Bio 322-Human Anatomy

Today’s topics •Blood

Circulatory system

• Blood – liquid connective tissue• Blood vessels – carry blood from heart, to lungs, to every part of our body and back again• Heart – contraction generates the force to push blood through the vessels

Note- “cardiovascular system” refers only to heart and blood vessels

Why is the circulatory system important???

1. Transport of a variety of chemical products, cells, and energy (heat)

Carries O2 and CO2 back and forth from lungs to tissuesCarries nutrients from GI tract to tissues and metabolic wastes to the kidney for excretionCarries hormones from glands to effector organs and tissuesCarries immune cells throughout the body to sites of infectionTransports heat to skin surface for release when needed (thermoregulation)

2. Protection – Inflammatory agents and cells in blood help coordinate wound healing and contain

infections Immune cells (leukocytes) work together to clear infections by bacteria, viruses, parasites

• Phagocytosis, antibody production, secretion of cytotoxic chemicals Clotting factors and platelets coordinate formation of blood clots, limit blood loss

3. Regulation –

Fluids can be released into or absorbed from tissues to help regulate fluid distribution throughout body

Blood contains buffers that help stabilize pH of body tissues Dilation and constriction of blood vessels are important for thermoregulation

Blood Composition

-2 main components : Plasma (55%) and Formed elements (45%)-“Average” person has about 5L of blood (8-10% of body weight)

Plasma : The ground substance of blood (remember blood is connective tissue!)

Mostly water (<90%)Remaining 10% is:• Nutrients :glucose, amino acids, lipids, etc…• Electrolytes :Na, Ca, K, Cl, etc…• Nitrogenous waste (byproducts from metabolism)• Gases (O2, CO2, N2 )• Enzymes• Hormones (many)• Plasma proteins (most produced by liver)

• Albumin – helps pull water into circ. system, acts as a carrier for some hormones, drugs, lipids

• Globulins-generic term for many proteins (including antibodies)

• Fibrinogen – converted to fibrin, critical for blood clotting

Often isolated from donated plasma

Formed elements of blood

A. Erythrocytes (red blood cells)• Transport O2 and CO2

• ~95% of formed elementsB. Platelets (small cell fragments)

• Critical for clotting, wound healingC. Leukocytes (white blood cells)

1. Neutrophils2. Eosinophils3. Basophils4. Lymphocytes5. Monocytes

- The 7 visible structures in blood

Complete Blood Count (CBC)

•Collection of clinical tests designed to assess number and condition of formed elements in blood

•Gives information on # of RBCs, platelets, WBCs

•Hematocrit measures packed cell volume (estimates # of RBCs)

•Differential WBC count determines the # of various types of WBCs

Changes in the # of WBCs often indicate disease (infection, inflammation, cancers, etc…)

•May also look at morphology (shape) of cellsOdd shaped cells indicate disease (sickle cell

anemia)

Blood Viscosity and Osmolarity

Viscosity basically refers to the “thickness” or “stickiness” of blood• Thick fluids have greater viscosity, thin fluids have less

Consider viscosity of honey versus water…

• Affects flow through small vessels (venules, capillaries)

• Variations in # of cells (RBCs, WBCs), body temperature, and protein content affect viscosity

Polycythemia (too many RBCs), some leukemias (WBCs)Hypothermia – contributes to limited blood flow to extremities

• High OR low viscosity has negative consequences• Low viscosity can trigger over-perfusion, damage to capillaries, venules• High viscosity can limit perfusion, damage vessels • Both cause excess strain on heart

Water distribution in body

Water is distributed between three “compartments”

• Intracellular, extracellular (interstitial), and PLASMA

• Osmolarity determines distribution of water in these compartments

Osmolarity refers to the concentration of dissolved molecules in the blood (mainly proteins and electrolytes)• VERY important for regulating the movement

of water between tissue and bloodstream (OSMOSIS!!!)

