PSL301H

Lecture 5: Hemostasis
Learning objectives
Describe the three phases of hemostasis
Learn about the coagulation cascade
Describe the newer cell-based model of blood coagulation
Explain how anticoagulants act
Predict the effect of an excess or inadequate levels of
clotting factors on the coagulation pathways
Understand some of the clinical relevance of coagulation

Textbook reading: 8th ed. 522-528 (7th ed. 523-530; 6th

ed. 557-564; 5th ed. 558-565) and
https://cmijournal.files.wordpress.com/2016/04/53-58-
cell-based-model.pdf
 Case studies

1) Dave is a 55-year-old man who

recently had a mild heart attack. His
physician has prescribed one baby
aspirin per day.

2) Kristy is 18 and a competitive figure

skater. She has von Willebrand
disease. She constantly worries about
internal bleeding injuries.

For more see: http://www.hemophilia.ca/en/our-stories/

 Case studies cont’d

3) Dilan has hemophilia A. His parents infuse

him each week with factor VIII.

4) Jason is a 50-year-old man who

was taken to the hospital because
he was having vision problems,
weakness in one arm and a severe
headache. His doctor confirms that
he has just had a stroke caused by
a blood clot and quickly administers
tissue plasminogen activator (tPA).

For more see: http://www.hemophilia.ca/en/our-stories/

Recall: Hematopoiesis

Figure 16.2
 Platelets are needed for blood clotting

Half-life of platelets = 10 days

Thrombopoietin increases platelet numbers

Figure 16.7
 Three phases of hemostasis

3. Coagulation
phase
1. Vascular
phase

2. Platelet phase

Figure 16.8
 1) Vascular phase

Neurogenic and myogenic control

Vasoconstriction prolonged by:

Serotonin
Endothelin-1
Thromoboxane A2
2. Platelet phase

Exposed collagen
- Binds & activates
platelets

Factors released
from platelet

Factors attract
more platelets

Platelets aggregate;
form plug

Figure 16.9
 Platelet phase details
Exposed collagen via vonWillebrand
- Binds & activates factor
platelets

Factors released e.g. ADP, platelet

from platelet activating factor
(PAF), serotonin,
Factors attract
more platelets thromboxane A2

Platelets aggregate;
form plug

• von Willebrand factor made by endothelial cells

and platelets. Binds to both collagen and platelets.
ADP
PAF Platelet
Serotonin aggregation Vasoconstriction
Thromboxane A2 Figure 16.9
Platelet activation

Figure 16.7
Note: Without injury platelets are
NOT activated

Prostacyclin (prostaglandin I2, PGI2)

and nitric oxide (NO)
- prevent platelet adhesion
and are vasodilators

Figure from Silverthorn 5th ed

 Dave: Mild heart attack; one baby aspirin/day
Arachidonic acid
Cyclooxygenase
_
PGH2
Aspirin

Prostaglandins Thromboxane A2 Prostacyclin

Given the pathways, how does aspirin reduce the risk of a subsequent heart
attack?

a) Reduces platelet aggregation by inhibiting thromboxane A2 synthesis

b) Reduces vasoconstriction by inhibiting thromboxane A2 synthesis
c) Reduces platelet aggregation by inhibiting prostacyclin synthesis
d) Reduces vasoconstriction by inhibiting prostacyclin synthesis
3. Coagulation cascade

Figure 16.11
 Common pathway details

Inactive plasma clotting factors (white boxes)

converted to active enzymes.
Figure 16.10
 Extrinsic pathway

Figure 16.10
• von Willebrand factor regulates levels of VIII
• Vitamin K needed for the synthesis of thrombin, VII, IX and X
Anticoagulant called Coumadin (Warfarin) – blocks the action of
Vitamin K
 Instrinsic pathway

Figure 16.10

• von Willebrand factor regulates levels of VIII

• Vitamin K needed for the synthesis of thrombin, VII, IX and X
Anticoagulant called Coumadin (Warfarin) – blocks the action of
Vitamin K
Summary

Figure 16.10
But problems with this model
e.g. Individuals with factor IX or factor VIII
deficiency have severe bleeding even though their
extrinsic and common pathways are normal
and should be sufficient to promote clotting

Newer model: Cell-based theory of coagulation

 Tissue factor (factor III)

Watch video at: https://www.youtube.com/watch?v=T4MG7bzQ2NI

 Cell-based: Initiation phase

Cell membrane of smooth muscle cells or fibroblasts in sub-endothelial layer

Exposure of tissue factor (TF) starts this phase produces small

amount of thrombin

https://cmijournal.files.wordpress.com/2016/04/53-58-cell-based-model.pdf
 Amplification phase

Thrombin activates factors V, XI, and VIII on surface

of platelets

https://cmijournal.files.wordpress.com/2016/04/53-58-cell-based-model.pdf
 Propagation phase

Active factors on the surface of platelets form tenase and then

prothrombinase results in LARGE amounts of thrombin =
thrombin burst
Thrombin cleaves fibrinogen and factor XIII to result in fibrin
formation and crosslinking
https://cmijournal.files.wordpress.com/2016/04/53-58-cell-based-model.pdf
Summary

Figure 16.10
 Case study #2
Kristy competitive figure skater with
has von Willebrand disease

• Most common coagulation disorder (1:100)

• Problems in quality or quantity of von Willebrand factor
(vWf)
• Areas with high number of small capillaries (skin, gi tract,
uterus) most susceptible

Question: What are the step(s) in hemostasis that are

impaired in Kristy?
a) Platelet aggregation at wound site
b) Ability to bind factor VIII on the surface of platelets
c) Ability to fully activate factor X
d) All of the above
 Case study #3
Dilan has hemophilia A; regularly infused with
factor VIII
X-linked recessive trait; deficiency in factor VIII
Factor VIII forms a complex with factor IX to activate factor X
Suffer internal and external bleeds

Question: What are the step in hemostasis that are

impaired in Dilan?
a) Platelet aggregation at wound site
b) Ability to form the tenase complex
c) Ability to fully activate factor X
d) b and c

Figure 16.10 (Note: Hemophilia B due to deficiency in factor IX)

How is the clot removed after healing has taken place?

tPA released slowly by damaged endothelium

Figure 16.11
 Case study #4

Jason just had a stroke caused by

a blood clot.

Thrombus – Blood clot attached to vessel wall

Embolus – Floating blood clot

 Case study #4 cont’d

Doctor quickly administers tissue

plasminogen activator (tPA)

tPA must be administered within 3-4 hours following a stroke

Helps to breakup clot and reduces tissue damage
Must ensure stroke not caused by hemorrhage

How does tPA act as an anticoagulant?

a) Inhibits the action of thrombin
b) Blocks the action of Vitamin K
c) Stimulates the conversion of plasminogen to plasmin
d) Enzymatically breaks down fibrin
 Physiological anticoagulants
Name Released from Activated Function
by
Plasminogen/ Liver tPA and Breaks down fibrin
plasmin thrombin
Tissue Many tissues Normally Activates
plasminogen present plasminogen
activator (tPA)
Antithrombin III Liver Heparin Blocks IX, X, XI, XII,
thrombin
Prostacyclin Endothelial N/A Inhibits platelet
cells aggregation
See Table 16.5
 Next class
Cardiovascular system with Professor Scott Heximer

Dr. Heximer would like to watch this video to help you

understand action potentials in the heart

This will help you with cardio lectures 1 and 2 (best to watch
before these lectures)

https://play.library.utoronto.ca/NFo421uzmKj2