Drabrh Human Blood and Related Disease Thrombosis by DR A B Rajib Hazarika PHD FRAS AES

HUMAN BLOOD AND
RELATED DISEASE
THROMBOSIS
MATHEMATICAL MODEL AND MEDICAL CURE
WITH MEDICINE AND CHEMICAL COMPOSITIONS
OF THROMBOSIS
Dr A B RAJIB HAZARIKA PhD

FRAS AES
Copyright © 2022 Dr A B Rajib Hazarika PhD FRAS
AES
All rights reserved.
ISBN: 9798444523278 (PAPERBACK)

ISBN: 9798841680468(HARD COVER)
DEDICATION
TO MY PARENTS
ROSMAT ALI HAZARIKA AND ANJENA HAZARIKA
TO MY WIFE
HELMIN HAZARIKA
TO MY KIDS
LAQUIT ALI HAZARIKA AND DANISHA BEGUM HAZARIKA
TO MY SISTER
SHAMIM ARA RAHMAN
TO MY BROTHER-IN-LAW
WAZUR RAHMAN
TO MY NIECE
KASHMIRA RAHMAN
TO MY DOCTORS WHO CURED MY THROMBOSIS

DR. S RAJENDERAN AND DR. REFAI ALI SHAKATWALA
TO MY SO MANY LOVED ONES
.
ABOUT THE AUTHOR
Dr.A.B.Rajib Hazarika, PhD, FRAS, AES ,Assistant Professor and

Head, Dept. of Mathematics, Diphu Govt. College, Diphu.
Gazetted officer -I of Assam Education Service (AES), Govt. of
Assam. MSc(Maths)in
1992,JRF(UGC,NET),1993,SRF(UGC,NET),PhD(Maths) 1995 ,JNV
University, 1995,Best PhD Thesis award Triple Gold Medal for Best
Mathematics Thesis, Best Science stream Thesis award, Best
Thesis for all stream from Association of Indian Universities, Post
Doctoral Fellow, 1998,Plasma Physics division, IASST, Guwahati as
Research Associate (DST),Govt. of India. Elected Fellow of Royal
Astronomical Society (FRAS), London in 2010. Authored 20 books,
Peer reviewer of 10 Journals. Elected Member of 23 Foreign
professional academies. Guided two scholars for MPhil degree.
9.2. PERSPECTIVES
v
CONTENTS
Acknowledgments i
1 Blood, its type composition 2
2 Blood and its composition 23
3 Blood related diseases: Thrombosis 57
4 Blood Disorders 80
5 Home remedies and natural 84

treatment
6 Blood coagulation 92
7 Mathematical model for coagulation 126
8 Anticoagulant Model 130
9 Thrombosis model and simulation 138
10 Precautions for Thrombosis 161
11 Diet for thrombosis patients 183
12 Health and exercises for thrombosis 195

ACKNOWLEDGMENTS
I WISH TO acknowledge to all dedicated persons involved in study

of Thrombosis worldwide and researchers in this field doing
modeling of Thrombosis and into the medicine field. Doctors such
as Neurosurgeons, Cardiologist and many more especially the
persons involved with Hematology and Haematasis .and
Mathematicians busy in modeling Thrombosis.
i
1
DR A B RAJIB HAZARIKA PHD FRAS AES
1 HUMAN BODY AND BLOOD DISORDERS
Our body consists of muscles, bone, tissues, different organs and

most important BLOOD, which covers whole body through
circulation to different organs, muscles, tissues and bone marrow
and also brain which central processing unit of human body. Most
of diseases are due to this blood. This book is dedicated to all
those who are suffering from different blood disorders ,such
Anaema, blood clotting or thrombosis,HIV,Thalesemia etc.
Most common of disorders is thrombosis i.e. blood clotting due

which most of dreaded diseases such as Heart
attack,stroke,paralysis ,liver scerolisis ,kidney disorder, urinary
tract infection,pencrease disorder, etc. Basically what happens is
blood clotting problem if is solved hope if not all most of diseases
get rectified.
This book wholly concentrated on blood is disorders such as
blood clotting, medical term Thrombosis. There are two aspects to
look into the matter one is medical/pharmaceutical and another is
mathematical modeling. Here in this we will start from the very
basic or fundamental to most complicated model.
I am interested in presenting the basic model, newly invented

medicine with chemical composition and its intricacies. As some
of medicines are available in market with some side effects, here I
have tried to remove some of intricacies /side effects by adding
the additional chemical composition to make it best suited for the
2
patients of thrombosis/blood clotting.
9.2. PERSPECTIVES
Two most important compositions are invented by Dr A B Rajib
Hazarika ,PhD,FRAS,AES namely.
AZADI tablet (Aspirin + Clopidorel+Clavunate) and ABRH-dimer

(Clopidogrel + Theophylline) .
AZADI tablet is for blood clotting patients, heart and stroke

patients.Anticogualant, antithrombin, antiplatelet.
Clopidogrel Is
used to prevent
heart attack and
strokes in
person with
heart disease or
blood
circulation
disease
(peripheral
vascular).It is
used with
Aspirin to treat
new /worsening
chest pain (new
heart attack,
unstable angina)
an to keep
blood vessel
open and
prevent blood clots after certain procedure (such as cardiac
stent).Clopidogrel works by blocking platelets from sticking
together and prevents them from forming harmful clots.
It helps to keep blood flowing smoothly in body.
3
Aspirin
Clinical data
Pronunciation acetylsalicylic acid /əˌsiːtəlˌsælɪˈsɪlɪk/
Trade names Bayer Aspirin, others
2-acetoxybenzoic acid
acetylsalicylate
Other names
acetylsalicylic acid
o-acetylsalicylic acid
Clopidogrel
4
Clavulanic acid
9.2. PERSPECTIVES
Clinical data
Pronunciation /ˌklævjʊˈlænɪk/
Another one ABRH-dimer for blood clotting as well for breathing

problem patients such as covid,asthama,bronchial and lungs
patients etc. Antihistamine, anticogualant, antiplatelet,
antithrombin, antiasthamatic, coronary vasolilator and diuretic.
Theophylline common name 1, 3-dimethylxanthine is used for
respiratory problem such as chronic obstructive pulmonary
disease (COPD) and asthma.
5
6
Clavulanic acid
9.2. PERSPECTIVES
Clinical data
Pronunciation /ˌklævjʊˈlænɪk/
Theophylline
7
Clinical data
Trade names Theolair, Slo-Bid
Here I have tried very old basic model of single cold pill and
course of pills. In later on chapters mathematical model with
Navier –Stokes equation is used and many more other equations.
Exhaustive model consists of a system advection-reaction-

diffusion equations coupled with the NavierStokes equations that
contain an additional term describing the deceleration of flow as
it goes through the clot. For each blood clotting factor Fi, we
describe its concentration during clot growth using an equation of
the following form:
(dFi/ dt) +∇.(vFi) = DΔFi +Ri,
where v is the blood flow velocity, D is the diffusion coefficient,

and Ri is a the reaction term. Similar equations will be used to
describe the densities of different subtypes of platelets. To this
system of equations, we add the Navier-Stokes equations in order
to capture the effect of hemodynamics on the distribution of
blood clotting factors:
ρ (∂u/ ∂t) +u(∇.u) = −∇p+ μΔ.u − μ/ K(x) u
8
∇.u = 0, where u = (ux,uy) is the velocity vector, p is the
pressure, ρ the density of blood, μ the viscosity. We consider
9.2. PERSPECTIVES
laminar incompressible flow. K is the hydraulic permeability of the
thrombus which can be expressed as a function of fibrin polymer
concentration and platelets density. The above model considers
the thrombus as a porous medium whose permeability diffuse.
What is high blood pressure (hypertension)?
High blood pressure, also known as hypertension, affects nearly a

third of all people around the world. With hypertension, too much
force is exerted on the arteries as blood is pumped through. This
results not only in damage to the blood vessels themselves, but to
other organs forced to bear the stress.
Blood pressure is assessed using two parameters -- the systolic

and diastolic pressures -- which measure, respectively, the
maximum pressure exerted in the arteries as the heart contracts,
and the minimum pres
sure in those vessels between cardiac contractions. In adults,

blood pressure is considered normal if the top number (systolic
pressure) is between 90 and 120 and the bottom number
(diastolic) is between 60 and 80.
What are the most common blood pressure medications?
In terms of dollar sales, there are 5 top high blood pressure

