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Lecture 3
Blood
Blood
• The only fluid tissue in the body
• Composed of both cellular and liquid
components
• Considered a specialized liquid, connective
tissue
– contains fibrous proteins for clotting
Composition of Blood
• Plasma – non-living fluid matrix
• Blood cells
– Erythrocytes (red blood cells)
– Leukocytes (white blood cells)
– Platelets (cell fragments)
Figure 17.1 The major components of whole blood.
Slide 4
Formed
elements
1 Withdraw blood
and place in tube.
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2 Centrifuge the
blood sample.
Plasma
• 55% of whole blood
• Least dense component
Buffy coat
• Leukocytes and platelets
• <1% of whole blood
Erythrocytes
• 45% of whole blood
(hematocrit)
• Most dense component
Interesting Facts about blood
• Sticky, opaque fluid with metallic taste
• Color varies with O2 content
– High O2 - scarlet; Low O2 - dark red
• pH 7.35–7.45
• ~8% of body weight
• Average volume is 5–6 L for males; 4–5 L for
females
Function of Blood
• Distribution
– O2, metabolites, hormones, and metabolic waste
• Regulation
– pH of both blood and tissues
– fluid volume
• Protection
– blood loss
– infection
Blood Plasma
• 90% water
• Over 100 dissolved solutes
– Nutrients, gases, hormones, wastes,
proteins, inorganic ions
– Plasma proteins:
• Remain in blood; not taken up by cells
• Produced mostly by liver
• 60% albumin; 36% globulins; 4% fibrinogen
Blood Cells
• WBCs are complete cells (heterogenous)
• RBCs have no nuclei or organelles
• Platelets are cell fragments
• Survive in bloodstream only few days
– originate in bone marrow and do not divide
– terminally differentiated cells
Figure 17.2 Photomicrograph of a human blood smear stained with Wright's stain.
Platelets
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Inc.
Neutrophils
Erythrocytes
Lymphocyte
Monocyte
Erythrocytes (RBCs)
• Biconcave discs, anucleate
• Filled with hemoglobin (Hb) (97%) for gas
transport
• Contain spectrin for structural support and
flexibility
• Major factor contributing to blood viscosity
Figure 17.3 Structure of erythrocytes (red blood cells).
2.5 µm
Side view (cut)
7.5 µm
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Top view
Erythrocyte Function
• Dedicated to respiratory gas transport via the
protein hemoglobin
• Hemoglobin binds reversibly with oxygen
– binds irreversibly to carbon monoxide
– less tightly binds CO2, most CO2 in plasma as
bicarbonate (HCO3-)
Figure 17.4 Structure of hemoglobin.
 Globin chains
Heme
group
 Globin chains
Hemoglobin consists of globin (two alpha and two beta
polypeptide chains) and four heme groups.
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Iron-containing heme pigment.
Binding of Oxygen Contributes to Color
of Blood
• O2 loading in lungs
– Produces oxyhemoglobin (ruby red)
• O2 unloading in tissues
– Produces deoxyhemoglobin or reduced
hemoglobin (dark red)
Oxygen Binding Affinity
• Lower binding affinity
– Higher levels of carbon dioxide
– Lower pH (acidic)
– Higher temperature
Working muscle = hot, acidic, high CO2, needs
oxygen.
(Lungs)
(Tissues)
Formation of RBCs
• Hematopoiesis
• Blood cell formation in red bone marrow
– In adult, found in axial skeleton, girdles, humerus
and femur
– 15 days to maturation, fully mature within 2 days
of entering bloodstream
Figure 17.5 Erythropoiesis: formation of red blood cells.
