CB Quiz 1 Flashcards
How are we able to observe the main components of blood?
Centrifugation
After Centrifugation, what main components of blood can be observed? Describe them.
We are able to observe blood through the centrifugation which will separate blood into 3 main parts with the lightest being on top. Blood is composed of:
• Plasma: Largest component of blood - Contains water, proteins, electrolytes - Serum may be produced after clotting removing proteins
• Buffy Coat: Smallest component of blood - Formed Element - Found in the middle of the centrifuge - Composed of Leukocytes and Platelets
• Erythrocytes: Heaviest component of blood - Contains RBCs
Describe Erythrocytes. Talk about what they contain, primary function, replication, structural significance, and where they are disposed of.
Erythrocytes:
• Also known as red blood cells, erythrocytes contain hemoglobin (Fe) and has the primary function of carrying and transporting oxygen (and some CO2) throughout the body.
• They do not replicate. They are disposed off in the spleen
• Erythrocytes have a flat, donut shaped, structure which allows for an increased surface area. This aids in the exchange of oxygen and CO2 between the blood and cell/tissue. It lacks a nucleus which allows for this shape to occur
Where are RBCs Disposed?
Spleen
Describe the Structure of Erythrocytes and it’s significance
• Erythrocytes have a flat, donut shaped, structure which allows for an increased surface area. This aids in the exchange of oxygen and CO2 between the blood and cell/tissue. It lacks a nucleus which allows for this shape to occur
What is the primary function of Leukocytes
Also known as white blood cells, leukocytes are large blood cells that serve the immune system function. Their primary function is to fend off and eliminate pathogens and infection
What are thrombocytes and what is their function
Also known as platelets, thrombocytes are non-cellular components of blood. Their primary function is clotting.
What is Thrombosis?
Blood clotting
LEARNING OUTCOME: Describe the sites of production of blood in embryos and adults.
In embryos, blastocysts have a yolk sack which is the first tissue to take the role of hematopoiesis. As it grows, the liver is formed and assumes function. Later, the spleen begins to form blood cells. Finally, 4 months into development, the bone marrow is formed.
In adults, hematopoiesis occurs in the blood marrow of bones in the axial skeleton
LEARNING OUTCOME: Describe the Main Components of Blood
We are able to observe blood through the centrifugation which will separate blood into 3 main parts with the lightest being on top. Blood is composed of:
• Plasma: Largest component of blood - Contains water, proteins, electrolytes - Serum may be produced after clotting removing proteins
• Buffy Coat: Smallest component of blood - Formed Element - Found in the middle of the centrifuge - Composed of Leukocytes and Platelets
• Erythrocytes: Heaviest component of blood - Contains RBCs
Erythrocytes:
• Also known as red blood cells, erythrocytes contain hemoglobin (Fe) and has the primary function of carrying and transporting oxygen (and some CO2) throughout the body.
• They do not replicate. They are disposed off in the spleen
• Erythrocytes have a flat, donut shaped, structure which allows for an increased surface area. This aids in the exchange of oxygen and CO2 between the blood and cell/tissue. It lacks a nucleus which allows for this shape to occur.
• Too many Erythrocytes cause a condition called erythrocytosis. Too little causes Anemia which causes fatigue due to the lack of oxygen
Leukocytes:
• Also known as white blood cells, leukocytes are large blood cells that serve the immune system function. Their primary function is to fend off and eliminate pathogens and infection
Thrombocytes:
• Also known as platelets, thrombocytes are non-cellular (non-living) components of blood with the primary function of clotting or thrombosis
Hematopoiesis
Hematopoiesis is the process in which hematopoietic stem cells give rise to blood cells
LEARNING OUTCOME: Outline the Derivation of Cellular Elements of Blood
Hematopoiesis is the process in which hematopoietic stem cells give rise to blood cells. Embryos have pluripotent stem cells that can turn into any type of cell (blood cell) but adults only have multipotent stem cells that can only turn into a select few. In both cases these stem cells become unipotent stem cells that undergo a process to become the desired blood cell type.
What are the Primary and Secondary lymphoid organs
Bone Marrow
Thymus
Lymph Nodes
Spleen
MALT
What are the main functions (not each one) of the lymphoid tissues/organs
Lymphoid tissues/organs are responsible for immune system function. Primary lymphoid tissues include the bone marrow and the thymus. They are responsible for the production and maturation of lymphocytes. The secondary lymphoid tissues include the lymph nodes, spleen and MALT. They are responsible for detecting infection, handling blood, maintenance, and protection against infection.
Describe the Location and Function of the Bone marrow. Also give the function of what they produce.
Bone marrow found in the axial skeleton is a primary lymphoid. It’s primary function is the production of B-lymphocytes.
B lymphocytes are responsible for the body’s Humoral Immune Response. This involves the production of antibodies against an antigen presented by pathogens or infecting bodies. They also produce memory cells which allow for a quicker and more efficient immune response if the same infection occurs again.
Describe the location and function of the Thymus gland. Also give the function of what it produces.
The Thymus gland is a primary lymphoid organs that is found in the front of the thorax anterior to the heart. T cells are responsible for the Cellular Immune Response where they identify and destroy already infected cells.
Where is the Thymus Gland Located
Found in the front of the thorax and anterior to the heart
What is the Humoral Immune Response
It is where B-lymphocytes produce antibodies in response to antigens presented by pathogens or an infecting body
What is the Cellular Immune Response
It is where T-lymphocytes identify and destroy already infected cells.
Where is the hematopoietic bone marrow located
Axial Skeleton
What are lymph nodes and where are they located? Indicate its functions.
Lymph nodes are secondary lymphoid tissues that are found within capillary beds that carry a high concentration of lymphocytes. Their functions are:
- Carry excess fluid back to the venous system
- Act as strainers filtering pathogenic material, cancer material, and large objects from entering the blood (causes swelling when infected)
Describe the spleen with its location. Explain it’s function
The spleen is a secondary lymphoid organ located behind the left ribs and next to the stomach. It is highly vascular which can cause heavy bleeding from trauma. The spleen is contained within a capsule and has white and red pulps where it stores a high concentration of lymphocytes and disposes of RBCs.
Describe MALT giving its location and function.
How is MALT different between children and adults
MALT or Mucosa Associated Lymphoid Tissue is located in the Tonsils and Peyer’s patch in the small intestine. It contains a large amount of B and T lymphocytes to fight infection.
More MALT is found in children when compared to adults as children explore the world with their mouth.
What Does MALT Stand For
Mucosa Associated Lymphoid Tissue
LEARNING OUTCOME: Describe the Primary and Secondary Lymphoid Organs
Lymphoid tissues/organs are responsible for the immune system function. The primary lymphoid tissues include bone marrow and thymus which are involved in producing and maturing lymphocytes (B and T cells). The secondary lymphoid tissues include lymph nodes, spleen, and MALT which are responsible for detecting infection, handling blood and maintenance, and protection against infection.
Bone Marrow: Primary lymphoid - Found in the Axial Skeleton - Responsible for the production of B lymphocytes (B cells) - B cells are responsible for the Humoral Immune Response which involves the production of antibodies in response to antigens presented by the pathogens or infecting body - Also responsible for the production of memory cells/antibodies which allow for a quicker and more efficient response if the same infection occurs again - Researchers are using this to fight COVID
Thymus Gland: Primary lymphoid - Found in the front of the thorax and anterior to the heart - Responsible for the production of T lymphocytes (T cells) - T cells are responsible for the cellular immune response where they identify and destroy already infected cells - Major components are Cortex (outer tissue, dark staining) and Medulla (inner tissue, paler staining)
Note: B cells cannot recognize when a pathogen has already invaded a cell, so the T cells handle infected cells
Lymph Nodes: Secondary lymphoid - Located within capillary beds - Responsible for carrying excess tissue fluid back to the venous system - High concentration of lymphocytes - They act as strainers preventing larger substances and infectious material from passing - Will enlarge when infected
Spleen: Secondary lymphoid - Located behind the left ribs, next to the stomach - Extremely vascular and can cause heavy bleeding after trauma - Young people can handle keeping BP stable with a sudden drop later but elders will have a steady decline in blood pressure - Responsible for filtering the blood from foreign antigens - The spleen is contained within a capsule and has white pulp for WBCs and red pulp for RBCs (check diagram)
MALT: Secondary Lymphoid - Located in the Tonsils and Peyer’s patches in the small intestine - Known as Mucosa Associated Lymphoid Tissue - Contains B cells and T cells to fight infection- More MALT is found in children rather than adults because they explore with their mouth and hence high risk of infection which causes extreme swelling of the tonsil. This does not affect adults that much if they are removed
LEARNING OUTCOME: Explain the Circulation of Lymphs
The lymphatic system is responsible for carrying tissue fluid back to the venous system. The fluid generally passes through lymph vessels located around the body to lymph nodes where they are filtered. Upon arriving to the lymph nodes, the lymph enters through afferents and pass through the Cortex, where B cells are located, the Paracortical, where T cells are located, and the Medulla, where Plasma cells are located. They then finally exit through efferents. These lymphs go across the body passing through several lymph nodes that are either Superficial lymphatics (run with veins) or Deep lymphatics(run with arteries)
Example: Lymphatics found in the leg will move up towards the superficial Inguinal lymph nodes found next to the pelvis and then move upwards towards the Deep lymph nodes found at the aorta which then feeds into the one found at the Thoracic duct and finally feed into the Subclavian veins
Where are the main lymph nodes located? Up top down
- Cervical Nodes: Along course of internal Jugular Vein
- Pericardial Ring: Base of Head
- Tracheal Nodes: Nodes along the trachea and bronchi
- Axillary Nodes: Arm pits (Axilla)
- Deep Nodes: Nodes along the Aorta, Celiac Trunk, and Superior and Inferior Mesenteric Arteries
- Inguinal Nodes: Along the Course of Inguinal ligament (near pelvis)
- Femoral Nodes: Along Femoral Vein
Describe the pathway of lymph within lymph nodes along with its parts
Upon arriving to the lymph nodes through the afferent vessel, it passes through the Cortex, where the B cells are located, the Paracortical, where the T cells are located, and the Medulla where plasma cells are located and then finally exit through the efferents
Draw the pathway of the Lymph from the leg till its end point.
- Lymphatics begin in the legs
- Superficial Inguinal lymph nodes
- Deep Lymph nodes
- Thoracic Duct
- Subclavian Veins
Erythrocytosis
Too many RBCs
Define Anemia with one symptom
Erythrocytes below reference level, may cause fatigue due to lack of oxygen
Name the 5 types of Leukocytes
Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes
Describe Neutrophils (including staining and function) What does a high count of neutrophils indicate?
Most common type of WBC. It cannot be stained and hence neutral. They are the phagocytic and are the first line of defense against bacterial infection. Neutrophils last longer at the site of infection than when circulating in the blood. A high count of neutrophils indicates a site of infection.
Discuss Eosinophils.
Eosinophils are the second most common granulocyte and is basic, hence stained by Eosin (acidic). They have a clear multilobe nucleus when stained. Survival in tissue is a lot longer. Granules contain histamine, RNAase, and DNAase to combat viral and parasitic infections.
Describe Basophils
Least Common WBC and acidic hence stained by hematoxylin. When stained, it is hard to distinguish granules from nucleus as DNA is also acidic. It contains large cytoplasmic granules. It synthesizes and stores Histamine and Heparin. It’s release speeds up the removal of fat particles from the blood
Describe monocytes
Monocytes are phagocytes that
- Ingest bacteria by engulfing them.
- Enter tissues and become tissue macrophages.
- Process and remove aged RBCs.
- Are modulators of immune response
- Have a long lifespan when not in circulation. - Are characterized by it’s kidney-shaped nucleus
- Can differentiate into Dendritic Cells and Macrophages
Describe Thrombocytes along with their function.
Also known as platelets, thrombocytes are non-cellular components (cell fragments) of blood with the primary function of clotting or thrombosis. They are the second most numerous blood component and lack nuclei. They have cytosolic enzymes for generating energy. They are stored in blood-filled spaces in the spleen and are released when needed by sympathetically induced splenic contractions. It plats an important role in homeostasis as it seals leaks in blood vessels.
What are the formed elements of the blood
RBCs, WBCs, and Platelets
Erythrocytes, leukocytes, and thrombocytes.
Explain the bone marrow’s role in hematopoiesis/Hemopoiesis along with how it divides its role and why. Trace its production in the bone marrow.
