Physiology π« Flashcards
What are the properties of cardiac fibers?
rhythmicity, excitability, conductivity and contractility
What is the definition of rhythmicity?
The ability of cardiac fibers to give regular impulses (action potentials) causing the heart to beat regularly.
What is the origin of rhythmicity?
Myogenic (not neurogenic; nerves do not initiate it but control it).
What is the evidence that rhythmicity is myogenic?
The transplanted heart (no nerve supply) continues to beat.
What has the fastest rhythm?
SAN has the fastest rhythm (so, it is the pace maker of the heart).
What is the self-excitation of SAN due to?
Natural leakiness of the membrane to Na+
What is the rhythmicity of SAN, AVN, Bundle tissues, Purkinje fibers, and ventricles respectively?
Rhythmicity without vagus 120 / min
90 / min
45 / min
35 / min
25 / min
What is the mechanism of rhythmicity of SAN? (SAN action potential)
- Na influx through funny (If) slow Na channels, Ca influx through T (transient) Ca channel, decreased K efflux β membrane potential changes gradually from - 55 mV (resting) to - 40 mV. This is called Phase 4 (Pacemaker potential = pre-potential = diastolic depolarization (DD)).
- Ca influx through L (long-lasting) (Ica) Ca channels β membrane potential changes from β 40 mV (firing or threshold level) to + 10 mV. This is Phase 0 (Upstroke phase.
- K efflux (Ik) β membrane potential returns to - 55 mV (resting). This is Phase 3 (Repolarization).
- Then, the process is repeated throughout life.
What is the reason for the changing of the membrane potential from (-55mv) to (-40mv) in SAN action potential?
Na influx through funny (If) slow Na channels, Ca influx through T (transient) Ca channel, decreased K efflux
What is the reason for the changing of the membrane potential from (-40mv) to (+10mv) in SAN action potential?
Ca influx through L (long-lasting) (Ica) Ca channels
What is the reason for the changing of the membrane potential from (+10mv) to (-55mv) in SAN action potential?
K efflux (Ik)
What is the excitability of cardiac fibers?
The ability of cardiac fibers to respond to an adequate stimulus (to generate action potentials).
What is the ionic basis of action potential (AP) of cardiac muscle?
- Rapid Depolarization (Phase 0):
- Opening of fast Na channels β rapid Na influx β membrane potential changes from - 85 (resting) to + 20 mV (overshoot) (total voltage of AP = 105 mV) - Early Fast Partial Repolarization (phase 1):
- Due to: K efflux & Inactivation of fast Na channels. - Slow Prolonged Plateau (Phase 2):
- The membrane remains depolarized (for 150 msec in atrial muscles & 300 msec in ventricular muscles) due to: slow Ca influx & decreased K efflux - Rapid Repolarization (Phase 3) due to: increased K efflux & closure of Ca channels.
- Complete Repolarization to resting membrane potential (Phase 4):
- The Na-K pump derives excess Na out and excess K in.
What causes rapid depolarization in cardiac muscle AP?
-85mv to +20mv
Opening of fast Na channels
What causes early fast partial repolarization in cardiac muscle AP?
K efflux & Inactivation of fast Na channels.
What causes the slow prolonged plateau in cardiac muscle AP?
slow Ca influx & Decreased K efflux
What causes rapid repolarization in cardiac muscle AP?
Increased K efflux & closure of Ca channels.
What is the function of the Na-K pump in cardiac muscle AP?
derives excess Na out and excess K in.
What is the conductivity of cardiac muscle fibers?
The ability of cardiac fibers to conduct excitation waves from one part of the heart to another.
What is the value of atrial conduction?
0.4 m/sec
From where to where does action potential travel in atrial conduction and what does it travel through?
The action potential travels from the SAN into the atria and to the AVN through:
- Atrial mass & Internodal bundles (Anterior, middle, and posterior).
What is the value of AV nodal conduction?
Velocity = 0.04 m/sec.
Total delay: 0.16 sec
What are the causes of slow conductivity in AVN?
the small size of fibers & few gap junctions.
What is the significance of AVN delay?
- Gives time for atria to empty blood into ventricles.
- Protects ventricles from high pathological atrial rhythms.
What is the value of Purkinje fibers conduction?
Velocity: 4 m/sec
What are the causes of high velocity in conduction in Purkinje fibers?
large fibers & high permeability of gap junctions.
What is the significance of high-velocity conduction in Purkinje fibers?
immediate transmission of cardiac impulse in the ventricles.
What is the contractility of cardiac fibers?
The ability of the muscle to do mechanical work (contraction & relaxation).
What are the steps of contraction of cardiac fibers? (Excitation-contraction coupling)
Action potentials pass over the muscle fiber membrane β spread to the interior along the transverse (T) tubules β open Ca++ channels β inc. entry of Ca++ into the sarcoplasm β act on the longitudinal sarcoplasmic reticulum (SR) β inc. release of Ca++ into the sarcoplasm β Ca++ bind to troponin β sliding between actin & myosin filaments β muscle shortening (contraction).
What are the sources of calcium for myocardial contraction?
ECF: via Ca channels in the cell membrane & down the T tubules
S.R: via calcium-induced calcium-release.
What does the force of contraction depend on?
the concentration of Ca++ in extracellular fluids
What are the ionic reasons for the relaxation of cardiac muscle fibers?
Stoppage of Ca++ influx & pumping back of Ca++ from the sarcoplasm into SR & ECF via Ca++ pumps & Na+ Ca++ exchangers.
What is a statement of starling law?
βWithin limit, the greater the initial length of the cardiac muscle fiber, the greater the force of contractionβ.
What is the initial length of the cardiac fibers determined by?
diastolic filling (end-diastolic volume = EDV).
How does EDV affect the force of contraction?
Inc. venous return (e.g., muscle exercise) β inc EDV (filling) β stretch of the muscle β inc the force of contraction
What is the significance of increasing the force of contraction of cardiac muscle fibers in response to high venous return?
prevents stagnation of blood in the CVS.
What happens in cases of overstretching concerning cardiac muscle fibers?
Dec. Contractility
What is the nature of Starling law?
Myogenic
What time does mechanical response take in relation to action potential?
1.5 times as long as AP.
When does Contraction begin in relation to AP?
just after the start of depolarization
When does contraction reach maximum in relation with action potential?
BY the end of plateau.
When does relaxation begin in relation to action potential?
AT the end of plateau.
When does Relaxation reach its med?
When RP is complete
What are the excitability changes during action potential?
Absolute refractory period (ARP)
Relative refractory period (RRP)
Supernormal phase
What is the excitability in ARP, RRP, and supernormal phase respectively?
Zero
Gradually increase
Above normal
What is the stimulation in ARP, RRP, and supernormal phase respectively?
No response, whatever the strength of the 2nd stimulus
Strong stimulus β weak contraction
Weak stimulus β Strong contraction
When do ARP, RRP, and supernormal phase occur respectively?
Rapid depolarization & plateau = Contraction
Rapid repolarization = 1st half of relaxation
At the end of AP = 2nd half of relaxation
What is the effect of ARP, RRP, and supernormal phase respectively?
Prevents tetanus (continuous contraction)
Null
May cause extrasystole
What are the Factors affecting rhythmicity (chronotropic), excitability (bathmotropic), conductivity (dromotropic), and contractility (inotropic)?
1- Nervous: Sympatyhaeic, Parasympathetic
2- Physical: Warming, Cooling, and Excessive warming/cooling
3- Chemical: Drugs and Hormones, Blood gases, Ions and typhoid/bacteria toxins
How does the sympathetic nervous system affect cardiac properties?
- Sympathetic β noradrenaline β inc Na influx β rapid depolarization β inc rhythmicity, excitability & conductivity.
- Sympathetic β B1 adrenergic receptors β inc Ca influx β inc contractility of all cardiac muscles.
How does the parasympathetic nervous system affect cardiac properties?
- Basal parasympathetic discharge (vagal tone) to atrial structures only β acetylcholine β inc K efflux β hyperpolarization (inhibition)β dec rhythmicity (of SAN from 120 β 70 /min), excitability & conductivity.
- Strong vagal stimulation can stop rhythmicity, excitability & conductivity in atrial structures only. βLike in shocksβ
- Parasympathetic stimulation β muscarinic receptors β dec Ca influx β dec contractility of atrial muscle only.
How does warming (fever) affect cardiac properties?
- Moderate warming (fever) β inc ionic fluxes across the membrane β inc rhythmicity (10 beats/1Β°F), excitability, conductivity, and inc contractility (due to Increased metabolic reactions, Ca influx, and decreased viscosity).
How does moderate cooling affect cardiac properties?
- Moderate cooling: opposite effects to moderate warming.
How does excessive cooling or warming affect cardiac properties?
- Excessive warming or cooling β cardiac damage β stop the heart.
How do drugs or hormones affect cardiac properties?
- Catecholamines, Thyroxine, xanthene-derivatives (theophylline & caffeine) β inc all cardiac properties.
- Cholinergic β dec all cardiac properties.
How do blood gases affect cardiac properties?
Decreased O2: Mild hypoxia β inc rhythmicity, excitability, conductivity, and dec contractility βdue to fatigueβ
Increased CO2 (hypercapnia) β inc H+ (acidosis = dec pH) β dec rhythmicity, excitability, conductivity, and contractility (dec affinity of troponin to Ca)
How do ions affect cardiac properties?