medications.
 the angiotensin II receptor blocker valsartan (Diovan) in the lead

for high blood pressure medications,
 the beta-blocker metoprolol,
 the generic combination of valsartan and HCTZ,
 olmesartan (Benicar), and
9
 olmesartan and HCTZ (Benicar HCT).
In terms of prescriptions written, here are the top 4 high blood

pressure medications,
 the ACE inhibitor lisinopril (Prinivil, Zestril) tops the list,

 followed by amlodipine besylate (Norvasc),
 a calcium channel blocker, and
 Generic hydrochlorothiazide (HCTZ).
How to Lower Blood Pressure:
What is the best high blood pressure medication?
Selecting the "best" high blood pressure medication depends on

several things, including the general health of the patient, his or
her age, ethnicity, and whether or not they have any co-existing
medical issues or drug sensitivities.
For example, in a hypertensive patient with asthma, it may be

inadvisable to prescribe a beta-blocker, as these drugs can
aggravate that respiratory condition. Similarly, in patients prone
to constipation (the elderly, for example) use of certain calcium
10
channel blockers might best be avoided -- along with diuretics --
as both these classes of drugs can inhibit proper bowel function.
9.2. PERSPECTIVES
African-American patients respond to some antihypertensive
medications better than others.
Certain groups of patients require the use of a specific class of

high blood pressure medication. These include:
Pregnant Women
 The drug of choice for hypertensive, pregnant women is one of

the oldest high blood pressure medications on the market.
Methyldopa, which works to lower blood pressure through the
central nervous system, has the lowest risk of harming the
mother and developing fetus.
 Other possible safe options include labetalol, beta-blockers, and
diuretics.
 Two classes of drugs that should never be used during
pregnancy include ACE inhibitors and angiotensin II receptor
blockers.
African-Americans
Hypertension in African-Americans tends to occur earlier in life

and tends to be more severe. Plus, some medications that work to
lower blood pressure in other ethnicities may have limited effect
on African-Americans. Thiazide diuretics (such as HCTZ) or a
calcium channel blocker are recommended first choices along
with the possible add-on of a second drug from either the ACE
inhibitor class or the angiotensin II receptor blocker group.
Elderly Patients
With age, comes an increased risk for systolic hypertension which

can be aggravated by severe atherosclerosis.
11
 According to one study, the diuretic chlorthalidone (Hygroton)

had significant benefits in elderly patients with systolic
hypertension.
 Along with a diuretic, some calcium channel blockers, ACE
inhibitors, and angiotensin II receptor blockers may also be
good choices.
 However, beta-blockers may not be as effective for
hypertension in those over 60; though they may be good
choices if co-existing heart disease is present.
 It also may be preferable in elderly patients to give two high
 blood pressure medications at a low dose versus one at a higher
dose.
High blood pressure medication list
There are several classes of blood pressure medications. Each

class lowers blood pressure in a different way.
 Diuretics
 Beta-blockers
 ACE inhibitors
 Angiotensin II receptor blockers
 Calcium channel blockers
 Alpha-blockers
 Alpha-2 receptor agonist
 Central agonists
 Peripheral adrenergic inhibitors
 Vasodilators
Diuretics
Diuretics increase urination which reduces sodium and fluid in the

body. That can help lower blood pressure because it lowers blood
12
volume. Mild hypertension can sometimes be treated using
diuretics alone, although they are more commonly used in
9.2. PERSPECTIVES
combination with other high blood pressure medications.
Examples of diuretics include:
 Bumetanide (Bumex)
 Chlorthalidone (Hygroton)
 Chlorothiazide (Diuril)
 Ethacrynate (Edecrin)
 Furosemide (Lasix)
 Hydrochlorothiazide HCTZ (Esidrix, Hydrodiuril, Microzide)
 Indapamide (Lozol)
 Methyclothiazide (Enduron)
 Metolazone (Mykroz, Zaroxolyn)
 Torsemide (Demadex)
One side effect of diuretics is a loss of potassium, which is carried

out of the body in urine along with the sodium. Potassium is
needed for proper muscular movement and a deficiency of this
mineral can result in fatigue, weakness, leg cramps, and even
problems with the heart. So often, patients on traditional diuretics
will be advised to take their medication with a potassium-rich
food, such as orange juice or a banana, or they'll be prescribed a
potassium supplement.
Some diuretics were subsequently developed to address the issue

of potassium loss. These blood pressure medications are known
as "potassium-sparing" diuretics. They include amiloride
(Midamor), spironolactone (Aldactone), and triamterene
(Dyrenium).
Finally, there are the combination diuretics, which include a

potassium-sparing agent and a traditional diuretic. These include
amiloride hydrochloride and hydrochlorothiazide HCTZ
(Moduretic), spironolactone and HCTZ (Aldactazide), and
triamterene and HCTZ (Dyazide, Maxzide).
13
Salt and sodium are the same
Beta-blockers
Beta-blockers lower blood pressure by acting directly on the

heart. These high blood pressure medications reduce heart rate
and force of pumping, as well as reduce blood volume. Beta-
blockers include:
 Acebutolol (Sectral)
 Atenolol (Tenormin)
 Bisoprolol fumarate (Zebeta)
 Carvedilol (Coreg) -- Combined alpha/beta-blocker
 Esmolol (Brevibloc)
 Labetalol (Trandate, Normodyne) -- Combined alpha/beta-
blocker
 Metoprolol tartrate (Lopressor) and metoprolol succinate
(Toprol-XL)
 Nadolol (Corgard)
 Nebivolol (Bystolic)
 Penbutolol sulfate (Levatol)
 Propranolol (Inderal)
 Sotalol (Betapace)
 HCTZ and bisoprolol (Ziac) is a beta blocker plus diuretic
14
ACE inhibitors
9.2. PERSPECTIVES
Angiotensin is a hormone in the body that causes blood vessels to
narrow. The angiotensin-converting enzyme (ACE) inhibitors
decrease the production of angiotensin and, in turn, that helps
lower blood pressure. Examples of ACE inhibitors include:
 Benazepril hydrochloride (Lotensin)

 Captopril (Capoten)
 Enalapril Maleate (Vasotec)
 Fosinopril sodium (Monopril)
 Lisinopril (Prinivil, Zestril)
 Moexipril (Univasc)
 Perindopril (Aceon)
 Quinapril hydrochloride (Accupril)
 Ramipril (Altace)
 Trandolapril (Mavik)
Angiotensin II receptor blockers
The hormone angiotensin narrows blood vessels, but to do its job

it needs a place to bind. That's where angiotensin II receptor
blockers come in. They prevent angiotensin from binding to
receptors on the blood vessels and that helps lower blood
pressure. Angiotensin II receptor blockers include:
 Azilsartan (Edarbi)
 Candesartan (Atacand)
 Eprosartan mesylate (Teveten)
 Irbesartan (Avapro)
 Losartan Potassium (Cozaar)
 Olmesartan (Benicar)
 Telmisartan (Micardis)
 Valsartan (Diovan)
15
Calcium channel blockers
Calcium increases the strength and force of contractions in the

heart and blood vessels. Blocking its entry into smooth muscle
tissue reduces this effect. Calcium channel blockers lower blood
pressure by relaxing blood vessels and reducing heart rate.
Examples of calcium channel blockers include:
 Amlodipine besylate (Norvasc, Lotrel)

 Clevidipine (Cleviprex)
 Diltiazem hydrochloride (Cardizem CD, Cardizem SR, Dilacor XR,
Tiazac)
 Felodipine (Plendil)
 Isradipine (DynaCirc, DynaCirc CR)
 Nicardipine (Cardene SR)
 Nifedipine (Adalat CC, Procardia XL)
 Nimodipine (Nimotop, Nymalize)

 Nisoldipine (Sular)
 Verapamil hydrochloride (Calan SR, Isoptin SR, Verelan, Covera
HS)
Alpha-blockers
Alpha-blockers cause blood vessels to dilate, thereby lowering

blood pressure. These medications are also used to treat prostate
enlargement in men. Alpha-blockers include
 doxazosin mesylate (Cardura),

 prazosin hydrochloride (Minipress), and
 terazosin hydrochloride (Hytrin).
16
Alpha-2 receptor agonist
9.2. PERSPECTIVES
Methyldopa, formerly known under the brand name Aldomet, is
one of the oldest blood pressure medications still in use.
 It was first introduced more than 50 years ago.