Stem cell
Committed cell
Developmental pathway
Phase 1
Ribosome synthesis
Hematopoietic stem
cell (hemocytoblast)
Proerythroblast
Basophilic
erythroblast
Phase 2
Hemoglobin accumulation
Polychromatic
erythroblast
Phase 3
Ejection of nucleus
Orthochromatic
erythroblast
Reticulocyte Erythrocyte
Three stages:
1) Stem cell – Hematopoietic stem cell (hemocytoblast)
1) Committed cell – Proerythroblast
1) Developmental pathway – Basophilic erythroblasts
develops into a mature erythrocyte
Hematopoiesis
• Committed Stage
– Expression of protein receptors that respond to
hormones and growth factors for maturation
– Cell cannot revert back to a stem cell at this point
• Requires Vitamin B12, folic acid, iron, and
nutrients
Regulation of Erythropoiesis
• Too few erythrocytes leads to tissue hypoxia
(oxygen deprivation)
• Too many make the blood too viscous, poor
circulation
• Hormonal regulation
Hormonal Control of Erythropoiesis
• Erythropoietin (EPO) – a glycoprotein
hormone
• Stimulates Erythrocyte production from
committed cells (proerythroblasts)
• Kidney are major players in EPO production
– triggered by low O2 levels (hypoxia)
Figure 17.6 Erythropoietin mechanism for regulating erythropoiesis.
Slide 1
Homeostasis: Normal blood oxygen levels
1 Stimulus:
Hypoxia
(inadequate O2
delivery) due to
• Decreased
RBC count
• Decreased amount
of hemoglobin
• Decreased
availability of O2
5 O2-carrying
ability of blood
rises.
4 Enhanced
erythropoiesis
increases RBC count.
3 Erythropoietin
stimulates red
bone marrow.
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2 Kidney (and liver to
a smaller extent)
releases
erythropoietin.
Hormonal Regulation
• Triggers for hypoxia
– Loss of blood (hemorrhage or destruction)
– Iron deficiencies leading to insufficient Hb in RBCs
– Poor oxygen intake
• Conversely, too many RBCs will inhibit
erythropoietin production
– Excessive oxygen
Iron Requirements
• Iron essential for hemoglobin synthesis
– Iron from diet
• Fe2+, Fe3+ are toxic to the body
• Ferritin and Hemosiderin – protein-iron complex
stored inside cells
• Transferrine – transport protein for iron in blood
Lifespan of RBCs
• Between 100-120 days
• Unable to synthesize new proteins
• Engulfed by macrophage cells of spleen, liver
and bone marrow
– hemoglobin broken down into heme + globin
– heme degraded to bilirubin and secreted
Erythrocyte Disorders
• Anemia
– Blood has abnormally low O2-carrying capacity
– Symtome rather than disease
– Blood O2 levels cannot support normal
metabolism
– Accompanied by fatigue, pallor, shortness of
breath, and chills
Primary Causes of Anemia
• Blood loss (hemorrhagic anemia)
• Low RBC production
– Iron deficiency
– Autoimmune disease
– Lack of EPO (hormonal imbalance)
• High RBC destruction (hemolytic anemia)
– Sickle cell anemia
Figure 17.8 Sickle-cell anemia.
Val His Leu Thr Pro Glu Glu …
1
2
3
4
5
6
7
146
Normal erythrocyte has normal
hemoglobin amino acid sequence
in the beta chain.
Val His Leu Thr Pro Val Glu …
1
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2
3
4
5
6
7
146
Sickled erythrocyte results from a
single amino acid change in the
beta chain of hemoglobin.
Erythrocyte Disorders
• Polycythemia
– Excessive number of erythrocytes
• Polycythemia vera – a bone marrow cancer
– Severely impair blood circulation
• Secondary polycythemia
– when less O2 available or hypersecretion of EPO
Leukocytes (WBCs)
• Make up <1% of total blood volume
– 4,800 – 10,800 WBCs/μl blood
• Function in defense against disease
• Can leave blood stream via the capillaries
(diapedesis)
– Move through tissue spaces
Figure 17.9 Types and relative percentages of leukocytes in normal blood.
