PHYSIO

Guyton and Hall Medical Physiology (Chapter 33) REVIEW RBCs,

2 Fluids
● The needs of body tissues are met by 2 fluids:

Blood
a. a Connective Tissue
i. “cells separated by matrix”
b. various cells & cell fragments
c. suspended in liquid matrix: Plasma
i. lacks collagen & elastic fibers
d. dissolved fibrous proteins become visible as fibrous strands during clotting
Interstitial fluid - middle man between blood & the tissues
a. bathes body cells
b. Blood meets the needs of the body tissues - does not directly drop off substances, but rather acts via Diffusion

Functions of Blood

Transportation
a. transports to cells:
i. O2, Nutrients, Hormones
diffuse from:
a. blood → ECF → cells
b. transports away from cells:
i. CO2
ii. other metabolic Wastes
iii. Hormones
Regulation
a. helps maintain homeostasis in all body fluids
b. regulates pH
i. many blood proteins act as buffers - keeps pH from swinging wildly
c. adjusts body temp (delivers heat to skin)
d. influences H2O content of cells
i. blood proteins prevent excessive fluid loss to tissues
Think oncotic pressure - vacuum pressure that proteins provide. Acts as a magnet to keep inside vascular system
Protection
a. prevents blood loss: blood clots
b. prevents infection:
i. WBCs, antibodies protect against pathogens

Blood Components

Formed elements: not cells, more correct to call them formed elements
a. Erythrocytes: 45%
b. Platelets (Thrombocytes) Not a cell, just a fragment
c. Leukocytes
i. Granulocytes
Neutrophils
Eosinophils
Basophils
ii. Agranulocytes
Lymphocytes
Monocytes

Blood Components, cont.
2. Plasma
a. 91.5% H2O & 8.5% solutes
i. most solutes (by weight) are Proteins

Except for Hormones & Gamma globulins, most proteins are produced by the Liver
ii. also contains Electrolytes, Nutrients, Enzymes, Gasses, Wastes

Plasma Proteins
● Albumin (60%)
○ major contributor to Osmotic pressure
■ Provides magnetic pull that pulls H2O towards it
○ transport protein, buffer
■ Protein that drugs bind to, which will ↑ half life of the liphophilic drugs (TH from last quarter)
■ Keeps things centered

● Globulins (36%) (Globulins need salt water dissolved, & albumins don’t - don’t need to know for exam)
○ alpha & beta:
■ transport Proteins made by the Liver
■ transport Lipids & Metal ions
○ gamma:
■ Antibodies from plasma cell
○ fibrinogen (4%) forms fibrin threads of clots, made by liver

Composition of Plasma
● Lays out all the different concentrations of plasma

Important Properties of Blood
● 2 important properties of blood:

Viscosity - resistance to flow
a. whole blood is 4 - 5 times as viscous as H2O
i. Mostly d/t RBCs
b. plasma is 2X as viscous as H2O
i. Mostly d/t protein
c. important in circulation
i. viscosity too high or too low strains the heart
Osmolarity - total molarity of dissolved particles
a. important in maintaining normal fluid volumes
i. Not just Na, but everything that is in there. Important for maintaining normal fluid volumes in all fluid compartments

Blood Osmolarity
● if blood osmolarity is too high:
○ the vessel absorbs too much fluid from tissues
■ this results in:
● ↑ blood pressure
● strain on heart & arteries
● if blood osmolarity is too low:
○ too much fluid flows into tissues
■ this results in:
● Tissue Edema
● ↓ BP

● blood osmolarity is mainly a product of its:
○ All solutes - Na+ ions, Proteins & Erythrocytes
○ blood levels of these solutes are closely maintained to keep a stable osmolarity

Erythrocyte Function
● 2 functions:

pick up O2 in the Lungs:
a. deliver it to tissues
pick up CO2 in the tissues
a. unload it in Lungs
○ Attraction is important for all of these factors to take place. When we talk about these substances, loading and unloading will be referred to.

● major contributor to blood viscosity
○ ♀: 4.2 – 5.4 million cells /mm3 roughly 4-5
○ ♂: 4.7 – 6.1 million cells/µl roughly 5-6
■ Viscosity = hematocrit. Having a higher hematocrit can predispose you to blood clots.