 Methyldopa works in the central nervous system to lower blood
pressure.
 While its general use has declined over the years, methyldopa is
considered the first-line of treatment for high blood pressure
that develops during pregnancy.
Central agonists
Some hypertension medications work in the central nervous

system rather than directly on the cardiovascular system. Central
agonists thus have a tendency to cause drowsiness. Drugs in this
class include
 clonidine hydrochloride (Catapres) and

 guanfacine hydrochloride (Tenex).
Peripheral adrenergic inhibitors
There was a time when the high blood pressure medication list
was very short indeed. In the 1950s, reserpine was one of the few
products on the market to treat hypertension. It is rarely used due
to its numerous side effects and drug interactions. The peripheral
adrenergic inhibitors work in the brain to block signals that tell
blood vessels to constrict. They are mostly used when other high
blood pressure medications fail to solve the problem.
The peripheral adrenergic inhibitors include
 Guanadrel (Hylorel),
 guanethidine monosulfate (Ismelin), and
 reserpine (Serpasil).
17
Vasodilators
Vasodilators relax artery wall muscles, and that causes blood

pressure to drop. These drugs are usually not used alone -- and, in
the case of Minoxidil (Loniten) -- used only in severe
hypertension. The vasodilators include
 Hydralazine (Apresoline) and

 minoxidil (Loniten).
What are common high blood pressure side effects?
Different classes of blood pressure medications have different

side effects.
Diuretics

 Diuretics can lead to an increase in potassium loss, known as
hypokalemia, which, in turn, can affect muscular function –
including the muscles of the heart.
 There is also an increased risk for gout with diuretics -- as well

as the possibility of weakness, thirst, dehydration, and
increased urination.
 Changes in blood sugar levels are also possible.
 Skin reactions, some severe, are possible with thiazide diuretics
(such as hydrochlorothiazide).
 Potassium-sparing diuretics, such as spironolactone (Aldactone)
may cause breast enlargement in males.
Beta-blockers
Beta-blockers cause the heart to slow down and so some of their

side effects can be traced to that mechanism of action.
18
 Dizziness, weakness, fatigue, and fainting are possible.
 Beta-blockers also affect the respiratory system, so other side
effects include shortness of breath, difficulty breathing, and
9.2. PERSPECTIVES
chest pain.
 Beta-blockers should not be withdrawn suddenly, as that could
result in a heart attack or sudden death.
ACE inhibitors
 The most common side effect from ACE Inhibitors is also an

unusual one -- a dry cough. Usually, it goes away with continued
use of the drug, but that could take weeks.
 ACE Inhibitors could reduce blood pressure too much, resulting
in hypotension which could, in turn, lead to headache, dizziness,
fainting, and reduced kidney function.
Angiotensin II receptor blockers
 The most common side effect from the angiotensin receptor

blockers (ARBs) is an increased potassium level in the blood,
known as hyperkalemia.
 Dizziness is also common, along with fatigue.
 Upper respiratory tract infections have also been reported --
along with gastrointestinal issues such as upset stomach and
diarrhea.
Calcium channel blockers
Up to a third of patients may experience the following side effects

with calcium channel blockers:
 Swelling of the ankles and other extremities,

 flushing, and
 dizziness.
 Other common side effects include heartburn and nausea.
19
Alpha-blockers
A common, transient, but distressing initial side effect of the

alpha-blockers is
 postural hypotension.
 This is a sudden drop in blood pressure when standing up.
 It can be severe enough to cause dizziness or even fainting.
 Also, alpha-blockers can result in increased heart rate,
headache, nausea, and weakness.
Methyldopa
Methyldopa is mostly well-tolerated, but some patients may

experience
 dizziness,
 drowsiness,
 weakness,
 headache, and dry mouth.
Central agonists
 Up to 40% of patients taking clonidine (Catapres) will

experience dry mouth and about a third will have drowsiness,
headache, and sleepiness.
 Other common side effects include constipation, dizziness, and
local skin reactions with the use of the Catapres-TTS skin patch.
 Reserpine use is linked with possible side effects including

nightmares, stuffy nose, depression, and an inability to fall
asleep. Diarrhea and heartburn are also possible.
 Guanadrel and guanethidine can cause diarrhea and other
gastrointestinal issues – as well as dizziness and drowsiness.
20
Vasodilators
9.2.
 PERSPECTIVES
Taking minoxidil might result in excessive body hair growth, as
well as weight gain and dizziness.
 Hydralazine is linked to headaches, heart palpitations, swelling
around the eyes, and aches and pains in the joints.
Is it safe to take high blood pressure medication during pregnancy?
Some high blood pressure medications should absolutely NOT be

used during pregnancy as they may harm the mother and
developing fetus. These medications include
 ACE inhibitors and

 angiotensin II receptor blockers.
 Reserpine may also be harmful during pregnancy and should
only be used when no other alternatives exist.
Safe medications to use include methyldopa and potentially some

diuretics and beta-blockers, including labetalol.
Is it safe to drink alcohol while taking high blood pressure

medications?
Some high blood pressure medications initially cause drowsiness,

dizziness, and lightheadedness. Some even cause fainting on the
first dose. The body usually adjusts to the effects of these
medications and the side effects disappear. Consuming alcohol
during the early phase of antihypertensive treatment could be
risky because alcohol can also cause
 dizziness,
 drowsiness, and
 lightheadedness.
21
Also, alcohol consumption causes a transient rise in blood

pressure that could persist if the drinking is beyond the level of
"moderation."
Does high blood pressure lead to weight gain?
Some high blood pressure medications can, in fact, lead to weight

gain. Common offenders include older beta-blockers such as
propranolol (Inderal) and Atenolol (Tenormin). There could be
several reasons for this -- including the fact that the medications
can make patients feel tired and thus less likely to exercise.
 Minoxidil tablets (Loniten) -- used only when other

antihypertensive medications have failed -- can also cause
weight gain.
 Weight gain is also listed as a common side effect of doxazosin
(Cardura). Diuretics are more likely to cause weight loss.
22
‘
23
2 BLOOD AND ITS COMPOSITION
Our blood is a fluid that is also a type of connective tissue. It is

composed of blood cells and an aqueous fluid known as plasma.
Two major functions of the blood include transporting substances
to and from our cells and providing immunity and protection
against infectious agents such as bacteria and viruses. Blood is a
component of the cardiovascular system. It is circulated through
the body via the heart and blood vessels.
Blood Components
Blood consists of several elements. The major components of

blood include plasma, red blood cells, white blood cells, and
platelets.
 Plasma: This major constituent of blood comprises about

55 percent of blood volume. It consists of water with
several different substances dissolved within. Plasma
contains salts, proteins, and blood cells. Plasma also
transports nutrients, sugars, fats, hormones, gases, and
waste material contained within blood.
 Red Blood Cells (erythrocytes): These cells determine
blood type and are the most abundant cell type in the
blood. Red blood cells have what is known as a biconcave
shape. Both sides of the cell's surface curve inward like the
interior of a sphere. This flexible disc shape helps to
24
increase the surface area-to-volume ratio of these
extremely small cells. Red blood cells do not have
9.2. PERSPECTIVES
a nucleus, but they do contain millions of hemoglobin
molecules. These iron-containing proteins bind oxygen
molecules obtained in the lungs and transport them to
various parts of the body. After depositing oxygen to tissue
and organ cells, red blood cells pick up carbon dioxide
(CO2) for transportation to the lungs where the CO2 is
expelled from the body.
 White Blood Cells (leukocytes): These cells play an

important role in the immune system and lymphatic
system by defending the body against infection. These
cells locate, destroy, and remove pathogens and foreign
matter from the body. There are several different types of
white blood cells, each with different functions. Examples
include lymphocytes, monocytes, neutrophils, basophils,
and eosinophils.
 Platelets (thrombocytes): These cell components are
formed from pieces of cells found in the bone marrow
called megakaryocytes. Fragments of the megakaryocytes
circulate through the bloodstream and play a major role in
clotting. When platelets encounter an injured blood vessel,
they clump together to block the opening in the vessel.
Blood Cell Production

