Exam 2 Flashcards
von Willebrand Factor
Secreted by endothelial cells and platelets
vWF will form bridge between the collagen so platelets can bind
Platelet binding to collagen triggers
Release of secretory vesicles containing ADP and Serotonin and platelet activation (change in shape, metabolism, etc)
Thromboxane A2
Released after adhesion to locally stimulate further adhesion and vesicle release
Causes vasocontstriction
Platelet Aggregation
Platelets binding to platelets which have been activated to create a platelet plug
Fibrinogen role in platelet aggregation
Forms bridges between aggregating platelets by binding to receptors that became exposed during platelet activation
Platelet contraction
Platelets contain a high level of myosin and actin which cause compression and strengthening of the plug
Platelet Factor
Phospholipids displayed by activated platelets which function as cofactors for bound clotting factors
Prevention of platelet plug spread
Non-damaged endothelial cells produce
- Prostacyclin (as opposed to Thromboxane A2)
- Nitrix Oxide
Clot (aka Thrombus)
Consists mainly of Fibrin, supports and reinforces platelet plug
Prothrombin
Cleaved to produce Thrombin by Xa
Thrombin
- converts fibrinogen to fibrin
- positive feedback to create more Thrombin
Fibrin
Produced from Thrombin-mediated cleavage of Fibrinogen
8a
Covalently cross-links fibrin
Importance of platelets in clotting
Form a surface which allows the clotting reactions to happen and display PF
Intrinsic Pathway
12, 11, 9, 10, Thrombin
Factor 12 activation
Triggered by contact with collagen (or glass)
Factor 8
Triggered to 8a by Thrombin, activates 9a to convert 10 to 10a
Deficiency leads to class hemophilia
Extrinsic Pathway
TF, 7, 10, Thrombin
7 also activates 9, which activates the intrinsic pathway
Extrinsic pathway activation
Blood outside of vessels binds to Tissue Factor (Tissue Thromboplastin), which then activates factor 7
Thrombin activates:
1) Fibrin (cleavage of Fibrinogen)
2) Intrinsic pathway
3) 5,8,9
4) Platelets
Vitamin K
Used to produce Prothrombin and other clotting factors
3 factors that limit clot formation
1) TFPI
2) Thrombomodulin
3) Antithrombin III
TFPI
- binds 7a, prevents it from generating 10a
- secreted by endothelial cell
- why extrinsic pathway generates so little Thrombin
Thrombomodulin
- cell receptor
- eliminates Thrombin clot-producing effects, binds it to protein C
- bound thrombin causes inactivation of 7a and 5a in healthy cells
Antithrombin III
- inactivates Thrombin
- augmented by Heparin
Fibrinolytic system
- tPA and Plasminogen bind to clot
- tPA cleaves Plasminogen to Plasmin
- Plasmin digests fibrin
- tPA has low activity without presence of Fibrin
Aspirin anticoagulative mechanism
Inhibits COX, which inhibits production of Thromoboxane A2 which prevents platelet aggregation
Platelet production
Pinching cytoplasm off of megakaryocytes (large bone marrow cells
Adult marrow producing locations
Chest, base of skull, spinal vertebrae, pelvis, ends of limb bones
Bone marrow = liver weight
HGFs (Hematopoietic Growth Factors)
Stimulate differentiation of progenitors into RBC
Example: EPO
Necessary nutrients for RBC production
1) Iron
2) Folic Acid
3) Vitamin B12
EPO
- regulates RBC production
- stimulates progenitor differentiation into RBC
- stimulated by low O2
- stimulated by testosterone release
Sickle cell
mutation in beta chain, fiber like polymers that distort RBC membrane
Only present in homozygotes, unless low pO2 in atmosphere, such as at high altitude
Polycythemia
Increase in viscosity cause by an increase in RBC, strains heart and vessels
3 proteins in plasma
Albumin, Fibrinogen, Globulin
Serum
Plasma - Fibrinogen and other clotting factors
Reticulocytes
- young RBC that still have some ribosomes
- lose ribosomes after one day
- make up 1% of circulating RBC
- survive 2 days
RBC destruction
- Occurs in spleen and liver
- 1% per day (250 milly)
Ferritin
Binds Iron, storing it in the liver
Hemochromatosis
Excess of Iron, abnormal deposits in various organs
Transferrin
Binds Iron in plasma, delivers it to bone marrow to make new RBC
Recycling vs absorption of Iron
20x more Iron recycled than ingested
Where is Iron in the body?
