Normal Physiology Flashcards
Apoptoic cell characteristics
The entire cell may shrink, Chromatin condenses, Pieces of the nucleus appear spherical or abnormal
Embryological Hematopoiesis
18 days- Hematopoiesis starts
3 months- Hematopoiesis moves to liver, some in kidney and lymphoid tissues
6 months- Hematopoiesis moves to bone marrow
Hematopoietic micro environment
Cellular: stromal cells
Extra cellular: extra cellular matrix
Primary Lymphoid Tissues
Bone marrow, Thymus
Secondary Lymphoid Tissues
Spleen, Lymph nodes
Red Marrow contains
Stromal cells:
Macrophages: production of cytokines to stimulate cell development
Adipocytes: cells that produce fatty yellow bone marrow
Fibroblasts: produces a support network of collagen for developing cells (extracellular matrix)
Hematopoietically Active sites
After four years it is only in the medulla of the ends of the long bones and the pelvis; everywhere else is fatty yellow marrow
Hyperplasia
Higher than normal red cell production, red marrow moves into areas of yellow marrow; caused by infection, anemia, leukemia; can cause fractures of cortical bones in severe cases
Thymus activity
Active in young children when immunity is developing, atrophied in adults but can be reactivated if new T cells are necessary
Spleen functions
The removal of old or damaged RBCs from circulation (RBCs must squeeze through very small areas and endure hypoglycemia and hypoxia), Culled RBCs are phagocytized by macrophages
Remove abnormal inclusions from RBCs
Reservoir for PLTs and RBCs
Splenectomy
Helpful for patients with hemolytic anemia’s, letting abnormal RBCs live longer; liver can take over some of the culling function
Extramedullary Hematopoiesis
Occurs in Liver and Spleen (fetal organs)
Differentiation
The process of generating several “different” cell lines by allowing the expression of certain genes while restricting others
Hematopoietic Stem Cells
Pluripotent or multipotent; become myeloid/lymphoid stem cells or non-differentiating self replicating cells
Progenitor Cells
CFU: colony forming units
BFU: burst forming units
Highly mitotic and become more committed with each cell division
Normoblasts
Erythroblasts (nucleated RBCs) that go through maturation normally, all four stages of nRBC maturation, spend 5-7 days in bone marrow
Reticulocytes
Polychromatophilic RBCs
Not quite fully mature RBCs (spend 2-3 days maturing in BM), Do not have a nucleus, Not biconcave shaped, Stains somewhat more basophilic due to residual RNA
Erythrocyte Maturation
Rubriblast- Prorubricyte- Rubricyte- Metarubricyte- Reticulocyte- Erythrocyte
Gradual decrease in cell size, Gradual decrease in N:C ratio, Chromatin pattern condenses, Eventual expulsion of the nucleus, Cytoplasm becomes less basophilic, Increase in hemoglobin as the cell matures
Erythropoietin (EPO)
Hormone that is produced by specialized kidney cells, stimulated by hypoxia (Anemia, respiratory disease, etc)
Responsible for the development of the erythrocyte precursors
Difference between EPO and CSFs
CSFs are:
Responsible for the proliferation of precursor cells
Produced locally by stromal cells
Other hormones affecting Hematopoiesis
Adrenal cortical hormones: Androgens (Testosterone, Estrogen), Aldosterone, Cortisol
Miscellaneous: Thyroid hormone, Growth hormone
Rubriblast (Pronormoblast)
Earliest recognizable RBC precursor
Cytoplasm: Stains deeply basophilic
Pale area next to nucleus (Golgi apparatus)
Only small amounts of hemoglobin are present
Nucleus takes up 80% of cell
Chromatin is fine, May contain few faint nucleoli
Prorubricyte (Basophilic Normoblast)
Similar to the rubriblast
Cytoplasm- Deeply basophilic
Nucleus- Chromatin is more coarse than the rubriblast, Start to show parachromatin clearing, The “cracked” appearance of the nucleus, Nucleoli are usually not apparent
Rubricyte (Polychromatic Normoblast)
last stage capable of undergoing mitosis
Cytoplasm: Less basophilic than earlier stages, Due to synthesis of large amounts of hemoglobin and lower RNA concentration
Described as blue-gray or light purple
Nucleus: lower N:C Ratio due to condensation of the nuclear chromatin, Chromatin is irregular and coarsely clumped, Increased parachromatin clearing
Metarubricyte (Orthochromic Normoblast)
Cytoplasm: Mostly pink or salmon color, Due to concentration of hemoglobin, Looks very similar to the surrounding RBCs, Retains a slight basophilic hue
Nucleus: Last stage with a nucleus, Low N:C Ratio, Dark, heavily condensed chromatin, Often eccentric
Reticulocyte
Before a developing RBC enters circulation the nucleus is extruded from the cytoplasm and digested by BM macrophages
After nuclear extrusion the cell is known as a reticulocyte
Flattened-disc shape, membrane is not biconcave, Central pallor is not apparent on smear, Last 20% of hemoglobin is made in this stage
Normally 0.5-2.5% of all circulating RBCs are retics
Reticulocyte Identification
Supravital stain
Microscopic ID can only be made using a supravital stain
New Methylene Blue commonly used (makes residual RNA visible)
Wright stain
Cannot definitively visualize residual RNA
Retics have a slight bluish tinge- polychromatophilic erythrocytes
Erythrocytes
Unable to synthesize new proteins (hgb) or lipids
Pink color
Biconcave disc shape (During the retic stage, the membrane is remodeled until it becomes biconcave), Size 7-8 µm in diameter, volume 80-100 fL, Central pallor
Erythrocyte Membrane Functions