- increased K+ (hyperkalemia) β dec K efflux β prolong repolarization β dec all cardiac properties. Marked K increase β stop the heart in diastole (irreversible
relaxation) - increased Ca++ (hypercalcemia) β increases K efflux β hyperpolarization β dec rhythmicity, excitability, conductivity, and inc contractility. Marked Ca increase β stop the heart in systole (calcium rigor = irreversible contraction).
How do typhoid or diphtheria toxins affect cardiac properties?
Dec rhythmicity, excitability, conductivity, and contractility (direct inhibition).
βHowever other organisms that cause fever increase cardiac properties due to warmingβ
What is the definition of the cardiac cycle?
The cardiac events that occur from the beginning of one heartbeat to the beginning of the next.
What does the cardiac cycle include?
A period of contraction (systole) and a period of relaxation (diastole) occur during the cardiac cycle
What are the events studied in the cardiac cycle?
Valves. Heart sounds (ECG) Atrial pressure Ventricular pressure Ventricular volume Aortic pressure
What are the phases of the cardiac cycle?
Atrial systole (0.1 sec)
Ventricular systole (0.3 sec)
- Isometric contraction phase
- Maximum ejection phase.
- Reduced ejection phase
Ventricular diastole /0.5 sec)
- Isometric relaxation phase
- Rapid filling phase.
- Reduced filling phase
What is the state of the valves in atrial systole?
AV opened
Semi-lunar closed
Are there any sounds in atrial systole?
Yes, 4th heart sound Normally inaudible but can be recorded by the phonocardiogram.
What appears in the ECG in atrial systole?
P wave (atrial depolarization) starts 0.02 second before systole.
What is the atrial pressure in atrial systole?
Increase from zero -βΊ 2 mmHg (due to atrial contraction), Then, pressure returns zero due to evacuation into the ventricles. βInc then decβ
What is the state of ventricular pressure in atrial systole?
Inc slightly (due to rush of blood from the atria), then dec again as the ventricles are still relaxed.
βInc then decβ
What is the state of ventricular volume in atrial systole?
slightly (30%) due to rush of blood from the atria.
βIt was already passively filled with 70%β
what is the state of aortic pressure in atrial systole?
Dec gradually, due to flow of blood to the peripheral vessels.
What is the state of valves in isometric contraction phase?
AV close
Semilunar closed
What appears in ECG in isometric contraction phase?
QRS complex, starts 0.02 second before this phase
What is atrial pressure in isometric contraction phase?
Slight sharp increase, due to sudden closure of AV valve and ballooning of its cusps towards the cavity of the atrium by the sudden rise of ventricular pressure.
What is the ventricle pressure in isometric contraction phase?
The ventricle contracts so ventricular pr > atrial pr so sudden closure of the AV valves.
- All valves are closed, and the ventricle becomes a closed chamber full of blood which is incompressible, so the ventricle contracts isometrically
(without change in the length of fibers)
Is there any sounds in isometric contraction phase?
Early part of the 1st sound due to closure of AV valves
what is a ventricular volume in isometric contraction phase?
No change. (a closed chamber)
what is the state aortic pressure in isometric contraction phase?
Dec gradually, due to flow of blood to the peripheral vessels.
What is the state of valves in maximum ejection phase??
AV closed
Semilunar open
Is there any sounds in maximum ejection phase?
1st heart sound continues, due to flow of blood from ventricles to the aorta and pulmonary arteries.
What appears in ECG in maximum Ejection phase?
Early part The T wave starts in the late of this phase.
What is the atrial pressure in maximum Ejection phase?
sharp dec (due to pulling down the AV ring) Then gradual inc (due to Accumulation of venous blood in the atria and Upward displacement of AV ring to its normal position.)
βDec then incβ
What is the ventricular pressure in maximum ejection phase?
Marked inc (due to continuous contraction of the ventricles).
Ventricular pressure is higher than aortic or pulmonary pressure.
what is a ventricular volume in maximum ejection phase?
Dec rapidly, due to ejection of blood into the aorta or pulmonary artery.
What is the aortic pressure during maximum ejection phase?
Inc rapidly, due to ejection of blood from the left ventricle but remains βΉ ventricular pressure.
What is the state of valves in reduced ejection phase?
AV closed.
Semilunar opened
What appears in ECG in reduced ejection phase?
The top of T wave.
Are there any sounds in reduced ejection phase?
No sounds
what is the atrial pressure in reduced ejection phase?
Gradual inc (due to venous return)
What is the ventricular pressure in reduced ejection phase?
Slightly decrease
What is ventricular volume in reduced ejection phase?
Still decreasing
What is the aortic pressure in reduced ejection phase?
Slightly decrease, because the blood leaving the aorta is greater than the blood pumped into the aorta
What is ABP?
It is the lateral force exerted by the blood on the arterial wall.
What are the characteristics of ABP?
- Pulsatile.
- It is not constant during a cardiac cycle.
- The systolic BP is caused by the sudden ejection of blood into the aorta during systole.
- The diastolic BP is caused by the passive elastic recoiling of the arteries (elastic recoil or windkessel effect)
What is systolic pressure?
It is the highest arterial pressure during a cardiac cycle, It is measured after the heart contracts (systole) and blood is ejected into the arterial system.
What is diastolic pressure?
It is the lowest arterial pressure during a cardiac cycle, It is measured when the heart is relaxed (diastole) and blood is returned to the heart via the veins.
What is pulse pressure?
is the difference between the systolic and diastolic pressures.
What is the most important determinant of pulse pressure?
SV
What does pulse pressure equal?
40mmHg
What is mean arterial pressure?
It is the average arterial pressure with respect to time.
How can we calculate mean arterial pressure?
Can be calculated approximately as diastolic pressure plus one-third of pulse pressure.
What is the importance of arterial blood pressure?
1) It maintains sufficient pressure to keep the blood flowing.
2) It provides enough hydrostatic pressure inside the capillaries essential for the formation of interstitial fluid, urine, etc.
βThe pressure in the capillaries causes the ejection of nutrients and vitamins to the cells, it also allows the absorbance of wastes from themβ
How does age affect arterial blood pressure?
- The ABP is about 50/30 mmHg.
- After birth, Increase of age will increase ABP till adulthood where it is 120/80.
- After the age of 50 years it increases gradually due to normal gradual loss of arterial elasticity.
- It may become normally 140/90
How does gender affect arterial blood pressure?
- ABP is generally slightly higher in adult males than in females.
- However, it becomes slightly higher in females after menopause.
How does the bodybuilt affect arterial blood pressure?
ABP is higher in obese persons
how does environmental temperature affect arterial blood pressure?
Exposure to cold increases both Systolic and systolic pressures due to cutaneous vasoconstriction.
How do emotions affect arterial blood pressure?
Increase the ABP considerably
How does exercise affect arterial blood pressure?
Systolic ABP increases while the diastolic is often not changed or decreases due to arteriolar vasodilatation.
How do meals affect arterial blood pressure?
The ABP increases slightly after meals due to VD of the splanchnic area which increases both VR and COP.
How does posture affect arterial blood pressure?
On standing, the force of gravity increases the mean ABP below a reference point in the heart and decreases it above that point by about 0.77 mm/cm height.
What are the factors maintaining normal ABP?
- Cardiac output
- Peripheral resistance
- Elasticity of the arterial wall
- The total blood volume in relation to the capacity of the circulatory system
What do changes in stroke volume affect?
Changes in the stroke volume with the HR constant affect the systolic more than the diastolic pressure.
What do changes in heart rate affect?
Changes in the HR with constant SV affect the diastolic more than the systolic blood pressure.
What are the factors that determine peripheral resistance?
PR = VL/r4
a) Viscosity of blood (V): It is the property by which a fluid resists a change in shape, It represents the force with which the fluid particles adhere to each other and resists
their separation
b) Length of the blood vessels (L)
c) The diameters of arterioles (r)
What does atherosclerosis cause in terms of ABP?
there is a marked increase in systolic βpushing of bloodβ and a decrease in diastolic blood βdecrease in elasticityβ pressure resulting in higher pulse pressure.
The effect of the factor: (The total blood volume in relation to the capacity of the circulatory system) in ABP?
Changes in blood volume:-
- Mild to moderate
- Severe
Changes in the capacity of the circulatory system:
- Increase
- Decrease
What are the most important mechanisms in the regulation of ABP?
1- Fast, neurally mediated baroreceptor mechanism
2- Slower, hormonally regulated renin-angiotensinβaldosterone mechanism
What are the characteristics of the Baroreceptor reflex?
fast, neural mechanisms.
What is the definition of baroreceptor reflex?
- It is a negative feedback system that is responsible for the minute-to-minute regulation of arterial blood pressure
- Baroreceptors are stretch receptors located within the walls of the carotid sinus near the bifurcation of the common carotid arteries.
What are the steps in baroreceptor reflex?
1) A decrease in arterial pressure decreases stretch on the walls of the carotid sinus and aortic arch.
2) Decreased stretch decreases the firing rate of the baroreceptors (which send information to the vasomotor center in the brain stem).
3) The vasomotor center responds to the decrease in mean arterial blood pressure by decreasing parasympathetic outflow to the heart and increasing sympathetic outflow to the heart and blood vessels to increase mean arterial pressure to 100mmHg
What are the effects caused by baroreceptor reflex?
β heart rate
β contractility and stroke volume
β vasoconstriction of arterioles
β vasoconstriction of veins (venoconstriction)
What causes β heart rate?
resulting from the decreased parasympathetic tone and increased sympathetic tone to the SA node of the heart.
