Module 1: Normal blood components, production and erythrocytes Flashcards
Hematopoiesis
Production and development of blood cells, characterized by the constant restoring of the various cells of the blood
Hematopoietic system consists of (5):
Bone marrow Liver Spleen Thymus Lymph nodes
Types of cells maintained through hematopoiesis (3)
Erythropoiesis
Leukopoiesis
Thrombopoiesis
Erythropoiesis
Production of erythrocytes (rbc’s)
Leukopoiesis
Production of leukocytes (wbc’s)
Thrombopoiesis
Production of thrombocytes (platelets)
Myeloid Cells
NORMAL IN ADULTS
Blood cells produced in bone marrow
Include: erythrocytes, platelets, neutrophils, eosinophils, basophils, monocytes
Non-Myeloid Cells
NORMAL IN ADULTS
Blood cells produced outside the bone marrow (primarily in lymph nodes but CAN be produced in the bone marrow)
Lymphocytes
Medullary hematopoiesis
production of blood cells (myeloid cells) in the bone marrow
Extra-medullary hematopoiesis
Production of myeloid cells OUTSIDE the bone marrow
Usually in spleen or liver
ABNORMAL IN ADULTS
NORMAL IN FETUS-2MO.
If something is wrong with bone marrow, liver/spleen with kick in (can happen at any age)
3 phases of Hematopoiesis
Mesoblastic phase (2wk gestation-12wk gestation) Hepatic phase (6wks gestation-2wks post partum) Myeloid phase (20wk gestation-death)
Mesoblastic Phase
2wk gestation- 12wk gestation
In yolk sac and embryo primitive blood stem cells are formed
Hepatic Phase
6wk gestation - 2wks post partum
Liver and spleen involved in production of increasingly mature forms of RBC’s first, then granulocytes, then monocytes
Lymph nodes being to produce lots of lymphocytes
Bone/Bone marrow formation begins in 8th wk
Myeloid Phase
20wk gestation- death
Lymph nodes continue to produce lymphocytes
All other blood cells produced in bone marrow
Liver/spleen retain potential for hematopoiesis in adults but remain INACTIVE
Production location of myeloid cells in infants/children
Bone marrow
All bones contain red marrow
Production location of myeloid cells in adults
Bone marrow
Limited to iliac crests of pelvis, sternum, proximal ends od long bones, spinous process of the vertebrae
Production location of non-myeloid cells (lymphocytes) in all ages
Lymph nodes and other lymphatic tissue
Including spleen, tonsils, liver, AND MARROW
Hematopoietic Inductive Microenvironment
The bone marrow: complex, semi-fluid mix of various connective tissue cells
Includes fibrobasts, endothelial cells, blood cells, blood vessels and nerves
Red Marrow
ACTIVE
Much hematopoiesis
Equal numbers of fat cells and developing blood cells
Yellow Marrow
INACTIVE
Little hematopoiesis
Few blood cells and lots of fat
Liver and Hematopoiesis
Begins in 2nd trimester when it is the principle site of all cell production
In adults, liver functions as extra-medullary hematopoiesis, synthesizing transport proteins, storing minerals and vitamins, break down of hemoglobin
Spleen and Hematopoiesis
Largest lymphoid organ
Involved in production of cells during hepatic phase and during times of extra-medullary hematopoiesis.
