2025 Physiology Exam 2 Flashcards
Lectures 6-11: Cardiovascular, Vascular and Lymphatics, Chemical Senses, Cardiovascular Physiology
Pathway of Heartbeat
Begins in the sinoatrial (S-A) node… has natural and quickest leakage to Na+
Internodal pathway to atrioventricular (A-V) node
Impulse delayed in A-V node and bundle (allows atria to contract before ventricles to give 20% more blood into ventricle (which is already flowing down due to gravity))
A-V bundle takes impulse into ventricles.
Left and right bundles of Purkinje fibers take impulses to all parts of ventricles.
Sinus Node
Specialized cardiac muscle connected to atrial muscle
Acts as pacemaker because membrane leaks Na+ and membrane potential is −55 to −60mV. The constant leak of Na+ makes resting potential to gradually rise
At −55 mV, fast Na+ channels are inactivated.
When membrane potential reaches −40 mV, slow Na+ and Ca++ channels open causing action potential.
After 100–150 msec Ca++ channels close and K+ channels open more thus returning membrane potential to −55mV.
Normal rate of discharge in sinus node is 70–80/min.
A-V node—40-60/min.
Purkinje fibers—15-40/min.
Sinus node is pacemaker because of its faster discharge rate.
Internodal Fibers
Transmits cardiac impulse throughout atria
Anterior, middle, and posterior internodal pathways
Anterior interatrial band carries impulses to left atrium.
Flow of Electrical Impulse
SA Node to Internodal Pathways to AV Node (slows down) to AV Bundles to Purkinje System
Parasympathetic Nerves Effects on Heart Rate
Parasympathetic (vagal) nerves, which release acetylcholine at their endings, innervate S-A node and A-V junctional fibers proximal to A-V node.
Acetylcholine decreases SN discharge and excitability of A-V fibers, slowing the heart rate.
Cause hyperpolarization because of increased K+ permeability in response to acetylcholine (increased negativity inside)
This causes decreased transmission of impulses maybe temporarily stopping heart rate.
Ventricular escape occurs.
Sympathetic Nerves Effects on Heart Rate
Releases norepinephrine at sympathetic ending
Causes increased sinus node discharge
Increases rate of conduction of impulse
Increases force of contraction in atria and ventricles
Norepinephrine increases permeability to Na+ and Ca+, causing a more + resting potential, accelerating self-excitation, and excitability of AV fibers.
The Heart Anatomy
Action Potential of Cardiac Muscle
Know this!!!
Refractory Period
Absolute Refractory - can not excite no matter what
Relative refractory - can excite if the stimulus is more than the original
Results of Action Potential
Ca++ release from T- tubules, which are large, is a very important source of Ca++.
T-tubule Ca++ depends strongly on extracellular Ca++ concentration.
Heart’s T-tubules are bigger than those in skeletal muscle and rich in mucopolysaccharides.
Mucopolysaccharides bind and store Ca++.
Ca++ release from sarcoplasmic reticulum (after stimulation of ryanodine receptors)
Actin-Myosin Cycle Post Ca++ Release
Steps of the actin-myosin cycle
Ca++ release: Nerve impulses trigger the release of Ca++ from the SR.
Ca++ binding: Ca++ binds to troponin C, which shifts tropomyosin.
Cross-bridge formation: Myosin heads bind to actin filaments, forming cross-bridges.
Power stroke: Myosin heads flex, pulling actin filaments into the myosin channel.
ADP release: ADP is released from the myosin head.
ATP binding: ATP attaches to myosin, allowing the cycle to repeat.
Regulation of the cycle
The cycle continues as long as Ca++ ions remain bound to troponin and ATP is available.
Muscle contraction usually stops when signaling from the motor neuron ends.
Muscle fatigue
Muscle contraction can also stop when the muscle runs out of ATP and becomes fatigued.
Cardiac Cycle
Systole: ventricular muscle stimulated by action potential and contracting (electrical conducting system)
Diastole: ventricular muscle reestablishing Na+/K+/Ca++ gradient and is relaxing
EKG
P: atrial wave
QRS: Ventricular wave (hides the atria repolarization)
T: Ventricular repolarization
KNOW THIS GRAPH… tells all need to know about the Cardiac Cycle
Ventricular Pressure and Volume Curves
Diastole
Isovolumic relaxation
A-V valves open
Rapid inflow
Diastasis—slow flow into ventricle
Atrial systole—extra blood in and follows P wave
Accounts for 10–25% of filling
*** Coronary arteries get filled during the diastole due to the back fill of blood
Systole
Isovolumic contraction
A-V valves close (ventricular press > atrial press)
Aortic valve opens
Ejection phase
Aortic valve closes
Ejection Fraction
End diastolic volume = 120 mL
End systolic volume = 50 mL
Ejection volume (stroke volume) = 70 mL
Ejection fraction = 70 mL/120 mL = 58%
(normally 60%)
If heart rate (HR) is 70 beats/minute, what is cardiac output?
Cardiac output = HR * stroke volume = 70/min * 70 mL = 4900 mL/min
Way to Increase Blood Pumped by Heart in a Minute
Chronotropic = beat faster, contract more often
Inotropic = beat harder, contraction harder
However, blood can only pump out the amount of blood it receives = Preload = Venous Return
Afterload
Amount of blood/pressure to be pumped against
Ex. Left Ventricle = pressure in the Aorta
Preload
Amount of blood the heart receives
Aortic Pressure Curve
Aortic pressure starts increasing during systole after the aortic valve opens.