Blood cells are produced by bone marrow within the bone. Bone
marrow stem cells develop into red blood cells, white blood cells,
and platelets. Certain white blood cells mature in the lymph
nodes, spleen, and thymus gland. Matured blood cells have
varying life spans. Red blood cells circulate for about 4 months,
platelets for about 9 days, and white blood cells range from about
a few hours to several days. Blood cell production is often
regulated by body structures such as the lymph nodes,
25
spleen, liver, and kidneys. When oxygen in tissues is low, the body

responds by stimulating the bone marrow to produce more red
blood cells. When the body is infected, more white blood cells are
produced.
Blood Pressure
0Blood pressure is the force at which blood exerts pressure
against artery walls as it circulates throughout the body. Blood
pressure readings measure systolic and diastolic pressures as the
heart goes through the cardiac cycle. In the systole phase of the
cardiac cycle, the heart ventricles contract (beat) and pump blood
into the arteries. In the diastole phase, the ventricles are relaxed
and the heart fills with blood. Blood pressure readings are
measured in millimeters of mercury (mmHg) with the systolic
number reported before the diastolic number.
Blood pressure is not constant and can fluctuate depending on
various conditions. Nervousness, excitement, and increased
activity are a few things that can influence blood pressure. Blood
pressure levels also increase as we get older. Abnormally high
blood pressure, known as hypertension, can have serious
consequences as it can lead to hardening of the arteries, kidney
damage, and heart failure. Persons with elevated blood pressure
often experience no symptoms.
Elevated blood pressure that persists for the majority of the time
can lead to increased risk for health issues.
Blood Type
Blood type describes how blood is classified. It is determined by

the existence or lack thereof of certain identifiers (called antigens)
located on red blood cells. Antigens help the body's immune
system to identify its own red blood cell group. This identification
is crucial so that the body will not build up antibodies against its
own red blood cells. The four blood type groupings are A, B, AB,
and O. Type A has A antigens on red blood cell surfaces, type B
has B antigens, type AB has both A and B antigens and type O has
no A or B antigens. Blood types must be compatible when
26
considering blood transfusions. Those with type A must receive
blood from either type A or type O donors. Those with type B
9.2. either
from PERSPECTIVES
type B or type O. Those with type O can receive blood
from only type O donors and type AB may receive blood from any
of the four blood type groups.
Sources
 Dean L. Blood Groups and Red Cell Antigens [Internet]. Bethesda (MD): National Center for
Biotechnology Information (US); 2005. Chapter 1, Blood and the cells it contains. Available from:
(http://www.ncbi.nlm.nih.gov/books/NBK2263/)
 What Is High Blood Pressure? National Heart, Lung, and Blood Institute. Updated 08/02/12
(http://www.nhlbi.nih.gov/health/health-topics/topics/hbp/)
©
2014 WebMD, LLC. All rights reserved.
Blood is a constantly circulating fluid providing the body with

nutrition, oxygen, and waste removal. Blood is mostly liquid, with
numerous cells and proteins suspended in it, making blood "thicker"
than pure water. The average person has about 5 liters (more than a
gallon) of blood.
27
A liquid called plasma makes up about half of the content of blood.

Plasma contains proteins that help blood to clot, transport
substances through the blood, and perform other functions. Blood
plasma also contains glucose and other dissolved nutrients.
About half of blood volume is composed of blood cells:
• Red blood cells, which carry oxygen to the tissues

• White blood cells, which fight infections
• Platelets, smaller cells that help blood to clot
Blood is conducted through blood vessels (arteries and veins). Blood
is prevented from clotting in the blood vessels by their smoothness,
and the finely tuned balance of clotting factors.
Blood Tests
 Complete blood count: An analysis of the concentration of

red blood cells, white blood cells, and platelets in the blood.
Automated cell counters perform this test.
 Blood smear: Drops of blood are smeared across a

microscope slide, to be examined by an expert in a lab.
Leukemia, anemia, malaria, and numerous other blood
conditions can be identified with a blood smear.
 Blood type: A test for compatibility before receiving a blood
transfusion. The major blood types (A, B, AB, and O) are
determined by the protein markers (antigens) present on the
surface of red blood cells.
 Coombs test A blood test looking for antibodies that could
bind to and destroy red blood cells. Pregnant women and
 people with anemia may undergo Coombs testing.
28
 Blood culture: A blood test looking for infection present in
the bloodstream. If bacteria or other organisms are present,
9.2. PERSPECTIVES
they may multiply in the tested blood, allowing their
identification.
 Mixing study: A blood test to identify the reason for blood
being "too thin" (abnormally resistant to clotting). The
patient's blood is mixed in a tube with normal blood, and the
mixed blood's properties may provide a diagnosis.
 Bone marrow biopsy: A thick needle is inserted into a large
bone (usually in the hip), and bone marrow is drawn out for
tests. Bone marrow biopsy can identify blood conditions that
simple blood tests cannot.
Blood Treatments
 Chemotherapy: Medicines that kill cancer cells. Leukemias

and lymphomas are usually treated with chemotherapy.
 Blood transfusion: A blood donor's red blood cells are
separated from their plasma and packed into a small bag.
Transfusing the concentrated red blood cells into a recipient
replaces blood loss.
 Platelet transfusion: A blood donor's platelets are separated
from the rest of blood and concentrated into a plastic bag.
Platelet transfusion is generally only performed when
platelet counts fall to very low levels.
 Fresh frozen plasma: A blood donor's plasma (liquid blood) is
separated from the blood cells, and frozen for storage.
Plasma transfusion can improve blood clotting and prevent
or stop bleeding that's due to clotting problems.
 Cryoprecipitate: Specific proteins are separated from blood
and frozen in a small volume of liquid. Cryoprecipitate
transfusion can replace specific blood clotting proteins when
their levels are low, such as in people with hemophilia.
 Anticoagulation: Medicines to "thin" the blood and prevent
clotting in people at high risk from blood clots. Heparin,
29
enoxaparin (Lovenox) and warfarin (Coumadin) are the

medicines most often used.
 Antiplatelet drugs: Aspirin and clopidogrel (Plavix) interfere
with platelet function and help prevent blood clots, including
those that cause heart attacks and strokes.
 Antibiotics: Medicines to kill bacteria and parasites can treat
blood infections caused by these organisms.
 Erythropoietin: A hormone produced by the kidney that
stimulates red blood cell production. A manufactured form
of erythropoietin can be given to improve the symptoms of
anemia.
 Bloodletting: In people with problems caused by too much
blood (such as from hemochromatosis or polycythemia),
occasional controlled removal of blood may be necessary.
Blood is one of the most important components of life. Almost

any animal that possesses a circulatory system has blood. From an
evolutionary perspective, blood was speculated to have risen
from a type of cell that was responsible for phagocytosis and
nutrition. Billions of years later, blood and the circulatory system
have drastically helped the evolution of more complex lifeforms.
Types of Blood Cells

We have seen blood consist of cells known as formed elements of
blood. These cells have their own functions and roles to play in
the body. The blood cells which circulate all around the body are
as follows:
Red blood cells (Erythrocytes)
RBCs are biconcave cells and without nucleus in humans; also

known as erythrocytes. RBCs contain the iron-rich protein called
haemoglobin; give blood its red colour. RBCs are the most
copious blood cells produced in bone marrows. Their main
function is to transport oxygen from and to various tissues and
organs.
30
White blood cells (Leucocytes)
Leucocytes are colourless blood cells. They are colourless because

9.2. PERSPECTIVES
it is devoid of haemoglobin. They are further classified as
granulocytes and agranulocytes. WBCs mainly contribute to
immunity and defence mechanism.
Courtesy BYJUS
Red Blood Cells are red due to Hemoglobin, which is a transport
molecule and also a pigment. As a result, blood is red.
Types of White Blood Cells

There are five different types of White blood cells and are
classified mainly based on the presence and absence of granules.
 Granulocytes
 Agranulocytes
31
There are five types of white blood cells present in the blood
Granulocytes
They are leukocytes, with the presence of granules in their

cytoplasm. The granulated cells include- eosinophil, basophil, and
neutrophil.
Eosinophils
 They are the cells of leukocytes, which are present in the

immune system.
 These cells are responsible for combating infections in
parasites of vertebrates and for controlling mechanisms
associated with allergy and asthma.
 Eosinophil cells are small granulocyte, which are produced
in the bone marrow and makes 2 to 3 per cent of whole
WBCs. These cells are present in high concentrations in the
digestive tract.
32
Basophils
They are the least common of the granulocytes, ranging

 PERSPECTIVES
9.2.
from 0.5 to 1 per cent of WBCs.
 They contain large cytoplasmic granules, which plays a
vital role in mounting a non-specific immune response to
pathogens, allergic reactions by releasing histamine and
dilates the blood vessels.
 These white blood cells have the ability to be stained when
exposed to basic dyes, hence referred to as basophil.
 These cells are best known for their role in asthma and
their result in inflammation and bronchoconstriction in the
airways.
 They secrete serotonin, histamine and heparin.
Neutrophils
 They are normally found in the bloodstream.