What causes β contractility and stroke volume?
resulting from increased sympathetic tone to the heart.
What are the results of increased heart rate and increased contractility, Stroke volume?
They produce an increase in cardiac output that increases arterial pressure.
What causes β vasoconstriction of arterioles?
resulting from the increased sympathetic outflow.
What is the result of β vasoconstriction of arterioles?
TPR and arterial pressure will increase.
What causes β vasoconstriction of veins (venoconstriction)?
resulting from the increased sympathetic outflow.
What are the results of β vasoconstriction of veins?
causes a decrease in unstressed volume and an increase in venous return to the heart.
What are the characteristics of the renin-angiotensin-aldosterone system?
- slow, hormonal mechanism.
- used in long-term blood pressure regulation by adjustment of blood volume.
What are the chemicals in the renin-angiotensin-aldosterone system?
- Renin is an enzyme.
- Angiotensin I is inactive.
- Angiotensin II is physiologically active.
- Angiotensin II is degraded by angiotensinase.
- One of the peptide fragments, angiotensin III, has some of the biologic activity of angiotensin II.
What are the steps in reninβangiotensinβaldosterone system?
1) A decrease in renal perfusion pressure causes the juxtaglomerular cells of the afferent arteriole to secrete renin.
2) Renin is an enzyme that catalyzes the conversion of angiotensinogen to angiotensin I in plasma.
3) Angiotensin-converting enzyme (ACE) catalyzes the conversion of angiotensin I to angiotensin II, primarily in the lungs.
4) angiotensin II has many effects
What are the effects of angiotensin II?
a) It stimulates the synthesis and secretion of aldosterone by the adrenal cortex.
b) It increases Na+βH+ exchange in the proximal convoluted tubule.
c) It increases thirst and therefore water intake.
d) It causes vasoconstriction of the arterioles, thereby increasing TPR and arterial pressure.
What is the importance of stimulation and secretion of aldosterone in the RAAS?
- Aldosterone increases Na+ reabsorption by the renal distal tubule, thereby increasing extracellular fluid (ECF) volume, blood volume, and arterial pressure.
Why is the action of aldosterone slow?
because it requires new protein synthesis.
What is the importance of the increase of NA - H exchange in the proximal convoluted tubules in the RAAS?
- This action of angiotensin II directly increases Na+ reabsorption, complementing the indirect stimulation of Na+ reabsorption via aldosterone.
- This action of angiotensin II leads to contraction alkalosis.
What are other regulation systems of ABP?
1) Cerebral ischemia
2) Chemoreceptors in the carotid and aortic bodies
3) Vasopressin [antidiuretic hormone (ADH)]
4) Atrial natriuretic peptide (ANP)
What are the steps of regulation of ABP in the case of cerebral ischemia?
- When the brain is ischemic, the partial pressure of carbon dioxide (PCO2) in brain tissue increases.
- Chemoreceptors in the vasomotor center respond by increasing sympathetic outflow to the heart and blood vessels.
- Constriction of arterioles causes intense peripheral vasoconstriction and increased TPR.
- Blood flow to other organs (e.g., kidneys) is significantly reduced in an attempt to preserve blood flow to the brain.
What is an example of the response to cerebral ischemia?
- The Cushing reaction is an example of the response to cerebral ischemia. Increases in intracranial pressure cause compression of the cerebral blood vessels, leading to cerebral ischemia and increased cerebral PCO2.
- The vasomotor center directs an increase in sympathetic outflow to the heart and blood vessels, which causes a profound increase in arterial pressure.
Where are chemoreceptors located?
located near the bifurcation of the common carotid arteries and along the aortic arch.
What are chemoreceptors in carotid and aortic bodies sensitive to?
have very high rates of O2 consumption and are very sensitive to decreases in the partial pressure of oxygen (Po2).
What does a decrease in pressure of oxygen do to the chemoreceptors in the carotid and aortic bodies?
Decreases in PO2 activate vasomotor centers that produce vasoconstriction, an increase in TPR, and an increase in arterial pressure.
What is vasopressin hormone involved in?
It is involved in the regulation of blood pressure in response to hemorrhage, but not in minute-to-minute regulation of normal blood pressure.
How do atrial receptors respond to a decrease in blood volume or blood pressure?
Atrial receptors respond to a decrease in blood volume (or blood pressure) and cause the release of vasopressin from the posterior pituitary.
What are the effects of vasopressin?
Vasopressin has two effects that tend to increase blood pressure toward normal:
- It is a potent vasoconstrictor that increases TPR by activating V1 receptors on the arterioles.
- It increases water reabsorption by the renal distal tubule and collecting ducts by activating V2 receptors.
From where is ANP released?
from the atria in response to an increase in blood volume and atrial pressure.
What are the effects of ANP?
- ANP causes relaxation of vascular smooth muscle, dilation of arterioles, and decreased TPR.
- causes increased excretion of Na+ and water by the kidney, which reduces blood volume and attempts to bring arterial pressure down to normal.
- inhibits renin secretion.
What is cardiac output?
The is the volume of blood pumped by each ventricle per minute, It is also called minute volume.
What does cardiac output normally equal?
Normally, it is about 5 liters/minute during rest and is equal for both ventricles.
What is the definition of end-diastolic volume? And what does it equal?
Is the volume of blood in the ventricle at the end of diastole, it is about (110-130 ml).
What is the definition of end-systolic volume and what is its value?
Is the volume of blood in the ventricle at the end of the systole, is about (40-60 ml).
What is the definition of stroke volume and what is its value?
- It is the volume of blood pumped by each ventricle per beat.
- SV = EDV (130) β ESV (60) = 70 ml.
What is the formula used to calculate cardiac output or minute volume?
The COP = SV x HR. = 70 x 70 = 4900 ml/minute, at rest.
What is the definition of the cardiac index?
Is the volume of blood pumped by each ventricle/square meter of body surface area/minute.
What does cardiac index equal?
about 3.2 litres/m2/min.
What is the importance of cardiac index? (CI)
It is used to compare the COP between the different individuals.
What is the definition of ejection fraction? (EF)
Is the percentage ratio of the SV to the EDV.
What is the formula used to calculate ejection fraction? and what it is normally equal to?
- EF = SV / EDV x 100
- Normally, it is about 65%.
What is ejection fraction considered an indicator for?
It is a sensitive indicator of myocardial contractility.
What is ejection fraction directly related to? And when does it decrease?
ventricular contractility, in Heart failure
How is cardiac output determined clinically?
by echocardiography.
What are the factors affecting cardiac output?
Venous return (preload)
Arterial blood pressure (afterload)
Heart rate (HR)
Strength of ventricular contraction
What mainly determines cardiac output?
- the volume of blood returned by the veins from the tissues i.e. by the metabolic activity of the tissues, particularly the voluntary muscles.
- So, VR β βCOP
What are the factors that affect venous return?
1) The pumping action of the heart (most important)
2) Pressure gradient
3) Respiratory movements
4) Gravity
5) Vascular system
6) Skeletal muscle contraction (a muscular pump)
7) Blood volume
how does the pumping of action of the heart affect venous return?
forcing blood into the blood vessels.
What is the effect of pressure gradient in Venous return?
- The pressure gradient for venous return is the difference between the mean circulatory pressure (MCP) and the right atrial pressure (RAP).
- In the recumbent position, (MCP ) is 7-8 mm Hg and (RAP) is 2 mm Hg, this leads to a venous return of about 5 liters/minute.
What is the mean Circulatory pressure and what does it equal?
Is the blood pressure in peripheral venules and veins in the recumbent position and is normally about 7-8 mm Hg.
What is the right atrial pressure and what does it equal?
It is the pressure in the right atrium, In the recumbent βpatients are carried in this positionβ position it is 2 mmHg.
What is the effect of respiratory movements on venous return?
Venous return increases with inspiration and decreases with expiration.
How does venous return increase during inspiration?
Normal inspiration makes the intrathoracic pressure more negative and the intraabdominal pressure more positive β blood is sucked from extra to intrathoracic veins β VR.
βBreathe to let blood inβ
How does venous return decrease during expiration?
During normal expiration, the negativity inside the thorax is decreased, and so the VR is less than during inspiration.
How does gravity affect Venous return?
- Gravity influences VR in a mechanical way.
- In the recumbent position, gravity has no effect on VR.
- In the erect position, gravity helps the VR from parts above the level of the heart but reduces it from parts below the level of the heart.
How does the diameter of arterioles affect venous return?
- Normally, the tone of the arterioles leads to partial VC.
- VD of arterioles ββVR.
How does the diameter of capillaries affect venous return?
- If all the capillaries of the body are widely dilated, as by injection of histamine, the whole blood volume will be retained in them β no VR, no COP, βshock and death i.e., βHistamine shockβ.βNo use of vasodilators in case of decreased cardiac outputβ
- Thus, VD of capillaries β βVR ββ COP.
Normally, how many capillaries are open during rest?
- About 10% only of the capillaries are opened and the other 90% are collapsed during the rest.
How does the diameter of veins affect venous return?
- Venous tone prevents full distension of veins with blood, So, it maintains VR.
- VD of veins β stagnation blood into veins ββ VR and COP and vice versa.
How does skeletal muscle contraction affect venous return?
- During muscular contraction, the muscle fibers compress the blood vessels lying in between them, squeezing the blood into veins towards the heart, so increasing the VR and COP.
- During muscular relaxation, the blood does not regurgitate back to the muscles because the veins possess very efficient valves which direct the bloodstream towards the thoracic veins.