The bone marrow (found in the axial skeleton) is the primary producer of RBCs and WBCs. It divides its work with 1/3 for RBC ans 2/3 for WBCs. Despite the fact that there are a lot more RBC than WBC in the blood, WBC have a much shorter life span. Progenitor Cells divide to produce erythrocytes, leukocytes and megakaryocytes (precursor of of platelets). All peripheral cells are derived from a single multipotent stem cell (adults). Stem cells grow and divide in the bone marrow and once differentiated, they lose their capacity for self-renewal and cell adhesion, which allows them to leave the marrow and enter circulation.
What are Progenitor Cells
They are cells found in the bone marrow that divide to produce RBC, WBC, and megacaryocytes
What are megakaryocytes
Precursors of platelets
What are the Growth Factors involved in Hemopoiesis
Erythropoietin: Stimulates erythrocyte production
Colony stimulating factors and Interleukins: Stimulate WBC production
Thrombopoietin: Stimulates the production of platelets or thrombocytes
The parts of the Axial skeleton where blood is produced is…
Pelvis, Cranium, and Sternum
When more blood is needed what organs assist in hematopoiesis?
Liver, thymus, and spleen
What Are the stages of Erythropoiesis
- Proerythroblast: Large nucleus with DNA to make RNA
- Basophilic (early) Erythroblast: Staining is stronger as RNA production is increased
- Polychromatic (intermediate) Erythroblast: Hemoglobin (protein) is being produced
- Orthochromatic (late) Erythroblast: Nucleus becomes significantly smaller to make room for more hemoglobin and gets excluded
- Reticulocyte: RBC will enter circulation and still has ribosomes left to finish hemoglobin production
- Mature RBC: Loses ribosomes occupying all space by hemoglobin and forming biconcave shape
Describe the Characteristics of Erythrocytes
Erythrocytes have a flat, biconcave, disc shaped structure which allows for an increased surface area. This aids in the exchange of gas’s between the blood and cell/tissue making it more efficient. RBCs also lack a nucleus which allows for flexibility when passing through capillaries and more space for hemoglobin.
Describe the Life Cycle of Erythrocytes
The life span of erythrocytes is approximately 120 days. RBCs are removed by macrophages such as monocytes and hemoglobin components are recycled:
- Globin is reutilized in amino acid formation
- Iron is reutilized to form more RBCs
- Heme is excreted in bile
RBC count indicates
Anemia and Polycythemia
Reticulocytes indicate
Erythropoietic activity in the bone marrow
Packed cell volume/Hematocrit Measures….
The fraction of blood occupied by RBC
Hemoglobin count indicates…
Iron Binding Capability
Mean Cell Volume measures
Volume of average RBC
Mean Cell Hemoglobin measures
Concentration of Hb in average RBC
Mean Cell Hemoglobin Concentration measures…
Concentration of Hb per dL of RBC
Discuss Anemia (without classification)
Anemia is classified as the deficiency of Hemoglobin/RBC in the blood. It occurs with patients who have iron deficiency, blood loss, B12 deficiency, and/or folate deficiency This has several indications: Decreased rate of erythropoiesis Excessive loss of erythrocytes Deficiency in hemoglobin content of Erythrocytes Decrease in Hb (below reference level)
How can we classify Anemia and what are the classifications
We classify anemia based on size and color of RBC:
- Hypochromic (less than normal amount) and Microcytic (smaller than normal)
- Normochromic (Normal amount) and Macrocytic (larger than normal)
- Polychromatophilic (more than normal) amount) and Macrocytic (larger than normal)
Describe Hypochromic and Microcytic Anemia
It describes anemia with iron deficienct or chronic disease.
- Iron deficiency: Iron deficiency caused by blood loss in adults can occur through trauma/bleeding or chronic blood loss such as menstrual bleeding and digestive tract bleeding. These prevent the body from reusing the iron and hence more intake is required. Another cause is lack of iron in diet.
- Anemia of chronic disease:
- Inflammatory Diseases: Causes the impairment to erythropoietin which is the growth factor for RBC production. During these conditions, there is an increase in inflammatory cytokines such as interleukin-6 (IL-6) which would cause the increase of hepsidin which will block iron update and absorption.
- Malignancies: Also causes impairment of EPO (erythropoietin) response due to cytotoxic treatments used to treat cancer which targets bone marrow
- Chronic Kidney Disease/Chronic Heart Failure: This prevents stimulation of RBC production by reducing renal flow which decreased production of EPO
Describe Normochromic and Macrocytic Anemia
Caused by vitamin B12 and folate deficiency. This deficiency occurs due to the lack of the gastric intrinsic factor which forms a complex with vitamin B12 for absorption or malnutrition. This causes RBCs to grow large and with odd shapes. The effects of this deficiency with anemia include
- Symmetrical feeling of tingling in the feet
- Loss of the sense of vibration
Occasional muscle weakness which causes difficulty in walking
How is Vitamin B12 absorbed in the body?
B12 is only absorbed when in a complex with the Gastric Intrinsic Factor (GIF) which is a glycoprotein secreted by parietal cells in the stomach. This complex cannot be broken down and is absorbed by a specific receptor found on cells in the ileum.
Discuss Polychromatophilic and Macrocytic Anemia
This is caused by hemolytic anemia which causes the reduced lifespan of erythrocytes where the rate of destruction exceeds the rate of production. These anemias can occur through genetic disorders that affect the shape of the RBC such as sickle cell anemia as well as acquired disorders such as immune system disease where there is an ABO or Rh incompatibility with blood transfusion.
What is Polycythemia and what are the primary types of it?
Polycythemia is characterized by having too many circulating RBCs. It can be indicated by increased Hb or RBC count above reference levels. The 3 types are:
- Primary Polycythemia
- Secondary Polycythemia
- Relative polycythemia
Discuss Primary Polycythemia giving an example
This occurs due to intrinsic factors to RBC precursors caused by an acquired or inherited mutation showing a tumor-like condition of the bone marrow with uncontrollable rate of production.
An example of this is polycythemia Vera which is a genetic aberration in the RBC precursor cells. This causes for excess production beyond what is sufficient for plasma circulation causing sluggish and slow circulation which increases the workload of the heart. Chemotherapy treats this.
Discuss Secondary Polycythemia
Physiological type of polycythemia which occurs as a mechanism to improve the blood’s oxygen-carrying capacity in response to prolonged reduction in oxygen delivery to the tissue. This occurs in high altitude athletes
What is Relative Polycythemia
This occurs when the body loses fluid and not RBCs. Too little plasma but good amount of RBCs
LEARNING OUTCOME: Explain the Clinical Evaluation of Anemia
Anemia is classified as the deficiency of hemoglobin in the blood. During clinical evaluation several indices may be examined:
- Blood Count (RBC indices), Hemoglobin concentrations in MCV, MCH, and MCHC
- Reticulocyte index
- Determination of acuteness or chronicity
Clinical signs of anemia include the following:
• Fatigue and weakness
• Pallor: Abnormal loss of skin or mucous membrane layer (ex. The eye)
• Koilonychia: Upward curvature of nails
• Angular stomatitis: Deep cracks and splits formation at the corners of the mouth
• Glossitis: Inflammation or infection of the tongue
LEARNING OUTCOME: Discuss the role of Heme in Oxygen Binding
Multicellular organisms need to transport and store O2 for aerobic metabolism. The heme group (found in both Hb and Mb) is tightly bound to proteins and allows them to bind oxygen to them. The heme group consists of a Protoporphyrin Ring consisting of Fe2+ which is held into position by 4 Nitrogen atoms
LEARNING OUTCOME: Describe the Structure and Function of Myoglobin
Structure: Compact protein
- Consists largely of alpha helices
- Hydrophilic exterior and hydrophobic interior with the exception of histidines
- Heme group positioned between 2 His groups binding to the proximal His and intermolecularly bound to the distal His
- Oxygen binds between the heme group and the distal His causing structural change between the heme and proximal His.
Function: O2 reservoir within heart & skeletal muscle cells to be released when O2 supply is insufficient
LEARNING OUTCOME: Describe the Structure and Function of Hemoglobin
3- Describe the Structure and Function of Hemoglobin (Hb):
Structure: 4 identical polypeptide chains (2 alpha and 2 beta chains or one alpha dimer and one beta dimer) - Each chain consists of a heme group => can bind 4 oxygens - Subunits held together by intermolecular interactions (non-covalent) => can be flexible and hence adds to the flexibility of the RBC
Function: Transports O2 to tissues and Transports CO2 and protons (H+) away from tissues
What does the Oxygen dissociation curve represent?
It represents how Hb and Mb bind to oxygen and their affinities.
Describe the normal dissociation Trend of Mb as PO2 increases
As PO2 increases there is a steep increase in % saturation with O2 and since Mb can only bind with one O2 there is no further binding and hence no co-cooperativity.
Compare Adult and Fetal Hb Values
Adults have less affinity than fetal Hb (To the right) and hence O2 can pass from maternal RBCs to Fetal RBCs.
What are the Co-Cooperativity and Allosteric Effects of Hb
- Heme-Heme Interaction
- Bohr Effect
- 2,3 Bisphosphoglycerate (2,3-BPG)
Discuss Heme-Heme interactions and the dissociation curve of Hb
Since Hb has 4 oxygen binding sites, it also has a sigmoid curve which is indicative of it’s COOPERATIVE BINDING. When one oxygen binds to a heme group, the other heme groups become more receptive and will bind following oxygen to other heme groups a lot easier. This is due to the structural changes that occur in Hb when oxygen binding occurs. Hb is in a Tense Form when there are no O2 molecules bound to the Hb and hence low affinity to O2 yet high affinity when in the relaxed form with up to 4 O2 molecules bound to it.
Discuss the Bohr Effect:
As cellular respiration increases, PCO2 increased which causes the pH to decrease which then causes the affinity to O2 to decrease. This allows O2 to be released more easily which shifts the curve to the right. This maximizes the efficiency of oxygen handling by Hb as it releases oxygen to cells that require O2 the most.
Discuss the effects of Bisphosphoglycerate
It is present in erythrocytes at equimolar concentration to Hb. It binds to deoxygenated Hb only forming salt bridges with positively charged residues between the Beta polypeptide chains in the central cavity decreasing its affinity for O2. This binding stabilized the Taut conformation (T) which causes the curve to move to the right. This can be reverted through oxygenation removing the cavity allowing Hb to have even higher affinity than it originally had. The body regulates the amount of 2,3-BPG in the blood to regulate oxygen affinity.
NOTE: As concentrations of 2,3-BPG increases, affinity of O2 decreases and hence O2 delivery to tissues increases. This tends to occur at high altitudes just.
What is included in CADET and what does this do?
The increase of CO2, Acid, DPG (another word for 2,3-BPG), Exercise, and Temperature shift the curve to the right which causes less oxygen affinity and more oxygen delivery
Outline the Metabolic Capability of RBCs
Erythrocytes have the ability to perform the Pentose-Phosphate Pathway which allows for the prevention of Oxidative stress by ROS (Reactive Oxygen Species) which, in turn, prevents hemolysis
LEARNING OUTCOME: Discuss the Molecular Basis of Sickle Cell Anemia giving rise to its clinical consequences, diagnosis, and treatment
Sickle Cell Anemia: Sickle cell anemia is caused by a point mutation that occurs in the beta chain in Hb from Glutamate to Valine. This causes the valine to adopt a Sticky patch in low O2 conditions which significantly reduces cell flexibility. This causes hydrophobic interactions to occur between Hb subunits which leads to stacking into long fibers. These fibers distort the erythrocyte into a sickle shape causing the blockage of capillaries and Anoxia (or lack of oxygen reaching tissues) which, in turn, causes pain and cell death. It is precipitated (occurs more often, other than genetically) through dehydration and infection.
Clinical Consequences:
• Bone pain (sickle cells stuck in capillary beds)
• Chronic anemia (destruction of erythrocytes)
• Organ damage (kidneys, heart, & lungs)
• Cerebrovascular accidents
Diagnosis: Protein or DNA analysis
Treatment:
• Treat symptoms
• Hydration, Analgesics (pain killers), and aggressive antibiotics
• Blood transfusion
• Hydroxyurea (raises fetal hemoglobin levels HbF)
Explain Sickle Cell Anemia
Sickle cell anemia is caused by a point mutation that occurs in the beta chain in Hb from Glutamate to Valine. This causes Valine to adopt a sticky patch in low O2 conditions which significantly reduces cell flexibility. This then causes hydrophobic interactions to occur between Hb subunits which leads to stacking in long fibers. These fibers distort the erythrocyte into a sickle shape causing blockage of capillaries and Anoxia (lack of oxygen reaching tissues) which causes pain and cell death.