Aortic pressure decreases toward the end of the ejection phase.
After the aortic valve closes an incisura occurs because of sudden cessation of back-flow toward left ventricle.
Aortic pressure decreases slowly during diastole because of the elasticity of the aorta plus blood flow to the periphery.
Valvular Function
To prevent back-flow
The close and open passively, driven by pressure: backward pressure-close; forward pressure-open
Chordae tendineae are attached to AV valves
Papillary muscle, attached to chordae tendineae, contract during systole and help prevent back-flow (keep them tight).
Due to smaller opening, velocity through aortic and pulmonary valves exceeds that through the Avs.
Most work is external work or pressure-volume work.
A small amount of work is required to impart kinetic energy to the heart (1/2 mV2).
What is stroke volume in Figure 9-11?
External work is area of P–V curve.
Work output is affected by “preload” (end-diastolic pressure) and “afterload” (aortic pressure).
Frank-Starling Law of the Heart
More stretch on the heart, more forceful the contractions… to a point because then actin-myosin can’t overlap anymore to help create more forceful a contraction
Within physiological limits the heart pumps all the blood that comes to it without excessive damming in the veins.
Extra stretch on cardiac myocytes makes actin and myosin filaments interdigitate to a more optimal degree for force generation.
Pressure-Volume Diagram
1st Heart Sound = Mitral valve closes
2nd Heart Sound = Aortic valve closes
… Happen during systole
Pressure-Volume Diagram: Preload
Pressure-Volume Diagram: Afterload
Autonomic Effects on Heart
Sympathetic stimulation causes increased heart rate, increased contractility, and vascular tone.
Parasympathetic stimulation decreases heart rate markedly and cardiac contractility slightly.
Vagal fibers go mainly to atria.
Fast heart rate (tachycardia) can decrease cardiac output because there is not enough time for heart to fill during diastole.
ANS = viscera efferent (controls the motor function of viscera)… any internal organ
Viscera = plural organs
Viscus = singular organ
Venous Return and Cardiac Output Must be Equal
Venous return is the quantity of blood flowing from the veins into the right atrium each minute.
… it doesn’t seem to be equal because of how some blood goes to lungs
Cardiac output is the quantity of blood pumped into the aorta each minute by the heart. This is also the quantity of blood that flows through the circulation. Cardiac output is the sum of the blood flows to all the tissues of the body.
Control of Cardiac Output by Venous Return
More the heart receives, the more it will pump out
Cardiac output is controlled by venous return. Various factors of the peripheral circulation that affect flow of blood into the heart from the veins are the primary controllers of cardiac output.
Factors:
Muscle Contraction
Gravity
Size of the lumen of the vessels
Venous Return Curves: Factors Affecting Venous Return
Three principal factors that affect venous return to the heart from the systemic circulation:
Right Atrial Pressure, which exerts a backward force on the veins to impede flow of blood from the veins into the right atrium.
Degree of filling of the systemic circulation (measured by the mean systemic filling pressure), which forces the systemic blood toward the heart (this is the pressure measured everywhere in the systemic circulation when all flow of blood is stopped).
Resistance to blood flow between the peripheral vessels and the right atrium (resistance to venous return)
Resistance to Venous Return
Two thirds of the so-called resistance to venous return is determined by venous resistance, and about one third is determined by the arteriolar and small artery resistance.
A decrease in this resistance to one-half normal allows twice as much flow of blood and, therefore, rotates the curve upward to twice as great a slope.
Conversely, an increase in resistance to twice normal rotates the curve downward to one-half as great a slope.
Venous Resistance is the #1 effector
Q= 1/R
Normal EKG
The P wave immediately precedes atrial contraction.
The QRS complex immediately precedes ventricular contraction.
The ventricles remain contracted until a few milliseconds after the end of the T repolarization wave.
The atria remain contracted until repolarized, but an atrial repolarization wave cannot be seen on the EKG because it is obscured by the QRS wave.
The P-Q or P-R interval on the electrocardiogram has a normal value of 0.16 seconds (0.12–0.20).
It is the duration of time between the beginning of the P wave and the beginning of the QRS wave.
This represents the time between the beginning of atrial contraction and the beginning of ventricular contraction.
The Q-T interval has a normal value of 0.36 seconds (0.36–0.40, QTc ≤ 0.46) and is the duration of time from the beginning of the Q wave to the end of the T wave
This approximates the time of ventricular contraction.
The heart rate can be determined with the reciprocal of the time interval between each heartbeat.
R-R interval = 0.83 sec
Heart rate = (60 sec)/(0.83 sec) = 72 beats/minute
Flow of Electrical Currents in the Chest Around the Heart
Ventricular depolarization starts at the ventricular septum and the endocardial surfaces of the heart.
The average current flows positively from the base of the heart to the apex.
At the very end of depolarization the current reverses from 1/100 second and flows toward the outer walls of the ventricles near the base (S wave).
Vectorial Analysis of EKG
The current in the heart flows from the area of depolarization to the polarized areas (from − to +).
