Hemostasis and Coagulation cascade

Chapter 1
Introduction and basic
knowledge
Rivaroxaban medical training
Mohamed Sabry
MSL

Intended Learning Outcomes (ILOs)
By the end of this chapter, the trainee should be able to:
➢ Know the components of the circulatory system, and the flow of blood in heart and
blood vessels.
○ Know the main components of the blood, and it’s functions in the body.
➢ Understand homeostasis, and hemostasis and their importance in the human body.
○ Understand the positive and negative feedback mechanism, and their role to
maintain homeostasis.
➢ Understand blood clotting and the role of platelets during it.
○ Understand the coagulation cascade (intrinsic, extrinsic and common pathway),
and the central role of factor Xa in blood clotting.

Topics
1. Physiology of cardiovascular system
a. Heart
b. Blood vessels & Blood
2. Homeostasis and Hemostasis
3. Blood clotting

1. Physiology of
cardiovascular system

➢ The heart pumps blood to the
body through a network of
arteries and veins (blood
vessels).
➢ The circulatory system can also
be defined as your
cardiovascular system. Cardio
means heart, and vascular refers
to blood vessels.
➢ It includes the systemic
circulation, pulmonary
circulation, and coronary
circulation.
What is the circulatory system ?

What is the circulatory system ?

Heart
➢ The heart itself is made up of 4 chambers, 2 upper chambers (atria) and 2 lower
chamber (ventricles).1

Heart
A large, significant vein responsible
for returning deoxygenated blood
collected from the body back into the
right atrium.
A large vein that carries the
deoxygenated blood from the lower
and middle body into the right atrium
of the heart.
An artery in the pulmonary circulation
that carries deoxygenated blood from
the right side of the heart to the lungs.
Transfer oxygenated
blood from the lungs to
the left atrium.
The main artery that
carries blood away from
your heart to the rest of
your body.

Heart Valves
➢ The heart itself is made up of has 4 valves, which open or close to control the
blood flow in the one direction (unidirectional valves).
Tricuspid valve between right atrium
and right ventricle
Pulmonary valve between right
ventricle and pulmonary artery
Mitral valve between left atrium and
left ventricle
Aortic valve between left ventricle
and aorta

The Atrial Kick
➢ Atrial kick is the phenomenon of increased force generated by the atria during
contraction.
➢ This event occurs late in atrial systole when blood flows from the left atrium into
the left ventricle.
➢ The purpose of the atrial kick is to increase flow across the mitral valve by
increasing the pressure gradient.

1. Anatomy and Physiology of the Heart - Normal Function of the Heart - Cardiology Teaching Package - Practice Learning - Division of Nursing - The University of Nottingham. (2022). Retrieved 16 June 2022, from
https://www.nottingham.ac.uk/nursing/practice/resources/cardiology/function/anatomy.php
Blood circulation through the heart
Deoxygenated
blood
Oxygenated
blood
Mitral
Valve
Aortic Valve
Inferior vena cava

Cardiac Conduction System
The SA node is the
natural pacemaker of
the heart.

➢ The SA node releases electrical stimuli at a
regular rate, the rate is dictated by the
needs of the body.
➢ Each stimulus passes through the
myocardial cells of the atria creating a
wave of contraction which spreads rapidly
through both atria. (1,2,3)

➢ The electrical stimulus from the SA node
eventually reaches the AV node and is
delayed briefly so that the contracting
atria have enough time to pump all the
blood into the ventricles.
➢ Once the atria are empty of blood the
valves between the atria and ventricles
close.
➢ At this point the atria begin to refill and
the electrical stimulus passes through the
AV node and Bundle of His into the Bundle
branches and Purkinje fibres. (4,5,6)

Question
➢ Complete the
sketch and
mention blood flow
direction in words.

Question
➢ Draw a sketch using simple lines to illustrate the heart
conduction system.

Blood vessels
1. Blood Vessels. (2022). Retrieved 16 June 2022, from https://www.fi.edu/heart/blood-vessels#:~:text=There%20are%20three%20kinds%20of,allows%20blood%20to%20flow%20easily.
➢ There are three kinds of blood vessels: arteries, veins, and capillaries. Each of
these plays a very specific role in the circulation process. It Forms a network
that carry blood from and back to the heart.1

Blood vessels
➢ Arteries carry oxygenated blood away from the heart.

