagulation
• Plasma inhibitors
• Fibrinolysis
• Role of the endothelial cells
Plasma inhibitors
Inhibitor
Mol. Weight
(kD)
Action
Plasma Conc.
(mg/ml)
Antithrombin
III
50
Antiserine
protease
240
2antiplasma
70
Antiplasmin
70
2macroglobulin
725
Antiprotease
2500
Protein c
56
Anti-factor
V and Viii
5
• Antithrombin III:
– Nonspecific protease inhibitors
– Produced in liver and endothelial cells
– Inhibit active sites of FIXa,FXa,FXIa,FXIIa, thrombin.
• Protein C:
– Vitamin K-dependent protein
– Is activated to activited protein C (aPC) by thrombin in
presence of endothelial cell-derived cofactor
thrombomodulin.
– aPC inactivates FV and FVIII in presence of another
vitamin K-dependent cofactor: protein S.
– See next slide.
Anticoagulation pathway
VIII
VIIIa
VIIIi
PS
X
X
aPC
PS
V
+
Va
FII
PC
Vi
Thrombin
FI
Fibrin
• Heparin:
–
–
–
–
–
A polysaccharide produced in basophilic mast cells
Distributed in the pericapillary tissue.
Abundant in lung, heart, liver, muscle tissues.
Inhibit thrombin conversion.
Promote antithrombin III activity.
• Calcium ions precipitants:
– Sodium citrate
Fibrinolysis
• Fibrinolysis:
– Process of liquefaction of fibrin
Activator
plasminogen
plasmin
Inhibitor
fibrin
fibrin degradation products
Activator: Tissue plasminogen activator (tPA), urokinase.
Plasmin, a serine protease, is inhibited by 2-antiplasma.
• tPA:
– Released from vascular endothelial cells following
injury;
– Binds to fibrin and is consequently activated.
• Urokinase:
– Produced as the precursor, prourokinase by
epithelial cells lining excretory ducts.
– Role: to activate the dissolution of fibrin clots.
• plasminogen activator-inhibitors:
– PAI-1 and PAI-2
Endothelial cells
• Endothelium produces several inhibitors of hemostasis:
– Prostaglandin I2:
• secreted by endothelial cells and is a potent inhibitor of platelet
aggregation.
– Thrombomodulin:
• Enhances the activiation of protein C by thrombin and results in
the inactivation of factor V and VIII.
– Heparans:
• a heparin-like molecule, produced by endothelial cells. Increase
the anticoagulant effect of antithrombin III.
– Plasminogen activator:
• necessary for dissolution of fibrin clots, such as tPA.
Coagulation disorders
• Hemophilia A:
– Deficiency of FVIII. The disease severity usually
parallels the factor VIII levels.
– Serve (< 1% VIII): with spontaneous bleeding;
– Moderate (1-5% VIII): with occasional bleeding, usually
with trauma;
– Mild (6-30% VIII): with bleeding only after surgery or
trauma.
– Therapy: administration of FVIII.
• Hemophilia B (Christmas Disease):
– FIX deficiency.
– Treatment requires IX-rich material: fresh frozen
plasma (FFP) or lyophilized concentrates
proagulatant proteins.
• Decreased production of coagulation factors:
– E.g. Liver disease, vitamin K malabsorption, dietary
deficiency of vitamin K.
• Inactivation of coagulation factors:
– e.g. specific inhibitors, excessive activation of
coagulation (DIC) and/or enzymatic destruction of
coagulation factors.
Blood grouping and transfusion
• The discovery of blood groups:
– 1901, Austrian Karl Landsteiner
discovered human blood groups.
– Blood agglutination was an
immunological reaction.
– Awarded the Nobel Prize in
Physiology or Medicine in 1930.
• Agglutination:
– Agglutinogen: antigen on membrane
of RBC.
– Agglutinin: antibody in the plasma.
• RBC grouping:
– ABO, Rh, MnSs, lewis
– The differences in human blood are
due to the presence or absence of
certain protein molecules called
antigens and antibodies.
ABO grouping
Blood group A:A antigens on the surface of RBC,
B antibodies in blood plasma.
Blood group B:B antigens on the surface of RBC,
A antibodies in blood plasma.
Blood group AB:both A and B antigens on the
surface of RBC, no A or B antibodies at all in blood
plasma.
Blood group O:neither A or B antigens on the surface
of RBC, but you have both A and B antibodies in blood
plasma
• Antigens and antibodies:
– Antigens:
• A, B.
• Carbohydrate
– Antibodies: Antibody A and B.
• Ig M: congenital,
• Bigger Mr.
Rh grouping
• Original discovery:
– Rhesus monkey: Red cells  injected into rabbits  got
serum  injected back to Rhesus monkey, or human 
agglutination happens.
• Rh antigen and antibody
– Antigen: D, E, C, c, e.
• 99% Chinese people are Rh+
• Minority in China 2-5% is Rh• 15% western people are Rh– Antibody: IgG
Which blood group do you belong to?
A Rh+
B Rh+
AB Rh+
O Rh+
A Rh-
B Rh-
AB Rh-
O Rh-
Blood Transfusion
• Clinical significance:
– ABO and Rh blood groups must be compatible between
the donor blood and the patient blood.
– Agglutinated RBC clog blood vessels or crack to
becomes toxic when HB outside the cell.
• Cross-match test:
– Main lateral: donor’s RBC and recipient’s serum.
– Co-lateral: donor’s serum and recipient’s RBC.
• Principle of blood transfusion:
– Agglutination of main lateral: absolutely no.
– Both of main and co-lateral do not agglutinate:
– Co-lateral agglutinates but Main lateral:
• slow and less amount of blood transfusion could be recommended.
People with blood group O are called
“universal donors”.
People with blood group AB are called
“universal receivers”.
• Clinical importance for Rh group:
– Blood transfusion between Rh+ and Rh- persons.
– A mother who is Rh- woman give birth a baby who
is Rh+.
– Preventive measure: given an injection of anti-Rh
antibodies.
Donor
RBC
Serum
Recipient
RBC (co-lateral)
Serum (main lateral)
Cross match test