The electrical potential generated can be represented by a vector, with the arrowhead pointing in the positive direction.
The length of the vector is proportional to the voltage of the potential.
The generated potential at any instance can be represented by an instantaneous mean vector.
The normal mean QRS vector is about 59 degrees.
P Wave
Begins at sinus node and spreads toward A-V node.
This should give a + vector in leads I, II, and III.
Causes of Electrical Axis Deviation: Right
Hypertrophy of right ventricle (right axis shift) is caused by pulmonary hypertension, pulmonary valve stenosis, and interventricular septal defect. All cause slightly prolonged QRS and high voltage.
2 Things that Influence BP
Amount of Blood
Size of vessels
What Are the Major Functions of Circulatory System?
Transporting nutrients to the tissues
Transporting waste products away from the tissues
Transporting hormones
What Are the Components of the Circulatory System?
Most Blood is in the Venous System
What Is the Function of the Aorta
and Large Arteries?
What Is the Function of Arterioles?
Slows the BP as they are smaller
What Is the Function of Capillaries?
Internal Respiration
Small to the size RBCs must go through them 1 by 1
What Are the Functions of Large
Veins and Venules?
The reservoir of blood
The Pressure is low
What Is the Function of the Pulmonary Circulation?
Site of gas exchange
External Respiration
Respiratory membrane makes this happen
Which Component of the Circulation Has the Largest Total Cross-sectional Area?
Which Component of the Circulation Has the Highest Velocity of Blood Flow?
Capillaries have smallest velocity of blood
Velocity is inversely proportional to cross sectional area
Blood Pressure Throughout the Circulatory System
Basic Theory of Circulatory Function
Blood flow to tissues is controlled in relation to tissue needs.
Cardiac output is mainly controlled by local tissue flow.
Arterial pressure is controlled independent of either local blood flow control or cardiac output control.
What Is Blood Flow?
There Are Dramatic Variations in Tissue Blood Flow in the Human Body
What Are the Major Determinants of Blood Flow?
Flow is inversely proportional to resistance
Inflammation leads to vasodilation, decrease in resistance, increase in flow
Characteristics of Blood Flow In Vessel
Turbulent Blood Flow
These causes are the causes of blood clots as well
Murmurs - noises in the heart
Bruits - noises in the vessels
What is Blood Pressure
Relationship Between Pressure, Flow, and Resistance
What is meant by Resistance in Blood Vessels
Parallel and Serial Resistance Sites in the Circulation
What Is Vascular Conductance?
How Do Changes in Hematocrit
or Viscosity Effect Blood Flow?
Veins Are Very Distensible!
Veins are 8x more distensible than arteries
What Is Vascular Capacitance?
Veins have more capacitance
Volume–Pressure Relationship in the Circulation
Any given change in volume within the arterial tree results in larger increases in pressure than in veins.
When veins are constricted large quantities of blood are transferred to the heart thereby increasing cardiac output.
Add more volume of blood to arteries as veins, more pressure in arteries due to their structure
What Are Arterial Pulsations?
What Are the Factors That Effect Pulse Pressure? (1 of 2)
What Are the Factors That Effect Pulse Pressure? (2 of 2)
Systolic and Diastolic Pressures in the Peripheral Circulation
Measurement of Systolic and Diastolic Pressures
First noise is the Systolic
Once noise disappears, that is diastolic
Result of turbulent blood flow
Measurement of Systolic and Diastolic Pressures
What Is Central Venous Pressure?
What Are Some Factors That Affect
Central Venous Pressure?
Venous Pressures in the Body
Venous Valves and “Venous Pump”
Local Control of Blood Flow
Each tissue controls its own blood flow in proportion to its needs.
Tissue needs include:
Delivery of oxygen to tissues
Delivery of nutrients such as glucose, amino acids, etc.
Removal of carbon dioxide hydrogen and other metabolites from the tissues
Transport various hormones and other substances to different tissues
Flow is closely related to metabolic rate of tissues.
Short-Term Control of Blood Flow
Increases in tissue metabolism lead to increases in blood flow.
Decreases in oxygen availability to tissues increase tissue blood flow.
Two major theories for local blood flow are
The vasodilator theory
Oxygen demand theory
Determinants of Blood Flow
Q = ∆P/R
Flow (Q) through a blood vessel is determined by:
The pressure difference (∆P) between the two ends of the vessel
Resistance (R) of the vessel
Vasodilator Theory for
Blood Flow Control
Effect of Tissue Oxygen Concentration on Blood Flow
How Do Changes in Tissue Oxygen Concentration Effect blood flow?
Laplace’s Law: Myogenic Mechanism
Long-Term Regulation of Blood Flow (1 of 2)
OXYGEN IS THE IMPORTANT TAKE AWAY
What Is Angiogenesis?
Angiogenesis is the growth of new blood vessels.
Humoral Regulation of Blood Flow
Vasoconstrictors
Norepinephrine and epinephrine
Angiotensin II
Vasopressin
Endothelin
Vasodilator agents
Bradykinin
Serotonin
Histamine
Prostaglandins
Nitric oxide
What Role Does the Nervous System Have in Regulation of the Circulation?