Also removes old and damaged red cells and stores platelets
Affect on blood after spleenectomy
Missing speen no longer cleans/filters the blood
Increased platelet count
Increased damaged cells (poikilocytosis)
increased denatured hemoglobin inside RBC (bite cells, Heinz bodies)
Increased retained nuclear material in young cells (Howell-Jolly bodies)
Poikilocytosis
Damaged cells (abnormal shapes)
Heinz bodies
denatured hemoglobin inside RBC
Howell-Jolly bodies
retained nuclear material in young cells
Thymus
involved in the production and maturation of T-lymphocytes (for immunity)
Lymph nodes
Involved in the formation of new lymphocytes
Cells involved in Hematopoiesis (3)
Stem cells
- Reticulum cells
- -CFU-S
- -CFU-L
- -CFU-GEMM
- Blast cells
Stem cells
Primitive, formative, unspecialized blood cells with potential to change into several types of more specialized offspring
Reticulum cells
Undifferentiated cell that may turn into the following:
CFU-S
CFU-L
CFU-GEMM
CFU-S
Colony forming unit - Stem
AKA pluripotential, multipotent stem cells
Partly differentiated from reticulum cells
May change to CFU-GEMM or CFU-L
CFU-L
Colony forming unit - Lymphoid
May differentiate into various levels of lymphocyte precursors (T and B lymphoblasts and NK (natural killer) cells)
CFU-GEMM
Colony forming unit- Granulocyte, Erythroid, Monocyte, Megakaryocyte AKA Myeloid stem cell Committed to formation of myeloid cells May change into: CFU-Eo CFU-baso CFU-GM BFU-E CFU-E BFU-meg CFU-meg
CFU-Eo
form eosinophils
CFU-baso
form basophils
CFU-GM
form CFU-M and CFU-G
CFU-G and CFU-M
form myeloblasts and monoblasts
BFU-E
Burst forming unit - Erythroid
Form CFU-E
CFU-E
(erythroid) form pronormoblasts (rubriblasts)
BFU-meg
(megakaryocyte) form CFU-meg
CFU-meg
form megakaryoblasts
Blast cells
Earliest stages of blood cells that can be recognized as precursor to a particular cell line
Blast cell undergoes mitosis (under influence of enriched bone marrow environment)
Youngest blood cell that bone marrow will release into blood
Young forms of blood cell in peripheral blood =
indicate a serious disorder of hematopoiesis
Growth factors
Proteins that bine to receptors on cell surface resulting in activation of cellular maturation
Most important:
Colony stimulating factors (CSF) and interleukins (IL)
Erythropoietin (EPO)
thrombopoietin (TPO)
Cytokines
multifunctional chemical mediators secreted locally and exert hormone-like effects by interacting with surface markers on their target cell
Thus inducing or inhibiting cellular RNA or protein synthesis
Produced mainly by T lymphocytes and monocytes/macrophages
Lymphokine
cytokine produced by a lymphocyte
Monokine
cytokine produced by a monocyte or macrphage
GF producer cell: Monocytes and macrophages
Produce Interleukin-1
Activate and stimulate cytokine production by T lymphocytes and bone marrow stromal cells
GF producer cell: T Lymphocytes
Produce Interleukin-3
Induce maturation and mitosis of the CFU-S into either CFU-GEMM (myeloid stem cell) or CFU-L (lymphoid stem cell
Also produces Interleukin-5
Induces eosinophil growth and function
GF producer cell: Bone marrow Stromal cells
Produces Granulocyte/monocyte stimulating factor
Induces differentiation and mitosis of the CFU-GEMM into CFU-Eo, CFU-GM, CFU-baso, BFU-E and BFU-meg
Also stimulates phagocytic and cytotoxic function of neutrophils an macrophages
GF producer cell: Kidney cells
Produces Erythropoietin
Induces maturation and mitosis in BFU-E, CFU-E, pronormoblast and developing nucleated RBCs
Raised concentration of EPO over time also induces production of other myeloid cells
GF producer cell: Liver cells
Produce Thrombopoietin