Blood vessels
➢ Capillaries connect the arteries to veins. The arteries deliver the oxygen-rich
blood to the capillaries, where the actual exchange of oxygen and carbon
dioxide occurs. The capillaries then deliver the waste-rich blood to the veins for
transport back to the lungs and heart.1
As blood plasma passes through capillaries,
hydrostatic pressure forces some of plasma
fluid out of the capillary wall to form tissue
fluid.

Blood vessels
➢ Veins carry the deoxygenated blood back to the heart.

Functions of the blood
1. InformedHealth.org [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. What does blood do? [Updated 2019 Aug 29]. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK279392/
1. Transportation 1
➢ The blood transports oxygen from the lungs to the cells of the body.
➢ The carbon dioxide produced is carried back to the lungs by the blood.
➢ Blood also provides the cells with nutrients, transports hormones and removes
waste products, which organs such as the liver, the kidneys or the intestine
then get rid of.

2. Regulation 1
➢ The blood makes sure that the right body temperature is maintained.
➢ When the blood vessels expand, the blood flows more slowly and this
causes heat to be lost. When the temperature outside the body is low,
the blood vessels can contract to reduce the amount of heat lost.

3. Protection1
➢ This involves parts of the blood such as blood platelets and coagulation factors
that are dissolved in the blood plasma, these parts of the blood stick together
(clot) very quickly and make sure that it stops bleeding.
➢ White blood cells and certain chemical messengers also play an important role
in the immune system.

Components of the blood
1. Blood Components. (2022). Retrieved 16 June 2022, from https://www.redcrossblood.org/donate-blood/how-to-donate/types-of-blood-donations/blood-components.html
2. Mathew J, Sankar P, Varacallo M. Physiology, Blood Plasma. [Updated 2022 Apr 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:
Adapted from reference 1
Plasma contains 91% to 92% of water and 8% to 9% of solids. It
mainly comprises of:2
➢ Coagulants, mainly fibrinogen, aid in blood clotting.
➢ Plasma proteins, such as albumin and globulin, that help
maintain the colloidal osmotic pressure at about 25 mmHg.
➢ Electrolytes like sodium, potassium, bicarbonate, chloride,
and calcium.
➢ Immunoglobulins help fight infection and various other
small amounts of enzymes, hormones, and vitamins.

2. Richard van Wijk, Wouter W. van Solinge; The energy-less red blood cell is lost: erythrocyte enzyme abnormalities of glycolysis. Blood 2005; 106 (13): 4034–4042. doi: https://doi.org/10.1182/blood-2005-04-1622
3. Rewar, Suresh. (2014). RESEALED ERYTHROCYTES AS CARRIERS AND ITS APPLICATION IN THERAPY. INTERNATIONAL JOURNAL OF CURRENT RESEARCH IN CHEMISTRY AND PHARMACEUTICAL SCIENCES. 1. 101-114.
Called Erythrocytes, they are flattened biconcave disc,
which increase surface area for gas exchange: 1,2
➢ Life span: 120 days.
➢ They lack nucleus (High flexibility) and lack
mitochondria (anaerobic metabolism).
➢ Contain haemoglobin which gives the blood its red
color.

2. What Are White Blood Cells? - Health Encyclopedia - University of Rochester Medical Center. (2022). Retrieved 16 June 2022, from
https://www.urmc.rochester.edu/encyclopedia/content.aspx?ContentID=35&ContentTypeID=160
3. Shirazi, Syed & Umar, Arif & Naz, Saeeda & Razzak, Muhammad. (2016). Efficient leukocyte segmentation and recognition in peripheral blood image. Technology and health care : official journal of the
European Society for Engineering and Medicine. 24. 10.3233/THC-161133.
➢ Called Leukocytes, contain nucleus and
mitochondria, they can move and squeeze through
capillaries to reach the inflammation site.1,2

Components of the blood 1,2
2. blood - Platelets (thrombocytes). (2022). Retrieved 16 June 2022, from https://www.britannica.com/science/blood-biochemistry/Platelets-thrombocytes.
➢ Platelets is the smallest blood element.
➢ After about 5-9 days in the circulation, platelets are
removed and destroyed.
➢ They lack nucleus but have the ability to move
(have mitochondria).