Modified according to the needs
Redistribution of blood flow
Increasing pumping activity of the heart
Rapid control of arterial pressure
Regulates via the autonomic nervous system (Visceral Efferent or Visceral Motor)
Sympathetic - constrict blood vessels (chronotropic and inotropic effects of the heart)
Parasympathetic - dilate blood vessels
The Autonomic Nervous System
Sympathetic chain ganglia on left side of spine.
Sympathetic only go to blood vessels
Sympathetic comes from T1 - L5
Parasympathetic comes out of cranial and sacral
Parasympathetic goes to the heart
Sympathetic Innervation of Blood Vessels
Vaso contrict = increase resistance
Vasomotor Center
In the brain stem
VMC Affects Vessel Function Via Neurotransmitters
Postsympathetic fiber and effector organ (LOOK INTO MORE???)
The neurotransmitter for the vasoconstrictor nerves is norepinephrine.
Adrenal medulla secretes epinephrine and norepinephrine which constricts blood vessels via alpha adrenergic receptors.
Epinephrine can also dilate vessels through a potent β2 receptor.
The Arterial Baroreceptor Reflex
Pressoreceptors
Anatomy of the Baroreceptors
How Do the Baroreceptors Respond to Changes in Arterial Pressure? (1 of 2)
Baroreceptors Maintain Relatively Constant Pressure Despite Changes in Body Posture
Carotid and Aortic Chemoreceptors
How Do Solutes and Fluids Cross the Capillary Wall?
Interstitial and Interstitial Fluid
How Do Changes in Plasma Colloid Osmotic Pressure Affect Net Fluid Movement Across a Capillary?
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Normal Capillary hydrostatic pressure is approximately 17 mm Hg.
Interstitial fluid pressure in most tissues is negative 3. Encapsulated organs have positive interstitial pressures (+5 to +10 mm Hg).
Negative interstitial fluid pressure is caused by pumping of lymphatic system.
Colloid osmotic pressure is caused by presence of large proteins.
What Factors Determine Plasma Colloid Osmotic Pressure?
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Taste and Smell
Taste Is a Function of the Taste Bud
Taste Perception
Bitter are located in back of mouth
Location of Taste Buds
Know they are on Papillae
Transmission of Taste Sensations
Know the Cranial Nerves
Know the Thalamus purpose in Taste
Adaptation of Taste
Taste sensations adapt rapidly.
Adaptation of taste buds themselves accounts for only about 50% of the adaptation.
Central adaptation must occur but the mechanism for this is not known.
Loss of Taste
Smell
Least understood of all senses.
Poorly developed in humans.
Olfactory membrane located on the superior part of each nostril.
Contains olfactory cells which contain cilia.
On the cilia are odorant-binding protein receptors.
Binding of chemical odorant to receptor induces the G-protein transduced formation of cAMP which opens sodium channels.
From Odorant to Action Potential
Substance must be volatile so that it can be sniffed into nostrils.
Substance must be at least slightly water soluble to penetrate the mucus to reach the olfactory cells.
Substance must be at least slightly lipid soluble to interact with the membrane.
Olfactory receptors adapt very slowly. But olfactory sensation itself adapts rather rapidly. Hence, must involve a central mechanism.
Primary Sensations of Smell
Transmission of Smell Sensation to CNS
Located in the temporal cortex
Coming to and from CN I
RBCs
Biconcave discs
Men: 5,200,000 (±300,000)/mm3
Women: 4,700,000 (±300,000)/mm3
RBC counts can be increased at higher altitudes.
Hemoglobin and Hematocrit
Normal hemoglobin concentration is 34 g per 100 mL of packed cells.
Normal hematocrit (packed cell volume) is 40–45% (slightly lower in women). KNOW THIS!!!
Thus normal hemoglobin is 14–15 g per 100 mL of blood.
O2 carrying capacity is 1.34 mL/g Hgb, or 19–20 mL O2/100 mL blood.
Sites of Erythropoiesis
First few weeks of gestation—yolk sac
Mid-trimester—liver (+ spleen, lymph nodes)
Last month of gestation through adulthood—bone marrow
Hematopoiesis
Pluripotent hematopoietic stem cells give rise sequentially to committed stem cells and mature cells.
Driven by
Growth inducers (factors; e.g., interleukin-3)
Differentiation inducers
Hematopoiesis responds to changing conditions.
Hypoxia: erythropoiesis
Infection/inflammation: WBC production
Erythropoiesis, and Distinctive Anemias
1% of RBCs in the body are Reticulocytes (Retics)… still have organelles in them before Erythrocytes
Regulation of Red Blood Cell Mass
Tissue Oxygenation and Erythropoietin
Body tissue isn’t getting enough O2, body says produce more RBCs to carry more O2
Compensatory Polycythemia
Sustained hypoxia can result in red cell mass above the usual normal range …
Prolonged stay at high altitude
Lung disease
Heart failure
Erythropoietin (Epo)
Circulating hormone, mw ~34,000
Necessary for erythropoiesis in response to hypoxia
~90% made in the kidney
Cells of origin not established
Hypoxia → HIF-1 → binds hypoxia response element → ↑ Epo transcription
Extra-renal hypoxia can stimulate Epo production …
epinephrine, norepinephrine, and some prostaglandins can promote Epo production.