• High osmolarity leads to removal of water from tissues→hypervolemic hypertension

• Low osmolarity prevents water from leaving tissues → edema (swelling of tissues)

•Electrolyte levels are mainly regulated by kidneysKidney disease, dehydration, diarrhea can alter

levels•Liver produces most plasma proteins

Liver disease can lead to reduced osmolarity of blood → accumulation of fluids in tissues (EDEMA)

•Severe dietary protein deficiency → KWASHIORKOR

Hemopoiesis - The process of blood formation - Sometimes called hematopoiesis

oFormed elements of blood are constantly being produced and recycled• Cells and platelets have a relatively short lifespan (about 120 day for RBCs), also lose

some through bleeding• Very different than most tissues of the body

oBody produces a STAGGERING number of new cells each day• 400 BILLION platelets• 200 billion RBCs• 10 billion WBCs

oNew formed elements don’t come from pre-existing RBCs, WBCs, or platelets • Mature, circulating cells don’t undergo mitosis• Formed elements are produced in HEMOPOIETIC TISSUES where stem cells reside

Hemopoietic Tissues

•During development, formed elements are produced in a variety of tissues

Bone marrow, liver, spleen, thymus•After birth, most formed elements are produced by red marrow

Skull, ribs, pelvis, head of femur, sternumAll 7 types of formed elements are produced hereRed marrow is considered MYELOID TISSUEBlood production here is known as MYELOID HEMOPOIESIS

•However, some lymphocytes are produced or travel to LYMPHOID TISSUES (thymus, spleen, lymph nodes, tonsils) where final maturation occurs

Known as LYMPHOID HEMOPOIESIS T-lymphocytes (T-cells)

•Myeloid and lymphoid tissues both contain very important stem cells known as PLURIPOTENT STEM CELLS

Pluripotent means they can differentiate or mature into several different cell types

Pluripotent stem cells give rise to ALL formed elements

Erythrocyte lineage

Leukocyte lineage

All formed elements can be traced back to a PLURIPOTENT STEM CELL

Platelets are fragments of a larger cell called a MEGAKARYOCYTE (which also can be traced back to a pluripotent stem cell)

Erythrocytes (red blood cells)

•Round, disc shaped with an indentation in the center

•2 main jobs

1. Carry O2 from lungs to tissues *****2. Carry small amount of CO2 from tissues to lungs

(most CO2 is dissolved in plasma)

•One of the only cells in the body WITHOUT a nucleus

•Basically are disc shaped bags of HEMOGLOBIN No nucleus, DNA, organelles (lost during development) Can’t carry out protein synthesis or cell division Without mitochondria they make energy via ANAEROBIC

FERMENTATION

•Interior of cell is supported by small amount of ACTIN and SPECTRIN (allows RBCs to squeeze through small capillaries and venules)

•RBCs do contain some enzymes that function to buffer pH

•1 “protein” made of 4 polypeptides2 alpha chains, 2 beta chains

•Each chain contains an iron (Fe2+) group called a HEME group•O2 binds to the heme group of hemoglobin

Each Hb molecule can transport 4 molecules of O2

Hemoglobin (Hb)

O2 binds to HEME groups Binding of O2 to heme group is COOPERATIVE AND COMPETITIVE

Cooperative binding – When O2 binds to one heme this makes it easier for O2 to bind to the other 3 heme groups

Competitive binding – Other molecules can also bind to heme group (i.e, they compete)• Carbon monoxide, cyanide prevent O2 from binding (poisonous)

Hemoglobin, cont….

Alternative forms of Hb

•Most adult Hb is known as HbA, contains 2 alpha chains and 2 beta chains•A small amount (~3%) is known as HbA2, containing 2 alpha chains and 2 delta chains – not a big deal physiologically

•Fetuses contain a different type of Hb known as fetal hemoglobin (HbF)Disappears shortly after birth HbF has a greater affinity for O2 than HbAAllows fetal blood to “steal” O2 from mother’s bloodstream and deliver it to the fetus

Erythropoiesis

•Like all formed elements, RBCs develop from pluripotent stem cells in bone marrow

•The hormone ERYTHROPOIETIN (EPO) stimulates maturation of RBCsProduced by kidney cells in response to blood loss or low O2 levels in the bloodstream

(HYPOXEMIA)

An old-fashioned performance enhancing drug for cyclists, runners, swimmers

Stimulated by EPO to become

erythroblasts

Rapidly multiply and synthesize

LOTS of Hb, then nucleus disappears

Reticulocyte leaves the bone marrow and enters blood

stream to undergo final maturation

EPO and RBC production….