How does blood volume affect venous return?
- Increased blood volume (e.g. during muscular exercise due to contraction of blood reservoirs ββVR and COP.
- Decreased blood volume ββVR, COP.
How does arterial blood pressure afterload affect cardiac output?
Changes in ABP have no effect on the COP provided the VR is kept constant.
1) When the blood pressure rises suddenly, the first systole will not be strong enough to pump all the blood received during diastole and some blood remains in the
ventricle, This residual blood is added to the diastolic fillingββEDV of the next systoleββforce of myocardial contraction (according to Starlingβs law).
2) When the ABP is lowered the opposite occurs, The first few beats expel more blood than that received during diastoleββ ESVββEDVββforce of myocardial contraction
(according to Starlingβs law).
What influences the change of COP by heart rate?
both the amount of VR and the extent of changes in heart rate.
What happens in the case of mild to Moderate changes in heart rate with constant VR? (Physiological or moderate changes of HR)
- If the venous return is kept constant, moderate changes in HR have no effect on COP, it affects only the SV.
- The SV increases when the heart slows (as it has enough time to fill with more blood) and decreases when the heart accelerates, So, the COP remains constant in both instances
What happens in case of excessive changes in heart rate with constant VR?
If the venous return is kept constant marked acceleration or slowing of the heart decreases the COP.
What are examples of excessive or physiological changes in heart rate with constant VR?
In paroxysmal tachycardia: (HR 200 beats/min or more).
- The diastolic period will be greatly shortened with no sufficient time for filing of the heart and so the COP decreases.
βͺ e.g. COP = SV x HR = 20 x 200 = 4000 ml/min.
In complete heart block: COP= SV x HR = 130 x 30 = 3900 ml/min
What are the cases in which heart rate changes with the change of VR?
- When the VR is increased, the acceleration of the heart becomes of fundamental importance in increasing the COP.
Why does COP increase with increased venous return of the heart?
This is because:
- Increased EDV
οΌ With an enhanced rate of blood flow, the heart can be filled to a maximum in a short diastolic period leading to an increase in the EDV. - Decreased ESV
οΌ Also, sympathetic stimulation during exercise β forced ventricular contraction ββESV. - These factors lead to a marked increase of the SV and so the COP increases 7-8 folds.
The factor: Strength of ventricular contraction in maintaining COP
- when the ventricles contract more strongly, they pump more blood.
- Starlingβs law of the heart represents an important mechanism of cardiac reserve power.
- In a normal heart within limits, when the VR increases as in muscular exercise, β the ventricle dilates i.e. increases the initial length of the cardiac muscle fiber during diastole ββforce of ventricular contraction ββSV and COP.
What are the methods of measurement of COP?
1) The direct Fickβs principle
2) Echocardiography
What does direct Fickβs principle state?
This principle states that: The amount of a substance taken up by an organ or by the whole body/min
= arterial content β venous content X blood flow/min.
What are the requirements for direct Fickβs principle?
- The O2 consumption/min
- The O2 content in the mixed venous blood (from the pulmonary trunk by a cardiac catheter).
- The O2 content in the arterial blood
- Therefore, the COP = 250/ (190-140) = 250/ 50 = 5 liters/min.
What is the regulation of COP?
Is the ability of the cardiac muscle to change its COP to meet the body requirements under different situations.
- COP may be changed by changing the SV or HR or both.
How is intrinsic regulation (autoregulation) studied?
Studied by the heart-lung preparation that allows the study of the cardiac muscle independent of nervous or hormonal factors in experimental animals.
What are the stages of intrinsic regulation?
Heterometric and homeometric
compare between Heterometric and homeometric regulations Acc to:-
Definition Nature Cause Starts Lasts EDV ESV SV Explained by
compare between Heterometric and homeometric regulations Acc to:-
Definition Nature Cause Starts Lasts EDV ESV SV Explained by
- Is the regulation of COP with the change of the initial length.
- Intrinsic
- βPreload (VR)
- Within 30 sec.
- Few minutes (Transient mechanism)
- Marked ββ βsudden return of bloodβ
- Slight β
- β
- Is the regulation of COP without change of the initial length.
- Intrinsic
- βAfterload (ABP)
- Within 5 min.
- Continues as long as after-load is β (Steady-state mechanism).
- returns to normal βblood is pumpedβ
- βbelow normal βdue to better contractionβ
- β βdue to better contractionβ
What explains heterometric regulation of COP?
β the initial length of the ventricle (EDV)
i.e starlingβs law.
What explains homeometric regulation of COP?
1) The preceding heterometric stage β better metabolic state i.e. More warmth and Ca++ etc.
βͺ This leads to forceful contraction.
2) Pressure-induced regulation: The rise in the aortic pressure will increase the coronary blood flow that will provide more O2 to the contracting myocardium.
3) Release of myocardial catecholamines.
When is the heterometric autoregulation observed?
Physiologically, the heterometric autoregulation is observed when a person goes from the standing position to the recumbent position, a relatively large volume of blood shifts from the veins of the lower limbs to the heart ββ EDV ββSV β βCOP.
What is the extrinsic regulation of COP?
The autonomic nerve supply of the heart and the circulating blood hormones regulate the COP by adjusting both the heart rate and the stroke volume.
How does the autonomic nervous system regulate COP extrinsically?
Sympathetic stimulation increases the COP by:
1) +ve chronotropic effect, it increases the heart rate.
2) It increases the strength of ventricular contraction, by:
β The increased forces of ventricular contraction, decrease the ESV β> increase SV
β Also forceful ventricular contraction βrapid relaxation acts as suction force β filling of the ventricles at the short diastole.
3) It increases the mean circulatory pressure β increases the pressure gradient of VR β increase VR and increases COP.
Parasympathetic stimulation decreases the COP by slowing the heart. (HR)
How do hormones and drugs regulate COP?
Inc COP by Inc Both: Catecholamines, Thyroxine
Inc COP by Inc SV βforce of contractionβ: Digitalis, Xanthine derivatives e.g. caffeine, theobromine, and theophylline, Glucagon, and corticosteroids
Dec COP by dec HR βchronotropic effectβ: Acetylcholine and other parasympathomimetic drugs such as methacholine, carbachol, and pilocarpine
What is the composition of blood and what is the composition of substances that forms blood?
β Blood is a complex reddish fluid that circulates within the cardiovascular system
β Blood consists of a yellowish fluid (plasma) (55% of blood volume) in which cellular
elements (45% of blood volume) are suspended.
Plasma:- consists of:
- 90% Water
- 0.9% Inorganic substance (Na+, K+, Cl-, HCO3, PO4, SO4)
- 9.1% Organic substances (plasma proteins, lipids, others)
Cellular elements:- Include:
- Red blood cells (RBCs)
- White blood cells (WBCs)
- Platelets
What is the volume of blood in humans?
Its volume is about 8% of the bodyweight i.e. 5600 ml in a 70 kg man. β One litter must be lost to show effectβ
What are the general functions of blood?
1) Major transport medium:
- Blood transports many substances like glucose, O2, CO2, end products of metabolism as urea, and hormones
2) Hemostatic function:
- Stoppage of bleeding from injured blood vessel by platelets and clotting
3) Homeostatic function:
- Keeping the composition (pH, electrolytes, and water) of the internal environment (ECF) constant.
- This is done by continuous exchange of substances between the interstitial fluid (ECF) and blood then between the blood and the external environment through the gastrointestinal tract, lungs, kidneys, and skin.
4) Defensive function:
- WBCs provide the main defense mechanisms against a wide variety of micro-organisms through phagocytosis and the formation of antibodies
What is the size of RBCs?
- Its diameter β 7.5 um.
- Its thickness β at the thickest point is about 2.5 um.
- Its average volume β 90 to 95 u3.
What is the structure of RBCs?
RBCs are not true cells, because they have no nuclei, so called corpuscles.
1) The cell membrane:
- They are surrounded by a plastic semipermeable membrane and has a large surface area, so RBCs are biconcave
2) Its contents:
- Hb is the main constituent of RBCs βcarry o2β (34% of their weight). βThird!β
- K ion is the chief intracellular cation.
- Carbonic anhydrase enzyme, which is important for CO2 transport.
- NO Mitochondria in the RBCs, so they obtain their energy from anaerobic glycolysis. βFor ion balance for exampleβ
What is hemoglobin and what are its levels?
- It is an iron-containing red pigment that is present inside RBCs.
- contents: ο² in adult malesβ 14-18 gm/dl "more RBCs" ο² in adult femalesβ 12-16 gm/dl ο² in newborn β 18 gm/dl ο² in children β 12 gm/dl
What are the functions of RBCs?
1) Functions of cell membrane:
β It has a large surface area than the actual cell volume:
- It gives RBCs its biconcave shape.
- It allows easy diffusion of gases through the cell membrane.
β It is plastic, so it enhances cell flexibility to allow RBCs to be squeezed in small capillaries without rupture of it.
β It keeps Hb inside RBCs, so prevent its loss in urine:
- Filtration of Hb into glomeruli causes its precipitation in
renal tubules and acute renal failure.
2) Functions of Hb:
β It transports CO2 βwith carbonic anhydrase enzymeβ and O2 between lungs and tissues.
β It is an excellent acid-base buffer. βMaintains pHβ
3) Functions of carbonic anhydrase enzyme:
β It helps in the transport of CO2. βIn the form of HCO3β
4) Blood viscosity:
β RBCs share in the production of blood viscosity, which maintains arterial blood pressure (ABP).