In anephric individuals, 10% residual Epo (mainly from liver), supports 30–50% needed RBC production …
Hematocrit (packed cell volume) ~23–25% rather than 40–45%
KNOW THIS IS THE HORMONE RESPONSIBLE FOR RBC PRODUCTION AND PRIMARILY PRODUCED IN KIDNEYS
Minutes to hours … ↑ Erythropoietin
New circulating RBCs … ~5 days
Thus, erythropoietin …
stimulates production of proerythroblasts from HSCs
accelerates their maturation into RBCs
Can increase RBC production up to 10× normal
Erythropoietin remains high until normal tissue oxygenation is restored.
Vitamin B12 and Folic Acid
Rapid, large-scale cellular proliferation requires optimal nutrition.
Cell proliferation requires DNA replication.
Vitamin B12 and folate both are needed to make thymidine triphosphate (and thus DNA).
Abnormal DNA replication causes failure of nuclear maturation and cell division …
→ maturation failure → large, irregular,
fragile “macrocytes”
NEED THESE TO PRODUCE RBCs
Formation of Hemoglobin
Occurs from proerythroblast through reticulocyte stage
Reticulocytes retain a small amount of endoplasmic reticulum and mRNA, supporting continued hemoglobin synthesis.
Types of Globin Chains
Each globin chain is associated with one heme group containing one atom of iron.
Each of the four iron atoms can bind loosely with one molecule (two atoms) of oxygen.
Thus each hemoglobin molecule can transport eight oxygen atoms.
Differences Among Globin Chains
Modest differences in O2 binding affinities
Sickle hemoglobin:
Glutamic acid → Valine at AA 6
(Gives resistance against Malaria)
Hemoglobin of homozygous individuals (SS) forms elongated crystals when exposed to low O2.
→ hemolysis, vascular occlusion
Oxygen Binding to Hemoglobin
Must be loosely bound—binding in settings of higher O2 concentration, releasing in settings of lower concentration.
Binds loosely with one of the coordination bonds of iron
Carried as molecular oxygen (not as ionic oxygen)
The iron binds to the O2
Iron Metabolism
Iron is a key component of hemoglobin, myoglobin, and multiple enzymes (cytochromes, cytochrome oxidase, peroxidase, catalase).
Thus iron stores are critically regulated.
Total body iron ~4–5 g
65% in hemoglobin
4% in myoglobin
1% in intracellular heme compounds
0.1% associated with circulating transferrin
15–30% stored mainly as ferritin in RES
Iron Absorption, Transport, and Storage
Absorbed from small intestine where it binds to apotransferrin → transferrin (transport iron)
Iron can be released to any cell.
RBC precursors have transferrin receptors and actively accumulate iron.
Particularly in hepatocytes and reticulo-endothelial cells, iron combines with apoferritin → ferritin (MW 460,000).
Ferritin is variably saturated (storage iron).
Hemosiderin is quite insoluble excess iron.
When iron in the plasma is low, iron is released from ferritin and bound to transferrin for transport.
It is delivered to the bone marrow, bound by transferrin receptors on erythroblasts, internalized, and delivered directly to the mitochondria for incorporation into heme.
RBC Senescence and Destruction
RBC life span is ~120 days
Though lacking a nucleus, mitochondria, and endoplasmic reticulum, RBCs have enzymes that can metabolize glucose and make small amounts of ATP. These enzymes …
maintain membrane pliability.
support ion transport.
keep iron in the ferrous form (rather than ferric).
inhibit protein oxidation.
As enzymes deplete with age, RBCs become fragile and rupture in small passages, often in the spleen.
Destruction of Hemoglobin
When RBCs rupture, hemoglobin is phagocytosed by macrophages, particularly in the liver and spleen.
Iron is released back to transferrin in the blood to support erythropoiesis or be stored as ferritin.
Macrophages convert the porphyrin portion, stepwise, into bilirubin, which is released into the blood and secreted by the liver into the bile.