•Typical negative feedback loop

•Body senses abnormally low O2 levels and takes steps to increase # of RBCs allowing more O2 to be carried in bloodstream

Body assumes that low RBC # is the cause of the hypoxemia (not always true)

Smokers with emphysema have chronic hypoxemia – body reacts by constantly making more RBCs (POLYCYTHEMIA)

Living at high elevations (less oxygen in air) can also trigger RBC production

Erythrocyte recycling

•Typical lifespan of RBC is 120 days•Cell membrane gets more fragile with age•Spleen is key organ in RBC recycling

Blood is forced through VERY small passageways in spleen

Old, fragile RBCs get trapped and are broken down

•Bilirubin is a by-product of hemoglobin breakdownBilirubin is removed from bloodstream by liver –

ends up in digestive system (gives feces its color!)

Liver disorders can cause JAUNDICE• Bilirubin accumulates in bloodstream

causes skin to look yellowish

RBC and Hemoglobin disorders

Anemia – disease of low RBC # or low Hb levels hypoxia3 types:

1. Caused by deficient erythropoiesis or Hb synthesis by erythroblasts2. Hemorrhagic anemia – caused by bleeding 3. Hemolytic anemia – caused by excessive RBC destruction

Polycythemia – overproduction of RBCs

Sickle – cell disease (anemia)

•Individuals contain a mutated Hb gene (HbS)•HbS tends to polymerize into long rods – can’t carry O2 efficiently (especially at low oxygen concentrations)•Sickle cells often clump together and clog blood vessels•Disease requires both Hb genes to be mutated (HOMOZYGOUS RECESSIVE)•A “carrier” = person with one good and one mutated Hb gene

½ Hb is mutated, ½ is OK•Actually gives person resistance to malaria!!!•Mutation is in ONE nucleotide (GAG → GTG)….leads to substitution of glutamate → valine

ABO Blood Typing

•All cells in our bodies have a variety of cell-surface proteins that identifies them as belonging to us (SURFACE ANTIGENS)•RBC antigens don’t vary as much•A, B, and O antigens differ in monosaccharide attached to galactose

“O” antigen does not have the extra monosaccharide attached to galactose

•If we receive the wrong type blood, antibodies in our plasma will bind to the foreign cells and cause them to clump together (AGGLUTINATION)

Rh Blood group

•RBCs also may contain an antigen known as the Rh antigenEither you have it or you don’t → i.e, Type A positive (A+) or A negative (A-), etc…

•Unlike ABO antigens, our plasma normally doesn’t have any antibodies against Rh antigenUNLESS we are exposed to Rh antigen…….

1. Rh+ blood into an Rh- person2. Rh- mother carrying an Rh+ fetus (small amt of blood is exchanged during

childbirth) Production of Rh antibodies is slow, so first exposure (transfusion, or pregnancy) is OK However, second pregnancy can be a problem Mother’s anti-Rh antibodies may pass into fetal circulation causing fetal blood to

agglutinate Today most pregnant Rh- women receive an injection of anti-Rh antibodies that will

bind up any Rh+ cells she is exposed to……this prevents her own immune system from producing Rh-antibodies

Leukocytes (WBCs)

•Least abundant of the formed elements in BLOODHowever, #’s are actually higher since many leukocytes exit bloodstream and enter tissues

•Unlike RBCs, WBCs possess nuclei, other organellesMore complex functions than RBCs

•5 types of WBCsDiffer in appearance , number, AND in functionFall into two main categories:

1. Granulocytes – contain many lysosomes and organelles (i.e., granules) that stain darkly on a microscope slide

a) Neutrophilsb) Eosinophilsc) Basophils

2. Agranulocytes – no visible granulesa) Lymphocytesb) Monocytes

•Like all formed elements, WBCs originate from pluripotent stem cellsOriginate in myeloid tissues, but some (T-lymphocytes) travel to and mature in lymphoid

tissues (thymus, lymph nodes, tonsils, etc…)

•Maturation of specific WBCs is triggered by a variety of hormones, biological agents, and environmental agents

Allows proliferation of specific WBCs in response to needAllergens, bacteria/viruses, inflammatory cytokines trigger maturation of specific WBCs

WBC development

Granulocytes

1. Neutrophils – • Most abundant of WBCs (60-70% of all WBCs)• Nucleus appears to have several lobes (3-5 per cell)• Function to kill bacteria/viruses

Phagocytosis (slow) Can secrete chemicals that kill pathogens in vicinity

of neutrophil (stored in granules within cell)

•When bacteria/viruses are present, neutrophil generates lots of oxygen free radicals which are then used to create H2O2 (hydrogen peroxide), and sodium hypochlorite (bleach)!!!•These chemicals are stored in granules and then released (DEGRANULATION)