What is the lifespan of platelets (thrombocytes)?
8- 12 days βShortβ
What is the function of platelets?
Have a role in hemostasis:
- Release of V.C. substances such as serotonin and thromboxane A2.
- Formation of a primary hemostatic plug.
- Release of platelet phospholipids (PF3) which is essential for blood clotting.
- Stabilization of the blood clot and induction of clot retraction.
- Help repair the damaged vessel wall.
Where are granular leukocytes formed?
Formed in the bone marrow
What percent does each type of granular leukocyte represent?
ο 60-70% (neutrophils) β as they are continuously lostβ
ο 1-5% (eosinophils)
ο 0.0-1.0% (basophils)
What is the lifespan of granular leukocytes?
4 -5 days
What is the function of neutrophils?
The first line of defense against bacterial infection by phagocytosis
What is the function of eosinophils?
- Defense against parasitic infection e.g. schistosomiasis
- Prevent the spread of the local inflammatory during an allergic reaction
What is the function of basophils?
- Synthesize and liberates heparin (anticoagulant) into the blood.
- Releases histamine, serotonin, and bradykinin during allergic reactions.
Where are lymphocytes formed what percent do they represent?
Formed in the lymphoid tissues.
20-30%
Where are monocytes formed and what are their percent?
Formed in bone marrow
3-8%
What is the lifespan of agranular leukocytes?
months or even years βVery longβ
What is the function of lymphocytes?
ο T lymphocytes for cell-mediated immunity
ο B lymphocytes secrete antibodies
What is the function of monocytes?
Phagocytosis β100 and doesnβt dyeβ of bacteria and old cells such as RBCs by forming tissue (fixed) macrophage system or reticuloendothelial system (RES)
What is the definition of hematopoiesis?
It is the process of formation of blood cells
What are the sites of hematopoiesis?
In the early few weeks of embryonic life
ο blood cells are produced in the yolk sac.
In the middle trimester of gestation
ο blood cells are produced in the liver, spleen, and lymph nodes. (RES)
In the last trimester and after birth
ο hematopoiesis is restricted to the red bone marrow (bone marrow of all bones).
After the age of 20 years
ο the bone marrow of all long bones becomes fatty and the RBCs are produced only by the membranous (flat) bones, such as the vertebrae, sternum, ribs, and ilia.
What are the steps of hematopoiesis?
All blood cells originate from pluripotential hematopoietic stem cells (PHSCs), which divide and differentiate into 2 cells lines by hemopoietic growth factors:
1) Lymphoid stem cells: gives rise to lymphocytes, which include the T cells, B cells, and natural killer (NK) cells. These cells quickly migrate from the bone marrow to lymphatic tissues e.g. lymph nodes, spleen, and thymus.
2) Myeloid stem cells: gives rise to all the other formed elements, including the RBCs; megakaryocytes that produce platelets; and a myeloblast lineage that gives rise to monocytes and granular leukocytes: neutrophils, eosinophils, and basophils
What are the factors affecting hematopoiesis?
Hemopoietic growth factors Healthy bone marrow. Healthy liver Hormones Nutritional factors
What is erythropoietin and where it is secreted?
- It is a glycoprotein hormone secreted in the adults by the kidney (90%) and liver (10%) and during fetal life, is formed mainly by the liver.
What stimulates the secretion of erythropoietin?
Its secretion is stimulated mainly by hypoxia βLow o2 due to low RBCsβ, cobalt and androgens.
What does erythropoietin act on?
It acts on stem cells to differentiate them into proerythroblasts and on proerythroblasts to differentiate them into mature RBCs.
What is Thrombopoietin and where is it secreted?
Is a glycoprotein hormone, is produced by the liver and kidneys.
What is the function of Thrombopoietin?
Stimulates the production of megakaryoblasts and the development of megakaryocytes into platelets
What is the percentage of platelets that are released in blood?
60-75% of platelets are released in the blood and 25% are trapped in the spleen, so splenectomy rises the platelets levels in the blood (thrombocytosis)
What are cytokines and from where are they secreted?
Are glycoproteins secreted by a wide variety of cells, including red bone marrow, leukocytes, macrophages, fibroblasts, and endothelial cells. It includes 2 groups:
What are the types of cytokines?
a) Colony-stimulating factors (CSFs):
1) Granulocyte CSFs: trigger the differentiation of myeloblasts into granular leukocytes (neutrophils, eosinophils, and basophils).
2) Monocyte CSF: induces the production of monocytes
3) GM-CSF: induce the production of both granulocytes and monocytes
4) granulocytes, monocytes, platelets, and erythrocytes are stimulated by multi-CSF.
b) Interleukins: interleukin 3, promotes the growth and reproduction of virtually all the different types of committed stem cells. βFirst stepβ
What is the role of healthy bone marrow in affecting hematopoiesis?
ο Healthy bone marrow is essential to produce RBCs and other blood cells
ο Destruction of bone marrow by irradiation or chemicals, drugs leads to deficiency of all blood cells (aplastic anemia).
What is the role of a healthy liver in hematopoiesis?
A healthy liver is essential for normal RBC formation and Platelets because it is the site for secretion of erythropoietin and thrombopoietin and stores iron and Vit B12
What is the role of hormones in hematopoiesis?
Most hormones including thyroid hormones, androgens βtestosterone, thatβs why males have more RBCsβ and glucocorticoids are essential for hematopoiesis, as they promote tissue metabolism in general.
What is the role of nutritional factors in hematopoiesis?
1) Proteins:
β Animal proteins (high biological value proteins) that present in the liver, kidney, and muscles are superior in the production of RBCs to other proteins
2) Minerals:
β Copper and cobalt act as cofactors in hemoglobin synthesis.
β Iron is essential for heme synthesis
3) Vitamins:
β All vitamins are needed for hematopoiesis especially vitamin B12 and folic acid
β Vitamin B12 and folic acid are important for the final maturation of the blood cells because they are essential for the synthesis of DNA
β Deficiency of either vitamin B12 or folic acid causes megaloblastic anemia, Leukopenia, and thrombocytopenia.
What is the definition of anemia?
is a β in O2 carrying capacity of blood due to deficiency of Hb which can be caused by either βed number of RBCs or too little Hb in the cells.
What are the causes of anemia?
1) Blood loss anemia: due to blood loss as in hemorrhage,
2) aplastic βALL BLOOD CELLSβ anemia: due to failure of functions of bone marrow
3) megaloblastic anemia: due to lack of Vit B12 and folic acid and βcauses ruptureβ
4) hemolytic anemia: due to excessive RBCs destructions as in thalassemia βdisturbance in HB synthesisβ
What is the definition of Purpura?
is a bleeding disorder (manifested by red spots in the skin) due to deficiency in platelets count (thrombocytopenia) or functions (non-thrombocytopenic purpura)
What are white blood cells disorders?
include:
1) Leucopenia means WBCs count is less than 4000/mm3
2) Leukocytosis means WBCs count is more than 11000/ mm3
3) Leukemia means an abnormal increase in the number of WBCs (cells are immature and undifferentiated cells)
What is administrated to various forms of cancer who are receiving chemotherapy?
Synthetic forms of CSF and interleukin hormones are often administered to patients, with various forms of cancer who are receiving chemotherapy, to revive their WBC counts.
What is the definition of hemostasis?
Prevention of blood loss after injury.
What are the steps of hemostasis?
- Vascular spasm: occurs immediately after the blood vessel has been cut
- Formation of a platelet plug (temporary hemostatic plug).
- Formation of a blood clot (definitive hemostatic plug).
- Fibrosis of the blood clot to close the hole in the vessel permanently.
What does vascular constriction result from?
- Nervous reflexes are initiated by the pain from the traumatized vessel.
- Local myogenic contraction due to direct damage.
- Local vasoconstrictor factors as serotonin and thromboxane A2 (from platelets).
What causes more constriction to the vascular walls?
Transverse cut & traumatized vessels βnervous reflexβ
What is the function of vascular spasms in blood clotting?
The vascular spasm reduces the flow of blood from the vessel rupture.
What is the functional structure of the platelet membrane?
βΊ It is extensively invaginated membrane with a complex canalicular system that allow contact with the ECF.
βΊ Contain a coat of glycoprotein
β’ Repulses adherence to normal endothelium
β’ Allow adherence to the injured vessel wall.
βΊ Contains large amounts of phospholipids
β’ Play several roles in the process of blood clotting.
What is the Functional structure of the platelets cytoplasm?
Contains many active structures as:
- Contractile proteins for platelet contraction as actin, myosin, and thrombosthenin
- Residual of both endoplasmic reticulum and Golgi apparatus for synthesis of enzymes and storage of Ca2+.
- Mitochondria
β’ Can form ATP & ADP. - Enzyme system
β’ Can synthesize prostaglandins - Clotting factors as fibrin-stabilizing & von Willebrand factors
- A growth factor that helps repair damaged vessel walls.
What are the steps of the formation of the platelet plug?
Platelet adhesion
Platelet activation
Platelet aggregation
What is the adhesion of platelets potentiated by?
Such adhesion is potentiated by the von Willebrand factor (a glycoprotein presents in the plasma and subendothelial tissue) and the platelets membrane glycoprotein
When do platelets adhesion take place?
When a blood vessel is injured, the platelets adhere to the exposed subendothelial collagen.
What initiates platelet activation?
Initiated by platelet adhesion.
What happens in platelet activation?