50% in Hb
25% in other heme (cytochromes)
25% in Ferritin
Folic Acid
Important for RBC precursor division
Vitamin B12 (Cobalamin)
- required for Folic Acid activity
- Intrinsic Factor needed for absorption
Pernicious Anemia
Lack of RBC due to lack of RBC due to lack of Intrinsic Factor
Average Hb in men and women
Men: 15.5g/100mL
Women: 14g/100mL
Spectrin
long, rod-shaped protein under membrane which maintains cell shape and integrity
Spherocytes
- Due to deficiency in Spectrin
- Fragile, 30-50day half life
Methemoglobin Reductase
Reduces Fe3+ to Fe2+ using NADH
Phosphogluconate pathway
Creates GSH to intercept ROS
- Uses NADPH to convert GSSG to GSH
G6PDH Deficiency
Leads to Hemolytic Anemia
2,3BPG
Produced from 1,3 BPG
Hemolytic Anemia
Decrease in RBC leads to decrease in O2 leads to increase in EPO
RBC Senescence
RBC lose flexibility and form lumps
Extravascular Hemolysis
Majority route
Macrophages scan RBCs as they pass sinusoids in the spleen
If they can’t pass, digested by macrophages
Disposal of RBC components
Iron sent to Transferrin
Globin sent to aa pool
Porphyrin ring disposed as BR
Intravascular Hemolysis
RBC breaks down into Hb dimer or Methemoglobin
Haptoglobin
Binds Hb dimer and goes to liver for disposal via BR
(finite source)
Hemopexin
Methemoglobin loses global, and heme binds to hemopexin, then liver for BR
Clinical detection of hemolytic event
If low haptoglobin, means intravascular hemolytic event occurred up to 5 days ago
If hemoglobinuria, up to 2 days ago
Erythroblastosis Fetalis
Rho- mother has a Rho+ child
Rhogam
Antibodies to D-antigen, masks Rho+ fetal blood so mother doesn’t make antibodies
Classic Hemophilia
Deficiency in factors 8 and 9
Activated Partial Thromboplastin Time
Use to assess intrinsic pathway, substitutes for platelet phospholipids and contact factor activator
Prothrombin Time
Use to assess extrinsic pathway, adds Thromboplastin which binds 7 to activate 10
How to evaluate Tissue Factor deficiency
Not possible lol
P wave
Both atrial contraction and relaxation
Ventricular Action Potential
1) Na+ comes in
2) Transient K+ open, closed Na+
3) L-type Ca2+ (DHP) counters slow K+
4) Ca2+ closed, K+ repolarizes
5) RMP, K+ leak channels offset by Na+ and Ca2+
Atrial AP
Same as ventricular AP, but plateau is shorter
Nodal APs
1) Na+ Funny channels
2) T-type Ca2+ open
3) L-type Ca2+ open at threshold
4) L-type close, normal K+ open (different from ventricular K+)
Funny Channels
non-specific cation channels, open only at negative values
HCN channels
AV vs SA
AV node pacemaker potentials are slower to reach threshold compared to SA node
Pacemaker Potential
- Driven by Funny current
- Allows for automaticity
AV conduction disorder
malfunction of AV node cells
- His and Purkinje 25-40 bpm
- unsynchronized with atria
- treated by artificial pacemaker
P-Q
Atrial Contraction
S-T
Ventricular conctraction
Lead 1
Across the top R>L
Lead 2
Down the Right side
Lead 3
Down the left side
aVR
Points at upper right side
aVF
Points down
aVL
Points at upper left side
Ca2+ release in regular muscle vs cardiac muscle
in muscle, enough Ca2+ released to saturate all sites
in heart, saturates only some troponin C sites
- exercise increases the release of Ca2+ from SR
Heart refractory period
Longer absolute RP to prevent summation and tetany, occurs because of plateau
Duration of AP
= Duration of contraction
MI troponin markers
Troponin I and Troponin T
Percentage of cells that have autorhythymicity
1%
Dromotropy
Conduction velocity
Effect of ACh on SA Node AP
Can slow down the repolarization via K+
Sympathetic stimulation to the heart goes mainly via which receptors
ß, with some alpha receptor input
Chronotropy
Heart rate
Inotropy
Contractility
Lusitropy
Rate of relaxation
Tachycardia limit
greater than 100
Bradycardia limit
less than 60
Exercise effect on SA Node AP
Increase in slope of AP
- affected by GPCR cascade
- triggers increased current through funny and T-type Ca2+ channels
PNS (vagal) stimulation of SA Node
Decreases slope and hyper-polarizes pre-potential
- GPCR cascade decreases opening of T-type Ca2+
- enhances K+ permeability
Isopreterenol
Non-selective ß agonist
- similar effect to exercise, increased HR
Interval-Duration relationship of ventricular AP
Increase in plateau amplitude leads to a decrease in plateau duration