Formed
elements
(not drawn
to scale)
Differential
WBC count
(All total 4800–
10,800/ µl)
Platelets
Granulocytes
Neutrophils (50–70%)
Leukocytes
Eosinophils (2–4%)
Basophils (0.5–1%)
Erythrocytes
Agranulocytes
Lymphocytes (25–45%)
Monocytes (3–8%)
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Two Categories
• Granulocytes – Visible cytoplasmic
granules
• Agranulocytes – No visible cytoplasmic
granules
• All of which play a role in the immune and
inflammatory response (Ch. 21)
Figure 17.10a Leukocytes.
Granulocytes
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Neutrophil:
Multilobed nucleus,
pale red and blue
cytoplasmic granules
Figure 17.10b Leukocytes.
Granulocytes
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Eosinophil:
Bilobed nucleus, red
cytoplasmic granules
Figure 17.10c Leukocytes.
Granulocytes
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Basophil:
Bilobed nucleus,
purplish-black
cytoplasmic granules
Figure 17.10d Leukocytes.
Agranulocytes
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Lymphocyte (small):
Large spherical
nucleus, thin rim of
pale blue cytoplasm
Figure 17.10e Leukocytes.
Agranulocytes
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Monocyte:
Kidney-shaped
nucleus, abundant
pale blue cytoplasm
Leukocyte Production
• Leukopoiesis – the production of white blood
cells (leukocytes)
• Stimulated by chemical messengers
– Interleukins (IL-1, IL-2, etc)
– Colony-stimulating factors (CSFs)
• named after cell population they stimulate (G-CSF)
Figure 17.11 Leukocyte formation.
Stem cells
Hematopoietic stem cell
(hemocytoblast)
Lymphoid stem cell
Myeloid stem cell
Committed
cells
Myeloblast
Developmental
Promyelocyte
pathway
Eosinophilic
myelocyte
Myeloblast
Myeloblast
Monoblast
Promyelocyte
Promyelocyte
Promonocyte
Basophilic
myelocyte
Neutrophilic
myelocyte
Eosinophilic
band cells
Basophilic
band cells
Neutrophilic
band cells
(b)
Basophils
Neutrophils
(c)
Monocytes
(d)
B lymphocytes T lymphocytes
(e)
(f)
Some become
Some become
Macrophages (tissues) Plasma cells
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T lymphocyte
precursor
Agranular
leukocytes
Granular
leukocytes
Eosinophils
(a)
B lymphocyte
precursor
Some become
Effector T cells
Granular Leukocytes
• Mature granulocytes are stored in bone
marrow
• production is 3:1 ratio of granulocytes to
erythrocytes
• Much shorter lifespan due to function
Agranular Leukocytes
• Progression of agranulocytes differs
• Monocytes – live several months
• Lymphocytes – live few hours to decades
– T lymphocyte precursors travel to thymus
– B lymphocyte precursors remain in bone marrow
Leukocyte Disorders
• Leukopenia - abnormally low WBC count
– drug induced (anti-inflammatory, anti cancer
drugs)
• Leukemias - Cancerous overproduction of
abnormal WBCs
– Named according to abnormal WBC clone
involved
Platelets
• Cytoplasmic fragments of megakaryocytes
• Contain granules that typically stain darker
than outer region of the fragments
– contain serotonin, Ca2+, enzymes, ADP, and
platelet-derived growth factor (PDGF) for clotting
• Development regulated by thrombopoietin
– produced in liver and kidneys
Figure 17.12 Formation of platelets.