Erythrocyte Structure
● have a perfect “structure/function” relationship
● biconcave discs (↑ surface area)
○ This makes them flexible/easier to flow through the capillaries that are small
● lose all organelles during development
○ No mitochondria
● rely exclusively on Anaerobic Glycolysis
● incapable of protein synthesis & mitosis
○ Not able to repair themselves
● plasma membrane has:
○ Glycoproteins & Glycolipids: determine Blood Type
■ Acts as signaling & identifiers

Erythrocytes, cont.:
● Cytoplasm contains:
○ mostly hemoglobin (Hb) ~ 250 million molecules
● Carbonic anhydrase
○ enzymes that catalyzes:
■ CO2 + H2O → H2CO3
● Converts CO2 & water to Carbonic acid

Hemoglobin (Hb)
● iron containing protein
● carries O2 & CO2
● buffers blood
● consists of 4 protein chains: Globins (2 beta & 2 alpha chains)
○ each bound to a red heme group

“Heme Group”
● the red heme group is an iron containing pigment
○ bound to Globins

● it binds 1 O2 to its
○ ferrous ion (Fe++)

● 1 Hb can transport 4 O2
● also transports 20% of blood CO2

A Few More Important RBC Facts
● RBC count & [Hb] of clinical importance bc they reflect one’s O2 carrying capability
○ Sometimes we just look at H/H, but it is also important to look at all indices on the CBC
● Hematocrit:○ % of whole blood volume composed of RBCs ~ 45%
● RBC count
○ 4-6 million/mm³ in men
○ 4-5 in women
● [Hb]
○ 16g/dL in men (per 100 mL)
○ 14g/dL in women

● Erythrocyte Life Cycle
○ RBCs live about 120 days
○ production & cell death closely controlled by homeostasis:
■ birth & death rate = 2.5 million cells/sec!

Hemopoiesis: Process of creating formed elements
● all formed elements are produced in:
○ Red bone marrow:
■ Reticular Connective tissue bordering on
● wide capillaries: Blood sinusoids
■ from a common stem cell: Hemocytoblast
● a Pluripotent stem cell
○ Pluripotent - Can differentiate in many ways depending on signal of the cell
■ Can be WBC, RBC, platelets, etc

Hemopoiesis, continued:
● numbers of each cell type produced varies:
○ depending on the body’s changing needs

● once the stem cell is “committed” to becoming a particular cell type, the maturation pathways differ
○ Intermediate cells can no longer retrograde differentiate to a different type of cell

Hemopoiesis: a better look
● Stem cell → committed cells (precursors to precursor cell)
● Cannot differentiate to a different cell line once it is a committed cell
○ I.e. Megakaryoblast cannot form a erythrocyte

Hemopoietic Growth Factors
● “Commitment” occurs:
○ once the cell has receptors in place for a specific hormone or growth factor
■ Mechanism of a hemocytoblast obtaining the receptors for a specific hormone is not well understood.
● Hematopoietic growth factors (HGFs):
○ “push” the cell toward specialization
○ they include (many more than this, but focus on these):

Erythropoietin: RBC
Thrombopoietin: Platelets
Colony-stimulating factors: WBCs
Erythropoiesis (production of RBCss)
● Pluripotent stem cell (hemocytoblast)
○ becomes a Proerythroblast (the committed cell)
■ after the receptors specific for erythropoiesis develop on Hemocytoblast d/t signaling by the body for more RBC
○ which has receptors for EPO (erythropoietin)
■ EPO transforms Proerythroblasts into: Erythroblasts
● Image: Stem cell → Committed cell → Developmental pathway (Phase 1, Phase 2, Phase 3) → Complete, mature erythrocyte
\
Erythropoiesis, cont.:
● Key part of erythropoiesis is when Proerythroblasts convert to Erythroblasts.● Erythroblasts are a phase where a bunch of cell development/construction.