Oxygen transport, Durability/strength to survive for 120 days, Balances ion and water concentrations, Flexibility to fit through small vessels
Some integral proteins are called anion exchange proteins: function in the exchange of CO2 at the lungs, Peripheral proteins are mostly on the cytoplasmic face of the RBC
Erythrocytes Membrane Structure
Phospholipid bilayer complex: Lipids – mostly cholesterol, Affects surface area and membrane permeability,
Integral proteins: Embedded in the bilayer, Function in the transport of molecules across membrane, Responsible for the zeta potential (negative charge), Blood group antigens
Peripheral proteins: Forms the cytoskeleton, Provides a flexible, fluid structure
Erythrocyte Abnormality Effects
Increased cholesterol absorbs onto RBC
Causes expansion of the outer phospholipid leaflet
Abnormal membrane projections
Erythrocyte Metabolism
Production of energy (ATP) through anaerobic glycolysis (Previously known as the Embden-Meyerhof pathway), No citric acid/TCA/Kreb’s cycle
ATP is necessary to maintain intracellular ion concentration
Important enzyme: Pyruvate kinase (PK)
Causes of Hypoglycemic Erythrocytes
Normal in splenic circulation, Deficiency in pyruvate kinase
Results: May disrupt intracellular ion balance, Allows excessive water to enter, Cell loses biconcave shape, Assumes spherocytic shape, Becomes fragile, Culled by spleen or hemolyzed
Hexose Monophosphate Shunt (HMP)
An offshoot of the glycolytic pathway, Protects hgb from being chemically oxidized (Oxidation prevents oxygen transport)
HMP maintains the function of glutathione, Glutathione becomes oxidized instead of hemoglobin, The main antioxidant is glutathione
Important enzyme: Glucose-6-phosphate dehydrogenase (G6PD)
Methemoglobin Reductase Pathway
An offshoot of the glycolytic pathway, Helps return methemoglobin (Fe3+) to reduced state (Fe2+), Ensures that hgb can bind and transport O2
Important enzyme: Methemoglobin reductase, Deficiency results in a buildup of oxidized heme, Decreased O2 carrying capacity, Hypoxia results in cyanosis
Structure of Hemoglobin
Porphyrin ring structure, Called “protoporphyrin IX”, Combines with one centrally located ferrous ion (Fe2+), Each iron ion can bind one molecule of O2
There are 4 heme subunits per hgb molecule, Each heme subunit is bound to a globin chain, 4 subunits and 4 globin chains
Deoxyhemoglobin
Iron ions in the ferrous state
Oxyhemoglobin
Iron ions in the ferric state
HGB Synthesis
Occurs in the mitochondria and cytoplasm of erythrocyte precursors
Rapoport-Leubering shunt
Produces 2,3 bisphosphoglycerate
Competes with O2 for a binding site; the concentration of O2 at the lungs is much higher than 2,3 BPG so O2 “wins” the competition at high concentrations bound and ready for transport
In hypoxic tissues 2,3 BPG facilitates the release of oxygen; 2,3 BPG pushes O2 off of the RBC where it diffuses into the tissue, increasing the amount of oxygen being released to tissues
Hemoglobin A
The predominant form in healthy adults
α2β2
Hemoglobin F
The predominant form in a developing fetus and newborns: α2γ2 A gamma (γ) globin chain is simply a beta chain with serine in place of histidine at the 143rd position, Serine interferes with the function of 2,3 BPG Allows a Hgb F to have a higher affinity for O2 than Hgb A; Hgb F essentially “takes” O2 from maternal circulation
Normal Adult Hemoglobin Composition
Hgb A: α2β2 >95% Hgb A2: α2δ2 1-4% Hgb F: α2γ2 <2%
Other hemoglobin types
Hgb S: Sickle cell anemia
Hgb C: Hgb C disease
Nonfunctional Hemoglobin
Methemoglobin: Hgb with iron in the ferric state, Cannot bind O2
Sulfhemoglobin: Sulfur bound to heme, Severely decreased O2 affinity
Carboxyhemoglobin: Hgb has much higher affinity for carbon monoxide (CO) than O2, Produces cherry red appearance to blood and skin, O2 cannot bind, CO poisoning can be lethal
Erythrocyte Destruction
Usually simply the result of aging Erythrocyte disorders Shorten the lifespan of the RBC, Or result in immediate destruction Two methods Extravascular/Intravascular destruction
Extravascular Destruction
Conserves and recycles important RBC components
RBCs are culled by the spleen (BM and liver can also participate)
RBCs are required to pass through small openings and endure hypoglycemia (Healthy cells survive unharmed) while aged, rigid, damaged or poikilocytic cells become spherocytic and are culled
Extravascular Recycling
Iron from heme, Amino acids from globin chains
Heme is further broken down to unconjugated bilirubin, Carried to the liver and converted to conjugated bilirubin and excreted in the feces
Excessive extravascular hemolysis: Caused by several types of anemia, May result in spleen overload/failure, Jaundice
Intravascular Destruction
Most RBCs are extravascularly destroyed but some lyse in circulation, Released hemoglobin circulates freely (Free hgb may be toxic in high levels-Can induce apoptosis in surrounding cells)
Hgb is bound by haptoglobin and rendered non-toxic then carried to the liver to be recycled
Excessive intravascular hemolysis: Caused by several hemolytic anemia’s, Causes a depletion of haptoglobin
What percent of whole blood is made up of leukocytes and platelets?
1%
What does a “shift to the left” in an oxygen dissociation curve mean?
That the hemoglobin is holding on to oxygen more tightly, reducing oxygen delivery
Serum Ferritin is an indicator of?
storage iron