- more phosphorylation of LTCC leads to a higher voltage (higher plateau)
- LTCC open time reduced by a high amount of Ca2+
Repolarization towards positive end
Negative deflection
Repolarization towards negative end
Positive deflection
Depolarization towards positive end
Positive deflection
Depolarization towards negative end
Negative deflection
What is the Q wave
septal depolarization towards the negative end (from L to R) of Lead 1 - negative deflection
S wave polarization
Late ventricular depolarization
- bc left side it thicker, vector points up and to the left of body
- causes a negative deflection on Lead aVF
- positive charge towards negative end
ST segment
Full depolarization, waiting for repolarization
T wave
Ventricular re-polarization from apex towards base
- negative charge going towards negative end (ex lead II), leads to positive deflection
EKG box values
Large box - 0.2 seconds
Small box - 0.04 seconds
EKG HR calculation
HR = 60 (sec/min) ÷ R-R interval (sec/beat)
Irregular rhythm HR calculation
Number of QRS in 30 boxes (6s) and multiply by 10
Paroxysmal Tachycardia
Sudden increase in HR
Intrinsic BPM of SA, AV, Purkinje
60-100, 40-50, 20-40
Supraventricular Rhythyms
Rhythms originated by SA, atrial or AV source
Premature atrial contraction
Ectopic AP before SA node
- shows up as extra P wave
Atrial flutter
Very high regular atrial rate
- not all impulse conducted through AV node
Atrial Fibrillation
SA node doesn’t trigger depolarization
- quick, irregular P waves
aFib stroke predisposition
Causes blood to swirl and pool in atrium, facilitating the creation of a possible clot in left atrial appendage
1st degree AV block
Delay in transmitting impulses to ventricles
- P-R interval greater than 0.2s
2nd degree AV block
Failure of some but not all atrial contractions to be transmitted
No atrial repolarization wave visible is evidence that it is disorganized
3rd degree AV block
Complete atrial and ventricular dissociation of electrical activity
Ventricular Rhythym
Activation from ventricular cells
- QRS is greater than 0.1s super wide
Calculation of mean electrical axis
Calculate heights of QRS complex on Leads 1 and 3
- starting at middle of leads, go towards positive end
- Where lines from those points intersect, is the tip of the axis arrow
Left axis deviation
Left ventricular hypertrophy
Right axis deviation
pulmonary HTN
Normal axis range
-30 to +90
Tissue Thromboplastin
Another name for tissue factor
CO units
L/min
SV definition
Blood ejected by each ventricle with each beat
Inherent discharge rate of SA node
100 bpm
Effect of sympathetic stimulation on HR
Increases slope of SA side AP via increase F-type Na+ channels
Effect of parasympathetic stimulation on HR
Increases permeability to K+ so that pacemaker potential starts from a more negative value
Effect of sympathetic stimulation on Dromotropy
Increase of conduction velocity
Effect of parasympathetic stimulation on Dromotropy
Decrease of conduction velocity
What are the three dominant factors that alter force of ejection?
1) Change in EDV
2) Change in magnitude of sympathetic input
3) Change in after load
3 major factors affect HR
1) activity of parasympathetic nerves to heart
2) activity of sympathetic nerves to heart
3) level of plasma Epinephrine
What is the Frank-Starling Mechanism
As EDV increase, so does SV
Effect of stretching cardiac muscle towards optimal length
1) Better overlap of thick-thin
2) decreased spacing between thick-thin
3) increased troponin sensitivity for binding Ca2+
3) increased Ca2+ release from SR
How does the Frank-Starling ensure equality between CO and VR
Increase in VR results in a higher EDV, which then means a higher SV and a higher CO to match VR
Effect of parasympathetic regulation on the ventricles
Trick question; Almost no parasympathetic innervation of the ventricles; would not affect contractility
2 factors that increase contractility
1) Norepinephrine from sympathetic nerves on ß receptors
2) Circulating plasma Epinephrine on ß receptors
Ejection Fraction
Method to quantify contractility
EF = SV/EDV
EF normally and during exercise
50-60% at rest
up to 85% during exercise
Effect of sympathetic stimulation on heart
Increased tension (contractility) and decreased duration of contraction and relaxation
Increase in Inotropy and Lusitropy