Induces maturation and mitosis in the CFU-meg and developing megakaryocytes
Colony Stimulating factors (CSF) and interleukins (IL)
growth factors secreted by macrophages, lymphocytes and bone marrow stromal cells
Erythropoietin (EPO)
secreted mainly by the kidneys
Produced by a lack of oxygen
Thrombopoietin (TPO)
secreted mainly by the liver
Effective hematopoiesis (normal)
85% or more of developing blood cells in bone marrow are successfully produced and released into blood stream
Ineffective Hematopoiesis (abnormal)
Less than 85% of developing cells make it into the blood stream before dying
Shift to the left
bone marrow releasing immature forms from the bone marrow into the blood
Increased demand for blood cells (4)
1) release immature cells into blood stream
2) Increase the number of mitoses in the developing cells
3) decreasing the maturation time
4) expanding hematopoiesis into inactive areas
Expanding hematopoiesis into inactive areas is done by (2)
- increasing # of blast cells by increase mitosis in the blast cell population
- activating stem cells to make blasts (conversion of yellow to red marrow)
Amplification
ability of bone marrow to produce many mature cells from a single original cell (usually a blast) by a series of cell divisions and differentiations
Maturation of: cell size
decreases with maturity
Maturation of: nuclear-cytoplasmic ratio
decreases with maturity
Maturation of: nucleus
Chromatin pattern becomes more condensed
Presence of nucleoli is not visible in mature cells
Maturation of: cytoplasm
color progresses from darker blue to light blue, blue-gray or pink
Granulation progresses from no granules to nonspecific to specific granules
Vacuoles increase with age
N/C Asynchrony or Dyspoiesis
Nuclear/cytoplasmic = N/C
when maturation developments are “out of sync” or lagging
Suggests metabolic disorder in the developing cells
Maturation of RBC
Pronormoblast Basophilic normoblast Polychromatic normoblast Orthochromic normoblast Polychromatophilic Erythrocyte
Pronormoblast
14-24um
Nucleus is round, central, reddish-purple unclumped chromatin, 0-2 nucleoli
N/C ratio 8:1 - 6:1
Cytoplasm is small relative to nucleus, deep blue/purple, no granules
Basophilic normoblast
12-17um
Nucleus is round or oval, central or eccentric, clumping slightly coarse, parachromatin, nucleoli not visible
N/C ratio 6:1 - 4:1
Cytoplasm small relative to nucleus, deep blue/purple, no granules
Polychromatic normoblast
10-15um
Nucleus is round or oval, central or eccentric, deep purple/black, heavily condensed chromatin, parachromatin, no nucleoli
N/C ratio 4:1 - 2:1
Cytoplasm is decreased in size but still larger than nucleus, polychromatic, no granules
Orthochromic normoblast
8-12um
Nucleus is round, central, pyknotic, dense homogenous, brown-black color, no chromatin structure
N/C ratio 1:1 - 2:1
Polychromatiophilic
7-10um
Nucleus has been extruded
Cytoplasm is clear gray-blue, polychromatic to pink
Erythrocyte
7-8um
Cytoplasm is pink
Structure of plasma membrane (3)
Lipids
Proteins
Carbohydrates
3 Functions of RBC membrane
Selective permeability:
Diffusion
Facilitated diffusion (with concentration)
Active transport (against concentration, uses enzymes and energy from ATP)
Sodium Pump
Na is continually moving into cell and K is continually moving out (naturally). Na pump reverses this.
1 molecule of ATP-ase to pump 2 molecules of K IN and 3 molecules of Na OUT
Calcium Pump
Ca accumulates in the RBC membrane (naturally)
Ca pump uses ATP to move Ca back into the plasma
Too much Ca in cell results in hardness and inability for cell to change shapes
RBC membrane negative charge
RBC membrane carries negative charge so that it repels all other RBC.