● Erythroblasts:
○ Protein synthesis happening like crazy, multiply, mostly to synthesize Hb, but also other organelles to create the structure
○ As phase progress, there is Hgb accumulation. When Hgb reaches capacity, eject most of their organelles
○ the nucleus shrivels & leaves the cell
○ now called a: Reticulocyte after nucleus & most organelles have left the cell
■ contains Ribosome clusters
● Stem cell to Reticulocyte takes about 15 days
● If they are needed, Reticulocytes leave Bone marrow
● Enzymes degrade the ribosomes
● become mature Erythrocytes in a few days

Erythropoiesis
● Hemocytoblast develops Receptors → Commit the cell → Proerythroblast → Erythroblast → goes through phases
○ Generation of a bunch of organelles/ribosomal synthesis → Basophilic erythroblast
○ Accumulate Hgb → Polychromatic erythroblast
○ Organelles start leaving/capped out on Hgb accumulation → Orthochromatic erythroblast
○ Nucleus & organelle ejected → Reticulocyte
○ Leaves bone marrow → enzymes degrade ribosomal clusters → mature Erythrocyte

Regulation of Erythropoiesis
● #s stay constant
○ good balance between
■ red cell production & destruction
● too few: Hypoxia
● too many: Viscous blood → Predispose to heart failure, blood clots, etc

● produced at the rate of: 2.5 million RBC/second

Erythropoiesis is Hormonally Controlled
● controlled hormonally based on blood O2 levels

● Hypoxemia (a big trigger) caused by:
○ hemorrhage, altitude, exercise, diet

● causes Kidneys to ↑ secretion of Erythropoietin (EPO)
○ also (10%) secreted by Liver
● in ~ 5 days RBC count rises

EPO
● EPO acts on Proerythroblasts, causing them to mature more rapidly
● patients w/ Kidney Failure have insufficient EPO (causes anemia)
● now genetically engineered
○ when endurance athletes inject EPO it can ↑ HCT
■ from 45% to 65%
● w/ dehydration after a long race (or blood doping/EPO), blood concentrates into a thick sludge
● Risk of clotting, stroke, & heart failure

Fate and Destruction of Erythrocytes
● RBCs live about 120 days
● Anucleate: unable to:
○ Synthesize new proteins, repair themselves, divide
■ Over time they lose flexibility, become rigid & fragile
■ trapped in smaller blood vessels usually of the Spleen:
● “RBC graveyard”

Hemolysis - Rupture & breakdown of RBCs
● RBCs rupture:
○ release Hb, leaving empty plasma membranes
○ Macrophages digest the membranes
● Hb disposal:
○ can block kidney tubules causing Kidney Failure

● Macrophages separate heme from the globins,
○ globins hydrolyzed to free amino acids
○ Iron is released into blood (recycled or stored)

Hemolysis, continued:
● the rest of the heme is converted to: Bilirubin
○ a yellow-green pigment
○ binds to albumin in plasma
○ transported to liver
○ Conjugated into water soluble form that is incorporated into bile
○ secreted into the Small intestine

● Jaundice
○ yellowish cast, eyes, skin
○ may indicate rapid hemolysis (overwhelms liver’s ability to process it) or liver disease (normal levels of hemolysis, but liver has reduced ability to process bilirubin into a form that can be incorporated into bile)

Erythrocyte Disorders
● an imbalance between Erythropoiesis & Hemolysis can cause:

Polycythemia
a. an excess of RBCs
or Anemia
a. a deficiency of RBCs or Hb

Polycythemia
● Polycythemia - abnormal excess of RBCs that ↑ blood viscosity

Primary Polycythemia or Polycythemia Vera
a. Cancer of the erythropoietic line in red marrow
b. ↑ of HCT of 80%, blood volume doubles
i. RBCs produced by this are not uniform. O2 transport is impaired d/t being weird shapes, sizes, missing heme, etc
c. Maintenance/Symptomatic TX: dilute it: drain some off, replace it w/ saline
Secondary Polycythemia
a. all other causes:
i. Dehydration, high altitude, blood doping, emphysema
ii. may be an appropriate response to lifestyle

b. Main danger is ↑ blood volume, blood pressure, viscosity
i. Same as w/ primary polycythemia