Question
➢ Mention the
representation of
each percentage,
then mention its
functions.

Homeostasis definition
Homeostasis can be defined as ‘preserving constancy in the internal
environment’.1
1. George F. Koob, Michel Le Moal, CHAPTER 10 - Drug Addiction: Transition from Neuroadaptation to Pathophysiology, Editor(s): George F. Koob, Michel Le Moal, Neurobiology of Addiction, Academic Press,
2006, Pages 429-461, ISBN 9780124192393, https://doi.org/10.1016/B978-012419239-3/50047-3.
2. 1.3A: Homeostatic Control. (2022). Retrieved 15 June 2022, from
https://med.libretexts.org/Bookshelves/Anatomy_and_Physiology/Book%3A_Anatomy_and_Physiology_(Boundless)/1%3A_Introduction_to_Anatomy_and_Physiology/1.3%3A_Homeostasis/1.3A%3A_Homeo
static_Control#:~:text=An%20effector%20is%20any%20organ,blood%20pressure%20is%20too%20low.
Homeostatic control mechanisms have at least
three interdependent components:2
1. A receptor.
1. integrating center (not
involved in some
responses).
1. Effector.

Homeostasis control mechanisms
1. The receptor senses internal or external stimuli, sending the information
to the integrating center.
2. The integrating center, generally a region of the brain called the
hypothalamus, signals an effector (e.g. muscles or an organ ) to maintain
homeostasis.
3. Effector responds to the stimuli.

➢ The body operates within a range of too much and too little, the limits of tolerance.
➢ As long as the disturbance is within the tolerance limit, the body will be able to regain
balance.
➢ If the change is beyond tolerance limit, the body won’t be able to regain balance.

https://med.libretexts.org/Bookshelves/Anatomy_and_Physiology/Book%3A_Anatomy_and_Physiology_(Boundless)/1%3A_Introduction_to_Anatomy_and_Physiology/1.3%3A_Homeostasis/1.3A%3A_Homeostatic_Control#:~:text=An%20effector%20is%20any%20organ,blood%20pressure%2
0is%20too%20low.
2. Research gate. (2022). Retrieved 15 June 2022, from https://www.researchgate.net/figure/Examples-of-causal-loop-diagrams-representing-positive-and-negative-feedback-loops-A_fig9_36712679
Positive and negative feedback are complicated mechanisms that maintain
homeostasis for more complex physiological processes.
Positive feedback Negative feedback

Positive feedback loop
https://med.libretexts.org/Bookshelves/Anatomy_and_Physiology/Book%3A_Anatomy_and_Physiology_(Boundless)/1%3A_Introduction_to_Anatomy_and_Physiology/1.3%3A_Homeostasis/1.3A%3A_Homeo
static_Control#:~:text=An%20effector%20is%20any%20organ,blood%20pressure%20is%20too%20low.
Positive feedback mechanisms are designed to accelerate or enhance the output
created by a stimulus that has already been activated in order to reach the goal of
maintaining homeostasis.
A positive feedback example is blood platelet accumulation and
aggregation, which in turn causes blood clotting in response to an injury
of the blood vessels.

Positive feedback loop
1. Michigan.gov. (2022). Retrieved 15 June 2022, from https://www.michigan.gov/-/media/Project/Websites/explorelabscience/pdf/Presentation_on_Homeostasis.pdf?rev=148b2304bd6340a99e3cccda43539499
1. Break or tear occurs in
blood vessel wall
2. Positive feedback cycle is initiated
3. Platelets adhere to site and
release chemicals that attract
more platelets
4. Platelet plug forms
Feedback cycle ends when plug is formed
Positive
feedback loop

Negative feedback loop
Negative feedback mechanisms reduce output or activity to return an organ or
system to its normal range of functioning.1
1
3
2
1`
2`
3`