Stem cell
Hematopoietic stem
cell (hemocytoblast)
Developmental pathway
Megakaryoblast
(stage I megakaryocyte)
Megakaryocyte
(stage II/III)
Megakaryocyte
(stage IV)
Platelets
Stage 1: Repeated mitoses but no cytokinesis
Platelets formed by rupture as it presses against the
capillaries in the red marrow
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Table 17.2 Summary of Formed Elements of the Blood (1 of 2)
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Table 17.2 Summary of Formed Elements of the Blood (2 of 2)
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Platelet Function
• Form temporary platelet plug that helps seal
breaks in blood vessels (clotting)
• Process called hemostasis
– fast, localized and controlled
• Circulating platelets kept inactive and mobile by
nitric oxide (NO) and prostacyclin from
endothelial cells lining blood vessels
Hemostasis
• Fast series of reactions for stoppage of
bleeding
• Requires clotting factors, and substances
released by platelets and injured tissues
• Three steps
– Vascular spasm
– Platelet plug formation
– Coagulation (blood clotting)
Figure 17.13 Events of hemostasis.
Step 1 Vascular spasm
• Smooth muscle contracts,
causing vasoconstriction.
Collagen
fibers
Step 2 Platelet plug
formation
• Injury to lining of vessel
exposes collagen fibers;
platelets adhere.
Platelets
• Platelets release chemicals
that make nearby platelets
sticky; platelet plug forms.
Fibrin
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Inc.
Step 3 Coagulation
• Fibrin forms a mesh that traps
red blood cells and platelets,
forming the clot.
Slide 1
Mechanism of Vascular Spasm
• Vasoconstriction of damaged blood vessel
– helps in preventing blood loss
• Triggers
– Direct injury to vascular smooth muscle
– Chemicals released by endothelial cells and
platelets
– Pain reflexes (pain receptors)
Platelet Plug Formation
• Positive feedback cycle
• Damaged endothelium exposes collagen fibers
– Normally release NO and prostacyclin (PGI2)
• Platelets stick to collagen fibers via von
Willebrand factor
– plasma protein
Collagen-Platelet Bridge
• Stabilized by von Willebrand factor
• Causes platelets to swell, become spiked and
sticky, and release chemical messengers
– ADP causes more platelets to stick and release
their contents
– Serotonin and thromboxane A2 enhance vascular
spasm and platelet aggregation
Coagulation
• Reinforces platelet plug with fibrin threads
– acts as a molecular glue
• Blood transformed from liquid to gel
• Series of reactions using clotting factors
(procoagulants)
– # I – XIII; many plasma proteins (Table 17.3)
Figure 17.15 Scanning electron micrograph of erythrocytes trapped in a fibrin mesh.
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Three Clotting Phases
1. Extrinsic and Intrinsic pathways to Prothrombin
Activation
• Intrinsic – factors required are within blood
• Extrinsic – factors required tissue factors outside
blood, tissue factor (TF)
• Platelet factor 3 (PF3) essential
– phosphatidylserine on platelet membrane
Ultimate Goal Phase 1
• Form prothrombin activator
– Complex of Factor X, Ca2+, PF3 and Factor V
• Prothrombin activator essential for phase 2
Figure 17.14 The intrinsic and extrinsic pathways of blood clotting (coagulation). (1 of 2)
Phase 1
Intrinsic pathway
Vessel endothelium
ruptures, exposing
underlying tissues
(e.g., collagen)
Extrinsic pathway
Tissue cell trauma
exposes blood to
Platelets cling and their
surfaces provide sites for
mobilization of factors
Tissue factor (TF)
XII
Ca2+
XIIa
VII
XI
XIa
VIIa
Ca2+
IX
IXa
PF3
released by
aggregated
platelets
VIII
VIIIa
TF/VIIa complex
IXa/VIIIa complex
X
Xa
Ca2+
PF3
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Va
Prothrombin
activator
V
Phase 2: Common Pathway
• Activation of thrombin via prothrombin
activator
• Prothrombin is cleaved to create and activate
thrombin
Phase 3: Common Pathway for Fibrin
Mesh
• Polymerization of Fibrin to create cross-linked
mesh
• Activated by the cleavage of Fibrinogen by
Thrombin
– thrombin stays bound to fibrin
• Requires Ca2+ and Factor XIII
Figure 17.14 The intrinsic and extrinsic pathways of blood clotting (coagulation). (2 of 2)
Phase 2
Prothrombin (II)
Thrombin (IIa)
Phase 3
Fibrinogen (I)
(soluble)
Ca2+
Fibrin
(insoluble
polymer)
XIII
XIIIa
Cross-linked
fibrin mesh
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Blood clot, now what?