 They are predominant cells, which are present in pus.
 Around 60 to 65 per cent of WBCs are neutrophils with a
diameter of 10 to 12 micrometres.
 The nucleus is 2 to 5 lobed and cytoplasm has very fine
granules.
 Neutrophil helps in the destruction of bacteria with
lysosomes, and it acts as a strong oxidant.
 Neutrophils are stained only using neutral dyes. Hence,
they are called so.
 Neutrophils are also the first cells of the immune system
to respond to an invader such as a bacteria or a virus.
 The lifespan of these WBCs extend for up to eight hours
and are produced every day in the bone marrow.
Agranulocytes
They are leukocytes, with the absence of granules in their

cytoplasm. Agranulocytes are further classified into monocytes
and lymphocytes.
33
Monocytes
 These cells usually have a large bilobed nucleus, with a

diameter of 12 to 20 micrometres.
 The nucleus is generally of half-moon shaped or kidney-
shaped and it occupies 6 to 8 per cent of WBCs.
 They are the garbage trucks of the immune system.
 The most important functions of monocytes are to migrate
into tissues and clean up dead cells, protect against the
bloodborne pathogens and they move very quickly to the
sites of infections in the tissues.
 These white blood cells have a single bean-shaped
nucleus, hence referred to as Monocytes.
Lymphocytes
 They play a vital role in producing antibodies.

 Their size ranges from 8 to 10 micrometres.
 They are commonly known as natural killer cells.
 They play an important role in body defence.
 These white blood cells are colourless cells formed in
lymphoid tissue, hence referred to as lymphocytes.
 There are two main types of lymphocytes – B lymphocytes
and T lymphocytes.
 These cells are very important in the immune systems and
are responsible for humoral and cell-mediated immunity.
Platelets (Thrombocytes)
 Thrombocytes are specialized blood cells produced from

bone marrow.
 Platelets come into play when there is bleeding or
haemorrhage.
 They help in clotting and coagulation of blood. Platelets
help in coagulation during a cut or wound.
34
9.2. PERSPECTIVES
Composition of Blood: Plasma, RBCs, WBCs and platelets
Components Of Blood
There are many cellular structures in the composition of blood.
When a sample of blood is spun in a centrifuge machine, they
separate into the following constituents: Plasma, buffy coat and
erythrocytes.
35
Plasma
The liquid state of blood can be contributed to plasma as it makes

up ~55% of blood. It is pale yellow in colour and when separated,
it consists of salts, nutrients, water and enzymes. Blood plasma
also contains important proteins and other components necessary
for overall health. Hence, blood plasma transfusions are given to
patients with liver failure and life-threatening injuries.
Red Blood Cells (RBC)
Red blood cells consist of Haemoglobin, a protein. They are

produced by the bone marrow to primarily carry oxygen to the
body and carbon dioxide away from it.
36
White Blood Cells (WBC)
White blood cells are responsible for fighting foreign pathogens

9.2. PERSPECTIVES
(such as bacteria, viruses, fungi) that enter our body. They
circulate throughout our body and originate from the bone
marrow.
Platelets
Tiny disc-shaped cells that help regulate blood flow when any part
of the body is damaged, thereby aiding in fast recovery through
clotting of blood.
The above-stated elements form the composition of blood in
humans. The only vertebrate without haemoglobin is
the crocodile icefish. It derives its oxygen requirement directly
from the cold, oxygen-rich water where it lives.
Blood Vessels
There are different types of blood vessels in our body each
carrying out specialized functions.
Blood vessels are categorized into arteries, veins and capillaries
37
Types of Blood Vessels
Three types of blood vessels are:

 Arteries
 Veins
 Capillaries
Arteries
Arteries are strong tubes and muscular in nature. These blood

vessels carry oxygen-rich blood from the heart to all the tissues of
the body. Aorta is one of the main arteries that arise from the
heart and branches further.
Veins
Veins are elastic blood vessels which carry deoxygenated blood

from all parts of the body to the heart. An exception is the
umbilical and pulmonary veins. The Pulmonary vein carries
oxygenated blood to the heart from the lungs and umbilical vein
carries oxygenated blood from the placenta to the foetus.
Capillaries
On reaching tissues, arteries branch further into extremely thin

tubes called capillaries. Capillaries bring about the exchange of
substances between blood and tissues.
Sinusoids
Sinusoids are a special type of wider capillaries present in bone

marrow, liver, lymph nodes, spleen and some endocrine glands.
They may be continuous, discontinuous or fenestrated.
Layers of Blood Vessels
Both arteries and veins consist of three layers.
38
 Tunica Intima: It is one of the innermost and thinnest
layers of arteries and veins. It comprises endothelial cells.
9.2. PERSPECTIVES
They are in direct contact with the flow of blood.
 Tunica Media: It is the middle layer of an artery or vein.
Tunica media is made up of smooth muscle cells.
 Tunica Externa: It surrounds tunica media. It is made up of
collagen and also supported by the elastic lamina in
arteries.
Functions of Blood
Blood is responsible for the following body functions:
Fluid Connective Tissue
Blood is a fluid connective tissue composed of 55% plasma and

45% formed elements including WBCs, RBCs, and platelets. Since
these living cells are suspended in plasma, blood is known as a
fluid connective tissue and not just fluid.
Provides oxygen to the cells
Blood absorbs oxygen from the lungs and transports it to different

cells of the body. The waste carbon dioxide moves from the blood
to the lungs and exhaled.
Transports Hormone and Nutrients
The digested nutrients such as glucose, vitamins, minerals, and

proteins are absorbed into the blood through the capillaries in the
villi lining the small intestine.
The hormones secreted by the endocrine glands are also
transported by the blood to different organs and tissues.
39
Homeostasis
Blood helps to maintain the internal body temperature by

absorbing or releasing heat.
Blood Clotting at Site of Injury
The platelets help in the clotting of blood at the site of injury.

Platelets along with the fibrin form clot at the wound site
Transport of waste to the Kidney and Liver
Blood enters the kidney where it is filtered to remove nitrogenous

waste out of the blood plasma. The toxins from the blood are also
removed by the liver.
Protection of body against pathogens
The White Blood Cells fight against infections. They multiply

rapidly during the infections.Composition, Functions, Transfusion
and Blood Group
Blood is a red colour pigment that circulates in the body. It

contains plasma, red blood cells, white blood cells, and platelets.
It performs various functions in the body. Let us study in detail
about the composition and function of blood, its components,
blood transfusion, blood pressure, and blood group.
40
9.2. PERSPECTIVES
Composition and Functions of Blood
Blood is a connective tissue that helps in the transportation of

substances, protects against diseases and regulates the
temperature of the body. Do you know why the colour of blood is
red?
It is red in colour due to a red pigment
called haemoglobin present in its red cells. The components of
Blood are Plasma, Red blood corpuscles (Red blood cells or RBCs),
White blood corpuscles (White blood cells or WBCs) and platelets.
First, we will study about Plasma.
Plasma is a liquid also known as the fluid matrix and consists of
three types of cells that keep floating in it namely red blood cells,
white blood cells, and platelets.Ads by Jagran.TV
41
Functions of Blood
Blood has three main functions in the human body i.e Transport
of substances from one part of the body to the other like
respiratory gases, waste products, enzymes, etc, protection
against diseases and regulation of body temperature.
 Blood regulates body temperature.