It can occur non-genetically through dehydration and infection.
What is Anoxia
Lack of Oxygen reaching tissues
What are the Clinical Consequences of Anemia (name 3)
- Bone pain (sickle cells stuck in capillary beds)
- Chronic Anemia (Destruction of Erythrocytes)
- Organ Damage (Kidneys, heart, and lungs)
- Cerebrovascular accidents
How is Sickle Cell Anemia Diagnosed
Through Protein or DNA analysis
How do you Treat Sickle Cell Anemia Patients (mention 3)
- Treat symptoms (clinical consequences)
- Hydration
- Analgesics (pain killers)
- Aggressive antibiotics
- Blood transfusion
- Hydroxyurea (Must include this)
LEARNING OUTCOME: Discuss the Molecular Basis of Glucose-6-Phosphate Dehydrogenase Deficiency
It is a metabolic enzyme that affects NADPH production. NADPH minimizes damaging effects of ROS (Reactive Oxygen Species) such as H2O2. ROS causes Oxidative Stress on cells by attacking DNA, protein, and lipids.
Deficiency of G6PD impairs the ability of the Erythrocyte to form NADPH which results in Hemolysis (cell death). Oxidative stress leads to Hemolytic Anemia (where body destroys more RBC than it produces)
Factors that increase Oxidative Stress include:
- Oxidant Drugs
- Favism (ingestion of Fava beans)
- Infection which causes inflammatory response leading to the generation of free radicals
- Neonatal Jaundice: Impaired catabolism of heme or increased production of Bilirubin
Hemolysis
Cell Death
Analgesics
Pain Killers
Neonatal Jaundice
Impaired catabolism of heme or increased production of bilirubin
What factors increase oxidative stress
Factors that increase Oxidative Stress include:
- Oxidant Drugs
- Favism (ingestion of Fava beans)
- Infection which causes inflammatory response leading to the generation of free radicals
- Neonatal Jaundice: Impaired catabolism of heme or increased production of Bilirubin
What does an increase of Oxidative Stress cause in terms of RBCs
Hemolytic Anemia (where the body destroys more RBCs than it produces)
LEARNING OUTCOME: Explain the Mechanism of Action of Hydroxyurea in the Treatment of Sickle Cell Disease
Hydroxyurea is traditionally a cancer treatment that changes gene expression levels and is used to increase fetal hemoglobin levels which are not expressed in adults. This allows for production of a normally functioning oxygen supplier to the body to assist in oxygen delivery.
What are the differences between Hb and Mb
- Mb is a storage protein whereas Hb is not
- Mb binds to O2 avidly and dissociates slowly whereas Hb carries Oxygen and transports them through RBC to the tissues to be released
- Mb is not co-operative as it only has one Heme group when compared to Hemoglobin’s 4 heme groups where when one oxygen binds to the protein, the next will bind more easily and better
- Mb is only 1 polypeptide whereas Hb has 4.
- Hb dissociates at a higher partial pressure than Mb
What is the distribution and composition of Body fluids in the body?
Extracellular fluids make up 20% but is split into plasma (5%) and interstitial fluid (15%). Plasma and interstitial fluid have the same electrolyte composition but plasma has additional protein anions. The dominant cation is Na+ and the dominant anion is Cl- with a smaller amount of HCO3-
Intracellular fluid make up 40%. Dominant cation is K+ and dominant anion is PO4^3- with a smaller amount of protein anions.
How is the composition of fluids in the ECF maintained at a constant level? Give an Example
Constancy of ECF composition is critical for cell function and is maintained by homeostasis. Everyday activities of the body changes the composition of the ECF. Homeostasis is controlled by Negative feedback ex. Glucose and insulin
How is the composition of body fluids in the ICF maintained at a constant level? Give an Example
Constancy of ICF is important for cell function as ionic strength has a major influence on Cellular Reactions. This constancy is maintained by Cell Mechanisms. The cell membrane separates ICF from ECF which maintains concentrations of electrolytes and hence water by osmosis. Ex Na/K pump
What is Osmotic Pressure?
The Osmotic Pressure of body fluids is a measure of the tendency of water to move into that solution due to relative concentrations but does not tend to happen since the osmotic pressure of ICF and ECF are similar. It is determined by number of particles and not mass. It is measured by OSMOLES (osm)=1 mole (mol)
What is the osmole concentration of 1 mole of glucose
1
What is the osmole concentration of 1 mol of NaCl
2
What is the osmole concentration of 1 mole of Na2SO4
3
What is the osmole concentration of CaCl2
2
What is the difference between Osmolarity and Osmolality
Osmolarity is expressed in Osmol/L of a SOLUTION
Osmolality is expressed in Osmol/Kg do a SOLVENT
The Osmolarity of body fluid is…
283 +/- 11 mOsmol/L
What is used clinically Osmolarity or Osmolality
Osmolality
Disturbances to water balance control are caused by:
- Diabetes Mellitus
- Dehydration
- Diabetes Insipidus
How does Diabetes Mellitus affect Water Balance
Diabetes Mellitus results from a deficiency of circulating insulin characterized by Hyperglycemia. Glucose is osmotically active and hence an increased amount of glucose causes water to shift into the plasma causing intracellular dehydration which affects cell function. This will also cause the patient to have Polyurea or glucose in urine, increased urination, and suffer from dehydration.
Hyperglycemia
High levels of glucose
How does Dehydration affect water balance
Due to insufficient water intake or excessive water loss due to heavy sweating, vomiting, or diarrhea. This causes water deficiency in the blood and in the tissues impairing cell function and metabolism
How does Diabetes Insipidus Affect water balance distribution
Diabetes Insipidus is characterized by a deficiency in Vasopressin which reduces urinary output to conserve water in the body. This leads to dehydration.
What are the Effects of Dehydration
Effects of Dehydration: Symptoms are mainly neurological as water loss from brain cells leads to shrinkage of cells:
Water content of ECF decreases -> Osmolarity of ECF increases -> Water leaves cells -> Osmolarity of ICF increases -> Disruption of cellular function
1. Mild Cases: Dry skin, Dry tongues, and Sunken Eyeballs
2. Moderate Cases: Mental confusion, Irrationality
3. Severe: Delirium, Convulsions, Coma
4. Non-Neural Symptoms: Circulatory disturbances: Vary from slight lowering of blood pressure to circulatory shock and death
What are the effects of Overhydration
Effects of Overhydration: Excess Excess water in ECF => Osmolarity of ECF decreases => Water moves into cells => Osmolarity of ICF decreases => Disruption of cellular function. Usually does not occur as any surplus of water is excreted immediately through urine. It does occur, however in:
- Patients with Renal Failure
- Low body mass infants
- Marathon runner who drink water only (must take electrolytes with it)
- Overheating (Overexertion/MDMA-Ecstacy)
- Syndrome of Inappropriate Vassopression/ADH Secretion (Opposite of Diabetes Insipidus => too much secretion)
What are the Symptoms of overhydration
Symptoms Include: Symptoms related mainly to water entry into brain cells making them swell
- Mild & Moderate: Confusion, Lethargy (fatigue), headache, dizziness, vomiting
- Severe: Coma and death
- Non-Neural Symptoms: Weakness (swelling of muscle cells) and Circulatory disturbances (Expansion of plasma volume)
Explain how Tonicity of Solutions is determined
Tonicity is a measure of the osmotic pressure gradient of 2 solutions seperated by a semi-permeable membrane. Solutes that are able to flow freely across plasma do not affect tonicity as they will automatically reach equilibrium. WATCH THE UNIT
Talk about hypertonic, isotonic, and hypotonic cuz you know it already lmao
LEARNING OUTCOME: Describe the Main Components of Blood
We are able to observe blood through the centrifugation which will separate blood into 3 main parts with the lightest being on top. Blood is composed of:
• Plasma: Largest component of blood - Contains water, proteins, electrolytes - Serum may be produced after clotting removing proteins
• Buffy Coat: Smallest component of blood - Formed Element - Found in the middle of the centrifuge - Composed of Leukocytes and Platelets
• Erythrocytes: Heaviest component of blood - Contains RBCs
Erythrocytes:
• Also known as red blood cells, erythrocytes contain hemoglobin (Fe) and has the primary function of carrying and transporting oxygen (and some CO2) throughout the body.
• They do not replicate. They are disposed off in the spleen
• Erythrocytes have a flat, donut shaped, structure which allows for an increased surface area. This aids in the exchange of oxygen and CO2 between the blood and cell/tissue. It lacks a nucleus which allows for this shape to occur.
• Too many Erythrocytes cause a condition called erythrocytosis. Too little causes Anemia which causes fatigue due to the lack of oxygen
Leukocytes:
• Also known as white blood cells, leukocytes are large blood cells that serve the immune system function. Their primary function is to fend off and eliminate pathogens and infection
Thrombocytes:
• Also known as platelets, thrombocytes are non-cellular (non-living) components of blood with the primary function of clotting or thrombosis
Hematopoiesis
Hematopoiesis is the process in which hematopoietic stem cells give rise to blood cells
LEARNING OUTCOME: Outline the Derivation of Cellular Elements of Blood
Hematopoiesis is the process in which hematopoietic stem cells give rise to blood cells. Embryos have pluripotent stem cells that can turn into any type of cell (blood cell) but adults only have multipotent stem cells that can only turn into a select few. In both cases these stem cells become unipotent stem cells that undergo a process to become the desired blood cell type.
What are the Primary and Secondary lymphoid organs
Bone Marrow
Thymus
Lymph Nodes
Spleen
MALT
What are the main functions (not each one) of the lymphoid tissues/organs
Lymphoid tissues/organs are responsible for immune system function. Primary lymphoid tissues include the bone marrow and the thymus. They are responsible for the production and maturation of lymphocytes. The secondary lymphoid tissues include the lymph nodes, spleen and MALT. They are responsible for detecting infection, handling blood, maintenance, and protection against infection.
Describe the Location and Function of the Bone marrow. Also give the function of what they produce.
Bone marrow found in the axial skeleton is a primary lymphoid. It’s primary function is the production of B-lymphocytes.
B lymphocytes are responsible for the body’s Humoral Immune Response. B cells proliferate to generate antibodies against an antigen presented by pathogens or infecting bodies. They also produce memory cells which allow for a quicker and more efficient immune response if the same infection occurs again.
Describe the location and function of the Thymus gland. Also give the function of what it produces.
The Thymus gland is a primary lymphoid organs that is found in the front of the thorax anterior to the heart. T cells are responsible for the Cellular Immune Response where they identify and destroy already infected cells.
Where is the Thymus Gland Located
Found in the front of the thorax and anterior to the heart
What is the Humoral Immune Response
It is where B-lymphocytes produce antibodies in response to antigens presented by pathogens or an infecting body
What is the Cellular Immune Response
It is where T-lymphocytes identify and destroy already infected cells.
Where is the hematopoietic bone marrow located
Axial Skeleton
What are lymph nodes and where are they located? Indicate its functions.
Lymph nodes are secondary lymphoid tissues that are found within capillary beds that carry a high concentration of lymphocytes. Their functions are:
- Carry excess fluid back to the venous system
- Act as strainers filtering pathogenic material, cancer material, and large objects from entering the blood (causes swelling when infected)
Describe the spleen with its location. Explain it’s function
The spleen is a secondary lymphoid organ located behind the left ribs and next to the stomach. It is highly vascular which can cause heavy bleeding from trauma. The spleen is contained within a capsule and has white and red pulps where it stores a high concentration of lymphocytes and disposes of RBCs.
Describe MALT giving its location and function.
How is MALT different between children and adults
MALT or Mucosa Associated Lymphoid Tissue is located in the Tonsils and Peyer’s patch in the small intestine. It contains a large amount of B and T lymphocytes to fight infection.
More MALT is found in children when compared to adults as children explore the world with their mouth.
What Does MALT Stand For
Mucosa Associated Lymphoid Tissue
LEARNING OUTCOME: Describe the Primary and Secondary Lymphoid Organs
Lymphoid tissues/organs are responsible for the immune system function. The primary lymphoid tissues include bone marrow and thymus which are involved in producing and maturing lymphocytes (B and T cells). The secondary lymphoid tissues include lymph nodes, spleen, and MALT which are responsible for detecting infection, handling blood and maintenance, and protection against infection.