Blood volume can double
Clogged capillaries
Strained heart

Anemia
● O2 carrying capability too low
● a symptom of another problem, is not a disease itself
● S/S: fatigued, pale, short of breath, chilled
● causes fall into 3 categories:

Categories of Anemia

Hemorrhagic anemia - blood loss
a. Acute or chronic: Trauma vs Colon CA or heavy periods
Inadequate Erythropoiesis or Hb synthesis due to:
a. Nutritional (or iron-deficiency) anemia:
i. dietary deficiency of Iron, Vitamin B12, Folic acid (B9)

b. Pernicious anemia (megaloblastic anemia)
i. gastric mucosa fails to secrete Intrinsic Factor (produced by Parietal cells)
ii. necessary for absorption of Vitamin B12
iii. may be age or autoimmune destruction of parietal cells

c. Renal anemia
i. lack of EPO caused by Kidney Failure, Age

d. Aplastic anemia
i. destruction of red marrow by:

Drugs, Radiation, or Viruses
ii. impairs production of All Formed Elements
Defects in clotting & immunity
Hemolytic anemia
a. erythrocytes rupture prematurely
i. Hb abnormalities, mismatched blood, bacterial & parasite infections
ii. Mushroom toxins, Snake, Spider venoms
iii. Drug allergies
iv. Malaria (huge killer in developing countries)
Image: 2 year old with cerebral malaria in Congo. GCS 8: hit criteria for Ebola (can share S/S of cerebral malaria) & needed quarantine. Gave 2 doses of Artesunate & was able to send out d/t GCS 15.
v. Erythroblastosis fetalis

Abnormal Hemoglobin
● Thalassemias
○ typically in Greeks, Italians
● 1 of the globin chains is absent or faulty
○ RBCs are thin, delicate, Hb deficient
○ different subtypes depending on which globin chain affected
● range in severity from mild to severe
● those require monthly transfusions
● Image: Pale, translucent RBCs indicative of thalassemias d/t ↓ Hgb content.

Sickle-cell Anemia
● hereditary Hb defect
● HbS differs in 1 amino acid of 1 globin in a 146 aa sequence
○ Image: Beta chain 6th position is normally Glutamate but is swapped out for a Valene
■ Have a HgbS (sickle) instead of HgbB (normal).
● at ↓ O2 conditions:
○ HbS polymerizes, becomes stiff, & spiky

Sickle-cell continued:
● RBCs become stiff, spiky
○ Agglutinate (clump together), rupture, & clog small BVs
○ tissues become ischemic
■ intense pain
○ triggers further sickling
○ positive feedback w/ more sickling occurring

One more Sickle-cell…..
● originated in Africa, in the malarial belt

● people w/ 2 copies of the gene: Homozygous
○ have sickle-cell anemia

● people w/ 1 copy: are Heterozygous
○ have “sickle-cell trait” but not the disease

● both survive Malaria at a ↑ rate
○ parasite carried by mosquitoes
○ Usually invades RBCs, feeds on Hb but can’t digest HbS

Consequences of Anemia
● 3 consequences of anemia:

tissues suffer Hypoxia (O2 deprivation)
a. lethargic, short of breath
b. skin is pale
c. life threatening necrosis of brain, heart, kidney
blood Osmolarity may be reduced
a. ↓ protein → ↓ oncotic pressure → H2O leaves & goes into ECF
b. tissue edema
c. BP drops
blood Viscosity may be reduced
a. rapid heart beat
b. BP drops

Blood Types
● blood types & transfusion compatibility are based on:
○ interactions between Plasma Proteins & Erythrocytes
○ or interactions between:
■ Antigens (Ag) which are on the surface of the RBC, antigens in this case are embedded proteins that act as identifiers of the erythrocyte
■ & Antibodies (Ab), those are the plasma proteins floating around in the cytoplasm

Antigens (Ag)
● Antigens = antibody generator - stimulates the body intentionally or unintentionally to induce antibodies. The definition is:

● Complex molecules capable of eliciting an immune response
○ a lot of molecules are too small to elicit an immune response
■ glucose, plastic, etc.
● Complex molecules: Proteins, Glycoproteins, Glycolipids, & Carbohydrates
○ genetically unique
○ occur on surfaces of all cells