• Clot retraction and fibrinolysis
• Clot retraction stabilizes clot
– Actin and myosin in platelets contract within 30–
60 minutes
– Contraction pulls on fibrin strands, squeezing
serum from clot
– Draws ruptured blood vessel edges together
Vessel Repair
• Concurrent with clot retraction
• Platelet-derived growth factor (PDGF)
– stimulates division of smooth muscle cells and
fibroblasts to rebuild blood vessel wall
• Vascular endothelial growth factor (VEGF)
– stimulates endothelial cells to multiply and restore
endothelial lining
Fibrinolysis
• Critical to remove clots for proper blood flow
• During clot formation, inactive plasminogen is
inserted into clot
• Plasminogen converted to plasmin by tissue
plasminogen activator (tPA), factor XII and
thrombin
• Plasmin is a fibrin-digesting enzyme
Regulating Clot formation
• Two mechanisms limit clot size
– Swift removal and dilution of clotting factors
– Inhibition of activated clotting factors
• Antithrombin III inactivates unbound
thrombin,
• Protein C inhibits clotting factors
• Heparin activates antithrombin III
Clotting is prevented in sites of no
damage
• Platelet adhesion is prevented by
– Smooth endothelium of blood vessels prevents
platelets from clinging
– nitric oxide and prostacyclin secreted by
endothelial cells
• Vitamin E quinone acts as potent
anticoagulant
Disorders of Hemostasis
• Thromboembolic disorders – undesirable clot
formation
– thrombus – clot in an unbroken vessel
– emobolus – thrombus floating in bloodstream
• Apirin, warfarin (coumadin) and heparin help
counteract
Disorders of Hemostasis
• Bleeding disorders - abnormalities that
prevent normal clot formation
– Thrombocytopenia - deficient number of
circulating platelets
– Impaired Liver Function – synthesis of most
clotting factors,
– Hemophilia – Deficiencies in coagulating factors
Human Blood Groups
• RBC membranes bear 30 types of glycoprotein
antigens
• Anything perceived as foreign; generates an
immune response
– antigens promote agglutinization via antibody
response
• Mismatched transfused blood perceived as
foreign
Table 17.4 ABO Blood Groups
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Rh Factor
• 52 named Rh agglutinogens (Rh factors)
• C, D, and E are most common
• Rh+ indicates presence of D antigen
– Rh was initially identified in Rhesus monkeys,
hence their name.
• No anti-Rh antibodies in Rh- person
– presence of Rh promotes an immune response
against the foreign factor
Rh Matching and Pregnancy
• Erythroblastosis fetalis
– Only occurs in Rh– mom with Rh+ fetus
• Rh– mom exposed to Rh+ blood of fetus
during delivery of first baby – baby healthy
– Mother synthesizes anti-Rh antibodies
• Second pregnancy
– Mom's anti-Rh antibodies cross placenta and
destroy RBCs of Rh+ baby
Figure 17.16 Blood typing of ABO blood types.
Serum
Blood being tested
Anti-B
Anti-A
Type AB (contains
agglutinogens A and B;
agglutinates with both
sera)
RBCs
Type A (contains
agglutinogen A;
agglutinates with anti-A)
Type B (contains
agglutinogen B;
agglutinates with anti-B)
Type O (contains no
agglutinogens; does not
agglutinate with either
serum)
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More bloodtyping
• Other blood groups (MNS, Duffy, Kell, and
Lewis) usually weak agglutinogens
• Bombay (hh) blood group very rare
– cannot receive blood from any ABO blood group
Lab Exercise
• First a quiz on Endrocrine system
• Lab exercise 29
– We will not be using real blood! Sorry!