Negative feedback loop1
Other examples of negative feedback loop?
Regulation of blood pressure is an example of negative feedback.
Normal Blood pressure
Blood pressure is high
➢ The heart rate
decreases
➢ vasodilation
➢ kidneys retain less
water.
Blood pressure is low
➢ The heart rate
increases
➢ vasoconstriction
➢ kidneys retain
more water.
1
2
1`
2`

Hemostasis definition
Hemostasis is the normal physiological response that
prevents significant blood loss following vascular
injury.1
1. Hemostasis: Stages and How the Process Stops Blood Flow. (2022). Retrieved 15 June 2022, from
https://my.clevelandclinic.org/health/symptoms/21999-
hemostasis#:~:text=Hemostasis%20is%20your%20body's%20natural,much%20or%20too%20little%20clotting.
Sometimes, the processes that control hemostasis
can malfunction, causing potentially serious — or
even dangerous — problems with bleeding or clotting
(thrombosis).1

Activity
➢ Draw a sketch to show the role positive feedback in hemostasis.

Blood Clotting
1. Blood Clots [Internet]. Hematology.org. 2022 [cited 19 June 2022]. Available from: https://www.hematology.org/education/patients/blood-clots
➢ Blood clotting, or coagulation, is an important process that prevents excessive
bleeding when a blood vessel is injured. 1
Promote hemostasis ( hemo = blood and stasis = standing)
➢ Platelets and proteins known as coagulation factors in your plasma work
together to stop the bleeding by forming a clot over the injury. 1
Under physiologic conditions platelets circulate without
adhering to intact and inactive endothelium.1

When endothelial lining of blood vessel is intact, platelets repel from each other and also
repel from the intact endothelium prostacyclin produced by the endothelium.
Other mechanisms to prevent platelets activation include:
➢ The protective effects of the glycocalyx.
➢ The endothelial production of nitric oxide (NO) which is potent platelet inhibitor.
➢ The production of the endothelial ecto-ADPase-CD39 metabolizes ADP, a strong platelet
activator, attenuating platelets activation indirectly.
1. Hamilos, M., Petousis, S., & Parthenakis, F. (2018). Interaction between platelets and endothelium: from pathophysiology to new therapeutic options. Cardiovascular diagnosis and therapy, 8(5), 568–580.
https://doi.org/10.21037/cdt.2018.07.01

Blood Clotting- How it all starts
TXA2: Thromboxane A2, ADP: Adenosine Diphosphate
1. 1. Smith, S. A., Travers, R. J., & Morrissey, J. H. (2015). How it all starts: Initiation of the clotting cascade. Critical reviews in biochemistry and molecular biology, 50(4), 326–336.
https://doi.org/10.3109/10409238.2015.1050550
Breakage of endothelial lining of blood
vessel 1
Circulating platelets adhere to the
site of trauma (collagen)
A series of enzymatic reactions
involving coagulation proteins
Platelets are activated and
aggregated
Fibrin is produced to form a stable
plug

Role of platelets
Sticky platelets release TXA2 and ADP inducing other platelets to stick (+ve
feedback).

Role of platelets
TXA2: Thromboxane A2
1. Periayah, M. H., Halim, A. S., & Mat Saad, A. Z. (2017). Mechanism Action of Platelets and Crucial Blood Coagulation Pathways in Hemostasis. International journal of hematology-oncology and stem cell
research, 11(4), 319–327.
➢ Phospholipids in the cell membrane of activated platelets activates clotting
factors that results in formation of fibrin. 1
➢ Release TXA2 and serotonin inducing vasoconstriction and reduce blood flow
to the injured area.1
➢ Release growth factors which maintain integrity of blood vessel.1

Blood Clotting- How it all starts
TXA2: Thromboxane A2, ADP: Adenosine Diphosphate
1. Smith, S. A., Travers, R. J., & Morrissey, J. H. (2015). How it all starts: Initiation of the clotting cascade. Critical reviews in biochemistry and molecular biology, 50(4), 326–336.
https://doi.org/10.3109/10409238.2015.1050550
Breakage of endothelial lining of blood
vessel. 1
Circulating platelets adhere to the
site of trauma (collagen)
A series of enzymatic reactions
involving coagulation proteins
Platelets are activated and
aggregated
Fibrin is produced to form a stable
plug
Sticky platelets release TXA2 and ADP inducing
other platelets to stick (+ve feedback?)