● enable body to distinguish:
○ own cells from foreigners

● detection of a foreign Ag:
○ activates immune response
■ response includes secretion of protein:

Antibodies (Ab)
● proteins produced by Lymphocytes
● bind to Antigens

● Do 1 or both things:

Render them Harmless &/or
Tag them for Destruction

● An example is in a mismatched blood transfusion:
○ recipient’s Abs bind donor’s Ags
○ causing agglutination (clumping) of the RBCs

Agglutination
● Because mismatched blood Agglutinates:
○ RBC antigens (on the surface of the RBC) called: Agglutinogens
○ Antibodies against agglutinogens: Agglutinins
■ Image: depicts when a wrong blood type is administered. Lab will take a small sample & do this before it is given to the patient to see if it agglutinates

Agglutination of RBCs
● Another picture of agglutination happening
● Agglutinins (antibodies) will be the “Y” shaped & are what is binds to the Antigens

ABO Group
● based on presence or absence of 2 Agglutinogens:
○ A & B:

● blood type A:
○ RBCs have the A agglutinogen
● type B:
○ RBCs have the B agglutinogen
● type AB: has both
● type O: has neither
Agglutinin Production
● After birth anti-erythrocyte antibodies are formed (arise naturally w/o exposure to Ag)
● against the antigen(s)
○ NOT present:

● Baby w/ Type A:
○ forms anti-B agglutinins w/o ever having been exposed to it
● Type B:
○ forms anti-A agglutinins
● Type O:
○ forms both anti-A & anti-B agglutinins
● Type AB:
○ forms none bc it has both antigens
● Normally for an immune response, you have to be exposed to an antigen (vaccines). Not the case w/ ABO grouping & development of blood antibodies. They develop naturally w/o exposure when people are still babies

Mismatched Blood
● 2 possible incompatibilities of mismatched blood:

recipient’s antibodies attack transfused cells
a. Usually what we call a transfusion reactions
donor’s antibodies attack recipient’s cells
a. usually of little consequence (dilution)

Transfusion Reactions
● Transfusion reactions ultimately cause: ranges from mild to life threatening CV collapse
○ Immune reaction
■ Hives, Fever, Respiratory Distress, HoTN

○ Hemolysis: bad d/t a TON of HgB being released
■ released Hb metabolized:
● converted to Bilirubin, excreted in Bile
● excess Bilirubin → Jaundice
○ liver is overwhelmed → can cause hemodynamic instability & effect homeostasis
○ Kidney shutdown
■ Toxic substances released from hemolyzing blood
● cause powerful Renal Vasoconstriction
■ Hb leaks through Glomeruli (causing red urine)
● precipitates & blocks kidney tubules → kidney failure & may need HD

Rh Factor - what gives you the +/- factor of your blood type
● another important RBC agglutinogen
● cells w/ the Ag are Rh +
● cells w/o: Rh -
● anti Rh agglutinins follow classic immunity
○ develop Abs upon exposure to Ag - unlike ABO you are born with
■ You can give an A- person A+ blood for the 1st time & they will not have a reaction, but they will the 2nd time bc the body will develop antibodies against it.

● RH typing is extremely important in pregnant women, if it is not evaluated it can result in Erythroblastosis Fetalis

Erythroblastosis Fetalis or Hemolytic disease of the newborn (HDN)
● Rh - mother carrying Rh + baby

● during delivery mom may be exposed to Rh Ag
○ she’ll form antibodies against Rh - this won't affect this baby but if she gets pregnant again it can be a huge problem

Erythroblastosis, cont.:
● if next pregnancy is Rh +
○ her anti-Rh antibodies will cross the placenta
○ Agglutinate (attack) baby’s RBCs

● baby is anemic & hypoxic
○ Jaundiced
○ Brain damage & Death can occur

● HDN is big deal & part of the screening process during prenatal care

Treatment of HDN
● RH - mom is given RhoGAM before or soon after first delivery
● RhoGAM is anti-Rh antibodies: are too big to cross the placenta so they stay in maternal circulation
○ bind antigenic sites on fetal Rh+ cells that may have entered mom’s blood rendering them neutral
○ blocking her immune response
■ Will need RhoGAM for every subsequent pregnancy

