The Circulatory System: Blood Chapter 18
• Functions and properties of blood
• Plasma
• Blood cell production
• Erythrocytes
• Leukocytes
• Blood Types
• Hemostasis
Functions and Properties of Blood
• Functions in respiration, nutrition, waste elimination,
thermoregulation, immune defense, water balance,
electrolyte and pH balance
• Adults have 4-6 L of blood composed of:
– plasma, a clear extracellular fluid
– formed elements = blood cells and platelets
• Properties of blood:
– viscosity = resistance to flow
– osmolarity = concentration of dissolved particles
Hematocrit
• Centrifuge separates formed elements from plasma
• Hematocrit is the percent of total volume that is cells
– Normal hematocrit values Female: 37-48% Male: 45-53%
Plasma and Plasma Proteins
• Plasma is a mixture of proteins, enzymes, nutrients, wastes, hormones, and gases – if allowed to clot, the liquid that remains is called serum
• 3 major categories of plasma proteins: – albumins are the most abundant plasma protein
• contributes to viscosity and osmolarity and influences blood pressure, flow and fluid balance
– fibrinogen is precursor of fibrin threads that help form blood clots
– globulins (antibodies) provide immune system defenses • alpha, beta and gamma globulins
• Albumens and fibrinogen plasma proteins are formed by the liver
• Globulins are antibodies produced by white blood cells called plasma cells
Blood to which no
anticoagulant has been
added will clot. Blood cells
get caught in the clot leave
serum behind.
Blood to which an
anticoagulant has been
added will not clot. Blood
cells will settle to the bottom
of the tube leaving plasma at
the top of the tube.
Plasma and Serum
Non-protein Components of Plasma
• Nitrogenous compounds
– amino acids from dietary protein or tissue breakdown
– nitrogenous wastes (urea and ammonia) are toxic end
products of catabolism that are normally removed from
the blood by the kidneys
• Nutrients (glucose, vitamins, fats, minerals)
• Dissolved gases like O2 and CO2 are transported in
plasma
• Many electrolytes (Na+, Cl+, K+, HCO3-, Ca+2, and
others)
– sodium makes up 90% of plasma cations accounting for
more of the blood’s osmolarity than any other solute
Formed Elements of Blood
• Formed Elements = Erythrocytes, Platelets, Leukocytes (neutrophil, eosinophil, basophil, monocyte, lymphocyte)
• Non-formed Elements = Plasma
erythrocyte
neutrophil eosinophil
basophil
lymphocyte
monocyte
platelets
Blood Cell Production
(Hematopoiesis/Hemopoiesis) • The following hematopoietic tissues produce blood cells:
– yolk sac of vertebrate embryos produce stem cells that colonize fetal bone marrow, liver, spleen lymph nodes and thymus
– liver stops producing blood cells at birth and the thymus stops at about age 10, but the other tissues continue to produce WBCs
– bone marrow contains stem cells that produce RBCs, WBCs and platelets
• Stem cells multiply continually and are pluripotent (capable of differentiating into multiple cell lines)
• Red bone marrow is active; yellow bone marrow is inactive and fatty
• Stem cells are stimulated by hormones including erythropoietin (EPO) from the kidney and the liver
amniotic sac
placenta
yolk sac
Stem Cells of
Hematopoiesis
Erythrocytes (RBCs) • Biconcave Disc-shaped cells
– 7.5 M diameter, 2.0 m thick at rim
– Flexible center allows folding so cells can pass through narrow capillaries
– More surface area than a simple disk facilitates diffusion rate of gasses in and out of the cell
• Major function of RBCs is gas transport – Loses nucleus and most organelles during
maturation resulting in increased surface area/volume ratio
– 33% of cytoplasm is hemoglobin (Hb)
– O2 delivery to tissues and CO2 transport back to lungs
– contains the enzyme, carbonic anhydrase (CA) that produces carbonic acid from CO2 and water which plays an important role in gas transport and pH balance
• RBC count normal values – men 4.6-6.2 million RBCs/L
– women 4.2-5.4 million RBCs/L
Erythrocytes on the tip of a Needle
Flexible center of
erythrocytes allows
folding so cells can
pass through narrow
capillaries.
Capillaries are formed
by cells called
Endothelial Cells
Erythrocyte Production
• Erythropoiesis from stem cells in bone marrow produces 2.5 million RBCs/second.
• In response to erythropoietin (EPO), some stem cells develop into proerythroblasts which multiply and develop into erythroblasts.