Protect cell from damage by softening collisions
If no ATP is available for active transport
Na moves into the cell, water follows
Cell swells and loses shape
Ca accumulates in RBC membrane (cell loses flexibility)
Results in early hemolysis of cell
Cytoplasm of RBC
Lack of nucleus
Composed of 90% Hb, 10% organelles, enzymes, electrolytes, carbohydrates, lipids, proteins
Hemoglobin (Hb) in cytoplasm
about 250mi per cell
Mature RBC equipped with enough material to function for 120 days
Hb/RBC determin persons ability to carry enough volumes of blood gases to and from the tissues
Hb produced during maturation stages but NOT in mature cells (65% normoblasts, 35% polychromatophilic)
Normal Hb productions is dependant on adequate supply of Iron
Composition of Hb
Globin: spherical protein composed of 4 polypeptide chains
Heme: protoporphyrin ring compounds containing iron aton (1 heme per globin)
Heme Synthesis
synthesized in mitochondria and cytoplasm of NRBC by a series of enzyme catalyzed biochemical reactions
Iron deficiency during heme synthesis
less heme is formed and protoporphyrin accumulates in the cell
If ANY enzymes in the reaction sequent are deficient, synthesis decreases/stops at that step and the “new end product” may accumulate and cause disease
Test for iron deficiency anemia
Measure protoporphyrin IX in the FEP (free erythrocyte protoporphyrin) assay
FEP is increased in the plasma and red cells
Globin Synthesis
Stimulated by presence of free heme in cytoplasm of NRBC
Globin produced in ribosomes
Amino acids are assembled into polypeptide chains
Chains are produced at different rates depending upon age of individual
α (alpha)
β (beta)
γ (gamma)
δ (delta)
ε (epsilon)
ζ (zeta)
Hb assembly
all Hb molecules contain 4 identical hemes Hb differ by types of polypeptide chains in the global 6 Types of Hb: Hb Gower1 (embryonic) Hb Portland (embryonic) Hb Gower2 (embryonic) HbF (fetal, present in adults) HbA2 (adult) HbA (adult)
Embryonic Hb (3 types)
Hb Gower1
Hb Portland
Hb Gower2
Produced in first 12 weeks of gestation in the embryo and early fetus
HbF
Fetal Hb
α2γ2 (alpha 2, gamma 2)
At birth, HbF > 75% of total Hb
In adults, HbF
HbA2
Adult Hb (minor component) α2δ2 (alpha 2, delta 2)
HbA
Adult Hb (major component)
α2β2 (alpha 2, beta 2)
96-98% of total Hb
Carries and delivers O2 the best
HbA1c
HbA molecule with a glucose attached to the β-polypeptides
In normal persons, HbA1c is less than 5% of total Hb
Glycosylated Hemoglobin
occurs in diabetics
HbA1c is more than 5% of total Hb
Reduced Hb
HbA in which iron atoms of the hemes are in the ferrous (fe2+) state
This reduced state is required for binding to O2
Oxyhemoglobin
Reduced HbA that is carrying O2 bound to some or all of the iron atoms of the hemes
Deoxyhemoglobin
Reduced HbA that is NOT carrying O2 bout to the iron atoms (but is in the correct state to carry O2)
Methemoglobin (MetHb) or Oxidized Hb
HbA in which the iron atoms of the hemes are in Ferric (fe3+) state
Fe3+ cannot bind to O2
Occurs when:
- normal reducing systems are overwhelmed by excessive oxidation
- reducing systems fail or are inhibited and can’t keep up with normal amounts of oxidation
This can cause HYPOXIA
Carboxylhemoglobin (HbCO)
results when HbA attaches to CO instead of O2
CO binds 200X tighter than O2 (this is bad!!!)
Sulfhemoglobin (aka verdoglobin)
Do no call HbS!! (call HbSulf instead)
Formed when HbA reacts with inorganic sulfides and H2O2
One S atom is introduced into the oxidized Hb and an IRREVERSIBLE bond is formed with Hb that prevents binding of O2
In mature RBC, energy is only used for (2)
Active transport Reducing Coenzymes (NADH converts methemoglobin to reduced Hb
Glycolysis
reactions to release energy and electrons from glucose
Energy is derived from 2 pathways of glycolysis:
The Embden-Meyerhof pathway (anaerobic glycolysis)
The Pentose Shunt Pathway (Hexose-Monophophate Shunt)
The Embden-Meyerhof Pathway
Anaerobic glycolysis
2 molecules of ATP are formed (ATP is for active transport to move Na, K, Ca across cell’s membrane)
2 molecules of NADH are produced by reduction of NAD (NADH allows methemoglobin reductase to convert metHb into reduced Hb)
2 NAD+ + 4e- = 2NADH
The Pentose Shunt Pathway
Hexose - Monophosphate Shunt