The coagulation cascade 1
https://doi.org/10.3109/10409238.2015.1050550
Extrinsic Pathway
Intrinsic Pathway
Common Pathway
Prothrombin is activated into thrombin, and fibrin is produced to form a stable
plug along with platelets
Generate
activated factor X
(factor Xa)

Intrinsic Pathway
➢ Coagulation initiated by components entirely within vasculature. 1
➢ Initiated by the contact system which is activated by blood contact with
nonendothelial surfaces.1
➢ It begins with the activation of Factor XII which becomes Factor XIIa after
exposure to endothelial collagen.

Intrinsic Pathway
XII
Binds to
subendothelial
surfaces exposed by
injury
XIIa
Prekallikrein to
Kallikrein
Ca++
XI to XIa
IX to IXa
Ca++, VIIIa, PL
X to Xa
➢ Quantitatively is the most important pathway, but slower than extrinsic
pathway.1

Extrinsic Pathway
1. Chaudhry R, Usama SM, Babiker HM. Physiology, Coagulation Pathways. [Updated 2021 Sep 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:
➢ The principle initiating pathway of invivo blood coagulation.
➢ The critical component is tissue factor embedded within and around blood
vessels and other tissue, under normal conditions it’s not exposed to blood.
➢ It’s main function is to augment the activity of the intrinsic pathway, it provides
a very rapid response to tissue injury.

Extrinsic Pathway
Tissue
factor
activation
VII to VIIa
Tissue factor
+ VIIa + PL +
Ca++
X to Xa

The common Pathway
X to Xa
Extrinsic Pathway Intrinsic
Pathway
Prothrombin (II)
to Thrombin
(IIa)
Fibrinogen (I)
into Fibrin (Ia)
Stable blood
clot
Fibrin
stabilizing
factor (XIII) to
XIIIa
Ca++, Va, PL

Factor Xa has a central role in thrombus
formation
➢ One molecule of factor Xa, activates 1000 thrombin
molecules.
➢ Factor Xa is a crucial site of amplification in the
coagulation process.
1. Ansell J. (2007). Factor Xa or thrombin: is factor Xa a better target?. Journal of thrombosis and haemostasis : JTH, 5 Suppl 1, 60–64. https://doi.org/10.1111/j.1538-7836.2007.02473.x

factor XII, prekallikrein and high
molecular weight kininogen

The coagulation cascade
https://doi.org/10.3109/10409238.2015.1050550
➢ Each enzyme is present in inactive form which on activation release the active
factor.1
➢ The ultimate goal is to produce thrombin which activates soluble fibrinogen into
insoluble fibrin that forms a clot.1
➢ Intrinsic and extrinsic pathways release factor Xa, while common pathway
release thrombin.1

Vitamin K is needed for the proper function of
factors II, VII, IX & X.
➢ Because of the indirect action of vitamin K on blood clotting,
vitamin K antagonists (e.g warfarin) take several days to
become effective as an anticoagulant.
1. Girolami, A., Ferrari, S., Cosi, E., Santarossa, C., & Randi, M. L. (2018). Vitamin K-Dependent Coagulation Factors That May be Responsible for Both Bleeding and Thrombosis (FII, FVII, and FIX). Clinical
and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis, 24(9_suppl), 42S–47S. https://doi.org/10.1177/1076029618811109

Question
➢ Which of the following initiates the coagulation cascade IN VIVO?
A. Factor XII
B. Thrombin
C. Tissue factor
D. Factor X
E. Prekallikrein
➢ Which of the following is true?
A. The extrinsic system is activated first, and then the intrinsic system is turned
on later
B. The intrinsic system is weak and short-lived
Which factor has a central role in the coagulation cascade ? why?