 It carries oxygen from lungs to different parts of the body.
 It carries carbon dioxide from the body cells to the lungs for
breathing out.
 It carries digested food from the small intestine to all parts of the
body.
 It carries hormones from the endocrine glands to different organs
of the body.
 It carries waste product urea from the liver to the kidneys for
excretion.
 Defends against infection.
On average, a healthy man has about 5 litres of blood in the body,
while a woman has about 500 ml less than man. So, total blood is
about 60-80 ml/kg of body weight.
Plasma
The fluid or liquid part of blood is called plasma. It is a colourless
liquid that contains 90% water, protein, and inorganic salts.
Plasma also contains some traces of other substances like amino
acids, organic acids, vitamins, pigments and enzymes. It carries
these dissolved substances from one part to another part in the
42
body. The protein in plasma includes antibodies to assist in the
body’s defence system against disease and infection.
9.2. PERSPECTIVES
Red Blood Corpuscles (RBC)
RBC is also known as erythrocytes. They are disc-shaped cells
concave in the middle and visible under a microscope. RBC carries
oxygen from the lungs to all the cells of the body. They have no
nucleus and contain a pigment called haemoglobin which is made
up of an iron-containing pigment known as haema and a protein
called globin. RBCs are produced in the spleen and the bone
marrow and live for about four months because they lack a
nucleus. So, when we donate blood to save the life of a person,
then the loss of blood from our body is recovered within a day
because red blood cells are made very fast in the bone marrow.
The life of the RBC is about 100-120 days.
Functions
 Haemoglobin in RBC picks up oxygen in the lung tissues by
forming a chemical compound with it.
 This oxygen is carried to the tissues where it is used in the
chemical reactions to produce energy.
 It then combines with carbon dioxide which is produced in these
reactions and returns to the lungs with the heart where the cycle
starts again.
What is Bombay Blood Group and how it is discovered?
White Blood Corpuscles (WBC)
WBC is also known as leukocytes. They fight with infection and
protect us from diseases because they eat up the germs which
cause diseases. That is why they are also known as ‘soldiers’ of
43
the body’s defence system. They are round or irregular, semi-

transparent cells containing a nucleus and visible under a
microscope. They are a little larger than RBC. Some White blood
cells make chemicals called ‘antibodies’ to fight against infection
i.e why they provide immunity in our body. WBC in the blood is
much smaller in number than red blood cells.
Functions
 Broadly, WBC acts as a defence system in the body.
 There are several varieties of WBC performing specific functions
such as, Neutrophils (65 to 70% of the total WBC) attack the
invading bacteria and engulf them. Lymphocytes (25% of WBC)
produces antibodies which protect the body against the antigen
and thus provide immunity against infection. Basophils secrete
anticoagulant called heparin which prevents clot within the blood
cells. Eosinophils and monocytes also assist in the defence
mechanism of the body by becoming active against specific
antigens.
Blood platelets
Blood Platelets are also known as thrombocytes. They are tiny,
circular or oval colourless cells formed in the bone marrow. They
lack a nucleus and help in the coagulation of blood (clotting of
blood) in a cut or wound, due to which bleeding stops. All the
blood cells are made in the bone marrow from the cells called
stem cells.
Blood clotting is a body’s defence system to combat bleeding.
Plasma contains soluble protein fibrinogen of the blood which
44
produces the insoluble protein called fibrin essential for blood
coagulation which is formed in the liver.
9.2. PERSPECTIVES
Process of clotting
In an injury blood platelets break down and release an enzyme
which helps in the formation of fibrin from fibrinogen. This fibrin
forms clot in the form of a mass of fibres which stops bleeding
from blood vessels. After clotting, a straw-coloured fluid called
serum is left.
Blood Grouping
In 1900-1902, K. Landsteiner classified human blood into four
groups A, B, AB and O. The cells of these group contains
corresponding antigens – A, B and AB except O. That is why O is
donated to any of the groups and so is known as Universal
donor. AB group is known as Universal recipient because it can
receive A, B, AB, and O blood groups.
Blood Group Can donate Can receive
blood to blood from
A A, AB A and O
B B, AB B and O
AB Only AB AB, A, B, and O
O AB, A, B, and O Only O
Rh factor
It is a blood antigen discovered in 1940 by Landsteiner and A.S
Weiner and played an important role during a blood transfusion.
The Rh factor is an agglutinogen found in RBC of most people
called Rh+. It was initially found in the rhesus monkey and later in
man. People who do not have this antigen in their blood are called
Rh-. The Rh- blood does not carry anti- Rh antibodies naturally but
45
could synthesize them if synthesized through blood transfusion of

Rh+ blood. If Rh+ blood is transfused into an Rh- patient, the
serum will produce anti-Rh agglutinin. If another dose of Rh+
blood is given, the anti-Rh agglutinin will cause clumping of RBC of
the donor’s blood as soon as it enters the patient receiving it.
Erythroblastosis Foetalis: If the father's blood is Rh+ and the

mother's blood is Rh- then the child to be born dies at the
pregnancy or short span of time after birth. Basically, this happens
in the case of the second issue.
Blood Transfusion
This technique was first developed by James Blundell in 1825. The
injection of blood from one person (donor) into the circulatory
system of another is called a blood transfusion. It is done after the
proper matching of blood groups and the Rh factor.
What is Blood Pressure and how it is measured?

Blood Pressure
Blood Pressure is the force exerted by the blood beating against
artery walls. The highest point in the pressure range is called
systolic pressure (upper reading) and the lowest point is called
diastolic pressure (lower reading). It is measured by an instrument
called a sphygmomanometer. The diastolic pressure is always
lower than the systolic pressure. The average systolic pressure of
a healthy young man is about 120 mm Hg and the diastolic
pressure is about 80 mm Hg that is, 120/80 is the normal blood
pressure. High blood pressure is known as hypertension and low
blood pressure is known as hypotension.
46
Transport in Humans
‘Circulatory system’ or ‘Blood circulatory system’ is the main
9.2. PERSPECTIVES
transport system in human beings. In this blood carries oxygen,
digested food and other chemicals like hormones and enzymes to
all parts of the body and take away waste products like carbon
dioxide and urea. Therefore, the human blood circulatory system
consists of the heart which pumps and receives blood and the
blood vessels through which blood flows in the body.
In the circulatory system, blood flows through three types of

blood vessels: Arteries, veins, and capillaries. The blood vessels
are present in all parts of the human body so, that blood reaches
everywhere in the body.
There is another system with the blood circulatory system for

transport in human beings is the Lymphatic System. Lymph is the
liquid that circulates and carries materials in the lymphatic
system. Thus, we can conclude that in Human beings, the various
substances are transported through two liquids called ‘blood ‘and
‘lymph’.
Haemolymph: Body fluid of Arthropoda is a colourless made of
plasma and haemocytes. It do not contain any respiratory
pigment like a cockroach.
47
How does blood work, and what problems can occur?
Structure
Functions
Blood groups
Disorders
Summary
Blood is a combination of plasma and cells that circulate through
the body. It supplies essential substances, such as sugars, oxygen,
and hormones, to cells and organs, and removes waste from cells.
Hematologists work to identify and prevent blood and bone

marrow diseases. They also study and treat the immune system,
blood clotting, and blood vessels.
Health conditions that affect the blood can be life threatening, but
effective treatment is often available. In the United States, blood
diseases accounted for 1066 deaths in 2008, mostly different
types of anemia.
48
Structure
9.2. PERSPECTIVES
Shar
e on PinterestMicro Discovery/Getty Images
The main components of blood are:
 plasma
 red blood cells
 white blood cells
 platelets
49
Plasma
Plasma accounts for around 55% of blood fluid in humans. Plasma

is 92% water, and the contents of the remaining 8% include:
 glucose
 hormones
 proteins
 mineral salts
 fats
 vitamins
The remaining 45% of blood mainly consists of red and white

blood cells and platelets. Each of these has a vital role to play in
keeping the blood functioning effectively.
Red blood cells, or erythrocytes
Red blood cells have a slightly indented, flattened disk shape.

They transport oxygen to and from the lungs. Hemoglobin is a
protein that contains iron and carries oxygen to its destination.
The life span of a red blood cell is 4 months, and the body
replaces them regularly. The human body produces around 2
million blood cells every second.
50
The expected number of red blood cells in a single drop
9.2. PERSPECTIVES
(microliter) of blood is 4.5–6.2 million in males and 4.0–5.2 million

in females.
What percentage of red blood cells should people have in their

body?
White blood cells, or leukocytes
White blood cells make up less than 1% of blood content, forming

vital defenses against disease and infection. The number of white
blood cells in a microliter of blood usually ranges from 3,700–
10,500. Higher or lower levels of white blood cells can indicate
disease.
What does it mean if a person has a high white blood cell count?
Platelets, or thrombocytes
Platelets interact with clotting proteins to prevent or stop

bleeding. There should be between 150,000 and 400,000 platelets
per microliter of blood.
51
Bone marrow produces red blood cells, white blood cells, and
platelets, and from there they enter the bloodstream. Plasma is
mostly water that is absorbed from ingested food and fluid by the
intestines. The heart pumps them around the body as blood by
way of the blood vessels.
What does it mean if a person has high or low platelet levels?
Functions
Blood has various functions that are central to survival. They

include:
 supplying oxygen to cells and tissues
 providing essential nutrients to cells, such as amino acids,

fatty acids, and glucose
 removing waste materials, such as carbon dioxide, urea,

and lactic acid
 protecting the body from diseases, infections, and foreign

bodies through the action of white blood cells
 regulating body temperature
The platelets in blood enable the clotting, or coagulation, of

blood. When bleeding occurs, the platelets group together to
create a clot. The clot forms a scab, which stops the bleeding and
52
helps protect the wound from infection.
9.2. PERSPECTIVES
Blood groups
A person’s blood type is determined by the antigens on the red

blood cells. Antigens are protein molecules on the surface of
these cells.
Antibodies are proteins in plasma that alert the immune system

to the presence of potentially harmful foreign substances. The
immune system protects the body from the threat of disease or
infection.
Knowing a person’s blood type is essential if they are receiving an

organ donation or blood transfusion. Antibodies will attack new
blood cells if the blood is the wrong type, leading to life
threatening complications. For example, anti-A antibodies will
attack cells that have A antigens.
Red blood cells sometimes contain another antigen called RhD.