ABO Incompatibility
● Can result from incompatibility of ABO types:
○ mom is A
○ baby is type AB
■ Ag is not strongly expressed in fetus (develop more after birth)
■ Ab don’t readily cross placenta (like the RH do)

● baby’s agglutinated RBCs hemolyze
○ infant is anemic
○ hemolyzed RBCs release Hb
■ converted to Bilirubin
● precipitates in neurons, killing many (if left untreated)
○ Kernicterus
■ UV exposure degrades bilirubin if they have elevated levels when they’re born

Leukocytes
● only formed elements that are intact cells w/ all the organelles
● account for less than 1% of blood volume - d/t being in bone marrow, lympthatics, etc.
● the mobile units of the defense system - only come into play when needed

● they prevent disease by:
○ phagocytosis of invaders
○ or by forming: Antibodies which then go on to destroy invaders
○ & sensitized lymphocytes that destroy the invader

Leukocytes, cont.
● red cells confined to blood stream
● but white cells leave blood vessels (Diapedesis), squeezing out between the junctions
○ migrate into the tissues - where the majority of them hang out○ where they mount Inflammation or Immune responses (localized or systemic)

Leukocytes; 2 Categories

Polymorphonuclear Granulocytes
a. Multi-lobed nuclei, abundant granules
b. All:
i. leave blood vessels & migrate into tissues
ii. are phagocytic
Agranulocytes
a. Spherical or Kidney shaped nucleus
b. lack visible granules

Leukocytes
● Difference between each category & the visible granules in the granulocytes

Neutrophils (50 – 70%)
● most abundant WBC
● phagocytize bacteria, foreign matter
● numbers ↑ in infections - reflected in lab values
● granules stain acidic & basic - called neutrophils bc they stain a “neutral” color of purple

● some of the granules are:
○ Lysosomes
■ merge w/ Phagosome
■ destroying the invader
● others contain a brew of antimicrobial proteins that kill different invaders

Neutrophils Phagocytize Bacteria
● Neutrophil in action extending a psuedopod reaching out for a bacteria & the other is engulfing an invader

Eosinophils (2 – 4%)
● large bi-lobed nucleus, red (acidic) granules
● ↑ in parasitic infections (worms) & allergies bc it eats Ag-Ab complexes that are formed when antibodies bind to an antigen
● Eosinophils aren’t large enough so they release enzymes that kill parasites (worms)
● weakly phagocytic
● eat Ag-Ab complexes

Basophils (0.5 – 1%)
● least abundant, large blue (basic) granules
● ↑ in allergies & inflammation

● Secrete:
○ Histamine: a vasodilator
■ ↑ blood flow
■ attracts other WBCs
○ Bradykinin & Serotonin○ Heparin
■ anticoagulant
■ promotes mobility of WBCs

Mast Cells
● similar to basophils
● granulated, Degranulate to secrete Histamine & Heparin
○ Mast Cell Degranulation - Immune Response & Histamine release
■ Responsible for a lot of internal & external allergic responses like flushing, hives, etc.
● found in Connective tissue near blood vessels - where they reside
● arise from a different cell line in the bone marrow, are released into the blood in an immature state & then mature in the tissues
○ There has been some confusion about how these are generated, they used to think that they were generated from fibroblasts, now they think they are coming from a cell line outside of the hematopoietic line

Agranulocytes: Lymphocytes
● Lymphocytes (25%)
● smallest, almost all nucleus (Image)
● mostly found in: Lymphoid tissues
○ Spleen, Tonsils, Thymus
● crucial to Immune response

● many different kinds but we’ll cover these 2:

B cells - give rise to:
a. Plasma cells - synthesize Antibodies
b. Antigen comes in → B cells give rise to plasma cells → antibodies are created
T cells – act directly against:
a. Virus infected cells & Tumor cells