• Erythroblasts multiply, synthesize hemoglobin and develop into normoblasts.
• Normoblasts synthesize more hemoglobin, discard their nucleus and develop into reticulocytes.
• Reticulocytes have a reticulated pattern of nuclear debris and a well-developed network of endoplasmic reticulum that was used for hemoglobin synthesis.
– a few reticulocytes enter the bloodstream before they fully mature into erythrocytes and can be 0.5% to 1.5% of the circulating RBCs
• Development from a stem cell to a RBC takes 3-5 days and involves:
– reduction in cell size, increase in cell number, synthesis of hemoglobin, loss of nucleus
– blood loss speeds up the process increasing reticulocyte count in circulating blood which is called a “shift to the left”
Erythrocyte Homeostasis
• Negative feedback control – kidney and liver hypoxia
– EPO production
– bone marrow stimulation
– RBC count in 3-4 days
• Causes of Hypoxia – low levels of atmospheric O2
• high elevation or altitude
– increase in exercise • Endurance-trained athletes
have RBC counts as high as 6.5 million/ l (normal range is 4-6 million)
– inhaling carbon monoxide
– hemorrhage
Nutritional Needs for Erythropoiesis • Iron is key nutrient for erythropoiesis
– Iron is lost daily through urine, feces, and bleeding
– on average, men lose 0.9 mg/day and women lose 1.7 mg/day
– low absorption rate requires consumption of 5-20 mg/day
– dietary iron comes in 2 forms: ferric (Fe+3) and ferrous (Fe+2)
• stomach acid converts Fe+3 to absorbable Fe+2
• gastroferritin from stomach binds Fe+2 and transports it to the intestines
• absorbed into blood & binds to transferrin to travel to bone marrow and liver
• liver binds surplus iron to apoferritin to create ferritin for storage
• erythrocytes use iron to make hemoglobin
• muscle uses iron to make myoglobin which stores O2
• all cells use iron to make cytochromes in mitochondria
• Other nutritional requirements include B12, Folic Acid, Vitamin C and Copper (Cu is used as a cofactor for enzymes)
Iron Absorption, Transport & Storage
Hemoglobin
• Normal, adult hemoglobin (HbA) consists of 4 protein chains called globins (2 alpha chains and 2 beta chains).
• Each globin has a heme group which binds oxygen to ferrous ion (Fe+2).
• Each Hb molecule can carry four O2 molecules. • Fetal hemoglobin (HbF) has gamma instead of beta chains
– HbF has a higher affinity for O2 than HbA enabling the fetus to extract O2 from the mother’s bloodstream
Erythrocytes and Hemoglobin
• RBC count and hemoglobin concentration determine the amount of oxygen the blood can carry.
• Hemoglobin concentration of whole blood:
– men 13-18g/dL
– women 12-16g/dL (dL = deciliter = 100ml)
• Why are values are lower in women?
– androgens that stimulate RBC production are lower in women
– women may have periodic menstrual loss of blood
Erythrocyte Disorders
• Polycythemia is an excess of RBCs
– primary polycythemia is due to cancer of
erythropoietic cell line in the red bone marrow
• RBC count as high as 11 million/L (normal range is 4-6
million /L)
• hematocrit of 80%
– secondary polycythemia can result from
dehydration, high altitude, or physical conditioning
• RBC count of 8 million/L
• Dangers of polycythemia
– increased blood viscosity can lead to embolism,
stroke or heart failure
Anemia = Deficiency of RBCs or Hb
• Types of anemia
– iron-deficiency anemia
– hemorrhagic anemias from loss of blood
– hemolytic anemias from RBC destruction
• Effects of anemia
– tissue hypoxia and resulting necrosis
– low blood osmolarity and resulting tissue edema
– low blood viscosity and resulting increased heart
rate
Sickle-Cell
Disease
Sickle-Cell Disease • Sickle-Cell is a hereditary defect in Hemoglobin (HbS)
– Recessive allele modifies hemoglobin structure
• Caused by a single amino acid substitution (valine is inserted in the
protein where a glutamic acid should be)
• homozygous for HbS have sickle-cell disease
• heterozygous for HbS have sickle-cell trait but rarely have symptoms
• Most common in African Americans and people from Mediterranean
region
– Implications of sickle-cell disease:
• HbS turns to gel (polymerizes) at low oxygen concentrations causing
cell elongation and inflexible sickle shape that is prone to lysis
• Sickle cells are sticky and agglutinate, blocking vessels, causing
intense pain, kidney and heart failure, paralysis, and stroke
• chronic hypoxia activates hematopoietic tissue producing more
deformed cells
– HbS gene persists despite its harmful effects to the homozygous
individual because it protects from malaria
• HbS indigestible by malaria parasites
The ABO Group
• Your ABO blood type is determined by presence or absence of antigens (agglutinogens) A and/or B on RBCs
blood type A has A antigens
blood type B has B antigens
blood type AB has both A and B antigens
blood type O has neither antigen
• Frequency of blood types varies among populations, but in the USA, O is the most common and AB is the rarest.