- The activated platelets swell, develop pseudopodia, become sticky, and discharge their granules mainly ADP.
- Also, its enzyme system is activated to form thromboxane A2. βVCβ
What happens in platelet aggregation?
- The released ADP and thromboxane βA2 activate the nearby platelets, Making them stickier and adhere to the originally activated platelets and release ADP and thromboxane β A2 which, in turn, activates more and more platelets.
- Thus, a vicious circle of platelets activation and aggregation is elicited leading to the formation of a loose platelet plug. βPurpura is due to non-formation or non-function of plateletsβ
What is the effect of salicylates (aspirin) on blood clotting?
Salicylates (aspirin) can inhibit the thromboxane βA2 formation and so inhibits platelets activation and aggregation.
What is the importance of platelet plugs?
Platelet plugs are extremely important for closing the minute ruptures occurring in the wall of vessels many thousand times daily
What is the duration of blood clot formation?
The active process occurs within 3-6 minutes.
What does blood clot formation need?
- The clotting process is initiated by active substances from the traumatized vascular wall, platelets, and coagulation factors.
- The clotting process to occur, certain factors named clotting factors (plasma protein of beta globulin type) must be activated.
What are the clotting factors?
- Plasma proteins of beta globulin type, are proteolytic enzymes present in an inactive form
Give examples of the clotting factors.
Factor I: Fibrinogen
Factor II: Prothrombin
Factor III: Tissue thromboplastin
Factor IV: Calcium ions (Ca++)
Factor V: Proaccelerin or labile factor
- ββ- Prekallikrein
- ββ- HMW kininogen
- ββ- Platelets F3
Factor VII: Proconvertin or stable factor
Factor VIII: Antihaemophilic factor
Factor IX: Christmas factor
Factor X: Stuart prewar factor
Factor XI: Plasma thromboplastin antecedent
Factor XII: Hegeman factor
Factor XIII: Fibrin stabilizing factor
What are the steps of clot formation?
ο Formation of prothrombin activator
ο Conversion of prothrombin into thrombin
ο Conversion of fibrinogen into fibrin
What initiates the extrinsic pathway?
It is initiated by contact of blood with traumatized vascular walls or extra-vascular tissues.
Mentions steps of the extrinsic pathway.
It is a rapid process and occurs according to the following steps:
- Traumatized tissues release a complex of several factors called tissue thromboplastin (composed of phospholipids and lipoprotein that functions as a proteolytic enzyme).
- The lipoprotein of tissue thromboplastin activates factor VII and then complexes with it.
β’ This complex in the presence of Ca2+ and tissue
phospholipids act on factor X to form activated factor X - Formation of the prothrombin activator.
β’ The activated factor X complexes immediately with the
tissue phospholipids, Ca2+and with activated factor V to form the complex called prothrombin activator.
What initiates the intrinsic pathway?
It begins with trauma to the blood itself or exposure of the blood to collagen from a traumatized vessel wall or contact of the blood with water β wettable surface e.g., glass.
What are the steps of the intrinsic pathway?
It continues through the following series of cascading reactions:
1) Trauma to the blood or exposure of the blood to vascular wall collagen βslow blood flow, roughy intimaβ
2) leads to 2 effects; first, activation of factor XII; second, the release of platelet phospholipids (platelet factor 3 or PF3).
3) The activated factor XII activates factor XI.
β’ This reaction requires high molecular weight kininogen
(HMW) and is accelerated by prekallikrein
4) The activated XI acts on factor IX to activate it.
5) The activated factor IX together with factor VIIIa and platelet phospholipids (PF3) activate factor X.
6) The activated factor X combines with activated factor V, Ca2+, and platelets phospholipids to form the prothrombin activator
Compare between the extrinsic and intrinsic pathway of blood clotting in terms of duration and site
In vivo, 15-20 sec
In vivo and vitro, 3-6 min
What are the steps of conversion of prothrombin into thrombin?
After the prothrombin activator has been formed, it causes the conversion of prothrombin to thrombin in the presence of sufficient amounts of Ca2+.
What are the steps of conversion of fibrinogen into fibrin?
- Formed thrombin removes 4 low-molecular-weight peptides from each molecule of fibrinogen, forming a molecule of fibrin monomer.
- Many fibrin monomer molecules polymerize within seconds into long fibrin threads that constitute the meshwork of the clot.
- Within a few minutes after the clot is formed a substance called fibrin stabilizing factor, released from the platelets, strengthens the fibrin meshwork by adding more and more bonds between the fibrin monomer molecules and formation of multiple cross-linkages between the fibrin thread.
- Finally, the firm blood clot is formed which is composed of a meshwork of fibrin threads running in all directions and entrapping blood cells, platelets, and plasma.
What is the fate of the clot?
- It can become invaded by fibroblasts, which subsequently form connective tissue till the clot is completely organized into fibrous tissue within about 1 to 2 weeks. βPermanent healingβ
β’ This course usually happened with the clot that is formed in a small hole in the vessel wall. - It can dissolve:
β’ This usually occurs with the clots formed in the tissues.
What is the role of calcium in clotting mechanisms?
- Except for the first two steps in the intrinsic pathway, Ca2+ is required for acceleration of all the blood clotting reactions.
- Therefore, in the absence of Ca2+, blood clotting by either pathway does not occur.
How is blood removed from a person prevented from clotting?
either by de-ionizing the calcium by addition of citrates or by precipitating the calcium by oxalates.
What is the importance of vitamin K in blood clotting?
Vitamin K βfrom the colonβ is necessary for the liver formation of five important clotting factors, prothrombin, factor VII, Factor IX, Factor X, and protein C. β1972β
What happens in cases of absence of vitamin K?
In the absence of vitamin K, deficiency of these coagulation factors results in serious bleeding tendencies (so it is called antihemorrhagic vitamin).
Why are platelets important for clot retraction?
- They become attached to the fibrin threads in a way that they bind different threads together.
- Platelets secrete fibrin stabilizing factor (factor XII) which causes more cross-linking bonds between the fibrin threads.
- Activation of the platelet contractile proteins by thrombin and Ca2+ cause strong contraction of the platelet attached to the fibrin.
What is the importance of clot retraction?
the edges of the broken blood vessels are pulled together, thus contributing to the ultimate state of hemostasis.
What happens after a clot is formed?
After a clot is formed, it begins to contract & a clear yellowish fluid is squeezed called serum
What are the functions of platelets in hemostasis?
1) Induces vascular spasm (serotonin & thromboxane A2)
2) Formation of primary platelet plug
3) Release of platelets phospholipid (Pf 3) which is essential for clotting mechanism.
4) Stabilization of blood clot (fibrin β stabilizing factor)
5) Clot retraction (Ca2+).
6) Repair of damaged vessels wall (platelet-derived -growth factor)
What are the factors that contribute to blood fluidity?
Endothelial surface factors and blood factors
What are the endothelial surface factors that contribute to blood fluidity?
βSmooth glycocalyx and thrombomodulinβ
1) The smoothness of the endothelial surface: prevent contact activation of the intrinsic system.
2) Presence of a layer of glycocalyx (mucopolysaccharide) on the endothelium: repels clotting factors and platelets, thereby preventing activation of clotting process.
3) Presence of Thrombomodulin:
- a protein bound with the endothelial membrane which binds thrombin.
- the thrombomodulin thrombin complex activates a plasma protein called Protein-C, that inactivates activated factor V and VIII.
What are the blood factors that contribute to blood fluidity?
βAdsorption of antithrombin III and heparin to the fibrinolytic systemβ
1) Adsorption of about 85 to 90% of the thrombin formed from prothrombin to the fibrin threads this prevents excess spread of the clot.
2) Antithrombin III: The thrombin that does not adsorb to the fibrin βthe remaining 15%β threads soon combines with antithrombin III, which further blocks the effects of thrombin, then inactivates it.
3) Heparin:
- A powerful anticoagulant that produced mainly by mast cells and small amounts formed by blood basophil cells.
- The heparin secreting mast cells are abundant in tissues surrounding lungs & liver.
4) The presence of fibrinolytic system that continuously removes small clots
What is the action of heparin?
- Heparin by itself, has little or no anticoagulant property.
- It acts as cofactor for anti-thrombin III. When it combines with antithrombin III, the effectiveness of anti-thrombin III in removing thrombin increases about 100-1000 times.
- Also, the heparinβantithrombin complex removes several other activated coagulation factors e.g., factor XII, XI, IX and X.
What is the definition of plasminogen (profibrinolysin)?
is one of plasma proteins present in an inactive form and when activated it is converted to plasmin (or fibrinolysin).
What is the definition of plasmin?
- A proteolytic enzyme that digests the fibrin threads as well as other coagulant factors as fibrinogen, factor V, factor VIII, prothrombin, and factor XII.
- Plasmin can cause complete lysis of the blood clot.
What activates plasminogen into plasmin?
This occurs via a group of substances called plasminogen activators.
They include:
1) Tissue plasminogen activator (t-PA)
2) Other plasminogen activators
Mentions the steps of the activation of tissue plasminogen activator
- When a clot is formed, a large amount of plasminogen is trapped in the clot along with other plasma proteins.
- The injured tissues and vascular endothelium very slowly release a powerful activator called tissue plasminogen activator that eventually converts plasminogen to plasmin few days after the clot has stopped the bleeding.
βUnlike tissue thromboplastin which is secreted quickerβ - The formed plasmin in turn removes the remaining blood clot.
Mention examples for other plasminogen activators
- Thrombin and active factor XII.