The ABO System
Red blood cell surface antigens: glycolipids or glycoproteins
Present on all cells in the body, not just blood cells
Agglutinogens: surface antigens (A,B)
Genes: A, B, O (maternal, paternal alleles)
Genotypes: OO, OA, OB, AA, BB, AB
Agglutinins (immunoglobulins): anti-A, anti-B
Blood Groups
Blood Typing
The Rh (rhesus) Antigens
Requires prior exposure to incompatible blood
Six common antigens (“Rh factors”)
C, D, E, c, d, e
Each person is CDE, CDe, Cde, CdE, cDE, cDe, or cde
D (“Rh positive”) is prevalent (85% EA, 100% Africans) and particularly antigenic
C and E can also cause transfusion reactions, generally milder
HLA Antigens
Encoded by the MHC
Six classes, total of >150 antigens expressed on all nucleated cells
MHC Class I: HLA-A, -B, and -C
MHC Class II: HLA-DP, -DQ and –DR
Seek the best match possible among the closest relatives possible
Important to Organ Transplants
Hemostasis: Prevention of Blood Loss
Vascular constriction
Formation of a platelet plug
Formation of a blood clot
Healing of vascular damage ± recanalization
Platelet Recruitment, Adhesion, Activation, and Degranulation
Virchow’s triad is a theory that three factors contribute to blood clotting, or thrombosis. The factors are:
Hypercoagulability: The blood’s tendency to clot
Stasis: Abnormal blood flow or pooling
Endothelial injury: Damage to the lining of blood vessels
Key Events in Hemostasis
Vascular Constriction (Step 1)
Myogenic spasm
Local autocoid factors from damaged tissues and platelets
Nervous reflexes
Smaller vessels: thromboxane A2 released by platelets
Platelet Functions (Step 2)
Contractile capabilities
Actin, myosin, thrombosthenin
Residual ER and Golgi
Synthesize enzymes, prostaglandins, fibrin-stabilizing factor, PDGF, store Ca++
Mitochondria/enzymes
Produce ATP, ADP
Formation of the Platelet Plug (Step 2)
Contact with damaged endothelium
Assume irregular forms
Contract and release granules (ADP, thromboxane A2)
Adhere to collagen and vWF
Other platelets accumulate, adhere, and contract, form plug, initiate clotting
Very low platelets → petechaiae, bleeding gums
Clot Formation and Progression (Step 3)
Begins in 15–20 seconds in severe vascular trauma
Occlusive clot within 3–6 minutes unless very large vascular defect
20–60 minutes: Clot retraction
1–2 weeks
Invasion by fibroblasts
Organization into fibrous tissue
Key Steps in Blood Clotting
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Formation of a Fibrin Clot
Makes a mesh work around the platelet plug
This mesh work traps RBCs in it
Fibrin Production
Thrombin (weak protease) cleaves four small peptides from fibrinogen
→ Fibrin monomer → spontaneous polymerization
Long fibers form clot reticulum
Fibrin stabilizing factor
In plasma and released from platelets
Activated by thrombin
Covalent cross-linking of fibrin monomers and adjacent fibrin fibers
Clot Extension
Thrombin is bound to platelets and trapped in the clot
Can act on prothrombin to generate more thrombin (positive feedback)
Thrombin also produces more prothrombin activator by acting on other clotting factors
Additional fibrin monomers and polymers are generated at the periphery of the clot
Clot Retraction
Begins within 20–60 minutes
Fibrin binds to damaged vessel wall
Platelets bind to multiple fibrin fibers
Contract via actin, myosin, thrombosthenin
Clot tightens, expressing serum, and closing the vascular defect
Serum is the blood without the cells and clotting factors, so when the clot retracts it squeezes out what is left… the clear, yellowish fluid = serum
Generating Prothrombin Activator
Two pathways
Extrinsic pathway—Trauma to vessel wall and adjacent tissues
Intrinsic pathway—Trauma to the blood or exposure of the blood to collagen
Both pathways involve “clotting factors”—mostly inactive proteases that are activated in cascades
Extrinsic Pathway to Initiate Blood Clotting
Intrinsic Pathway to Initiate Blood Clotting
Know the last steps with all the Prothrombin
Synergy Between The Intrinsic and Extrinsic Pathways
Tissue injury …
Tissue factor activates the Extrinsic Pathway
Exposure of Factor XII and platelets to collagen activates the Intrinsic Pathway
Extrinsic pathway can be explosive, with clotting in <15 seconds
The Intrinsic pathway is slower
→ 1–6 minutes
Common Point is the Prothrombin Activator (Fibrin Strands?)
Clot Lysis
Plasminogen is trapped in the clot.
Over several days, injured tissues release tissue plasminogen activator (tPA).
Plasminogen is activated to plasmin, a protease resembling trypsin.
Plasmin digests fibrin fibers and several other clotting factors.
Often results in reopening repaired small blood vessels
Vitamin K = big in clotting factors (deficiency is not good)
Thrombocytopenia
Low numbers of platelets
Blood Coagulation Tests
Bleeding Time (from small cut)
Normally 1– 6 minutes
Largely reflects platelet function… they are first on scene
Clotting time
Invert tube every 30 seconds
Normally 6–10 minutes
Not reproducible, generally not used… reflects the coagulation
Prothrombin Time
Add excess calcium and tissue factor to oxalated blood, measure time to clot
Assesses Extrinsic and Common Pathways
Usually about 12 seconds
Defense Against Infection: White Blood Cells and Inflammation
Our world is teeming with microorganisms, which can be beneficial or harmful.
Phagocytes can ingest and destroy invading organisms, and participate in tissue reactions that “wall off” infection.
Other white cells (lymphocytes, next chapter) mediate responses that destroy or neutralize specific microorganisms.
White Blood Cells
Total WBC ~7,000/mm3
(almost 1000-fold fewer than RBCs)
Proportions:
Neutrophils 62%
Eosinophils 2.3%
Basophils 0.4%
Monocytes 5.3%
Lymphocytes 30%
*** Know Neutrophils and Basophils proportions
Platelets
~300,000/mm3
Erythrocytes, Neutrophil, Lymphocyte
Lymphocyte - the big one with whole nucleus
Neutrophil - horseshoe, multi nucleus
Monocyte
Basophil
Eosinophil
Leukopoiesis
Granulocytes and monocytes develop in the bone marrow, and most remain there until needed peripherally (number in marrow ~3× blood; 6-day supply).
Lymphocytes develop mostly in the peripheral lymphoid organs (thymus, spleen, tonsils, lymph nodes, Peyer’s patches).
Megakaryocytes develop and reside in the marrow, fragment to release platelets.
Functions of Neutrophils and Macrophages
Neutrophils are mature cells that can respond immediately to infection.