Bone Marrow: Primary lymphoid - Found in the Axial Skeleton - Responsible for the production of B lymphocytes (B cells) - B cells are responsible for the Humoral Immune Response which involves the production of antibodies in response to antigens presented by the pathogens or infecting body - Also responsible for the production of memory cells/antibodies which allow for a quicker and more efficient response if the same infection occurs again - Researchers are using this to fight COVID
Thymus Gland: Primary lymphoid - Found in the front of the thorax and anterior to the heart - Responsible for the production of T lymphocytes (T cells) - T cells are responsible for the cellular immune response where they identify and destroy already infected cells - Major components are Cortex (outer tissue, dark staining) and Medulla (inner tissue, paler staining)
Note: B cells cannot recognize when a pathogen has already invaded a cell, so the T cells handle infected cells
Lymph Nodes: Secondary lymphoid - Located within capillary beds - Responsible for carrying excess tissue fluid back to the venous system - High concentration of lymphocytes - They act as strainers preventing larger substances and infectious material from passing - Will enlarge when infected
Spleen: Secondary lymphoid - Located behind the left ribs, next to the stomach - Extremely vascular and can cause heavy bleeding after trauma - Young people can handle keeping BP stable with a sudden drop later but elders will have a steady decline in blood pressure - Responsible for filtering the blood from foreign antigens - The spleen is contained within a capsule and has white pulp for WBCs and red pulp for RBCs (check diagram)
MALT: Secondary Lymphoid - Located in the Tonsils and Peyer’s patches in the small intestine - Known as Mucosa Associated Lymphoid Tissue - Contains B cells and T cells to fight infection- More MALT is found in children rather than adults because they explore with their mouth and hence high risk of infection which causes extreme swelling of the tonsil. This does not affect adults that much if they are removed
LEARNING OUTCOME: Explain the Circulation of Lymphs
The lymphatic system is responsible for carrying tissue fluid back to the venous system. The fluid generally passes through lymph vessels located around the body to lymph nodes where they are filtered. Upon arriving to the lymph nodes, the lymph enters through afferents and pass through the Cortex, where B cells are located, the Paracortical, where T cells are located, and the Medulla, where Plasma cells are located. They then finally exit through efferents. These lymphs go across the body passing through several lymph nodes that are either Superficial lymphatics (run with veins) or Deep lymphatics(run with arteries)
Example: Lymphatics found in the leg will move up towards the superficial Inguinal lymph nodes found next to the pelvis and then move upwards towards the Deep lymph nodes found at the aorta which then feeds into the one found at the Thoracic duct and finally feed into the Subclavian veins
Where are the main lymph nodes located? Up top down
- Cervical Nodes: Along course of internal Jugular Vein
- Pericardial Ring: Base of Head
- Tracheal Nodes: Nodes along the trachea and bronchi
- Axillary Nodes: Arm pits (Axilla)
- Deep Nodes: Nodes along the Aorta, Celiac Trunk, and Superior and Inferior Mesenteric Arteries
- Inguinal Nodes: Along the Course of Inguinal ligament (near pelvis)
- Femoral Nodes: Along Femoral Vein
Describe the pathway of lymph within lymph nodes along with its parts
Upon arriving to the lymph nodes through the afferent vessel, it passes through the Cortex, where the B cells are located, the Paracortical, where the T cells are located, and the Medulla where plasma cells are located and then finally exit through the efferents
Draw the pathway of the Lymph from the leg till its end point.
- Lymphatics begin in the legs
- Superficial Inguinal lymph nodes
- Deep Lymph nodes
- Thoracic Duct
- Subclavian Veins
Erythrocytosis
Too many RBCs
Define Anemia with one symptom
Erythrocytes below reference level, may cause fatigue due to lack of oxygen
Name the 5 types of Leukocytes
Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes
Describe Neutrophils (including staining and function) What does a high count of neutrophils indicate?
Most common type of WBC. It cannot be stained and hence neutral. They are the phagocytic and are the first line of defense against bacterial infection. Neutrophils last longer at the site of infection than when circulating in the blood. A high count of neutrophils indicates a site of infection.
Discuss Eosinophils.
Eosinophils are the second most common granulocyte and is basic, hence stained by Eosin (acidic). They have a clear multilobe nucleus when stained. Survival in tissue is a lot longer. Granules contain histamine, RNAase, and DNAase to combat viral and parasitic infections.
Describe Basophils
Least Common WBC and acidic hence stained by hematoxylin. When stained, it is hard to distinguish granules from nucleus as DNA is also acidic. It contains large cytoplasmic granules. It synthesizes and stores Histamine and Heparin. It’s release speeds up the removal of fat particles from the blood
Describe monocytes
Monocytes are phagocytes that
- Ingest bacteria by engulfing them.
- Enter tissues and become tissue macrophages.
- Process and remove aged RBCs.
- Are modulators of immune response
- Have a long lifespan when not in circulation. - Are characterized by it’s kidney-shaped nucleus
Describe Thrombocytes along with their function.
Also known as platelets, thrombocytes are non-cellular components (cell fragments) of blood with the primary function of clotting or thrombosis. They are the second most numerous blood component and lack nuclei. They have cytosolic enzymes for generating energy. They are stored in blood-filled spaces in the spleen and are released when needed by sympathetically induced splenic contractions. It plats an important role in homeostasis as it seals leaks in blood vessels.
What are the formed elements of the blood
RBCs, WBCs, and Platelets
Erythrocytes, leukocytes, and thrombocytes.
Explain the bone marrow’s role in hematopoiesis/Hemopoiesis along with how it divides its role and why. Trace its production in the bone marrow.
The bone marrow (found in the axial skeleton) is the primary producer of RBCs and WBCs. It divides its work with 1/3 for RBC ans 2/3 for WBCs. Despite the fact that there are a lot more RBC than WBC in the blood, WBC have a much shorter life span. Progenitor Cells divide to produce erythrocytes, leukocytes and megakaryocytes (precursor of of platelets). All peripheral cells are derived from a single multipotent stem cell (adults). Stem cells grow and divide in the bone marrow and once differentiated, they lose their capacity for self-renewal and cell adhesion, which allows them to leave the marrow and enter circulation.
What are Progenitor Cells
They are cells found in the bone marrow that divide to produce RBC, WBC, and megacaryocytes
What are megakaryocytes
Precursors of platelets
What are the Growth Factors involved in Hemopoiesis
Erythropoietin: Stimulates erythrocyte production
Colony stimulating factors and Interleukins: Stimulate WBC production
Thrombopoietin: Stimulates the production of platelets or thrombocytes
The parts of the Axial skeleton where blood is produced is…
Pelvis, Cranium, and Sternum
When more blood is needed what organs assist in hematopoiesis?
Liver, thymus, and spleen
What Are the stages of Erythropoiesis
- Proerythroblast: Large nucleus with DNA to make RNA
- Basophilic (early) Erythroblast: Staining is stronger as RNA production is increased
- Polychromatic (intermediate) Erythroblast: Hemoglobin (protein) is being produced
- Orthochromatic (late) Erythroblast: Nucleus becomes significantly smaller to make room for more hemoglobin and gets excluded
- Reticulocyte: RBC will enter circulation and still has ribosomes left to finish hemoglobin production
- Mature RBC: Loses ribosomes occupying all space by hemoglobin and forming biconcave shape
Describe the Characteristics of Erythrocytes
Erythrocytes have a flat, biconcave, disc shaped structure which allows for an increased surface area. This aids in the exchange of gas’s between the blood and cell/tissue making it more efficient. RBCs also lack a nucleus which allows for flexibility when passing through capillaries and more space for hemoglobin.
Describe the Life Cycle of Erythrocytes
The life span of erythrocytes is approximately 120 days. RBCs are removed by macrophages such as monocytes and hemoglobin components are recycled:
- Globin is reutilized in amino acid formation
- Iron is reutilized to form more RBCs
- Heme is excreted in bile
RBC count indicates
Anemia and Polycythemia
Reticulocytes indicate
Erythropoietic activity in the bone marrow
Packed cell volume/Hematocrit Measures….
The fraction of blood occupied by RBC
Hemoglobin count indicates…
Iron Binding Capability
Mean Cell Volume measures
Volume of average RBC
Mean Cell Hemoglobin measures
Concentration of Hb in average RBC
Mean Cell Hemoglobin Concentration measures…
Concentration of Hb per dL of RBC
Discuss Anemia (without classification)
Anemia is classified as the deficiency of Hemoglobin/RBC in the blood. It occurs with patients who have iron deficiency, blood loss, B12 deficiency, and/or folate deficiency This has several indications: Decreased rate of erythropoiesis Excessive loss of erythrocytes Deficiency in hemoglobin content of Erythrocytes Decrease in Hb (below reference level)
How can we classify Anemia and what are the classifications
We classify anemia based on size and color of RBC:
- Hypochromic (less than normal amount) and Microcytic (smaller than normal)
- Normochromic (Normal amount) and Macrocytic (larger than normal)
- Polychromatophilic (more than normal) amount) and Macrocytic (larger than normal)
Describe Hypochromic and Microcytic Anemia
It describes anemia with iron deficienct or chronic disease.
- Iron deficiency: Iron deficiency caused by blood loss in adults can occur through trauma/bleeding or chronic blood loss such as menstrual bleeding and digestive tract bleeding. These prevent the body from reusing the iron and hence more intake is required. Another cause is lack of iron in diet.
- Anemia of chronic disease:
- Inflammatory Diseases: Causes the impairment to erythropoietin which is the growth factor for RBC production. During these conditions, there is an increase in inflammatory cytokines such as interleukin-6 (IL-6) which would cause the increase of hepsidin which will block iron update and absorption.
- Malignancies: Also causes impairment of EPO (erythropoietin) response due to cytotoxic treatments used to treat cancer which targets bone marrow
- Chronic Kidney Disease/Chronic Heart Failure: This prevents stimulation of RBC production by reducing renal flow which decreased production of EPO
Describe Normochromic and Macrocytic Anemia
Caused by vitamin B12 and folate deficiency. This deficiency occurs due to the lack of the gastric intrinsic factor which forms a complex with vitamin B12 for absorption or malnutrition. This causes RBCs to grow large and with odd shapes. The effects of this deficiency with anemia include
- Symmetrical feeling of tingling in the feet
- Loss of the sense of vibration
Occasional muscle weakness which causes difficulty in walking
How is Vitamin B12 absorbed in the body?
B12 is only absorbed when in a complex with the Gastric Intrinsic Factor (GIF) which is a glycoprotein secreted by parietal cells in the stomach. This complex cannot be broken down and is absorbed by a specific receptor found on cells in the ileum.
Discuss Polychromatophilic and Macrocytic Anemia
This is caused by hemolytic anemia which causes the reduced lifespan of erythrocytes where the rate of destruction exceeds the rate of production. These anemias can occur through genetic disorders that affect the shape of the RBC such as sickle cell anemia as well as acquired disorders such as immune system disease where there is an ABO or Rh incompatibility with blood transfusion.
What is Polycythemia and what are the primary types of it?
Polycythemia is characterized by having too many circulating RBCs. It can be indicated by increased Hb or RBC count above reference levels. The 3 types are:
- Primary Polycythemia
- Secondary Polycythemia
- Relative polycythemia
Discuss Primary Polycythemia giving an example
This occurs due to intrinsic factors to RBC precursors caused by an acquired or inherited mutation showing a tumor-like condition of the bone marrow with uncontrollable rate of production.
An example of this is polycythemia Vera which is a genetic aberration in the RBC precursor cells. This causes for excess production beyond what is sufficient for plasma circulation causing sluggish and slow circulation which increases the workload of the heart. Chemotherapy treats this.