- Urokinase: it prevents the formation of blood clots in the urinary tract.
- Streptokinase: derived from certain types of bacteria known as haemolytic streptococci and is used for treatment of early acute myocardial infarction to dissolve the clot.
What does the liver produce βrelating to hemostasisβ and what inactivates it?
- The liver produces a t-PA inhibitor called antiplasmin that inhibit the t- PA and delays the fibrinolysis.
- The protein-C inactivates this inhibitor and consequently stimulates fibrinolysis. βAs well as inactivation of factor five and factor eightβ
What are the significance of fibrinolysis?
βSUMIIIIIβ
S: Many Small blood vessels in which the blood flow has been blocked by clots are reopened by fibrinolysis.
U: It prevents the blood clotting inside the Urinary tract βurokinaseβ and prevents clotting of the menstrual blood.
MI: The stimulation of fibrinolysis is used clinically in early management of acute Myocardial Infarction. This is accomplished either by intravenous injection of t-PA or injection of Streptokinase or urokinase locally in the clot via a cardiac catheter.
What is the definition of Anticoagulants?
These are the substances used to prevent blood clotting.
What is the classification of Anticoagulants?
A) In vitro anticoagulants βprevent intrinsicβ
B) In vivo anticoagulants
how are blood samples collected without clotting?
1) Collecting blood in smooth bags lined with silicone.
2) Precipitation of calcium by citrate.
3) Addition of heparin.
4) Addition of EDTA (ethylene β diamine tetra-acetic acid). It chelates the Ca2+ in the blood.
What is the definition of in vitro anticoagulants?
Are used to prevent clotting outside the body.
What is the definition of in vivo anticoagulants?
Are used to prevent clotting inside the body.
what are examples of in vivo anticoagulants?
Heparin
Coumarin derivatives as dicumaroul & warfarin
What is heparin? And what forms it?
It is a naturally occurring anticoagulant used in the treatment of intra-vascular thrombosis, It is formed by mast cells and basophil leucocytes.
What antagonizes the action of heparin?
The action of heparin (acidic) can be neutralized by adding protamine (basic protein) which forms an irreversible complex with heparin.
What is the action of coumarin derivatives like dicumarol and warfarin?
They inhibit the action of vitamin K in the liver through competitive inhibition with subsequent decreased synthesis of factors II, VII, IX, and X as well as protein C.
Compare between Heparin and dicumarol acc to:
Origin Mode of action Site of action Route of administration Onset Duration Antidote
Origin: Mast cells and basophils - Plant
Mode of action:
-Activates antithrombin III thereby inactivating thrombin, factors IX, X and XI
-Competitive inhibition with vit. K in liver, so it inhibits the formation of prothrombin, factors VII, IX & X.
Site of action: in vivo and in vitro - only in vivo
Route of administration: I.V or I.M. βMay cause hematomaβ - oral
Onset: Rapid - slow
Duration: short βshould be repeatedβ - long
Antidote: Protamine sulphate 1% + Fresh blood transfusion - Vit K
What are in vitro Anticoagulants?
In vitro anticoagulants :
β’ Ca++ β deionization by citrate. β Precipitation by oxalate. β Chelation of Ca++ by EDTA
- Collecting of blood in ββunwettableββ silicone coated tubes , that prevent activation of factor XII.
- Addition of heparin.
What are the disorders of Hemostasis ?
A) Conditions that cause excessive bleeding.
- Purpura
- Vitamin K deficiency
- Hemophilia: deficiency of factors VIII, IX, or X
B) Conditions that cause excessive intra vascular clotting.
What is the nature of hemophilia?
- It is a congenital sex linked; recessive disease carried on X chromosome.
- It is carried by females and manifested always in males.
What causes hemophilia?
Deficiency of factor VIII, IX, or XI. So, there are three types of hemophilia.
What are the types of hemophilia and what causes each one?
-Hemophilia A:
ο Is the classic hemophilia.
ο It is caused by deficiency of factor VIII and represents 85% of cases of hemophilia.
-Hemophilia B:
ο Is due to absence of factor IX.
-Hemophilia C:
ο Is due to absence of factor XI.
What is hemophilia characterized by?
-Hemophilia is characterized by:
ο Excessive bleeding after mild trauma.
ο Whole blood coagulation is prolonged.
What is the definition of capillaries?
- Capillaries are the smallest blood vessels in the body, connecting the smallest arteries to the smallest veins. These vessels are often referred to as the βmicrocirculation.β
What is the function of capillaries?
- They are responsible for facilitating the transport and exchange of gases, fluids, and nutrients in the body.
What do meta-arterioles branch into and what is found at the junction of arterioles and capillaries?
- Metarterioles branch into the capillary beds. At the junction of the arterioles and capillaries is a smooth muscle band called the precapillary sphincter.
do capillaries have smooth muscles?
- True capillaries βthose of nutritional benefitβ do not have smooth muscle; they consist of a single layer of endothelial cells surrounded by a basement membrane.
What do Clifts between the endothelial cells allow?
- Clefts (pores) between the endothelial cells allow passage of water- soluble substances. The clefts represent a very small fraction of the surface area.
How do substances pass through the capillary walls?
- Lipid-soluble substances: include O2 and CO2; cross the membranes of the capillary endothelial cells by simple diffusion.
- Small water-soluble substances: include water, glucose, and amino acids; cross via the water-filled clefts between the endothelial cells.
- Generally, protein molecules are too large to pass freely through the clefts. - In the brain, the clefts between endothelial cells are exceptionally tight (bloodβbrain barrier).
- In the liver and intestine, the clefts are exceptionally wide and allow passage of protein. These capillaries are called sinusoids. - Large water-soluble substances: can cross by pinocytosis.
How does blood flow in the capillaries?
- Blood usually does not flow at a continuous rate through capillaries, but it flows intermittently. The cause of this intermittency is the phenomenon called vasomotion.
What is vasomotion?
- is intermittent contraction of the metarterioles and precapillary sphinctersβalternating cycle of constriction and relaxation for 5-10 times/minute so that only 10-20% of cap are opened at a time.
What regulates vasomotion?
it is controlled mainly by O2 concentration in the tissues.
-Decrease O2 concentration leads to:
β Increase intermittent periods of BF.
β Increase duration of each period. βTo supply more o2β
Which Allows blood to carry increased quantities of O2 to tissues.
What is the capillary blood pressure?
- At the arterial end, the pressure is about 30-35 mmHg.
- At the venous end it is about 10-15 mmHg.
- At the middle of the capillary is 25 mmHg.
What are the factors affecting capillary blood pressure and capillary blood flow?
The capillary BP may be influenced passively by extracapillary factors, and actively by the contraction of the capillaries themselves.
What are the extra Capillary factors that affect the capillary blood pressure?
a. The diameter of arterioles: Arteriolar VDβ Inc. capillary BF andβ>capillary BP and vice versa.
b. The venous pressure:the venous pressureβ Inc. capillary BP and dec. capillary BF. βDue to the closure of the Venous outflow and continuous flow from arteriolesβ
c. Gravity: in areas above the heartβ Dec. capillary BP, however in areas below the heartβ Inc. capillary BP by antagonizing venous return.
What are the active factors that affect capillary blood pressure?
The actual cause of capillary contraction is not yet known, but it may be due to:
a. Contraction of the precapillary sphincter.
b. Contraction of smooth muscle fibers in the wall of the metarterioles.
What are the two forces that govern fluid flux across the capilllaries?
-Fluid flux across the capillary is governed by the 2 fundamental forces that cause water flow:
β’ Hydrostatic force, which is simply the pressure of the fluid.
β’ Osmotic (oncotic) force, which represents the osmotic force created by solutes that do not cross the membrane.
- Each force exists on both sides of the membrane. Filtration is the movement of fluid from the plasma into the interstitium, while absorption is movement of fluid from the interstitium into the plasma.
What is the amount of fluid filtered every day?
- About 20 liters of fluid are filtered every day at the arterial ends of capillaries, 18 liters of them are reabsorbed back at the venous ends, and the remaining 2 liters are drained by the lymphatic system.
What are the forces which are called Starling forces and what does starling principle state?
- The capillary hydrostatic pressure (Pc). βThe main filtering forceβ
- The interstitial fluid hydrostatic pressure (Pi).
- The plasma colloid osmotic pressure (Οc).
- The interstitial fluid colloid osmotic pressure (Οi).
Starling βs principle states that: β the rate & direction of fluid movement is proprotional to the algabric sum of hydrostatic and osmotic forcesβ
What does increase in hydrostatic pressure in the capillary favor?
An increase in Pc favors filtration out of the capillary.
What is the hydrostatic pressure in the Capillary in determind by?
β Pc is determined by arterial and venous pressures and resistances.
β An increase in either arterial or venous pressure produces an increase in Pc; increases in venous pressure have a greater effect on Pc.
What is hydrostatic pressure in the capillary?
β It is 30 mmHg in the arterial end, 10 mmHg in the venous end. The functional mean capillary pressure is about 17.3 mmHg (i.e. it is the average effective pressure).
What does increase in osmotic force in the interstitium favor?
An increase in Οi favors filtration out of the capillary.
What determines the osmotic force in the interstitium?
- is determined by the concentration of protein in the interstitial fluid. Normally the small amount of protein that leaks to the interstitium is minor and is removed by the lymphatics. Under most conditions, this is not an important factor influencing the exchange of fluid.
What is the average protein concentration in the interstitium and what pressure does it result in?