One molecule of NADPH is produced / molecule of glucose
Protects cell from oxidation of important membrane components and protects cellular enzymes and Hb molecules fro oxidation
Functions of erythrocytes (3)
Oxygen transport
CO transport/ buffering of Hydrogen Ion
Nitric Oxide Transport
RBC Oxygen Transport
One hemoglobin can carry a max of 4 O2
Iron atoms are capable of reversible oxygenation so they can bind and release O2 several times without losing electrons
Iron atoms but me reduced (fe2+) to bind to O2
Oxygen Saturation
amount of o2 carried by the Hb expressed as a percentage of the total capacity to carry oxygen
90% saturations = 90% of available heme sites are filled with O2
Normal levels:
95% in arterial blood
70% in venous blood
Factors determining O2 saturation (3)
Availability of enough oxygen
Availability of enough reduced Hb
The oxygen affinity of Hb (chemical bonding attractiveness to O2)
High O2 affinity
Hb easily and quickly binds available O2 molecules and hangs on to them
Low O2 affinity
Hb released O2 molecules it is carrying and binds to O2 with difficulty
Factors affecting O2 affinity of Hb (4)
Heme-heme interaction (changes in molecular structure)
Temperature (variations from 37 celsius)
The Bohr Effect (pH)
2,3 Biphosphoglycerate (BPG)
Heme-Heme interactions
AKA cooperative Binding
O2 attaches to each heme one at a time
The structure changes with each bonding (O2 affinity also changes)
Low O2 affinity in deoxyHb (takes large increase pO2 of the plasma to attach first O2 to first heme
Change of first bond increases the O2 affinity for 2nd and 3rd hemes (those attach easiest)
Another molecular change that decreases the O2 affinity for the 4th heme so a large increase in plasma pO2 is required to totally oxygenate the hemoglobin
Temperature (affecting O2 affinity of Hb)
O2 affinity varies inversely with temp changes from 37 degrees celsius.
Body temp increases = O2 affinity decreases and O2 is released to the tissues
Body temp decreases = O2 affinity increases and O2 is bound
The Bohr Effect
Most important factor in delivery of O2 to tissues
O2 affinity of Hb varies directly with the pH of the blood plasma as it changes from 7.40
pH of plasma decreases (at tissues)= O2 affinity decreases and O2 is released
pH of plasma increases (at lungs)= O2 affinity of Hb increases and O2 is bound
2, 3 biphosphoglycerate
2,3 BPG by-product of the Embden-Meyerhof pathway -Hypoxic tissues -2,3 BPG from EM pathway takes shortcut Attaches to Hb Changes shape of Hb Decreases O2 affinity Hb releases O2 to the tissues
CO2 Transport (85% of CO2)
Enters cell as gas, attaches with H2O
Carbonic Anhydrase converts it to carbonic acid (H2CO3)
Carbonic Acid dissociates into H+ and HCO3-
Free H+ attach to Hb (because you don’t want the pH of the cell to change - buffering action of hemoglobin)
O2 is released from Hb as H+ attaches
O2 released out of the cell
HCO3- is released from the cell
Cl moves into the cell to ensure the charge of the cell does not change (chloride shift)
H2O continually moving into cell to attach to new CO2 molecules
CO2 Transport (10%)
carried as carbamino Hb
bound to amino acids in the globin
CO2 Transport (5%)
carried in the plasma as a dissolved gas
Nitric Oxide (NO) Transport by Hb
NO attaches to available iron atoms in heme (those that are not occupied by O2)
Is carried in blood mainly from tissues to the lungs
NO is a well known dilator of blood vessels, also maintain vascular patency in hemostasis (helps resist platelet adhesion to endothelium), bronchodilator
Extravascular Hemolysis
Outside of blood vessel
In normal person, more than 95% of old RBCs are destroyed by phagocytosis by hepatic and splenic macrophages
(see diagram)
Increase in extravascular hemolysis
Results in Hyperbilirubinemia
Increased urine urobilinogen
Increased CO exhaled through lungs
Hyperbilirubinemia
accumulation of indirect bilirubin in plasma (may occur in liver disease/failure)
Accumulation of direct bilirubin in plasma (due to obstruction or blockage of the bile duct)
Intravascular Hemolysis
Inside the blood vessels
In normal person, less than 5% of old RBC are destroyed while in circulation
Hb released directly into plasma which is bound by haptoglobin and macrophages remove the complex