Monocytes (3 – 8%)
● largest of the formed elements
● “U” shaped nucleus
● leave blood vessel, differentiate into Macrophages (large/huge)
● large phagocytic cells of the tissues - will consume anything in their path that needs consuming

Macrophages
● Phagocytize:
○ bacteria, dead cells, cell fragments, tissue debris - Anything that needs to be cleaned up
● activate lymphocytes to mount the immune response
○ Activate B & T cells - tell them “something is going on. Check this out & do your thing”
Never Let Monkeys Eat Bananas
● Know the percentage composition of WBCs
● Easy way to remember:
○ Never Let Monkeys Eat Bananas (most to least)
■ N: Neutrophils (50-70%)
■ L: Lymphocytes (25-45%)
■ M: Monocytes (3-8%)
■ E: Eosinophils (2-4%)
■ B: Basophils (0.5-1%)

WBC Lifespan - Depends on what kind & what it is attacking
● most circulate in blood 4 – 8 hours after release from marrow
○ Most reside in tissues & blood is just transportation● another 4 – 5 days in the tissues
● shorter during infection - fighting & being used up

● Monocytes can live for Months
● Lymphocytes: Weeks or Months
○ Depending on what is going on

Leukopoiesis - Creation of WBCs
● begins with the Hemocytoblast● proliferation & differentiation is stimulated by:
○ Hematopoietic growth factors aka Colony stimulating factors
■ What cause the differentiation to occur
● Chart: Top Hemocytoblast begins to proliferate & differentiate. Remember once it is Committed to a cell line it will go down that path to completion

Colony Stimulating Factors (CSFs)
● CSFs are:
○ Glycoprotein hormones or Paracrines
○ often secreted by mature leukocytes
■ in response to Infections & Immune challenges
● “hey, I need you to make more leukocytes to help me out”
● each CSF causes production of a different WBC
○ in response to a different need
■ When looking at the chart, they are specific for a specific kind of WBC

Leukocytosis
● (abnormal) ↑ production of WBCs* - Not in response to infection or inflammatory response
○ Not abnormal in that it does & shouldn’t happen in response to infection or inflammatory response, abnormal when you compare it to a healthy baseline
○ ↑ WBC from healthy baseline indicates something is wrong
● whenever they’re called into action:
○ the body speeds up production
○ numbers may double in a few hours
○ normal homeostatic response to infection or other issues

Early Division of Leukocyte Ancestry
● Hemocytoblast
○ branches early, into a Myeloid & a Lymphoid stem cell

Lymphoid stem cells:
a. produce lymphocytes (special - they only produce these)
Myeloid stem cells
a. give rise to all other formed elements
i. Platelets, red cells, monocytes, & granulocytes

Myeloid Line
● in each Granulocyte line, the committed cell is the: Myeloblast:
○ under the influence of a specific CSF, each Myeloblast accumulates Lysosomes, forms Granules (basophil, eosinophil, neutrophil)

● Chart: L side - committed cell is the myeloblast, w/ the RBC its the Proerythroblast, with CSFs the myeloblast will differentiate as it starts to accumulate lysosomes and form granules and become whichever kind of granulocyte is being stimulated to be produced (basophil, eosinophil, neutrophil)

WBCs Stored in Bone Marrow
● WBCs are produced & stored in bone marrow until needed
○ Released d/t Chemotaxis
■ Cells under duress will release chemicals to call/pull the WBCs out of the bone marrow to where they are needed
● Bone Marrow contains 10X more than blood (WBCs are in blood)

● ratio of granulocytes to RBCs produced: 3:1
○ reflects granulocytes on average shorter life span (< 10 days)
○ D/t the fact that they die combating invaders

Lymphoid Line
● Lymphoid stem cells produce: (Image)

T lymphocyte precursors:
a. leave bone marrow
b. go to the Thymus for further differentiation
B cell precursors
a. Mature in bone marrow

Leukopoiesis Overview
● Hemocytoblast differentiates into either a Myeloid stem cell which produces the bulk of things (all the granulocytes & formed elements) except for the B & T lymphocytes which are produced by the Lymphoid stem cell (highly specialized on that side)