- The average protein concentration of the interstitial fluid is about 3 gm/100 ml.
- resulting in average colloid osmotic pressure of about 8 mmHg. βSmall effectβ
What does increase in osmotic pressure of plasma favor?
An increase in Οc opposes filtration out of the capillary.
What increases or decreases the osmotic pressure of plasma?
β Οc is increased by increases in the protein concentration in the blood (e.g., dehydration).
β Οc is decreased by decreases in the protein concentration in the blood (e.g., nephrotic syndrome, protein malnutrition, liver failure).
β Small solutes do not contribute to Οc.
What is the most abundant plasma protein?
β Albumin is the most abundant plasma protein and thus the biggest contributor to this force.
What is the value of the osmotic pressure of plasma?
β The colloidal osmotic pressure or the oncotic pressure of normal human plasma average about 28 mmHg.
What does increase in the hydrostatic pressure of the interstitium favor?
β An increase in Pi opposes filtration out of the capillary.
What is the value of the hydrostatic pressure in the interstitium?
β It is about -3 mmHg βcauses suction as it is connected to lymphatics that drain fluidsβ and is called negative interstitial fluid pressure.
What are the forces affecting the fluid the arterial end of capillaries?
A. Forces moving the fluid outward:
- Capillary pressure 30
- Negative interstitial fluid pressure 3
- Interstitial fluid colloid osmotic pressure 8
Total outward force 41
B. Forces moving the fluid inward
- Plasma colloid osmotic pressure 28
Summation of the forces:
Outward force 41
Inward force 28
Net outward force: 13
Thus 13 mmHg filtration pressure occurs at the arterial ends of the capillaries.
What are the forces affecting the fluid at the Venous end of the capillaries?
At the venous end of the capillary:
A. Forces tending to move fluid outward:
- Capillary pressure 10
- Negative interstitial fluid pressure 3
- Interstitial fluid colloid osmotic pressure 8
Total outward force 21
B. Forces tending to move fluid inward:
- Plasma colloid osmotic pressure 28
Summation of forces:
Outward force 21
Inward force 28
Net inward force: 7
-Thus 7 mmHg is the reabsorbing pressure at the venous ends of the capillaries.
How does blood filtration equal blood absorption even though the reabsorbing pressure is lower than the filtration pressure?
the venous capillaries are more numerous and more permeable so it reabsorbs about 9/10 of the fluid, the remainder flows into the lymph vessels.
Why are veins called capacitance vessels?
- The veins conduct the blood from the tissues to the heart. They accommodate the main bulk of blood volume (about 60%)
What are the functions of veins? βDrain blood/lymph - reservoir - pumpβ
- Drainage of blood from all parts of the body to the heart. Also the lymph drainage opens into the venous system.
- They act as blood reservoirs; they contain about 3 liters of blood.
- By means of venous pump, it aids in propelling the blood forward (towards the heart) and helps to regulate the cardiac output.
What is the hydrostatic indifferent level or (HIP)?
- It is a point in the circulation, lies 5-7 cm below the diaphragm, at which the venous pressure (VP) is kept constant at 10-11 mmHg, independent of the body posture.
- VP below this point increases and above this point decreases.
What is central venous pressure and what are its values??
- It is the venous pressure in big veins at their entrance with the right atrium, or the intrathoracic portions of vena cavae.
- It averages 4.6 mmHg in recumbancy and 2 mmHg on standing It is 2 mmHg during inspiration and 6 mmHg during expiration.
What increases CVP? βBad thingβ
- Positive intrathoracic pressure like straining
- Congestive heart failure βDue to fullness with bloodβ
- hypervolemia (blood transfusion)
- Sympathomimetics due to venoconstriction and increasing the venous return
What decreases CVP?
- Negative intrathoracic pressure during respiration
- Standing (CVP decreases to 2 mm mercury)
- Hypovolemia (hemorrhage)
- Sympatholytics due to venodilation and decreasing the venous return
What are the factors affecting the venous pressure?
1- Gravity or posture 2- Rate of blood inflow into veins 3- Rate of blood outflow from veins 4- Venomotor tone 5- Blood volume 6- Muscular exercise 7- Respiratory movement
How does gravity or posture affect venous pressure?
- In recumbent position gravity has no effect on circulation.
- On standing, PVP is increased in lower limbs to 90 mmHg in feet veins and CVP is decreased from 4.6 mmHg to 2 mmHgβ Dec. venous returnβ Dec COP β decABP (postural hypotension) in prolonged standing.
How does the rate of blood flow into veins affect venous pressure?
- Vasodilatation of arterioles without capillary dilatationβInc CVP and PVP and vice versa.
- If the capillaries are dilated, they accommodate blood and decrease the blood inflow to veinsβ Dec CVP and PVP.
How does the rate of blood outflow from Veins affect venous pressure?
- Normally, the rate of blood inflow into veins equals the rate of its outflow. βDue to venous congestion or due to inc in intrathoracic pressureβ
- If the outflow is less than the inflowβ Dec the venous returnβInc CVP and PVP
How does the venomotor tune affect venous pressure?
- Tonic contraction in veins maintains normal VP.
- inc venous tone due to sympathetic stimulation or noradrenalineβ Inc CVP and PVP are vice versa.
How does blood volume affect venous pressure?
- CVP and PVP are increased in hypervolaemia (blood transfusion).
- CVP and PVP are decreased in hypovolaemia (haemorraghe).
How does muscular exercise affect venous pressure?
- Contracting skeletal muscle press on veins, increasing the VP.
- Arteriolar dilatation of active muscle, increasing the VP.
- However VP is not much increased in exercise, due to increase the outflow from veins because the heart rate and the stroke volume are increased during exercise.
How do respiratory movement affect venous pressure?
- Inspiration: The diaphragm descends β inc VP in abdominal veins and dec VP in intrathoracic veinsβ Inc VR.
- Expiration: the opposite effect occurs.
What is the nature of lymph flow in lymphatic vessels?
β One-way flap valves permit interstitial fluid to enter, but not leave, the lymph vessels.
β Flow through larger lymphatic vessels is also unidirectional.
What is the function of lymphatic system? βDAIβ
- Drainage of excess interstitial fluid filtered from capillaries back to blood.
- Drainage of filtered proteins.
- Absorption of fat from the intestine.
- The lymph nodes have the following functions:
- Filtration of lymph (i.e. by removing foreign substances from it).
- Formation of lymphocytes.
- Take part in the formation of immune bodies.
What are the factors that maintain lymph flow?
Normally, the lymph flows towards the thorax; it is maintained by the following factors:
- Rhythmic contraction of smooth muscles in the wall of the lymphatic vessels. βLike veins and arteriesβ
- Skeletal muscle contraction compresses the lymph vessels β inc lymph flow.
- Arterial pulsations are mechanically conducted to lymph vessels, which may help lymph flow.
- Gravity helps the lymph flow from parts above the level of the heart, but antagonizes it from parts below the level of the heart.
- The hydrostatic pressure of the interstitial fluid is normally negative (- 3 mmHg), this helps the lymph flow. βSuction forceβ
What are the factors that increase lymph flow? βInc filtrationβ
The lymph flow increases as a result of increased rate of tissue fluid formation. This occurs in the following conditions:
- Dilatation of the capillaries and arterioles β increase capillary filtration and increase lymph flow.
- Venoconstrictionβincrease capillary pressureβincrease filtration and lymph flow.
- Increased tissue activityβaccumulation of metabolitesβdilatation of the arterioles and precapilalry sphincters.
- Lymphagogues: These are substances that increase the lymph flow. They act mainly by increasing fluid filtration into the tissue spaces as histamine and bradykinin.
What is the definition of edema?
Edema is the accumulation of fluid in the interstitial space
What are the two forms of edema?
Intracellular non-pitting and extracellular fitting
What causes intracellular edema? βDangerousβ
Means edema due to increased intracellular fluid (i.e. intracellular swelling). It results from disturbance of the membrane permeability.
βMay be Due to a problem in sodium potassium pumpβ
What causes extracellular Edema?
Occurs when there is excess fluid accumulation in the extracellular spaces i.e. increased interstitial fluid.
What are the factors that cause extracellular edema?
Significant alterations in the Starling forces, which then tip the balance toward filtration, increase capillary permeability and/or interrupt lymphatic function, resulting in edema.
What causes increase in the hydrostatic pressure of the capillaries?
βͺ Arteriolar dilatation as in fever.
βͺ Increased venous pressure as in congestive heart
failure, venous obstruction and pregnancy. βDue to enlarged uterusβ
βͺ Extracellular volume expansion.
What causes decrease in osmotic pressure of the capillaries?
Decreased plasma protein concentration to 5 gm% as in:
βͺ Severe liver disease (failure to synthesize
proteins).
βͺ Protein malnutrition.
βͺ Nephrotic syndrome (loss of protein in urine).
What increases the capillary permeability?
It leads to excessive fluid and protein filtration, so edema develops as in:
βͺ Burn
βͺ Inflammation (release of histamine; cytokines)
βͺ Allergy (allergic edema) due to histamine release
βͺ Vitamin C deficiency.
βͺ Bacterial toxins.
What causes lymphatic obstruction?
Accumulation of tissue fluid and protein in tissue spaces produces edema as in:
βͺ Infections (e.g. filaria) produce edema called elephantiasis and it is non pitting.
βͺ Cancer produces cancer edema and it is non pitting.
βͺ Surgical: due to interruption of lymphatic vessels.
βͺ Congenital absence of lymphatics.