The New Coagulation Cascade
Tissue factor: FT, APL: Acidic phspholipid
1. https://www.revespcardiol.org/en-the-new-coagulation-cascade-its-articulo-13114167

1. The complex formed by tissue factor and factor VII participates in the activation
of factor IX, indicating that the intrinsic and extrinsic coagulation pathways are
linked almost from the beginning of the process.
2. The complete process does not occur continuously but rather requires 3
consecutive phases: an initial phase, an amplification phase, and a propagation
phase. Platelets and thrombin are actively involved in the last 2 phases.

Initial Phase
The tissue factor - factor VII complex activates factor X, either directly or indirectly via factor IX, and
transforms prothrombin into thrombin in small amounts that are insufficient to complete the process of
fibrin formation.
Amplification Phase
The thrombin that has been formed, along with calcium from the blood and acidic phospholipids derived
from platelets, actively participates in a positive feedback process for the activation of factors XI, IX, VIII,
and V, and, especially, to accelerate platelet activation. Simultaneously, the factors mentioned are
attracted through chemotactic mechanisms to the surface of the platelets, where very rapid and
extensive activation and amplification occurs.
Propagation Phase
The amplification of the process through feedback mechanisms involving thrombin and platelets and the
activation of all these factors allow large quantities of factor X to be activated and form the
prothrombinase complex to convert prothrombin into thrombin and, through the action of thrombin,
fibrinogen into fibrin. The final process, always occurring on the surface of the platelets, accelerates and
leads to the explosive generation of large quantities of thrombin and fibrin.

Fibrinolysis
➢ Fibrinolysis is the process that dissolves fibrin leading to dissolution of the
thrombus.

Fibrinolysis
Fibrin degradation products

During initial thrombus formation
1. Chapin, J. C., & Hajjar, K. A. (2015). Fibrinolysis and the control of blood coagulation. Blood reviews, 29(1), 17–24. https://doi.org/10.1016/j.blre.2014.09.003
Inhibit
plasminogen
activators during
initial thrombus
formation.

Once a stable fibrin clot has formed and injured tissues have been
repaired
1. Chapin, J. C., & Hajjar, K. A. (2015). Fibrinolysis and the control of blood coagulation. Blood reviews, 29(1), 17–24. https://doi.org/10.1016/j.blre.2014.09.003
Restores blood
flow

Platelets
Hemostasis
Coagulation Fibrinolysis
Blood vessel
(Endothelial cell)
Coagulation system - Thrombin generation
Hemostasis
Thrombosis:
↑ Coagulation
↑ Platelets, or
↓ Fibrinolysis
Hemorrhage:
↓ Coagulation
↓ Platelets, or
↑ Fibrinolysis

Hemostasis imbalance
➢ Any imbalance may lead to risk of bleeding or clotting (Thrombosis).1
1. Flores, B., Trivedi, H. D., Robson, S. C., & Bonder, A. (2017). Hemostasis, bleeding and thrombosis in liver disease. Journal of translational science, 3(3), 10.15761/JTS.1000182.
https://doi.org/10.15761/JTS.1000182
2. Carlos Jerjes-Sanchez, Venous and arterial thrombosis: a continuous spectrum of the same disease?, European Heart Journal, Volume 26, Issue 1, January 2005, Pages 3–4,
https://doi.org/10.1093/eurheartj/ehi041
➢ Arterial Thrombus (White thrombi) : composed mainly of platelets aggregation
and fibrins.2
➢ Venous Thrombus (Red thrombi) : composed of fibrins and red blood cells.2

Major diseases associated with thrombosis:
➢ Venous thromboembolism (VTE):
a disorder that includes deep vein thrombosis (DVT) and
pulmonary embolism (PE).1
DVT: Deep Vein Thrombosis, PE: Pulmonary Embolism
1. Thrombosis: Types, Causes, Symptoms & Treatment [Internet]. Cleveland Clinic. 2022 [cited 20 June 2022]. Available from: https://my.clevelandclinic.org/health/diseases/22242-thrombosis
➢ Cardioembolic stroke:
occlusion of cerebral vessels with debris from a cardiac source.1
➢ Atherothrombosis:
a condition that occurs when a thrombus forms over an unstable
atherosclerotic plaque.

Hemostasis and Coagulation cascade

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