Frequency of ABO Blood Groups
Population O A B AB Cherokee, NC, USA 95% 4% 2% 0%
Pawnee, OK, USA 58% 40% 3% 0%
African-American, USA 51% 25% 19% 4%
Caucasian, USA 46% 42% 9% 4%
Eskimo, USA 47% 45% 6% 2%
Nikappu, Japan 31% 38% 22% 9%
Bengali, India 30% 26% 36% 7%
Agglutinins against the ABO Group
Antibodies (agglutinins) against the A and B antigens appear 2-8 months after birth and reach a maximum concentration at 10 about years.
– you do not normally produce antibodies that would react against your own antigens (agglutinogens).
– each antibody can attach to several antigens at the same time causing agglutination (clumping) of red blood cells.
ABO Blood Types • RBC antigens
called agglutinogens A & B
– inherited combinations of
proteins, glycoproteins and
glycolipids on red blood cell
membranes
• Plasma antibodies
called agglutinins anti-A & B
– agglutinins are gamma
globulins in blood plasma
that recognize (stick to)
foreign agglutinogens on
RBCs
– responsible for RBC
agglutination in mismatched
blood transfusions
ABO Blood Types
Agglutination of Erythrocytes
ABO
Blood
Typing
Mismatched Transfusion Reaction
• Agglutinated RBCs block blood vessels and RBCs can rupture
– free Hb can block kidney tubules and cause death
• Universal
donors and recipients
– AB called universal recipient since it lacks both antibody A and B; O called universal donor
– problem is donor’s plasma may have antibodies against recipient’s red blood cells
– solution is giving packed cells with minimum plasma
The Rh Group • Rh or D agglutinogens were discovered in the Rhesus monkey
in 1940, and then a similar system was found in humans.
The Rh Group • Blood type is Rh+ if type D agglutinogens are present on RBCs
• Anti-D agglutinins are not normally present in blood and only
form in Rh- individuals who are exposed to Rh+ blood:
– Rh- person gets a blood transfusion of Rh+ blood
– Rh- woman carrying an Rh+ fetus
• no problems result with either the first transfusion or the
first pregnancy
– Hemolytic Disease of the Newborn (HDN or
erythroblastosis fetalis) occurs if mother has formed
anti-D antibodies and is pregnant with 2nd Rh+ child
– RhoGAMTM can be given to a pregnant woman with a fetal
Rh incompatibility
• RhoGAM binds to fetal agglutinogens that get into in the
mother’s blood so her immune system will not mount an
attack against the fetus during pregnancy
Hemolytic Disease of Newborn
• In the first pregnancy, some fetal Rh+ blood crosses into the mother and she slowly develops anti-D agglutinins
• In second pregnancy, the mother’s antibodies can cross into the fetus and hemolyze the fetal blood causing severe anemia in the baby.
• Hemolyzed RBCs release hemoglobin which is converted to bilirubin.
• High bilirubin is toxic to the mother and child and can cause brain damage.
• Treat with transfusion or UV phototherapy to degrade bilirubin.