Doctors also note this as part of the blood group. A positive blood
group means that RhD is present.
Humans can have one of four main blood groups. Each of these
groups can be Rhd-positive or -negative, forming eight main
categories.
53
 Group A positive or A negative: A antigens are present on

the surfaces of blood cells. Anti-B antibodies are present in
the plasma.
 Group B positive or B negative: B antigens are present on

the surfaces of blood cells. Anti-A antibodies are present in
the plasma.
 Group AB positive or AB negative: A and B antigens are

present on the surfaces of blood cells. There are no
antibodies in the plasma.
 Group O positive and O negative: There are no antigens

on the surfaces of blood cells. Both anti-B and anti-A
antibodies are present in the plasma.
People with group O blood can donate to virtually any blood type,
and people with group AB+ blood can usually receive blood from
any group.
People can talk with their doctor to find out their blood type or
find out by donating blood.
Blood groups are important during pregnancy. If a pregnant

person has RhD-negative blood, for example, but the fetus
inherits RhD-positive blood, treatment will be necessary
to prevent a condition known as hemolytic disease of the
newborn.
54
Learn more about blood types in general and rare blood types.
9.2. PERSPECTIVES
55
56
9.2. PERSPECTIVES
3 BLOOD RELATED DISEASES: THROMBOSIS
Blood Conditions
 Hemorrhage (bleeding): Blood leaking out of blood vessels

may be obvious, as from a wound penetrating the skin.
Internal bleeding (such as into the intestines, or after a car
accident) may not be immediately apparent.
 Hematoma: A collection of blood inside the body tissues.
Internal bleeding often causes a hematoma.
 Leukemia: A form of blood cancer, in which white blood cells
multiply abnormally and circulate through the blood. The
abnormal white blood cells make getting sick from infections
easier than normal.
 Multiple myeloma: A form of blood cancer of plasma cells
similar to leukemia. Anemia, kidney failure and high blood
calcium levels are common in multiple myeloma.
 Lymphoma: A form of blood cancer, in which white blood
cells multiply abnormally inside lymph nodes and other
tissues. The enlarging tissues, and disruption of blood's
functions, can eventually cause organ failure.
 Anemia: An abnormally low number of red blood cells in the
blood. Fatigue and breathlessness can result, although
anemia often causes no noticeable symptoms.
 Hemolytic anemia: Anemia caused by rapid bursting of large
numbers of red blood cells (hemolysis). An immune system
malfunction is one cause.
57
 Hemochromatosis: A disorder causing excessive levels of iron

in the blood. The iron deposits in the liver, pancreas and
other organs, causing liver problems and diabetes.
 Sickle cell disease: A genetic condition in which red blood
cells periodically lose their proper shape (appearing like
sickles, rather than discs). The deformed blood cells deposit
in tissues, causing pain and organ damage.
 Bacteremia: Bacterial infection of the blood. Blood infections
are serious, and often require hospitalization and continuous
antibiotic infusion into the veins.
 Malaria: Infection of red blood cells by Plasmodium, a
parasite transmitted by mosquitoes. Malaria causes episodic
fevers, chills, and potentially organ damage.
 Thrombocytopenia: Abnormally low numbers of platelets in
the blood. Severe thrombocytopenia may lead to bleeding.
 Leukopenia: Abnormally low numbers of white blood cells in
the blood. Leukopenia can result in difficulty fighting
infections.
 Disseminated intravascular coagulation (DIC): An
uncontrolled process of simultaneous bleeding and clotting
in very small blood vessels. DIC usually results from severe
infections or cancer.
 Hemophilia: An inherited (genetic) deficiency of certain
blood clotting proteins. Frequent or uncontrolled bleeding
can result from hemophilia.
 Hypercoaguable state: Numerous conditions can result in the
blood being prone to clotting. A heart attack, stroke, or
blood clots in the legs or lungs can result.
 Polycythemia: Abnormally high numbers of red blood cells in
the blood. Polycythemia can result from low blood oxygen
levels, or may occur as a cancer-like condition.
 Deep venous thrombosis (DVT): A blood clot in a deep vein,
usually in the leg. DVTs are dangerous because they may
become dislodged and travel to the lungs, causing a
pulmonary embolism (PE).
58
 Myocardial infarction (MI): Commonly called a heart attack, a
myocardial infarction occurs when a sudden blood clot
9.2. PERSPECTIVES
 develops in one of the coronary arteries, which supply blood

to the heart.
What Is Thrombosis?
Right now, as you're sitting there reading this screen, blood is
flowing throughout your body. Your veins carry this blood towards
your heart to keep you alive. When something clogs them up,
things can get pretty dangerous.
Thrombosis is the term used for the development of blood clots
within deep veins in your body. It often occurs in the legs and,
more specifically, is called deep vein thrombosis (DVT). It is most
often caused by blood clotting disorders, but it can also happen if
you stay sedentary for too long. Blood clots are dangerous
because they can break apart, travel throughout the body, and
cause blockages in the heart, brain, or lungs (leading to heart
attack, stroke, or pulmonary embolism, respectively).
Causes of Thrombosis
59
Thrombosis is caused by blood clots forming in deep veins, most

often in the legs. Blood clots can form whenever there is any
condition that prevents blood from circulating or clotting
normally. For example, they can happen to people who tend to
lack physical movement after an accident, injury, surgery, or
during bed rest.
Symptoms of Thrombosis
The two main symptoms of thrombosis are pain and swelling. The
pain in the affected area (usually the leg) begins like a cramp and
may intensify. Swelling occurs in the vicinity of the blood clot. In
rare cases, there may be no symptoms at all.
The most serious symptoms may result from the formation of
a pulmonary embolism, when arteries in the lungs become
blocked by a blood clot. This can include sudden difficulty
breathing, chest pain that gradually intensifies or gets worse
when breathing in, dizziness, lightheadedness, increased heart
rate, and coughing up blood. All symptoms require physician
attention, but a pulmonary embolism requires immediate medical
attention.
Risk Factors
There are certain variables that increase the probability of
developing thrombosis. These include:
 Inheriting a genetic blood-clotting disorder that causes the

blood to clot more easily than normal
 Extended periods of bed rest that prevent blood from
circulating through the legs properly
 Injury or surgery
 Pregnancy and being overweight or obese, conditions
which cause an increase in pressure in the lower body
 Birth control pills or hormone therapy
60
 Smoking
 Cancer
9.2. PERSPECTIVES
 Heart failure
 Inflammatory bowel disease
 Age
 Sitting for extended periods of time (like flying or driving)
This list is not exhaustive but provides many of the commonly

reported problems that often lead to thrombosis.
What is thrombosis?
Thrombosis occurs when blood clots block your blood vessels.

There are 2 main types of thrombosis:
 Venous thrombosis is when the blood clot blocks a vein.