Discuss Secondary Polycythemia
Physiological type of polycythemia which occurs as a mechanism to improve the blood’s oxygen-carrying capacity in response to prolonged reduction in oxygen delivery to the tissue. This occurs in high altitude athletes
What is Relative Polycythemia
This occurs when the body loses fluid and not RBCs. Too little plasma but good amount of RBCs
LEARNING OUTCOME: Explain the Clinical Evaluation of Anemia
Anemia is classified as the deficiency of hemoglobin in the blood. During clinical evaluation several indices may be examined:
- Blood Count (RBC indices), Hemoglobin concentrations in MCV, MCH, and MCHC
- Reticulocyte index
- Determination of acuteness or chronicity
Clinical signs of anemia include the following:
• Fatigue and weakness
• Pallor: Abnormal loss of skin or mucous membrane layer (ex. The eye)
• Koilonychia: Upward curvature of nails
• Angular stomatitis: Deep cracks and splits formation at the corners of the mouth
• Glossitis: Inflammation or infection of the tongue
LEARNING OUTCOME: Discuss the role of Heme in Oxygen Binding
Multicellular organisms need to transport and store O2 for aerobic metabolism. The heme group (found in both Hb and Mb) is tightly bound to proteins and allows them to bind oxygen to them. The heme group consists of a Protoporphyrin Ring consisting of Fe2+ which is held into position by 4 Nitrogen atoms
LEARNING OUTCOME: Describe the Structure and Function of Myoglobin
Structure: Compact protein
- Consists largely of alpha helices
- Hydrophilic exterior and hydrophobic interior with the exception of histidines
- Heme group positioned between 2 His groups binding to the proximal His and intermolecularly bound to the distal His
- Oxygen binds between the heme group and the distal His causing structural change between the heme and proximal His.
Function: O2 reservoir within heart & skeletal muscle cells to be released when O2 supply is insufficient
LEARNING OUTCOME: Describe the Structure and Function of Hemoglobin
3- Describe the Structure and Function of Hemoglobin (Hb):
Structure: 4 identical polypeptide chains (2 alpha and 2 beta chains or one alpha dimer and one beta dimer) - Each chain consists of a heme group => can bind 4 oxygens - Subunits held together by intermolecular interactions (non-covalent) => can be flexible and hence adds to the flexibility of the RBC
Function: Transports O2 to tissues and Transports CO2 and protons (H+) away from tissues
What does the Oxygen dissociation curve represent?
It represents how Hb and Mb bind to oxygen and their affinities.
Describe the normal dissociation Trend of Mb as PO2 increases
As PO2 increases there is a steep increase in % saturation with O2 and since Mb can only bind with one O2 there is no further binding and hence no co-cooperativity.
Compare Adult and Fetal Hb Values
Adults have less affinity than fetal Hb (To the right) and hence O2 can pass from maternal RBCs to Fetal RBCs.
What are the Co-Cooperativity and Allosteric Effects of Hb
- Heme-Heme Interaction
- Bohr Effect
- 2,3 Bisphosphoglycerate (2,3-BPG)
Discuss Heme-Heme interactions and the dissociation curve of Hb
Since Hb has 4 oxygen binding sites, it also has a sigmoid curve which is indicative of it’s COOPERATIVE BINDING. When one oxygen binds to a heme group, the other heme groups become more receptive and will bind following oxygen to other heme groups a lot easier. This is due to the structural changes that occur in Hb when oxygen binding occurs. Hb is in a Tense Form when there are no O2 molecules bound to the Hb and hence low affinity to O2 yet high affinity when in the relaxed form with up to 4 O2 molecules bound to it.
Discuss the Bohr Effect:
As cellular respiration increases, PCO2 increased which causes the pH to decrease which then causes the affinity to O2 to decrease. This allows O2 to be released more easily which shifts the curve to the right. This maximizes the efficiency of oxygen handling by Hb as it releases oxygen to cells that require O2 the most.
Discuss the effects of Bisphosphoglycerate
It is present in erythrocytes at equimolar concentration to Hb. It binds to deoxygenated Hb only forming salt bridges with positively charged residues between the Beta polypeptide chains in the central cavity decreasing its affinity for O2. This binding stabilized the Taut conformation (T) which causes the curve to move to the right. This can be reverted through oxygenation removing the cavity allowing Hb to have even higher affinity than it originally had. The body regulates the amount of 2,3-BPG in the blood to regulate oxygen affinity.
NOTE: As concentrations of 2,3-BPG increases, affinity of O2 decreases and hence O2 delivery to tissues increases. This tends to occur at high altitudes just.
What is included in CADET and what does this do?
The increase of CO2, Acid, DPG (another word for 2,3-BPG), Exercise, and Temperature shift the curve to the right which causes less oxygen affinity and more oxygen delivery
Outline the Metabolic Capability of RBCs
Erythrocytes have the ability to perform the Pentose-Phosphate Pathway which allows for the prevention of Oxidative stress by ROS (Reactive Oxygen Species) which, in turn, prevents hemolysis
LEARNING OUTCOME: Discuss the Molecular Basis of Sickle Cell Anemia giving rise to its clinical consequences, diagnosis, and treatment
Sickle Cell Anemia: Sickle cell anemia is caused by a point mutation that occurs in the beta chain in Hb from Glutamate to Valine. This causes the valine to adopt a Sticky patch in low O2 conditions which significantly reduces cell flexibility. This causes hydrophobic interactions to occur between Hb subunits which leads to stacking into long fibers. These fibers distort the erythrocyte into a sickle shape causing the blockage of capillaries and Anoxia (or lack of oxygen reaching tissues) which, in turn, causes pain and cell death. It is precipitated (occurs more often, other than genetically) through dehydration and infection.
Clinical Consequences:
• Bone pain (sickle cells stuck in capillary beds)
• Chronic anemia (destruction of erythrocytes)
• Organ damage (kidneys, heart, & lungs)
• Cerebrovascular accidents
Diagnosis: Protein or DNA analysis
Treatment:
• Treat symptoms
• Hydration, Analgesics (pain killers), and aggressive antibiotics
• Blood transfusion
• Hydroxyurea (raises fetal hemoglobin levels HbF)
Explain Sickle Cell Anemia
Sickle cell anemia is caused by a point mutation that occurs in the beta chain in Hb from Glutamate to Valine. This causes Valine to adopt a sticky patch in low O2 conditions which significantly reduces cell flexibility. This then causes hydrophobic interactions to occur between Hb subunits which leads to stacking in long fibers. These fibers distort the erythrocyte into a sickle shape causing blockage of capillaries and Anoxia (lack of oxygen reaching tissues) which causes pain and cell death.
It can occur non-genetically through dehydration and infection.
What is Anoxia
Lack of Oxygen reaching tissues
What are the Clinical Consequences of Anemia (name 3)
- Bone pain (sickle cells stuck in capillary beds)
- Chronic Anemia (Destruction of Erythrocytes)
- Organ Damage (Kidneys, heart, and lungs)
- Cerebrovascular accidents
How is Sickle Cell Anemia Diagnosed
Through Protein or DNA analysis
How do you Treat Sickle Cell Anemia Patients (mention 3)
- Treat symptoms (clinical consequences)
- Hydration
- Analgesics (pain killers)
- Aggressive antibiotics
- Blood transfusion
- Hydroxyurea (Must include this)
LEARNING OUTCOME: Discuss the Molecular Basis of Glucose-6-Phosphate Dehydrogenase Deficiency
It is a metabolic enzyme that affects NADPH production. NADPH minimizes damaging effects of ROS (Reactive Oxygen Species) such as H2O2. ROS causes Oxidative Stress on cells by attacking DNA, protein, and lipids.
Deficiency of G6PD impairs the ability of the Erythrocyte to form NADPH which results in Hemolysis (cell death). Oxidative stress leads to Hemolytic Anemia (where body destroys more RBC than it produces)
Factors that increase Oxidative Stress include:
- Oxidant Drugs
- Favism (ingestion of Fava beans)
- Infection which causes inflammatory response leading to the generation of free radicals
- Neonatal Jaundice: Impaired catabolism of heme or increased production of Bilirubin
Hemolysis
Cell Death
Analgesics
Pain Killers
Neonatal Jaundice
Impaired catabolism of heme or increased production of bilirubin
What factors increase oxidative stress
Factors that increase Oxidative Stress include:
- Oxidant Drugs
- Favism (ingestion of Fava beans)
- Infection which causes inflammatory response leading to the generation of free radicals
- Neonatal Jaundice: Impaired catabolism of heme or increased production of Bilirubin
What does an increase of Oxidative Stress cause in terms of RBCs
Hemolytic Anemia (where the body destroys more RBCs than it produces)
LEARNING OUTCOME: Explain the Mechanism of Action of Hydroxyurea in the Treatment of Sickle Cell Disease
Hydroxyurea is traditionally a cancer treatment that changes gene expression levels and is used to increase fetal hemoglobin levels which are not expressed in adults. This allows for production of a normally functioning oxygen supplier to the body to assist in oxygen delivery.
What are the differences between Hb and Mb
- Mb is a storage protein whereas Hb is not
- Mb binds to O2 avidly and dissociates slowly whereas Hb carries Oxygen and transports them through RBC to the tissues to be released
- Mb is not co-operative as it only has one Heme group when compared to Hemoglobin’s 4 heme groups where when one oxygen binds to the protein, the next will bind more easily and better
- Mb is only 1 polypeptide whereas Hb has 4.
- Hb dissociates at a higher partial pressure than Mb
What is the distribution and composition of Body fluids in the body?
Extracellular fluids make up 20% but is split into plasma (5%) and interstitial fluid (15%). Plasma and interstitial fluid have the same electrolyte composition but plasma has additional protein anions. The dominant cation is Na+ and the dominant anion is Cl- with a smaller amount of HCO3-
Intracellular fluid make up 40%. Dominant cation is K+ and dominant anion is PO4^3- with a smaller amount of protein anions.
How is the composition of fluids in the ECF maintained at a constant level? Give an Example
Constancy of ECF composition is critical for cell function and is maintained by homeostasis. Everyday activities of the body changes the composition of the ECF. Homeostasis is controlled by Negative feedback ex. Glucose and insulin
How is the composition of body fluids in the ICF maintained at a constant level? Give an Example
Constancy of ICF is important for cell function as ionic strength has a major influence on Cellular Reactions. This constancy is maintained by Cell Mechanisms. The cell membrane separates ICF from ECF which maintains concentrations of electrolytes and hence water by osmosis. Ex Na/K pump
What is Osmotic Pressure?
The Osmotic Pressure of body fluids is a measure of the tendency of water to move into that solution due to relative concentrations but does not tend to happen since the osmotic pressure of ICF and ECF are similar. It is determined by number of particles and not mass. It is measured by OSMOLES (osm)=1 mole (mol)
What is the osmole concentration of 1 mole of glucose
1
What is the osmole concentration of 1 mol of NaCl
2
What is the osmole concentration of 1 mole of Na2SO4
3
What is the osmole concentration of CaCl2
2
What is the difference between Osmolarity and Osmolality
Osmolarity is expressed in Osmol/L of a SOLUTION
Osmolality is expressed in Osmol/Kg do a SOLVENT
The Osmolarity of body fluid is…
283 +/- 11 mOsmol/L
What is used clinically Osmolarity or Osmolality
Osmolality
Disturbances to water balance control are caused by:
- Diabetes Mellitus
- Dehydration
- Diabetes Insipidus
How does Diabetes Mellitus affect Water Balance
Diabetes Mellitus results from a deficiency of circulating insulin characterized by Hyperglycemia. Glucose is osmotically active and hence an increased amount of glucose causes water to shift into the plasma causing intracellular dehydration which affects cell function. This will also cause the patient to have Polyurea or glucose in urine, increased urination, and suffer from dehydration.
Hyperglycemia
High levels of glucose
How does Dehydration affect water balance
Due to insufficient water intake or excessive water loss due to heavy sweating, vomiting, or diarrhea. This causes water deficiency in the blood and in the tissues impairing cell function and metabolism
How does Diabetes Insipidus Affect water balance distribution
Diabetes Insipidus is characterized by a deficiency in Vasopressin which reduces urinary output to conserve water in the body. This leads to dehydration.
What are the Effects of Dehydration
Effects of Dehydration: Symptoms are mainly neurological as water loss from brain cells leads to shrinkage of cells:
Water content of ECF decreases -> Osmolarity of ECF increases -> Water leaves cells -> Osmolarity of ICF increases -> Disruption of cellular function
1. Mild Cases: Dry skin, Dry tongues, and Sunken Eyeballs
2. Moderate Cases: Mental confusion, Irrationality
3. Severe: Delirium, Convulsions, Coma
4. Non-Neural Symptoms: Circulatory disturbances: Vary from slight lowering of blood pressure to circulatory shock and death
What are the effects of Overhydration
Effects of Overhydration: Excess Excess water in ECF => Osmolarity of ECF decreases => Water moves into cells => Osmolarity of ICF decreases => Disruption of cellular function. Usually does not occur as any surplus of water is excreted immediately through urine. It does occur, however in:
- Patients with Renal Failure
- Low body mass infants
- Marathon runner who drink water only (must take electrolytes with it)
- Overheating (Overexertion/MDMA-Ecstacy)
- Syndrome of Inappropriate Vassopression/ADH Secretion (Opposite of Diabetes Insipidus => too much secretion)
What are the Symptoms of overhydration
Symptoms Include: Symptoms related mainly to water entry into brain cells making them swell
- Mild & Moderate: Confusion, Lethargy (fatigue), headache, dizziness, vomiting
- Severe: Coma and death
- Non-Neural Symptoms: Weakness (swelling of muscle cells) and Circulatory disturbances (Expansion of plasma volume)
Explain how Tonicity of Solutions is determined
Tonicity is a measure of the osmotic pressure gradient of 2 solutions seperated by a semi-permeable membrane. Solutes that are able to flow freely across plasma do not affect tonicity as they will automatically reach equilibrium. WATCH THE UNIT
Talk about hypertonic, isotonic, and hypotonic cuz you know it already lmao
What are IVs?