There is a dominant allele for the D antigen. The genetic pairs that can
exist in humans are as follows:
Genetic makeup Blood type
+ + Rh positive
+ - Rh positive
- - Rh negative
Parents' Possible allele Possible Rh
Rh types combinations in the children
Both + + + & + + + + positive
Both + + + & + - + + or + - positive
Both + + - & + - + + or + - or - - positive or negative
Both - - - & - - - - negative
One + & One - + + & - - + - positive
One + & One - + - & - - + - or - - positive or negative
Frequency of Rh Blood Groups
Population + - Cree, Quebec 98% 2%
African-American, USA 85% 15%
Caucasian, USA 85% 15%
Eskimo, USA 100% 0%
Bengali, India 95% 5%
Leukocytes (WBCs)
• 4,500-10,000 white blood cells/mcl (cells per microliter)
• Granulocytes contain specific granules – eosinophils - pink-orange granules and bilobed nucleus
(2-4%)
– basophils - abundant, dark violet granules (<1%) • large U or S-shaped nucleus hidden by granules
– neutrophils - multilobed nucleus (60-70%) • Very lightly stained reddish to violet granules in cytoplasm
• Agranulocytes contain no noticeable granules – lymphocytes - round, uniform dark violet nucleus (25-
33%) • variable amounts of bluish cytoplasm (scanty to abundant)
– monocytes – indented nucleus (3-8%) • large cell with abundant cytoplasm
Granulocytes
• Neutrophils ( in bacterial infections)
– phagocytosis of bacteria
– releases antimicrobial chemicals
• Eosinophils ( in parasitic infections or
allergies)
– phagocytosis of antigen-antibody complexes,
allergens and inflammatory chemicals
– release enzymes that destroy parasites such
as worms
• Basophils ( in inflammation or infection)
– secrete histamine (vasodilator)
– secrete heparin (anticoagulant)
Agranulocytes
• Lymphocytes ( in diverse infections and immune responses)
– destroy cancer cells, foreign cells, virally infected cells
– coordinate actions of other immune cells
– secrete antibodies and provide immune memory
– two groups: T-lymphocytes and B-lymphocytes
• Monocytes ( in viral infections and inflammation)
– mature into macrophages that consume (phagocytosis) pathogens and debris
– “present” antigens to activate other immune cells
Abnormalities of Leukocyte Count
• Leukopenia = low WBC count (<5000/L)
– causes: radiation, poisons, infectious disease
• Leukocytosis = high WBC count (>10,000/L)
– causes: infection, allergy and disease
• Leukemia = cancer of hemopoietic tissue
– myeloid (granulocyte) or lymphoid (lymphocyte)
– effects: patient subject to opportunistic infection,
anemia and impaired clotting
Normal and Leukemia Blood Smears
Megakaryocytes and Platelets
• Megakaryocytes are bone marrow cells that
repeatedly replicate their DNA without dividing
– megakaryocytes are gigantic cells (100 m
diameter) with a huge nucleus
– megakaryocytes remain in the bone marrow
• Megakaryocytes release fragments that enter
the bloodstream as platelets
– platelets live for about 10 days
– some platelets are stored in the spleen and can be
released as needed
Megakaryocytes & Platelets
Science volume 317 21 September 2007 p. 1689
Platelets
• Platelets are small fragments of megakaryocytes
– platelets are only 2-4 m diameter
– platelets contain granules used in clot formation
– platelets have pseudopods used for phagocytosis and clot
retraction
• Normal Count: 130,000 to 400,000 platelets/L
• Functions
– secrete clotting factors, growth factors for endothelial
repair, and vasoconstrictors in broken vessels
– form temporary platelet plugs
– attract WBCs to sites of inflammation
– retract and eventually dissolve old blood clots
Hemostasis
1) Vascular Spasm: Vasoconstriction reduces bleeding
2) Platelet Plug Formation: platelets adhere to exposed collagen fibers
3) Blood Clotting: RBCs and more platelets become enmeshed in fibrin
threads
1) Vascular Spasm
• Prompt constriction of a broken blood vessel
• Triggers for a vascular spasm:
– some pain receptors directly innervate smooth
muscle surrounding the blood vessel
• lasts only a few minutes
– injury to smooth muscle
• longer-lasting constriction
– platelets release serotonin which is a chemical
vasoconstrictor
2) Platelet Plug Formation
• Normal endothelium is very smooth and is coated with prostacyclin (an ecosanoid that repels platelets)
• Broken vessel exposes rough surfaces of collagen
• Platelet plug formation: – platelet pseudopods stick to damaged vessel and other
platelets
– pseudopods contract and draw walls of vessel together forming a platelet plug
– platelets degranulate releasing a variety of substances • serotonin is a vasoconstrictor
• thromboxane, an eicosanoid that promotes aggregation and degranulation of platelets and vessel vasoconstriction
• Positive feedback cycle is active until break in vessel is sealed
3) Blood Clotting (Coagulation) • Clotting is the most effective defense against bleeding
– conversion of soluble plasma protein fibrinogen into insoluble fibrin threads that form the framework of a clot
• Clotting Factors are always present in the plasma and in tissues
– activating one factor will activate the next to form a reaction cascade
• Factors released by damaged blood vessel tissues cause the extrinsic cascade pathway to begin.