Monocytes mature in the tissues to become macrophages.
Both exhibit motility:
Diapedesis
Ameboid motion
Chemotaxis (chemoattractants: bacterial or tissue degradation products, complement fragments, other chemical mediators)
Neutrophil Margination and Migration
Phagocytosis
“Phagocytosis” is the ingestion of particles.
Phagocytes must distinguish foreign particles from host tissues.
Appropriate phagocytic targets:
May have rough surfaces
Lack protective protein coats
May be immunologically marked for phagocytosis by antibodies or complement components that are recognized by receptors on the phagocytes
… this immunologic marking is called “opsonization”
Phagocytosis by Macrophages
After being activated in the tissues, macrophages are extremely effective phagocytes (up to ~100 bacteria).
They can ingest larger particles …
Damaged RBCs
Malarial parasites
Macrophages can extrude digestion products and survive and function for many more months.
In both neutrophils and macrophages, phagosomes fuse with lysosomes and other granules to form phagolysosomes (digestive vesicles).
These contain proteolytic enzymes, and in macrophages, lipases (important in killing tuberculosis bacillus and some other bacteria).
Bacteria may be killed even if they are not digested.
Enzymes in the phagosome or in peroxisomes generate strongly bactericidal reactive oxygen species …
Superoxide (O2−)
Hydrogen peroxide (H2O2)
Hydroxyl ions (OH−)
Myeloperoxidase catalyzes H2O2 + 2Cl− → … … → 2H+ + 2ClO−
After entering the tissues, macrophages become fixed and may be resident for years.
When appropriately stimulated they can break away and move to sites of inflammation.
Circulating monocytes, mobile macrophages, fixed tissue macrophages, and some specialized endothelial cells form the reticuloendothelial system, almost all derived from monocytes.
A phagocytic system is located in all tissues.
Specialized Macrophages
Skin, subcutaneous (histiocytes)
Lymph nodes
Ingest/sample particles arriving through the lymph
Alveolar macrophages
Digest or entrap inhaled particles and microorganisms
Kupffer cells
Surveillance of the portal circulation
Macrophages in the spleen and bone marrow
Surveillance of the general circulation
Inflammation: Role of Neutrophils and Macrophages
Inflammation is driven by chemical mediators and characterized by heat, redness, swelling, and pain.
Physiologically, it involves …
vasodilatation and increased blood flow.
increased capillary permeability.
coagulation of interstitial fluids.
accumulation of granulocytes and monocytes.
swelling of tissue cells.
Mediators: histamine, bradykinin, serotonin, prostaglandins, complement products, clotting components, lymphokines
“Walling Off” Sites of Inflammation
Fibrinogen clots minimize fluid flow in and out of the inflamed area.
Staphylococci cause intense inflammation and are effectively “walled off.”
Streptococci induce less intense inflammation and may be more likely to spread than staphylococci.
Neutrophil Migration to a Site of Inflammation
Tissue macrophages that encounter foreign particles enlarge and become mobile to provide a first line of defense.
Within an hour neutrophils migrate to the area in response to inflammatory cytokines (TNF, IL-1).
Upregulated selectins and ICAM-1 on endothelial cells are bound by integrins on neutrophils, leading to margination, followed by diapedesis, and chemotaxis directing neutrophils into the inflamed tissues, to kill bacteria and scavenge.
Neutrophilia
With intense inflammation neutrophil count …
4000–5000 → 15000–25000
Results from mobilization of mature neutrophils from the bone marrow by inflammatory mediators
Pus
Pus is composed of dead bacteria and neutrophils, many dead macrophages, necrotic tissue that has been degraded by proteases, and tissue fluid, often in a cavity formed at the inflammatory site.
Over days and weeks it is absorbed into the surrounding tissue and lymph and disappears.
Eosinophils
Eosinophils are weak phagocytes and exhibit chemotaxis.
Particularly important in defense against parasites (schistosomiasis, trichinosis)
Can adhere to parasites and release substances that kill them (hydrolases, reactive oxygen species, major basic protein)
Also accumulate in tissues affected by allergies, perhaps in response to eosinophil chemotactic factor from basophils (eosinophils may detoxify some products of basophils)
Basophils
Similar to mast cells adjacent to capillaries
both cell types release heparin
Basophils and mast cells both release histamine, bradykinin, and serotonin.
When IgE bound to receptors on their surfaces is cross-linked by its specific antigen, mast cells and basophils degranulate, releasing …
histamine, bradykinin, serotonin, heparin, leukotrienes, and several lysosomal enzymes
Leukopenia
Leukopenia, or low white blood cell count, is usually the result of reduced production of cells by the bone marrow.
Immunity
Innate = ability to resist damaging organisms and toxins:
skin, gastric acids, tissue neutrophils and macrophages, complement, microbicidal and lytic chemicals in blood and blood cells
Acquired = specific
humoral → circulating antibodies
cellular → activated cells
Acquired Immunity
Antibodies or activated cells that specifically target and destroy invading organisms and toxins
(Specificity)
Powerful: can neutralize 100,000 × lethal dose of some toxins
Two types of acquired immunity:
Humoral (B cell ) B Lymphocytes
Cell-mediated (T cell ) T Lymphocytes
Antigen
A substance that can elicit an immune response
Unique to each invading organism
Usually proteins or large polysaccharides
Most are large (MW > 8,000) and have recurring molecular groups on their surfaces
The molecular structures that are specifically recognized in acquired immunity are called “epitopes.”