Intravenous solutions (IV) are chemically prepared solutions given to the patient through injection directly into the blood tailored to the body’s needs and used to replace fluid and/or medications
What are the 3 principle forms of IV
Colloid Solutions
Crystalloid Solutions
Blood Products
Edema
Swelling
What are Colloid Solutions:
Expensive:
They are hypertonic solutions to reduce swelling. They are high molecular weight solutions that reduce abnormal accumulation of fluids in interstitial compartments. They stay almost entirely in the intravascular space for longer than Crystalloids as their contents do not readily cross membranes
How are Crystalloid solutions classified
Tonicity
What Are Isotonic Crystalloid solutions used for
Isotonic saline is used to replace salt loss to maintain water balance. It is given to almost every patient undergoing surgery. Routinely used for rehydration or administration of drugs to patients. When given to dehydrated patients it will redistribute throughout the ECF increasing its volume without altering Osmolarity
What are Hypotonic crystalloid solutions used for
To correct hypermolar state. Given to patients with renal disease who need to be hydrated without additional NaCl
What are hypertonic crystalloid solutions used for
Used to correct hypo-osmolar state or overhydration or to expand plasma volume. They are clear solutions consisting of sterile water and high electrolyte solutions to achieve equilibrium.
What are the sources of water input and output
Sources of Water Input:
• Drinking liquids (largest)
• Eating Solid Food
• Metabolically Produced water
Sources of Water Output:
• Urine (largest)
• Insensible loss (from lungs, evaporation)
• Sweat
• Feces
Usually kept about equal. All output are sensible except insensible lol
Name the Major Types of Plasma Proteins in Blood
Albumin (60%) constitutes for 80% of osmotic pressure of plasma
Globulins (25-30%) Alpha 1, Alpha 2, Beta, and Gamma Globulins
Fibrinogen and Clotting proteins
Regulatory Proteins
What are the methods used to determine the plasma levels of proteins in patient samples
Electrophoresis and Densitometry
Immunoassays
How is Blood prepared for Analysis
Point Care Use: For simple measurements, blood is collected from finger-pricks. Used to measure glucose and cholesterol levels in the blood
Further analysis: Blood is collected in Vaccutainers which are usually then stored in Anti-coagulant that is color-coded according on it’s type. Red for no anti-coagulants for the production of serum since coagulant proteins are attracted to negatively charged glass
Explain the Method of Electrophoresis in determining the plasma levels of proteins
Gel electrophoresis has the role of separating proteins from plasma using agarose gels which separates proteins according to size. The proteins are negatively charged and hence migrate towards the positive node. To do this, plasma is applied to a strip of agarose gel and an electric current is passed through it. This results in the formation of 5 groups of proteins, Albumin, Alpha 1, alpha 2, Beta, and Gamma Globulins Densitometry is then used to determine the amount present using the density/thickness of any family.
Explain the use of Immunoassays in determining the plasma levels of proteins.
Immunoassays are tests that use the specificity of certain antibodies for a particular protein to capture them and detect their levels. We use ELISA to detect levels of proteins in the blood. Steps are as follows:
- Prepare a well plate
- Place the specific antibody into the wells that attaches to a desired protein and then wash
- Spread the plasma in the plate to allow antibody to bind to the protein and wash the plate to remove anything else. Binded proteins will remain
- A second monoclonal antibody is placed into the wells which binds on top of the antigen or desired protein sandwiching it. This antibody is modified to have an enzyme on top which detects how much of the antigen is present in the well and then wash
- Substrate is then added into the well which binds to enzyme and is cleaved to release color. The strength of the color determines how much of the protein is present.
- Using a standard protein concentration curve, we can detect how much protein is present within the plasma at any time
Is electrophoresis and Immunoassays Qualitative or Quantitative
Electrophoresis is qualitative
Immunoassays are quantitative
What are biomarkers
A biomarker is any substance that is used as an indicator of a biological state. These substances, identified in plasma or urine of patients are indicative of disease or health. Clinical medicine uses many abundant plasma proteins as indicators of disease states.
What are Enzyme Activity Assays?
Used in determining the amount of enzymes for certain proteins. This allows us to determine the abundance of the proteins.
Explain What Signs and Symptoms are of high or Low Levels of Albumin
High Levels: Does not occur naturally
Low Levels are caused by:
- Protein malnutrition
- Hepatocellular Disease which causes decreased synthesis
- Nephrotic Syndrome which causes increased loss of albumin through kidney
Hepatocellular Disease
Liver Disease
Nephrotic Syndrome
Kidney Disease and Excess loss of fluid
Explain What Signs and Symptoms are of high or Low Levels of Alpha-1 Anti-Trypsin (Alpha 1 Globulin)
Explain what it is also…
It is the principle Serine Protease Inhibitor in the Plasma and an Elastase Inhibitor.
High levels: occur during inflammation which minimes host tissue damage particularly in the lung
Low Levels: Since its an elastase inhibitor, its deficiency would cause chronic breakdown of tissue which causes decreased elasticity of the lung
Explain What Signs and Symptoms are of high or Low Levels of Haptoglobin (Alpha 2 Globulin)
Also explain what it is…
Haptoglobin binds to free plasma hemoglobin during hemolysis to be recycled.
High Levels: Since Haptoglobin is an Acute-Phase Protein, it will increase with inflammation
Low Levels: Implies diagnosis of Hemolytic Anemia. If Haptoglobin levels are low but no anemia then it is indicative of liver damage
Explain What Signs and Symptoms are of high or Low Levels of Immunoglobulins (Gamma Globulins)
Also explain what it is and what is it made off
They are made by B-lymphocytes in response to recognition of foreign proteins. They are made specific for each foreign particle. Composed of Heavy and Light chains. Heavy chains define the class of immunoglobulins. The light chain is the specific part for foreign particles. This will remain at a low level after infection for along time in case of reinfection.
High Levels: When there is a spike in the gamma region, normal gamma globulins are decreased and the amount of a single monoclonal immunoglobulin will be produced excessively. This is due to a malignant B cell.
Low Levels: Suggest in underproduction of antibodies. Found in certain diseases such as leukemia
Explain What Signs and Symptoms are of high or Low Levels of Fibrinogen
And explain what they are…
Fibrinogen is a large protein synthesized in the liver that plays a central role in blood coagulation or clotting
High levels: indicate inflammation and/or pregnancy
Low Levels: Indicate dysregulated or uncontrolled blood coagulation (Coagulopathy)
Coagulopathy
Dysregulated or uncontrolled blood coagulation
Explain what The Acute Phase Response is and Give an Example of a Positive and Negative Acute Phase Response
The Acute Phase Response is regulated by Acute-Phase Proteins. They are a class of proteins whose plasma concentrations increase or decrease in response to trauma. Local inflammatory cells (neutrophils and macrophages) secrete a number of cytokines into the blood stream. The liver responds by producing a large amount of Acute-Phase reactants. These responses are induced by Malignancy, Autoimmune disease, and Trauma Infections
High levels of Positive Acute Phase proteins are observed in C-reactive proteins and Haptoglobin
Low Levels of Negative Acute Phase proteins are observed in Albumin and Transferrin
This card needs to be checked.
What Are the Three Main Functions of the Immune System?
- Defend against invading microbes and repair ourselves after injury
- Identify and Destroy Cancer cells that arise in the body
- Remove worn-out cells and tissue debris
How to innate cells deal with and destroy threat? Explain how it works
Phagocytosis: Process whereby the cell engulfs pathogens and expel waste products.
How it works:
1. Phagocytes engulf a pathogen which forms a phagosome
2. The fusion of lysosomes with the phagosome creates a phagolysosome
3. The pathogen is broken down by the lysosome’s digestive enzymes
4. Resulting waste material is discharged from the phagocyte by Exocytosis.
They destroy threat by:
1. Engulfing and Killing microbe
2. Sending signals for recruitment
3. Inducing inflammation
Explain the Role of Macrophages in the Immune system
- Macrophages are tissue residents and are present in nearly all tissues
- Patrol for foreign entities
- Functions include Phagocytosis, Antigen presentation, Inflammation
Explain the role of Dendritic Cells in the immune system.
- Tissue resident and Circualting
- They grow branches projections called dendrites which capture pathogens
- They are present in tissues that are in contact with the external environment such as skin and linings of the nose, lungs, stomach, and intestines.
- Immature Dendritic cells are found in the blood circulating
- They are phagocytic.
- Upon infection, they migrate to the lymph nodes and perform Antigen presentation to B and T cells.
List the Immune Cells Found in the Blood and their normal percentage range
- Eosinophils (2-4%)
- Basophils (0.5-1%)
- Neutrophils (60-70%)
- Mast Cells
- Monocytes (2-10%) —> Dendritic Cells and Macrophages
State the Hematopoietic Development of Immune Cells
Talk about the OG stem cells and the difference between Adults multipotent and Embryo Pluripotent stem cells.
The multipotent/pluripotent stem cell divides to produce either a:
Lymphoid Progenitor (Adaptive): Produces lymphocytes
—> B cell progenitor —> Plasma Cell or Memory Cell
Or
—> T cell progenitor —> T Helper Cell (Th) or Cytotoxic T Cell (Tc)
Or
—> Natural Killer Cell (Exception)
Myeloid Progenitor (Innate): Produces Granulocytes —> Neutrophil, Eosinophil, Basophil, Mast Cell, Monocyte (Dendritic Cell or Macrophage
Discuss Natural Killer Cells
Natural Killer Cells: NK cells differentiate from common lymphoid progenitor but act rapidly and hence are considered as Innate but take longer than normal innate cells and hence in a grey area. They do not express Antigen-specific receptors like B and T cells. They play a role in immune surveillance and quickly kill virally infected and tumor cells. They have cytotoxic granules that create pores in target cells causing cell death
LEARNING OUTCOME: List the Prominent Immune Cells Found in the Blood and their normal percentages and then give their primary function. Some cells do not have percentages
• Eosinophils (2-4%): Release Highly toxic granules to kill microorganisms and parasites whilst damaging host during allergic reactions
• Basophils (0.5-1%): Secretes Histamine which promotes blood flow to tissues and Heparin which prevents blood from clotting too quickly
• Neutrophils (60-70%): Phagocytosis
• Mast Cells: Defense against pathogens and wound healing
• Monocytes (2-10%) —> Dendritic Cells and Macrophages: Phagocytosis
Dendritic Cells: Phagocytosis and Antigen presentation
Macrophages: Phagocytosis and Antigen presentation
• B cells —> Memory Cell: Humoral antibody response
• Memory Cell: Allows quick response upon second infection
• T Cell —> T helper cell, Cytotoxic T cell: Cellular Immune Response
T Helper Cell: Help other cells in their immune function
Cytotoxic T Cell: Kill infected or altered cell
Natural Killer Cell: Immune surveillance, create pores in target cells and cause cell death
Where are antibodies released and what are the ways that it completes it’s function?
Secreted by plasma cells to fight infection.
- Neutralisation: Antibody binds to the pathogen or its products and block cell access
- Opsonisation: Antibody binds to the pathogen and and are recognized, ingested, and destroyed by macrophages and neutrophils
- Complement Activation: Antibody binds to bacteria and provide a platform for a complement to bind and become activated to go through metastasis.
What are the specific and Non-specific cells/components of the immune system?
Specific: B cells, T cells, Antibodies
Non-specific: Granulocytes, Monocytes, Macrophages, Dendritic Cells.
