Coagulation
• It is an amplification
pathway (cascade; positive
feedback).
• Requires clotting factors
such as:
I- Fibrinogen
II- Prothrombin
–
III- Tissue factor
–
IV- calcium
V
VI (doesn’t exist)
VII
VIII
IX
X
XI
XII Future Physiologists take
fun classes 5-13 years.
XIII
Calcium ions.
12 different factors,
some synthesized by the
liver
• Many are proenzymes
or zymogens (inactive
enzymes)
• The synthesis of some
of them requires Vit. K
(II, VII, IX, X)
Intrinsic
Pathway
Extrinsic
pathway
• Begins with the release of
tissue factor by damaged
endothelial cells or
peripheral tissues.
• Fast, but not as much
PAS made
• More damage, even
faster.
• 3+4= 7 to activate ten,
the extrinsic pathway is
fast to begin.
PF-3
• Begins with trauma to the
blood itself or exposure of
the blood to collagen
fibers at the injury site.
• Slower, but much more
PAS formed.
• platelet factor called PF-3
( a phospholipid)
• Twelve and platelet
factor three, eleven they
be; then comes four to
put nine on the floor,
then comes eight to get
ten to initiate.
Figure 36-3;
Guyton & Hall
Figure 36-4;
Guyton & Hall
Step 3: Clot Formation
(Coagulation)
Formation of Prothrombin Activator substance
(the beginning of the Common Pathway)
I. Extrinsic pathway
tissue trauma
tissue thromboplastin (+VII)
Rapid and explosive in nature (15 seconds)
Extrinsic Pathway
X activation
Intrinsic Pathway
Final Common Pathway
II. Intrinsic pathway
Prothrombin Activator Substance (PAS)
blood trauma, contact with collagen or activated platelets
XII
XI
IX (+VIII)
X activation
slower (2-6 minutes) many components (cascade)
Prothrombin
Thrombin
Common pathway
Xa combined with V and platelet phospholipids (PF3) + Ca++
•If ten plus 5, 4, and 3
equals two, then 1+13
equals glue.
Fibrinogen
Fibrin monomers
Polymers, threads
Fetal Circulation
• Foramen ovale- right
to left shunt. Most of
the blood goes
through here.
• Ductus arteriosusright to left shunt.
Blood Flow within the Fetal Heart
Right atrium
Foramen ovale
Left atrium
(Most of the blood)
Right ventricle
Pulmonary trunk
Left ventricle
Birth
•
•
•
•
Ductus arteriosus
Aorta
•
Pulmonary
circuit
Systemic circuit
Prostaglandin levels drop
Baby breathes- lowers
pressure in pulmonary circuit
Umbilical cord is clamped and
cut and increases systemic
pressure
Foramen ovale closes and
becomes fossa ovalis
Ductus arteriosus closes and
becomes ligamentum
arteriosum (oxygen content is
signal for vessel to close)
PDA- patent ductus arteriosus
• Left to right shunt
• Blood flows back to
lungs repeatedly- why?
• Net CO decreases so
blood vol. increase and
CO goes back toward
normal
• Left and right ventricular
hypertrophy
• Characteristic cyanosis
of baby
Dynamics of Streptococcal Damage
to Heart Valves
• Streptococcus
p
• release of M antigen
p
M Heart valve cell
M
with M antigens
attached
M
M p
• Antibody formed against combination
Tetralogy of Fallot
• “Blue Babies”
• Right to left shunt
• Tetralogy of Fallot is
made up of 4 heart
defects but not all
four are necessarily
present in each baby
with TF:
Dynamics of mitral stenosis
• Stenosis: blood flow
from left atrium to left
ventricle decreased
• Murmur heard in last
part of diastole- why?
• Reduced movement
of blood.
• Enlarged left atrium.
• Pulmonary edema.
Terms
• Prolapse- valve
doesn’t close properly
• Stenosis- valve has
difficulty opening
• Regurgitationbackflow of blood
• Auscultation“listening” to heart
sounds….more of
them when valves
don’t work correctly.
Mitral valve prolapse
• Blood goes back into
left atrium
• Blowing murmur
heard throughout
systole - high pitch
p
Mitral #1
• Complement damage to heart valves Aortic #2
Dynamics of Aortic valve Stenosis
• Stenosis: Contracting left
ventricle fails to empty
adequately (ESV?)
• SV decreased
• Left ventricle hypertrophy
• Leads to increased blood
volume (due to
decreased MAP)—
kidneys release
erythropoietin.
Aortic Regurgitation
• Murmur heard during
diastole
• May have stroke vol.
of 300ml with 70ml
going to periphery
and 230 leaking back
Anatomy of the Baroreceptors
• spray type nerve endings located in
the walls of the carotid bifurcation
called the carotid sinus and in the
walls of the aortic archpressoreceptors that respond to
stretch.