PKA phosphorylation targets after NE or Epi binding to ß receptors
1) L-type Ca2+ channels
2) Phosphalamban
3) TroponinI
4) Titin
PKA phosphorylation of L-type Ca2+ channels
Causes an increased influx of Ca2+ which activates RyR to release more Ca2+ from SR
Increases Inotropy
PKA phosphorylation of Phosphalamban
Causes inactivation, allowing SERCA to uptake more Ca2+ into SR
Increased Lusitropy
PKA phosphorylation of Troponin I
Causes a decreases in the affinity of TnC for Ca2+
Increased Lusitropy
PKA phosphorylation of Titin
Titin is usually more stiff in heart to prevent overfilling
- phosphorylation decreases stiffness
- allows for more filling of the ventricles
Label the PV loop, starting with A in bottom right corner
A: EDV
A-B: Isovolumetric contraction
B: DBP
B-C: Ejection phase
C: ESV
C-D: Isovolumetric relaxation
D-A: Relaxation
B-C peak: SBP
Frank-Starling graph of failing heart
Curve shifted downward
- compensation can occur by fluid retention to increase EDV
Effect of increased afterload on:
EDV
ESV
SV
E
Same EDV
Increased ESV
Decreased SV
Decreased EF
Effect of increased contractility on:
EDV
ESV
SV
EF
Decreased EDV (minimal)
Decreased ESV
Increased SV
Increased EF
Law of Laplace equation
σ = Pr/2h
σ = stress
h = wall thickness
Explain high pressure on capillaries does not cause thick walls using the Law of Laplace
Their radius is so small, that the effect on stress is minimized and the thickness does not need to increase as much
Long-term effect of increased Afterload
Weakens the heart an reduces SV
Fick’s method equation
CO = VO2/(Ca-Cv)
VO2 - oxygen taken in by the body (spirometer)
Ca - concentration of O2 leading the lung (blood)
Cv - concentration of O2 entering the lung (blood)
Explain indicator and thermo dilution
The average concentration of indicator tells you the volume into which the dye was diluted
- length of time the dye is detected allows you to determine the flow (vol/t) and CO
Explain Echocardiography
Sound used to measure LV volume at the end of systole and diastole
- EDV - ESV = SV
- CO = SV x HR
Active Hyperemia
Increased blood flow in response to an increase in metabolic activity
More metabolites leads to arteriolar dilation
Myogenic responses
Increased blood pressure activates stretch-activated Ca2+ receptors to constrict
Protects downstream vessels from massive increases in BP
Reactive Hyperemia
Massive increase in blood flow if the blockage is removed
Ex. Red finger after removing band-aid
Eicosanoids
Released during tissue injury, cause vasodilation and swelling
Sympathetic innervation of the blood vessels leads to what
Vasoconstriction
3 CVS Effectors
Arterioles, Veins, Heart
Arterioles contain which receptors
⍺1 and ß2 receptors
Heart, including conducting system contain which receptors
ß
Do arterioles have parasympathetic innervation?
No
Sildenafil and tadalafil mechanism of action
Bonus: which is cialis and which is viagra?
Enhance the NO pathway to mediate vasodilation
Sildenafil = Viagra, Tadalafil = Cialis
Norepinephrine
Vasoconstrictor or vasodilator, and which receptor does it bind to?
Vasoconstrictor, binds ⍺ receptors
Epinephrine
Vasoconstrictor or vasodilator, and which receptor does it bind to?
Vasoconstriction if ⍺ and vasodilation if ß2
Angiotensin II
Vasoconstrictor or vasodilator, and which receptor does it bind to?
Vasoconstrictor, ⍺
Vasopressin
Vasoconstrictor or vasodilator, and which receptor does it bind to?
Vasoconstrictor, ⍺
ANP
Vasoconstrictor or vasodilator, and which receptor does it bind to?
Vasodilator, ß2
How do substances released by endothelial cells induce vasoconstriction/dilation?
Secretion of paracrine agents from endothelial cells
3 paracrine agents released from endothelial cells to induce vasoconstriction/dilation
1) NO
2) Prostacyclin
3) Endothelin-1
Endothelin-1
Vasoconstrictor, and at high enough concentrations can function as a hormone and induce widespread arteriolar constriction
Endothelium-released NO
Dilator or constrictor, basal secretion level,release stimulated by what
Vasodilator, has high basal secretion, release stimulated by bradykinin and histamine
Endothelium-released Prostacyclin
Dilator or constrictor, basal secretion level
Dilator, low basal secretion level
5 auto regulatory vasodilators
1) ↓ pO2
2) ↑ pCO2
3) ↑ in H+
4) ↑ in K+
5) ↑ in adenosine
Where does the H+ as a metabolite come from?