How many circulations are in the cardiac cycle
2
Differentiate between systemic and Pulmonary circulation
Systemic is a high pressure circulation that pumps oxygenated blood around the body
Pulmonary is a low pressure, low resistance circulation that pumps deoxygenated blood out to the lungs to be oxygenated.
The average heart rate at rest is
70bpm
The duration of the cardiac cycle is typically… How much is diastole and how much is systole
850 ms
2/5 Systole, 3/5 diastole
Discuss the Electrophysiology of the heart
Cardiac Myocytes are electrically active and are connected by Intercalated Discs. Depolarization quickly spreads from one cell to the next. The Sino Atrial Node (SA) spontaneously generates an action potential and it spreads through both atria causing them to contract. Depolarization spreads to the Atrioventricular (AV) node and is delayed before entering the ventricles to allow for the blood to flow from the atria to the ventricles. This depolarization moves to the ventricles through the Bundles of His and Purkinje Fibers. As the Ventricles contract, pressure rises and blood is ejected from the ventricle
Note: When referring to systole and diastole states of the heart it is usually indicating that of the ventricles and not the atria
What is the best way to view the cardiac cycle
ECG
How do we measure the pressure in the right atrium? The Left Atrium
Jugular Venous Pressure
Pulmonary Capillary Wedge Pressure
Explain the changes in pressure in the Atrium throughout a cycle
A wave: Atrial systole causes increase in pressure
C wave: AV valves close and cusps bulge into atria
X descent: Atria relax, valves no longer budge
V wave: Ventricular systole, atria fill with venous return
Y descent: Blood enters the ventricles and atria relax causing pressure drop
Explain pressure changes in ventricle throughout the cycle
- During diastole, pressure drops to 0 which allows the chamber to enlarge as it relaxes.
- As chamber fills from the atrium, pressure starts to rise slowly.
- Ventricular pressure rises again as atrium contracts and expels blood into ventricle.
- AV valves close and ventricles contract causing pressure to rise. (No ejection as the semilunar valves havent opened yet)
- Once pressure exceeds that of the arterial pressure, there is a period of ejection as blood is expelled
- As ventricle relaxes, pressure drops and there is Isovolumetric Relaxation
Explain pressure changes in Aortic pressure throughout the cycle
Aortic Pressure:
- During ventricular systole, aortic pressure rises to peak systolic pressure of 120
- During diastole, ventricular pressure drops but back flow is prevented by aortic valve
- Elastic recoil of the large elastic arteries drives blood flow forward toward tissues
- As blood flows out towards tissues, aortic pressure drops to diastolic pressure of 80
Explain the changes in ventricular volume throughout the cycle.
Ventricular Volume:
- Ventricle fills during diastole (atrial contraction) and note that atrial contraction adds another 25% of blood
- Isovolumetric Contraction until pressure exceeds aortic (or pulmonary) pressure then ejection phase
- Ejection fraction is approximately 60% of the end-diastolic volume. (Note that there is rapid ejection at first that slows towards the end.
- As pressure drops, filling from the atria begins again
What instruments are used to listen to heartbeats
Stethoscope and Phonocardium
What are the 4 sounds that you hear?
- 1st Heart Sound: Closing of AV valves as the ventricles contract causes vibrations. The sound is low-pitched and relatively long (Lubb)
- 2nd Heart Sound: Rapid snap closing of the aortic and pulmonary valves (semilunar) causing vibrations. The sound is shorter than the first (Dub)
- 3rd Heart Sound: The transition between rapid filling and slow filling of the ventricle
- 4th Heart Sound: Atrial Systole. It is the rapid filling of a stiff ventricle
What is Resting Heart Rate?
Number of times the heart beats per minute while at complete rest. Lowers as fitness improves
What is the Cardiac Output of an individual
• The cardiac output of an individual is the volume of blood ejected from a ventricle per minute in L/min (typically 5). It is the product of stroke volume and heart rate. CO = HR x SV
How is cardiac output controlled and how is it done (briefly)
Cardiac output is controlled by controlling either or both of the heart rate and the stroke volume. This is done by:
- Sympathetic, Parasympathetic, and the Baroreceptor Reflex
- Intrinsic Regulation of the Cardiomyocytes (Next lecture)
- Regulation via Atrial Reflexes
What is the Autonomic Nervous System, what does it control, what types are their and define them.
Autonomic Nervous System (ANS): The ANS controls the multiple systems that maintain normal homeostasis including the heart and it occurs involuntarily. The ANS is split into the Sympathetic nervous system (SNS) or Parasympathetic nervous system (PNS). The only definition is the anatomical one where SNS is Thoraco-Lumbar and PNS is Cranio-Sacral
Rule of Thumb: SNS is fight or flight and PNS is rest and digest
How does the Sympathetic Nervous system work?
What effects does it have on the heart?
How is it Mediated?
Sympathetic Nervous System (SNS):
• Fight or Flight
• Primarily acts via Catecholamines: Noradrenaline released from nerve endings (neurotransmitter) and Adrenaline from Adrenaline gland (hormone)
• Broadly speaking, they will increase heart rate, stroke volume, and increase blood pressure.
• SNS action is mediated via the Alpha and Beta Adrenoceptors. The most important adrenoceptors for the heart are the Beta1 adrenoceptors which are present all throughout the heart namely the SA node, AV node, the Atria, and the Ventricles. These are stimulated by Noradrenaline from Sympathetic nerves AND by circulating Adrenaline in the blood
Myocytes
Cells within the heart tissue that generate tiny electrical impulses that cause the heart to contract
Explain the process of how the heart muscle contracts including the main components that allow it to happen
- The Beta-Adrenoreceptor is a G-protein Couple Receptor linked to Adenylate Cyclase. This increases cAMP which in turn activate PKA.
- The main depolarising current in the SA node is due to the Na/K HCN (hyperpolarizing) which is increased by the binding of cAMP
- In the Myocytes (atria and ventricles), cAMP/PKA increases the entry of Ca2+ into the cells which increases the force of contraction
- The Ca2+ comes from outside the cardiomyocytes through transmembrane flux down it’s concentration gradient activated by cAMP/PKA pathways. This influx of Ca2+ ions induces the release of Ca2+ from intracellular stores.
- Ca2+ is crucial for muscle contraction and binds to Troponin on the thin muscle filament which allows the thick muscle filament to interact.
- Overview: Beta-1 adrenoceptors stimulated by Noradrenaline/Adrenaline —> cAMP concentration increases through enzyme Adenylate Cyclase —> PKA activated —> cAMP and PKA cause influx of Ca2+ ions through transmembrane channel —> Ca2+ induces Ca2+ release from intracellular stores —> Ca2+ binds with Troponin on the thin muscle filament which allows the thick muscle filament to interact
What is a specific components that affects heart rate and force of contraction
- Sympathetic Agonists can be both positive Chronotropes and Inotropes. Positive Chronotropes increase rate, and positive Inotrope increase force of contraction.
- B-Blockers (Atenolol) are negative Chronotropes and Inotropes and hence decrease rate and force of contraction.
Inotrope
Agent that alters force of a muscle contraction
Chronotropes
Agent that alters rate of contraction
Discuss the effect of the PNS on the heart and compare it to SNS
- The SNS and PNS are antagonistic in the heart and will decrease cardiac output
- The PNS acts via Acetylcholine, which acts at Muscarinic and Nicotinic Cholinergic Receptors
- PNS innervation of the heart is via the Vagus Nerve and Cranial Nerve.
- The main Cholinergic receptor in the heart is the M2 (Muscarinic type 2)
- The Vagus nerve innervantes the SA node, the AV node, and parts of the Atria
- The M2 receptor inhibits the Adenylate Cyclase enzyme hence inhibiting cAMP production. It also decreases the Na+ influx and so the rate of depolarization also decreases causing the heart rate to decrease.
- It has a small effect on the force of ventricular contraction via the decrease in cAMP. The atrial effect has little effect on cardiac output
What is the Mean Arterial Pressure?
MAP is the Cardiac output x total peripheral resistance.
Describe the Baroreceptor Reflex and explain the process in which it controls blood pressure
• The Baroreceptor Reflex is a negative feedback loop. Sensory Afferents —> Sensory Processing (in the CNS or brain)—> Effector Efferents
• The Medulla is the primary site for regulating SNS and PNS (vagal) outflow to the heart.
Overview: Blood Pressure Decreases —> Decreased Firing of Baroreceptors —> Central Control (Medulla/Hypothalamus) —> Increase in SNS response and decrease in PNS response —> Increase in force of contraction and Heart Rate —> Increase in Cardiac Output —> Increase in Blood Pressure
Describe the effects of exercise on
Systolic pressure, MAP, Cardiac output, heart rate, stroke volume, Diastolic pressure, peripheral resistance, SNS activity, PNS activity
Then
Describe the Baroreceptor reflex in these conditions
Then answer
What is resting heart rate and what happens as fitness increases.
- Increase in Systolic pressure, Mean Arterial Pressure, and Cardiac Output (Heart rate and Stroke Volume but increase is not indefinite)
- Decrease in Diastolic Pressure and Peripheral Resistance
- SNS activity increases as exercise increases yet PNS decreases
- This, however does not cause the Baroreceptor Reflex to engage as it is perceived as BP is too low and the body need more.
- Resting heart rate is the heart rate present during rest. This decreases as fitness increases but stroke volumes increase
Myocardium
Heart Muscle
Explain the Frank-Starling Relationship
The Frank Starling Relationship:
• The cardiovascular system is a closed system => The amount of blood returning is equal to the amount of blood ejected
• The heart has the intrinsic ability to adopt to changes in blood volume and hence not dependent on external regulation such as nerves
• Frank and Starling conducted experiments to investigate the effect of Filling Pressure on Stroke Volume and found out that the greater the degree of stretch, the greater the force of contraction => Increasing the Preload (ventricular filling) increases the stroke volume. As the Myocardium is stretched, the Actin and Myosin are brought together increasing the stretch. The increased overlap allows for more Cross Bridges to be formed and an increased sensitivity to Ca2+ => Greater Force
Note: Too much stretching causes the number of bridges to fall and hence less force generated
Supine Position
Lying on your back
Prone Position
Lying on your stomach
What is Preload?
Ventricular filling by atrial systole
What factors affect Preload and explain 2 of them
Factors affecting the preload will affect stroke volume and cardiac output:
• Venous Pressure: Increase in blood volume will increase blood pressure in the venous system which will increase the preload
• Gravity: Blood pumping upwards has to work against gravity. Examples include arterial blood to the brain and venous blood returning to the heart. In the Supine Position (lying on your back) venous return increases. Veins have muscles which prevent back flow and only allow blood to move towards the heart. The Muscle Pump: Large veins pass through muscle blocks and are compressed as the muscle contracts displacing blood hence pushing it towards the heart + The Thoracic Pump causes blood to move from the legs into the abdomen during expiration and from the abdomen to the thorax during inhalation => increased activity and exercise increases venous blood return and hence increased preload (Including increased SNS increasing heart rate and stroke volume from last lecture
Note:
Expiration decreases pressure in the abdominal and inspiration decreases Thoracic Pressure (blood will always move to where there is less pressure). SNS, Inotropes, and Preload (including it’s factors) are all different mechanisms and hence additive
• Volume of Blood in Circulation (3rd factor)
• All this causes a shift upwards in Graph 1 above => increasing Stroke Volume and hence preload volume
What is Afterload and how does it affect Stroke Volume?
Afterload and Stroke Volume:
• Afterload is the pressure that the heart must work against to eject blood during systole
• An increase in the pressure in the arterial system causes cardiac output to decrease and hence stroke volume as well
• This pressure causes the end-diastolic volume (volume after contraction) to increase. This, however causes an increased stretch of the ventricles leading to a more forceful contraction the next time
What maintains water intake/water loss balance
Kidney
Vasoconstriction
Constriction of blood vessel
Describe how the body controls Blood volume
- Blood volume is affected by water intake and venous returns
- Water intake/Water loss balance is maintained by the kidney
- Renin-Angiotensin System (RAS): AngII is a potent Vasoconstriction which increases resistance. It also stimulates Aldosterone, increasing Na+ and water reabsorption from urine which causes the expansion of blood volume. (=> AngII constricts blood vessels causing aldosterone to increase reabsorption causing an expansion => increased BP)
- Anti-diuretic Hormone: Released in response to high Osmolality and low volume which drives water reabsorption from kidney (urine) and hence increasing volume by adding water.