Lymphocytes
Mediate acquired immunity
Develop in lymphoid tissues
Tonsils/adenoids, Peyer’s patches (GI), lymph nodes, spleen, thymus, marrow
Are strategically positioned
Lymphocyte Development
B Lymphocyte is involved in antibody production
Maturation of T Cells in the Thymus
Rapid expansion
Each clone is specific for a single antigen.
Self-reactive clones are deleted (up to 90%).
Migrate to peripheral lymphoid organs
Much of the above occurs just before and shortly after birth.
B-Cell Development
Initial growth and differentiation in the liver (fetal) and bone marrow (after birth)
Migrate to the peripheral lymphoid organs
Each clone is specific for a single antigen.
* Specific to what caused it*
Clonal development provides almost limitless antibody specificity.
Secreted antibodies destroy or neutralize molecules or organisms bearing their cognate antigen.
Immunologic Specificity
Each B- or T-cell clone is specific for a single epitope of a single antigen.
The genes for B-cell receptors (immuno-globulins) and T cell receptors have hundreds of “cassettes” that are used in varying combinations.
Permutations of these cassettes allow specificity for millions of distinct epitopes.
Antibody Production
B cells bind intact antigen
T cells bind presented antigenic peptides
B cells proliferate (with T cell help), developing lymphoblasts and plasmablasts
Up to 500 antigen-specific progeny in 4 days, each producing as many as 2,000 Ig molecules/sec
Can persist for many weeks, if antigenic stimulation persists
Antibody = Immunoglobulins
Each antibody has a steric configuration specific to its antigen.
Two types of light chain - Kappa and lambda
Name antibody based on the Heavy Chain
IgM (earliest produced, five pairs of heavy chains and light chains)
IgG (75% of all immunoglobulins)… produced at 2,3,4th reaction
IgA… found in secretions
IgD… appears to enhance mucosal homeostasis and immune surveillance
IgE (critically involved in allergic reactions)
Immunoglobulins make up about 20% of all plasma proteins. Involved with allergic reaction/hypersensitivity
Antibodies: Mechanisms of Action
Agglutination
Precipitation - example rheumatoid arthritis, a reaction that occurs when soluble antigens and antibodies combine to form insoluble complexes, also known as precipitates
Neutralization - the process by which antibodies prevent pathogens from binding to host cells. This process blocks the early stages of viral replication and prevents the pathogen from causing disease
Lysis - destroys
Complement activation
Agglutination
What we see when you mismatch blood = hemagglutination
“Clumping”
The Complement System
Ultimate result is Lysis
T-Cell Activation
Binds to cognate antigen presented by antigen-presenting cell
Rapid expansion of T-helper (CD4) cells
T-helper cells produce cytokines.
Drives expansion of both T-helper (CD4) and cytotoxic (CD8) T cells
Both types of cells also generate clonal memory T cells.
Antigen Presentation
Helper (CD4) T cells
~ 75% of all T cells
Regulate functions of other immunologic cells by producing cytokines …
Interleukin (IL-) 2, 3, 4, 5, 6, GM-CSF, Interferon-gamma
What HIV kills
Killing by Cytotoxic T Cells
They recognize the change in the cell by the 3 reasons on picture… so they destroy the cell
Immunologic Tolerance
Tolerance = we tolerate our cells, we recognize our own cells
“Tolerance” in acquired immunity is achieved mainly by clonal selection of T cells in the thymus and B cells in the bone marrow.
Clones that bind host antigens with high affinity are induced to undergo apoptosis, and are deleted.
Failure of Tolerance Produces Autoimmunity
Rheumatic fever (cross-reactivity with streptococcal antigens)
Poststreptococcal glomerulonephritis
Myasthenia gravis (antibodies to acetylcholine receptors)
Systemic lupus erythematosus (auto-immunity to multiple tissues)
Immunization
Injecting killed organisms or their products …
Typhoid, whooping cough, diphtheria, tetanus toxoid
Infection with attenuated organisms …
Smallpox, yellow fever, polio, measles, herpes zoster, other viral diseases
Passive immunity …
Infusing antibody or activated T cells from an immune individual (antibodies last 2–3 weeks)
Natural Active - exposed to people out in public and body does the work
Natural Passive - Mother gave it to you with breast milk, given the immunoglobin
Artificial Active - Vaccine
Artificial Passive - Given the immunity, given the immunoglobins in a non-natural way, ex. rabies vaccine
Allergy and Hypersensitivity
Patient has to be sensitized with the antibody the first time, its not the first bee sting… it was the IgE antibodies that were developed the first time… so when come in contact 2nd time, Mast Cells release histamine and others
T cell mediated (delayed) …
poison ivy, nickel allergies.
usually cutaneous; can occur in lungs with airborne antigens.
IgE mediated (immediate) …
typical allergies.
a single mast cell/basophil can bind 500,000 IgE molecules.
Mast Cell/Basophil Degranulation
Histamine
Proteases
Leukotrienes
Eosinophil and neutrophil chemotactic factors
Heparin
Platelet activating factor