Production of lactic acid
Where does the K+ as a metabolite come from?
K+/Na+ ATPase does not bring all K+ back into the cell
Where does the Adenosine as a metabolite come from?
Byproduct of reaction to convert ADP → ATP
produces a very small amount of ATP
Intrinsic mechanisms that cause arteriolar vasodilation
1) Hyperpolarization to make smooth muscle less excitable
2) Less cytosolic Ca2+ to not activate MLCK
3) Activation of myosin light chain phosphatase
What does stimulation of the Vagus nerve do?
Decrease in heart rate via parasympathetic nerve ACh release
Has no effect on contractility
Which is the dominant of the pressor and depressor regions
Pressor region
Depressor region
Drops BP via sympathetic inhibition
Pressor region
Increases BP via sympathetic activation
Why is the compliance of the aorta important for BP?
Low aortic compliance allows changes in blood volume to have a significant effect on the BP
Is the sympathetic or parasympathetic innervation of the heart dominant at rest?
Parasympathetic (Vagus) is dominant at rest
Both are active at basal levels
What percentage of the blood volume is contained in the veins?
over 60%
Contractility relation to velocity of shortening
More contractility = greater velocity of shortening
Effect of increased BP on CVCC
Increased Vagus and Depressor firing
Effect of decreased BP in CVCC
Decreased Vagus and Depressor firing, increased firing of Pressor region
Why does an increase in venous tone cause an increase in MAP and CO?
MAP: Increasing venous tone gives it an extra squirt, increase in resistance is negligible
CO: Increase in MAP with no TPR change will increase flow
How does an increase in venous tone affect diastolic pressure?
Because more blood into cup (heart), more blood for same runoff time, Pdia increases
Effect of increased HR on SP and DP
Increased DP (less time for runoff), no change in SP
What is the equation for MAP
MAP = CO x TPR
or
MAP = TPR x Q
Use the flow equation to get an equation for CO (and VR)
Q = ∆P/R = (Paorta - Pra)/TPR = CO = VR
Main driver of venous return
the heart (vis a tergo)
If someone is space does gravity get added to their venous pressure
NO
…
Endotherms
Can generate internal body heat
Homeotherms
Can maintain body temp in narrow range with big external fluctuations
What is the primary overall integrator of reflexes
Hypothalamus
Nonshivering thermogenesis
Chronic exposure to cold, leads to an increase in brown fat activity
Blood to skin is controlled by
sympathetic vasoconstrictor nerves
- heat causes inhibition
- cold causes activation
Insensible water loss
Loss via diffusion through skin and expiration
Sweat glands are stimulated by what type of nerve
sympathetic nerves
Thermoneutral zone
From 25-30C, outside of that, blood vessel regulation cannot compensate
Temperature Acclimatization
sweating begins sooner, more, sweat, etc
Fever
Increase in set point in the hypothalamus
Endogenous Pyrogens
Released from macrophages near the site of infection
- circulate to act upon thermoreceptors in the hypothalamus
-
Role of prostaglandins in fever
Immediate cause of set point reset
- EP cause local synthesis and release of prostaglandins
Aspirin
Inhibits prostaglandin synthesis
Benefits of fever
Stimulates WBC
Heat exhaustion
state of collapse (fainting) caused by hypotension due to loss of plasma volume (from sweating, dilation)
Benefit of heat exhaustion
Functions as a safety valve to prevent over-taxing of heat loss mechanisms and heat stroke
Heat stroke
complete breakdown of heat-regulating systems
- body temp keeps increasing
- sweating does not occur
Heatstroke as a positive feedback mechanism
Increased body temp stimulates increased metabolism
What are the three heat loss mechanisms dependent on temperature gradient?
1) Conduction
2) Convection
3) Radiation
Which heat loss mechanism is dependent on heat capacity
Convection
Which heat loss mechanism is depending on H2O vapor gradient
Evaporation
Peripheral temperature sensors
Free nerve endings sensitive to either cold or heat, firing rate increases in both cases
Why two types of thermoreceptors
Peripheral sensors alter the sensitivity of the core thermoreceptors
Vasodilation in acral skin
Occurs via withdrawal of sympathetic adrenergic tone
Vasodilation in non-sacral skin
Simulation of sympathetic vasodilator nerves via ACh
Fever in a cold environment
Might not get a fever, because heat loss mechanisms already turned up
How does UCP work
Cold stress triggers the realize of NE and T4
NE function in UCP
binds ß3/⍺1 receptors to move fatty acids into the mitochondria
T4 function in UCP
Gets converted into T3 which activates UCP