•These chemicals kill everything around the neutrophil (including the neutrophil itself)

Granulocytes

2. Eosinophil – • Far less abundant (2-4% of WBCs)• Many more reside in membranes of respiratory, digestive,

and urinary tract• Nucleus appears to have 2 lobes• Function to phagocytose antigen-antibody complexes,

allergens, inflammatory cytokines (help limit inflammation)• Proliferation of eosinophils is triggered by allergic reactions,

parasitic infections

•Like neutrophils, eosinophils can generate oxygen free radicals that are stored in granules and released to kill pathogens

Granulocytes

3. Basophils – • VERY rare type of WBC (less than 1% of WBCs)• Large number of dark staining granules prevents nucleus from

being seen• Play an important role in wound healing and coordinating

immune response to infections and inflammationSecrete HISTAMINE (a vasodilator) that allows more WBCs

to get to sites of infection, injurySecrete HEPARIN (an anticoagulant) that temporarily

prevents blood clot formation (also allowing more WBCs to get where they need to be!)

Agranulocytes

1. Lymphocytes – • Very common, (25-30% of WBCs)• Usually have a large, rounded nucleus that takes

up most of the cell – only a small amount of cytoplasm is visible

• Three different classes (T-cells, B-cells, NK-cells), but all look pretty similar – usually differ slightly in size

• Play various roles including coordinating immune responses and producing antibodies that “flag” invaders and damaged cells for destruction by other immune cells

Agranulocytes

2. Monocytes – • Largest of the WBCs, make up 3-8% of all WBCs• Nucleus usually takes on a U-shape or kidney bean

shaped appearance Less obvious in very large monocytes, but certainly

can distinguish from a lymphocyte since monocytes are much larger overall

•Numbers of monocytes increase rapidly in response to infection•Monocytes will further differentiate into MACROPHAGES and hang out in tissues where they phagocytose pathogens and damaged cells

Leukopoiesis

•All WBCs develop from pluripotent stem cells and begin development in red marrow

•Stem cells mature into WBC colony forming cells (CFUs) which have receptors for hormones and growth factors that trigger their further development•Some specific growth factors are released by MATURE WBCs in response to allergens, pathogens, etc…•Some immature lymphocytes migrate to LYMPHOID tissues (thymus, spleen) to undergo final maturation•Other WBCs stay in red marrow until needed

Life cycle of WBCs

•Once released into bloodstream, most WBCs rapidly enter tissues to carry out their assigned jobs (within hours)•Most WBCs only live for a few days (neutrophils, eosinophils, basophils), but some can live for years (macrophages) or decades (some lymphocytes)

Leukocyte disorders

1. Leukopenia – abnormally low WBC count• Can be caused by heavy metal poisoning (mercury, lead), radiation exposure, some

viral infections• Very common side effect of glucocorticoid therapies, anti-cancer therapy, and

immunosuppressive therapy for organ transplant recipients

2. Leukemia – very HIGH numbers of WBCs• Can occur in either myeloid or lymphoid tissues and either be acute (rapidly

developing) or chronic (more slowly developing)• A very serious type of cancer since cancerous leukocytes will overpopulate the

marrow and prevent normal leukocytes, RBCs, and platelets from maturing• Many patients die from opportunistic infections or hemorrhage due to lack of platelet

function

Platelets

•Relatively small proportion of whole blood (~1% of formed elements)•Are actually small fragments of larger cells known as MEGAKARYOCYTES

No nucleus, but do have lysozomes and a number of other organelles and GRANULES

•Carry out a variety of functions1. Secrete vasoconstrictors – cause blood vessels to constrict 2. Stick together to form a platelet plug3. Secrete factors that promote clotting (early) as well as clot dissolving substances (late)4. Secrete chemicals and growth factors that attract neutrophils and monocytes, as well

as cause proliferation of fibroblasts (wound healing)5. Can also act as phagocytes (not their main function)

Platelet formation….

•Pluripotent stem cells mature into MEGAKARYOCYTES•Huge cell that is actually visible to the naked eye!•Maturation of megakaryocytes can be triggered by several factors:

Thrombopoietin , inflammatory cytokines, EPO•Following maturation, the platelets bud off from the large megakaryocyte

One megakaryocyte can produce 1000’s of platelets

Platelets have a very short lifespan (~10 days)…..so platelets need to be CONSTANTLY produced