• Factors found only in the blood itself causes the intrinsic cascade pathway to begin (platelet degranulation).
• Both cascades normally occur together and lead to a fibrin clot.
Colorized scanning
electron micrograph of
a blood clot removed
from the coronary
artery of a patient with
acute myocardial
infarction showing he
fibrin meshwork
(brown) with trapped
red blood cells and a
cholesterol crystal
(yellow). Science Vol
335 February 10, 2012
Coagulation
Pathways
• Extrinsic Pathway
– Factors released by damaged tissues cause the extrinsic cascade pathway to begin which usually lasts about 15 seconds.
• Intrinsic Pathway
– Factors released by platelets start the intrinsic cascade pathway which usually lasts about 3-6 minutes.
• Calcium is required for both pathways.
Completion of Coagulation • Both the intrinsic and extrinsic pathways lead to production of
Factor X.
• Factor X produces key enzymes for activating Thrombin which converts soluble fibrinogen into an insoluble fibrin polymer.
• Thrombin also feeds back on the system to amplify its own production.
Coagulation Disorders
• Unwanted coagulations:
– Thrombosis = abnormal clotting in unbroken vessel
• most likely to occur in leg veins of inactive people
• clots can travel from veins to lungs producing a
pulmonary embolism
• death can occur from hypoxia
– Embolism: abnormal clot traveling in a blood vessel
• Infarction, or tissue death, may occur if clot blocks blood
supply to an organ
– Myocardial Infarction (MI)
– Stroke (brain clot or bleed)
– 650,000 Americans die annually of thromboembolisms
Clot Retraction and Dissolution
• Clot retraction occurs within 30 minutes – pseudopods of platelets pull on fibers of fibrin which
compacts the clot
• Platelet-derived growth factor is secreted by platelets and endothelial cells – the growth factor is a mitotic stimulant for fibroblasts and
smooth muscle that multiply and repair the damaged vessel
• Fibrinolysis or dissolution of a clot – Fibrin is broken down by the enzyme plasmin
– Plasmin is produced by the intrinsic enzyme kallikrein and the extrinsic enzyme TPA (tissue plasminogen activator)
Blood Clot Dissolution
Kallikrein in the plasma and TPA (tissue plasminogen activator) from
damaged tissues quickly convert inactive plasminogen into plasmin
Plasmin breaks down clots and promotes formation of more kallikrein
Positive
Feedback
TPA
Dissolving Clots • Streptokinase
– Enzyme made by the Streptococcus bacteria dissolves clots when administered intravenously.
– Relatively non-specific and digests many proteins.
• Tissue plasminogen activator (TPA)
– Specifically converts inactive plasminogen into the clot-dissolving enzyme plasmin
– Now produced by transgenic bacteria.
• Hementin
– Anticoagulant produced by the giant Amazon leech, Haementeria.
– Used to dissolve clots in cardiac patients.
– Now produced in transgenic bacteria.
Medicinal Leeches Removing Clots
from a postsurgical hematoma
Prevention of Clots
• Platelet Repulsion:
– platelets do not adhere to prostacyclin-coating that normally lines blood vessels
• Thrombin Dilution:
– thrombin is normally diluted by circulating blood
• heart slowing, as during shock, can result in clot formation
• slow venous return in legs due to prolonged sitting can also result in clot formation
• Anticoagulants
– heparin secreted by basophils and mast cells during inflammatory response interferes with formation of clotting factors (prothrombin activator)
• Drugs like coumadin
Hemophilia
• Genetic lack of clotting factors
– hemophilia A is missing factor VIII (83% of cases)
– hemophilia B is missing factor IX (15% of cases)
– hemophilia C is missing factor XI (rare)
• Symptoms:
– physical exertion can cause bleeding and
excruciating pain
• Treatments:
– transfusion of plasma or purified clotting factors
– factor VIII is now produced by transgenic bacteria
Normal Blood Values
Adults have 4-6 L of blood
Female Male
Hematocrit: 37-48% 45-53%
Hemoglobin: 12-16g/dL 13-18g/dL
RBC count: 4.2-5.4 million/L 4.6-6.2 million/L
WBC count: 4,500-10,000/L
neutrophils 60-70%
eosinophils 2-4%
basophils <1%
lymphocytes 25-33%
monocytes 3-8%
platelet count: 130,000 to 400,000/L