- Atrial Natriuretic Peptide (ANP): Opposite of other 2 - Inhibits salt reabsorption and promotes water loss => increasing Osmolality
Increase in Volume = Increase in Blood Pressure = Increase in Preload = Decrease in SNS
True or False
True
Define:
Hemostasis
Thrombosis
Embolus
Hemostasis: Normal response of the vessel to injury by forming a clot that served to limit bleeding proportional to bleeding
Thrombosis: Pathological Clot Formation that results when Hemostasis is excessively beyond what is needed to stop bleeding.
Embolus: A blood clot that has been carries in the bloodstream to lodge in a vessel and clogging it, causing Embolism
Describe Venous Thrombosis
Describe Arterial Thromboses
State the Differences
Venous Thrombosis (Deep Vein Thrombosis): Occurs in the deep veins (normally leg) and caused by blood stasis. It is associated with pain/swelling/redness, but can be symptomless. The venous clot is RBC rich along with clotting proteins and created close to the valves in veins. If the clot becomes detached and enters the blood stream, it can be lodged or stuck in the lungs causing Pulmonary Embolism (Blockade of pulmonary artery by clot originating from other parts of the body)
Arterial Thrombosis: Arterial clots (white clots) are characterized by Plaques underneath epithelial cells (line blood vessels) as opposed to RBC over them in Venous Thrombosis. Excess Plaque buildup causes a blockade in the artery such as in Myocardial Infarction which occurs in the Coronary Artery which leads to the death of heart tissue due to lack of oxygen supply. Similarly, An Ischemic Stroke occurs when an artery leading to the brain is blocked.
Note: Venous clots are more fibrin rich and RBC rich whereas arterial clots are more platelet rich
LEARNING OUTCOME: Review the Major Components of the Coagulation Cascade and the Role of the Intrinsic, Extrinsic, and Final Common Pathways
Extrinsic Pathway (Outside of the Blood vessel) cuz of TF:
- Exposure of tissue factor initiations coagulation cascades. The Tissue factor (TF) lines outside of the blood vessels all over the body which prevents unnecessary exposure to blood which would initiate the cascade unintentionally.
- Xase (10ase) Complex: Once TF is exposed, it acts as a cofactor to the enzyme F VIIa (F7a). FX (F10) will then act as a substrate in this complex creating FXa (F10a). This occurs on the phospholipid layer on the surface of platelets.
- Prothrombinase Complex: FXa (activated form), generated by the Xase Complex now acts as an enzyme along with FVa as its cofactor to act on the substrate Prothrombin forming the product Thrombin.
- The extrinsic Xase complex is rapidly inhibited by anticoagulants or Tissue Factor Pathway Inhibitor. This causes the Prothrombinase Complex to also be blocked. Not enough thrombin gets generated to convert Fibrinogen into Fibrin which means no clot is formed. The tiny amount of thrombin generated is intentional and creates the Thrombin Spark. This activates the Intrinsic Pathway.
Intrinsic Pathway:
- Intrinsic Xase Complex: FXI is activated (into FXIa) by the Thrombin Spark and is converted into FIXa. FIXa then acts as the enzyme along with FVIIIa as its cofactor to convert the FX into FXa.
- Thrombin Burst: As a result of the Intrinsic Xase Complex, a lot of FXa has been generated which is now able to form Thrombin from Prothrombin using the same cofactor FVa.
- Fibrin Burst: Thrombin now acts as an enzyme to convert Fibrinogen into Fibrin (tadaaaa)
Final Common Pathway: Ends in Formation of Crosslinked Fibrin through the enzyme FXIIIa
Explain the 2 problems that can occur to prevent blood coagulation.
- Prothrombin and factors VII, IX, and X (Gla Domains) undergo post-translational modification prior to release into the plasma in a Vitamin K reaction which is essential for normal function otherwise its binding to phospholipid membranes will not occur and hence no clot. Warfarin prevents Gla Domain function in coagulation enzyme which annihilates several reactions to occur within the Extrinsic and Intrinsic Pathways.
- Not all Coagulation Factors are enzymes: FV and FVIII act as cofactors which speed up enzyme reactions. Without these, such as in hemophilia A where they are deficient in FVIII cofactor, reactions might not occur (or rarely occur correctly) which prevents the Intrinsic Xase complex from occurring
What are Agglutinogens
What are Aglutinins
Antigens
Antibodies
LEARNING OUTCOMES: Discuss how blood is prepared for Transfusion and the storage of blood
Blood Processing: Blood is taken by an aseptic technique. It is spun to separate red cells from plasma, platelets, and white cells (to prevent Leucodepletion). Blood is then tested for pathogens and blood type so that it can prevent spread through transfusion (syphilis, Hepatitis B and C, ABO and Rh blood groups). This enables Blood Type Grouping and Cross-Matching to determine the suitable recipient.
Storage: RBCs are then diluted and have preservatives added to them to increase shelf life. Sodium Citrate binds Calcium to prevent clumping and Dextrose provides energy for metabolism
Distinguish Between Grouping and Cross-Matching
- Both occur prior to blood transfusion.
- Grouping: Determining red cell antigens in blood of donor and recipient
- Agglutination: The clumping of cells in the presence of an antibody
- Cross Matching: Mixing of donor and recipient samples of blood. If agglutination occurs then they are incompatible. This ensures no error in ABO grouping of donor or recipient as well as no naturally occurring or immune antibodies active against donor cells. Also ensures that recipient has no naturally occurring or immune antibodies active against donor cells
Explain the Hemolytic Disease of Newborn
Hemolytic Disease of Newborn: This occurs when the mother is Rh-, Father is Rh+, and fetus os Rh+. The transfer of fetal Rh+ antigen to maternal circulation at birth stimulates production of anti-Rh antibodies in mother. In addition to that, the transfer of anti-Rh antibodies to Rh positive fetus across placenta in subsequent pregnancies leads to agglutination and hemolysis of fetal RBCs. This causes anemia, jaundice, and death in baby. The mother is given small treatments of Rh anti-D antibodies (typically after the baby is delivered) to reduce incidence of disease by 90
Describe the muscle that the heart is composed of, explain how the structure supports its function.
Cardiac Muscle: The heart is composed of a unique type of muscle called Cardiac Muscle or Cardiomyocytes:
• Involuntary
• Mostly singularly nucleated
• Striated
• Connected to each other by Intercalated Discs
The Intercalated Discs means that the myocardium is a functional Syncytium (one cell; Atria is one and ventricle is the other). Once one cell depolarizes, current will flow to the adjacent cell via intercalated discs. Depolarization is quick and multidirectional
How does the body transport messages quickly throughout it?
Membrane Potential:
Changes in membrane potentials of excitable cells (neurons and muscles) occurs rapidly and is controlled by changing the permeability to various ions. This allows excitable cells to transport messages via electrical signals or Action Potentials
Describe normal resting potential and the steps in normal action potential
Resting Potential: Fixed anions in the cell with negatively charged species such as proteins and phosphates cannot leave the cell. Na+/K+ always pumps out a net of +1 charge leaving the cell relatively negative.
Action Potential:
1. Initial ligand depolarisation
2. Voltage gated Na channels open (Na influx making the cell positive)
3. Voltage gated K channels open (K efflux making the cell even more negative than it was and then stabilizes at the resting potential
What are the Ion Channels in the Heart
Cardiac muscle involved different channels and currents than nerves but not all cardiomyocytes are the same: The 4 major channels are: • Inward “Funny” Na/K • Inwards Fast Na+ Channels • Inward Slow L-type Ca2+ Channels • Outward K+ Repolarization Channels
Titanic Contraction (twitch)
Really fast contraction that lacks efficient function (of the heart)
Describe the membrane of the SA Node and Explain the process of Depolarization.
Also mention how this is modified
The SA node is the pacemaker because it has a Leaky Membrane and is Unstable which allows it to have a higher resting potential than usual. Steps of the SA Node Action Potential:
1. At rest, Na+ and some K+ leak into the cell slowly depolarizing it.
2. At around -40mv, slow L-type Ca2+ channels open and the cell depolarizes.
3. It is time dependent so after about 200 ms, the Ca2+ channels close and K+ open leading to K+ efflux.
4. Cell depolarizes (and has less down time) and the process starts again.
Notes:
• The Sloping resting phase in the SA node gives rise to the automaticity of the myocardial muscle (heart)
• The Autonomic Nervous System (ANS) affects heart rate via the gradient of the slope. It will increase the gradient of the slope to increase heart rate (SNS) or decrease it (PNS)
What are the differences between SA and AV nodes in terms of depolarization?
- The Sloping phase is not as steep in the AV node, so the rate of the AV node is slower (it also has slightly different ion channels). This allows for increased ventricular filling
- Ventricular cells have a lower resting potential which is -90mV
Explain the steps of depolarization at the AV node
• Action potential is triggered by depolarization spreading via intercalated discs. Steps are as follows:
- Fast influx of Na+ (Voltage gated Na+ channels)
- Initial repolarization K+ => K+ Efflux (Voltage gated K+ channels)
- L-type Ca2+ channels open right after and causes a plateau to occur since it cancels efflux of K+
- Ca2+ channels close, K+ repolarization continues
- Resting potential is achieved
Explain the significance of the Plateaux an Refractory Period
What node does this occur at
The plateaux that is formed allows the ventricle to fully contract and relax before the next action potential arrives and allows enough time to fill up. It also prevents the cardiac muscle from entering Titanic Contraction. This is due to the refractory period and means that the heart must contract rhythmically.
Refractory Periods: After opening, the Na+ channels do not just close, but become inactive for a time and cannot open irrespective of how strong the stimuli is and hence it is an Absolute Refractory Period. This ensures that transmission keeps going in one Direction
Describe the Cardiac Conduiction System
- Depolarization starts in the right atrium at the SA node and spreads via intercalated discs to the left Atria
- The depolarization reaches the AV node and is slowed allowing for increased ventricular filling
- From the AV node, it spreads down the Bundle of His onto the Purkinje Fibers and onto the ventricular muscle
Describe the Conduction Velocity in the various parts of the conduction system
The Speed of conduction depends on the diameter and number of gap junctions: more gap junctions = quicker, larger diameter = quicker
Endocardium vs Epicardium
Endocardium is the inside of the heart and the epicardium is the outside
Define the PR interval
The PR Interval: Depolarization spreads through the AV node towards the ventricle where the AV node is slowed allowing ventricular filling. Slowed conduction produces the PR interval
Describe all the components of the ECG Waveform
P Wave: Represents the first event in the cardiac cycle representing the depolarization of the sinoatrial node. Depolarization spreads through the right and to the left atria. => the P wave is a reflection of SA node activity but not specifically the SA node.
The PR Interval: Depolarization spreads through the AV node towards the ventricle where the AV node is slowed allowing ventricular filling. Slowed conduction produces the PR interval
The QRS Complex: Conduction spreads from the AV node down to the Bundle of His and through the Purkinje Fibers and up through the Epicardium. The spread produces the different QRS complexes in each of the Leads. The QRS complex does not need to have all 3 components.
The Q Wave:
• A negative wave preceding an R wave
• Caused by depolarization of the ventricular septum
• Seen in left pointing leads (I, II, AvL, V5, V6)
The R Wave: An upward deflection whether preceded by a Q wave or not
The S Wave: A deflection below the Isoelectric Line whether preceded by a Q wave or not
The T wave: Depolarization flows from the Endocardium to the Epicardium. Repolarization flows in the opposite direction (Epicardium to Endocardium). As it moves in the opposite direction, the T wave is in the same deflection as the QRS complex. U Waves are small deflections in the same direction as the T wave (unknown origin
how many Leads are there and what are they classified as
12 total Leads classified into
Limb Leads
Augmented Leads
Chest Leads
What are the Bipolar Leads and what do they span?
The Bipolar Limb Leads:
• Lead I: Right arts to Left Arm
• Lead II: Right Arm to Left Leg
• Lead III: Left Arm to Left Leg
What are the Augmented Leads and where do they span
The Augmented Leads:
• Lead AvF: Lead I to Left Leg
• Lead AvL: Lead II to Left Arm
• Lead AvR: Lead III to Right Arm
What Leads show the Anterior Surface Lateral Surface Inferior Surface Right side of the heart
The 12 Lead ECG: Each lead gives us a different view of the heart.
The Anterior Surface is seen in Leads V1, V2, V3, and V4
The Lateral Surface is seen in Leads I, AvL, V5, and V6
The Inferior Surface is seen in Leads II, III, and AvF
The Right Side of the Heart is seen in Leads AvR and V1