• Signals from the carotid sinus are
transmitted by the glossopharyngeal
nerves .
• Signals from the arch of the aorta are
transmitted through the vagus into the
NTS.
• Important in short term
regulation of arterial pressure.
– Opposes either increases or decreases
in arterial pressure thereby reducing
daily variations in arterial pressure.
– They are unimportant in long term
Figure 18-5; Guyton and Hall
Response of the Baroreceptors
to Arterial Pressure
BP rises
Detected by
baroreceptors in
aortic arch &
carotid sinus
Decreased
vasomotor
activity
Decreased NE
release on
arterioles
Figure 18-7; Guyton and Hall
Vasodilation
Constrict
Common Carotids
•
Pressure at
Carotid Sinuses
changes in body posture.
Decreased PR
Arterial Pressure
Info sent to cardiac
and vasomotor
centers
Increased
cardioinhibitory
activity
Increased vagus
activity
Decreased
BP
Increased ACh
release on heart
Constrictors
Decreased
cardioacceleratory
activity
Functions of the
Baroreceptors
Maintains relatively constant pressure despite
Decreased CO
Decreased NE
release on heart
Supine
•
Baroreceptors respond to changes in
arterial pressure.
Sympathetic
Nervous Activity
•
As pressure increases the number of
impulses from carotid sinus increases
which results in:
Vasomotor
Center
Decreased SV
and HR
Figure 18-5; Guyton and Hall
1) inhibition of the
vasoconstrictor
2) activation of the vagal
center
Decrease
Central
Blood Volume
Standing
Decrease
Cardiac Output
Sensed By
Baroreceptors
Decrease
Arterial Pressure
Factors of
Resistance
Cardiac Cycle (cont’d)
Poiseuille’s Law =
Q =_S'Pr4
8Kl
• Blood viscosity
• Total vessel length
• Vessel diameter
Figure 9-5; Guyton & Hall
Drugs Affecting CO
• Atropine- parasympathetic
blocking (blocks muscarinic
AchR) agent, (+,+)
• Pilocarpine- drug that causes
cholinergic neurons to release
ACH. Since Ach decreases heart
rate, it causes (-, ) effect on
heart.
• Propranalol- Reversible,
competitive blocker of Beta1
receptor. So blocks
sympathetics effect of heart (-,-)
Decrease heart rate and force of
contraction, and lowers blood
pressure.
Drugs Affecting CO (2)
•
Digoxin (shorter ½ life) or
Digitoxin- come from group of
drugs derived from digitalis.
Digitalis derived from foxglove
plant. It has a (-,+) effect, neg
chronotropic and positive
inotropic effect; slows heart rate
but increases force of contraction.
Is only drug with this effect on
heart.
– increases intracellular concentration
of Ca.
– increase force of contraction by
inhibiting Na+/K+ pump. So cells
start to accumulate Na.
– Disadvantage of using digitalis is that
it’s extremely toxic. The optimal dose
is very close to lethal dose- stops
heart
adrenergic or sympathomimetic
drugs act like norepi and epi
• these drugs have an effect which is much more prolonged
than that of either norepi or epi
– phenylephrine stimulates alpha receptors
– isoproterenol stimulates both beta1 and beta2 receptors
– albuterol stimulates only beta2 receptors
• some drugs act indirectly by increasing the release of
norepi from its storage terminals
– ephedrine, amphetamine
Pharmacology of the Sympathetic
Nervous System
• drugs that block the
effect of norepi and
epi
• alpha blockers
– phentolamine
• beta blockers
– beta1 and 2 propranolol
Terminology
• Chromasia- indication
of MCH
– Hyper/hypochromic
– normochromic
• Anisocytosis – cells of
abnormal size; indication
of MCV
– Microcytic
– Macrocytic/ Megalocytic
– normocytic
• Poikilocytosis – cells of
abnormal shape
– Spherocytosis
– Sickle cell
– Echinocyte
Aplastic anemia
Pharmacology of the
Parasympathetic Nervous System
•
• Drugs - chemotherapy,
antibiotics,
Compare the 2 slides of red bone marrow.
• Chemicals - benzene
Blue dots indicates developing blood cells.
Left-hand slide is during aplastic anemia;
• Radiation
right-hand slide is almost back to normal
• Immune suppression of
stem cell
Hypoproliferative from reduced erythropoietin
• Malignancy
Therapy--
•Renal Disease, AIDS, chronic infections
•Hypometabolic state--protein deprivation,
hypothyroidism, hypopituitarism
1. Too few circulating erythrocytes (low RBC count, low HCT, low Hb
concentration, but normal MCH and MCHC values)
2. Normal erythrocyte counts, but each RBC contains lower than
normal amt of Hb (normal RBC count, low Hb concentration, and
low MCH and MCHC values; microcytic/hypochromic)
• activates nicotinic receptors
– pilocarpine
• activates muscarinic
receptors, cause profuse
sweating
•
•
cholinesterase inhibitors
– neostigmine, potentiates the
effect of acetylcholine
antimuscarinic drugs
– atropine blocks the effect of
acetylcholine on effector cells
Hemolytic,
Hemorrhagic
(Blood Loss)
• Hereditary/ intrinsic-• Sickle cell (hemoglobin); normochromic, normocytic poikilocytic, during
episode
• Spherocytosis (membrane)-microcytic, normochromic, and spherical
(poikilocytic). Easily ruptured. MCHC is INCREASED!