Leukocyte Disorders
● Leukopenia - insufficient WBCs
○ caused by:
■ Anticancer drugs (target fast dividing cells includes WBCs in bone marrow) & Glucocorticoids (suppress the WBC production)

○ the human body is normally covered with bacteria, especially:
■ Eyes, Respiratory, GI, & Urinary tracts

○ ↓ in WBCs allows these bacteria to invade
■ within 2 days of stopped WBC production:
● Sores in mouth, Respiratory infection
● Death in less than a week - crucial to homeostasis
○ Not just fending off invaders when you’re sick

Leukemia
● Cancerous production of WBCs, either:

Lymphocytic leukemia
a. Cancerous production of lymphocytes
b. usually begins in lymphoid tissue, spreads
i. Will see specific responses in lymphocytes
Myelogenous leukemia
a. Cancerous production of Myeloid cells
b. begins in bone marrow, spreads
c. May see multiple different cell lines attacked bc myeloid cells are where a formed elements & erythrocytes are formed

Acute v Chronic Leukemia
● Leukemic cells are nonfunctioning & often undifferentiated
● Acute leukemia
○ cells are very undifferentiated
○ quickly advancing
○ Precursor cell → long line of intermediate stages before the final product.
■ Cells are pushed out in the intermediate stages where they cannot function = Useless & do nothing in terms of immune response
● Chronic
○ cancer begins in later cell stages
○ more differentiated
○ advances slowly
○ (picture shows chronic lymphocytic leukemia)

● Acute Vs Chronic: Chronic you will be able to see differentiated cell lines & can see what cell lines are elevated vs Undifferentiated where it is too early for them to truly differentiate
Effects of Leukemia
● leukemic cells proliferate, displace normal bone marrow
● deficiency of normal WBCs, RBCs, platelets being produced in this bone marrow:
○ Infection, severe anemia, bleeding

● most common causes of Death:
○ Hemorrhage & Overwhelming infection

● Leukemic cells have a high metabolic rate
○ compete w/ healthy tissue for nutrition bc of their high metabolic rate
■ Leukemic cells win: healthy cells starve

Platelets: Thrombocytes
● small fragments of Megakaryocytes
● Even though they are a fragment of a cell their cytoplasm contains:

Actin & myosin
a. they contract!
ER, Golgi, & Lysosomes
a. synthesize various enzymes
Mitochondria
a. make ATP, ADP

● Image: Small, you can see the thrombocytes surrounding a RBC

Platelets, continued:
● platelets form pseudopods (can migrate & move around)
○ He used to think of them as static pieces of yellow rock candy (???) but they are actually very dynamic elements
● they secrete:

Clotting factors - promote clotting
Vasoconstrictors - serotonin cause vascular spasms
a. Usually platelets are activated its bc there is a bleeding issue
Growth factors that stimulate mitosis in:
a. endothelial cells, fibroblasts, & smooth muscle
b. Usually platelets are released when injury occurs → want GF there to stimulate the repair of the injured site
Chemicals that:
a. attract neutrophils & monocytes to sites of inflammation
i. & that help dissolve clots - resolves everything once control has been established
Don't want those things to hang around forever

Thrombopoiesis
● Undifferendiated hemocytoblast gains receptors for:
○ Thrombopoietin
■ hormone secreted by the Liver & Kidneys

● once receptors are in place:
○ it’s a committed cell: Megakaryoblast

Thrombopoiesis, cont.:
● in response to Thrombopoietin:
○ Megakaryoblast goes through repeated Mitosis w/o cytokinesis
■ Cytokinesis - part of mitosis where the 1 cell will split into 2 identical cells
○ it grows to a gigantic cell:
■ Megakaryocyte
● Push up against blood vessel wall which breaks up into pieces called Platelets (still very active individually)
● Not like cytokinesis where the daughters cells that are exactly alike with all the same functioning organelles and nucleus, its just the mitosis part

Megakaryocyte
● Bone marrow smear where you can see how large the Megakaryocyte is compared to the other formed elements

Platelets are Stored
● Once they are produced 25-40% stored in the Spleen
● released as needed
● rest live in the blood
○ 4 - 10 days