• Why are anemic individuals often short of breath, fatigued,
and chilly?
• Types:
–
–
–
–
–
•
Gene defect; defect in code for
E chain leads to HbS
•
Amino acid substitution in
peptide chain
•
Valine (nonpolar) is
substituted in place of
glutamic acid (polar) in
position #6 of E chain
•
When peptide chain folds, it
doesn’t take on the proper
shape (conformation)!
• Immune responses, mismatch typing, HDN
• Blood Loss- normocytic, normochromic
– Acute, leads to hypovolemia, shock
– Chronic hemorrhage can lead to microcytic, hypochromic RBC due
to lack of iron absorption (can’t absorb fast enough)
Hemolytic/ Hemorrhagic
Aplastic and hypoproliferative
Thalassemia
Megaloblastic
Iron-deficiency
Sickle Cell Anemia
• Acquired/ extrinsic- normocytic, normochromic
Anemia
• Iron-Deficiency
• idiopathic
capacity from low Hb concentration
• Can arise from either
parasympathomimetic drugs
– nicotine
• Primary
• Secondary
Anemia- Condition where the blood has an abnormally low oxygen-carrying
• almost always blood loss
• exceptions (children, pregnancy)
– Understand iron metabolismtransport and storage of iron
(apotransferrin to transferrin;
apoferritin to ferritin; hemosiderin)
– Cells can be hypochromic and
microcytic and poikilocytotic (too
little Hemoglobin) due to
insufficiency
– Decreased MCHC and MCV
– Pica
Megaloblastic
anemias
• deficiency in dietary Folic acid or Vitamin B12
• Coenzymes in synthesis of thymidine; DNA synthesis is halted
and therefore mitosis rates are low
• RNA production is elevated, Elevated rates of protein synthesis
• Cells become megaloblastic, irregularly shaped (poikilocytotic)
and have fragile membranes so they are removed sooner
(hemolytic)
• Increased MCV and normal MCHC (increased Hb synthesis)
Megaloblastic Anemias-2
• Folic acid
– Green veggies
– Greater demand during pregnancy for neural tube
closure.
– Stored supply- 6-9 months
– Alcoholism, sprue, and anti-cancer drugs interfere
• Stomach mucosa produces intrinsic factor which is
necessary for Vitamin B12 absorption. -pernicious
– Gastrectomy or gastric atrophy- lack of intrinsic
factor
– Stored supply- 3-5 years
What are the Thalassemias?
• A group of diseases
characterized by defects in
synthesis of one or more
globin chains (D-, Ethalassemia)
• Some severe, others mild
• Unaffected chain is in excess
and accumulates in
erythropoietic cell and causes
impaired DNA synthesis
• Hypochromic, microcytic
• Organ failure
• Splenomegaly/hepatomegaly
Thalassemia- 2
• Thalassa (Greek) = Sea
• E-Thal or Thal. major
(Cooley’s anemia)
– Shortened RBC lifespan,
early removal (hemolysis)
– Expansion of
intramedullary spaces
(erythropoiesis)
– Skeletal abnormalities
– Increased iron absorption,
iron overload and its
consequences
– HbF can persist
http://sickle.bwh.harvard.edu/menu_thal.html
Classification of Anemias
category
1
MCV
Hgb Content
(fl)
(MCHC) (g/dl)
Causes
Normocytic Normochromic Bone marrow failure, renal
failure, hemolytic anemia,
(80-100)
(32-36)
Major
Intracellular
Transduction
Pathways
Used by
metabotropic
receptors
Cell surface
receptor
G protein
Effector protein
2
Macrocytic Normochromic Megaloblastic anemia
(>100)
(32-36)
Microcytic Hypochromic Iron deficiency, thalassemia,
hemorrhagic anemia (chronic)
(<80)
(<32)
GsD
EJ
hemorrhagic anemia (acute)
1
E adrenergic
receptor mechanism
NE
Signaling molecule
cAMP
Second messenger
IP3/
DAG
Late effectors
EJ
D A
GTP
P
C
C
C
R
PKA
C
C
Target protein
cAMP Pathway
cAMP
IP3 Pathway
cAMP
Inositol Trisphosphate & DAG
Summary
DNA
transcription (in nucleus)
mRNA
translation (at the ribosome, in cytoplasm)
protein
(chain of aa, sequence determines structure,
structure determines function)