Veins carry blood from the body back into the heart.
 Arterial thrombosis is when the blood clot blocks an
artery. Arteries carry oxygen-rich blood away from the
heart to the body.
What causes thrombosis?
Venous thrombosismay be caused by:
 Disease or injury to the leg veins

 Not being able to move around (immobility) for any reason
 A broken bone (fracture)
 Certain medicines
 Obesity
61
 Inherited disorders, or a greater likelihood of having a

certain disorder based on your genes
 Autoimmune disorders that make it more likely your blood
will clot
 Medicines that increase your risk of clotting (such as
certain birth control medicines)
Arterial thrombosismay be caused by a hardening of the arteries,

called arteriosclerosis. This happens when fatty or calcium
deposits cause artery walls to thicken. This can lead to a buildup
of fatty material (called plaque) in the artery walls. This plaque
can suddenly burst (rupture), followed by a blood clot.
Arterial thrombosis can occur in the arteries that supply blood to

the heart muscle (coronary arteries). This can lead to a heart
attack. When arterial thrombosis occurs in a blood vessel in the
brain, it can lead to a stroke.
What are the risk factors for thrombosis?
Many of the risk factors for venous and arterial thrombosis are
the same.
Risk factors for venous thrombosis may include:
 A family history of a blood clot in a vein deep in the body,

called a deep vein thrombosis (DVT)
 A history of DVT
 Hormone therapy or birth control pills
 Pregnancy
 Injury to a vein, such as from surgery, a broken bone, or
other trauma
 Lack of movement, such as after surgery or on a long trip
 Inherited blood clotting disorders
 A central venous catheter
 Older age
 Smoking
62
 Being overweight or obese
 Some health conditions, such as cancer, heart disease,
9.2. PERSPECTIVES
 lung disease, or Crohn's disease
Risk factors for arterial thrombosis may include:
 Smoking
 Diabetes
 High blood pressure
 High cholesterol
 Lack of activity and obesity
 Poor diet
 Family history of arterial thrombosis
 Lack of movement, such as after surgery or on a long trip
 Older age
What are the symptoms of thrombosis?
Each person’s symptoms may vary. Symptoms may include:
 Pain in one leg (usually the calf or inner thigh)

 Swelling in the leg or arm
 Chest pain
 Numbness or weakness on one side of the body
 Sudden change in your mental state
The symptoms of thrombosis may look like other blood disorders

or health problems. Always see your healthcare provider for a
diagnosis.
How is thrombosis diagnosed?
Your healthcare provider will take your medical history and give
you a physical exam. Other tests may include:
63
 Ultrasound. This test uses sound waves to check the blood

flow in your arteries and veins.
 Blood tests. These may include tests to see how well your
blood can clot.
 Venography. For this test, a dye is injected into your veins.
Then X-rays are taken to show blood flow and look for
clots. The dye makes your veins easier to see on the X-
rays.
 MRI, MRA or CT. The imaging procedure that is used will
depend on the type of blood clot you have and where it is
located.
How is thrombosis treated?
Your healthcare provider will create a treatment plan for you

based on:
 Your age, overall health, and medical history

 How sick you are
 How well you handle certain medicines, treatments, or
therapies
 If your condition is expected to get worse
 What you would like to do
Treatment may include:
 Blood-thinning medicines (anticoagulants)

 Thin tubes (catheters) to widen the affected vessels
 A wire mesh tube (stent) that holds a blood vessel open
and stops it from closing
 Medicines to interfere with or dissolve blood clots
Your healthcare provider may advise other treatments.
What are the complications of thrombosis?
Thrombosis can block the blood flow in both veins and arteries.
64
Complications depend on where the thrombosis is located. The
most serious problems include stroke, heart attack, and serious
9.2. PERSPECTIVES
breathing problems.
Can thrombosis be prevented?
You can reduce your risk of thrombosis by:
 Being active
 Getting back to activity as soon as possible after surgery
 Exercising your legs during long trips
 Quitting smoking
 Losing weight
 Managing other health problems such as diabetes, high
blood pressure, and high cholesterol
Key points
 Thrombosis occurs when blood clots block veins or

arteries.
 Symptoms include pain and swelling in one leg, chest pain,
or numbness on one side of the body.
 Complications of thrombosis can be life-threatening, such
as a stroke or heart attack.
 Treatment includes medicines that thin the blood or
prevent clots, and using stents or catheters to open
blocked vessels.
 Prevention includes being active, quitting smoking, losing
weight, and managing other health conditions.
Next steps
Tips to help you get the most from a visit to your healthcare
provider:
 Know the reason for your visit and what you want to
happen.
65
 Before your visit, write down questions you want

answered.
 Bring someone with you to help you ask questions and
remember what your provider tells you.
 At the visit, write down the name of a new diagnosis, and
any new medicines, treatments, or tests. Also write down
any new instructions your provider gives you.
 Know why a new medicine or treatment is prescribed, and
how it will help you. Also know what the side effects are.
 Ask if your condition can be treated in other ways.
 Know why a test or procedure is recommended and what
the results could mean.
 Know what to expect if you do not take the medicine or
have the test or procedure.
 If you have a follow-up appointment, write down the date,
time, and purpose for that visit.
 Know how you can contact your provider if you have
questions.
Types of Thrombosis

66
How Thrombosis Starts
1
9.2. PERSPECTIVES
Arteries carry blood from your heart to your organs; veins send it
back to your heart. Sometimes the smooth flow of blood through
these "pipes" slows down or gets blocked. Or, there's damage
inside a blood vessel. That's when blood cells can stick together
and form a clot. Doctors call this thrombosis. Serious problems
can happen, depending on where the clot is.
Deep Vein Thrombosis (DVT)

2
A "deep vein" is farther inside your body, away from your skin.
DVT mainly happens in your leg or pelvis (lower-extremity
thrombosis), but you can get it in your arm or shoulder (upper-
extremity thrombosis), too. Small clots sometimes dissolve on
their own. Big clots that don't move or go away can block blood
flow in the vein. They're dangerous if they break off because they
could travel to your lungs.
67
Pulmonary Embolism (PE)

3
This is a blood clot that formed somewhere else and has traveled
through your bloodstream to your lungs. Most often, it's from a
vein in your leg or pelvis. It can block the flow of blood in your
lungs, so they don't work as well as they should. It can also harm
other organs because your lungs can't supply them with enough
oxygen. If the clot's very large or you have more than one, PE can
be fatal.
68
9.2. PERSPECTIVES
Femoral Vein Thrombosis

4
This is a clot in the long vein in your thigh. It usually doesn't cause
symptoms, but sometimes you could have swelling, redness, and
pain in your leg. Femoral vein clots can happen for many reasons:
after surgery, when you're on bedrest, or if you sit for a long time,
take birth control pills, or have had DVT before.
69
Paget-Schroetter Syndrome (PSS)

5
It's a rare kind of DVT that typically happens to a young, healthy

person who plays sports that use the upper arms a lot, like
swimming and baseball. The vein can get squeezed by the muscles
around it. This pressure, along with repeated movements, can
cause a clot in your shoulder. Symptoms like swelling, chest pain,
and a blue color to your skin may come on suddenly. PSS can be
serious if it's not treated right away.
Myocardial Infarction (Heart Attack)

6
Your heart's arteries can get clogged with a sticky fat called
plaque. A clot that forms on the plaque could cut off blood flow to
your heart. If it's not treated quickly, part of your heart muscle
may die. A heart attack usually causes a squeezing pain in your
chest. Women might have other symptoms, like back pain or
fatigue.
70
9.2. PERSPECTIVES
Superior Vena Cava Thrombosis

7
This big vein in your chest returns blood from your upper body to
your heart. You usually get this type of clot because you have a
tube called a central line (used to carry medicine into your body)
or a catheter in the vein. Your doctor might take out the tube to
treat the clot or leave it in. Either way, you'll probably need blood
thinning medicine to prevent more clots.
71
Jugular Vein Thrombosis

8
The two sets of jugular veins in your neck bring blood from your
head and neck back to your heart. Clots tend to form in these
veins when you have a central line in them. Cancer, surgery, or
using IV drugs can also cause jugular vein thrombosis. These clots
might break loose, travel to your lungs, and become PEs.
Thrombotic Stroke
9
When a clot blocks blood flow in one of your brain's arteries, that
part of your brain starts to die. Warning signs of a stroke include
weakness in your face and arms, and trouble speaking. If you
think you're having a stroke, you must act fast. It may cause
lasting problems with talking or using one side of your body. The
sooner you're treated, the better chance your brain has of
recovering.
72
9.2. PERSPECTIVES
Cerebral Venous Sinus Thrombosis

10
This is a rare type of stroke. A clot in this part of your brain stops
blood from draining out and back to your heart. The backed-up
blood can leak into brain tissue and cause a stroke. This mainly
happens in young adults, children, and babies. A stroke is life-
threatening.
73
Cavernous Sinus Thrombosis

11
It doesn't happen often, but a blood clot can form in a vein that
runs through the space behind your eye sockets. The most
common cause is an infection that spreads from your nose, face,
or teeth. Other things, like a head injury, can cause it, too. The
main symptoms are eye problems. Your eyes may hurt, seem
irritated or swollen, or bulge out, or you could find it hard to
control their movements.
Retinal Vein Occlusion

12
It's one of the most common reasons older people lose their sight.
A clot that blocks blood flow in the central vein in your retina (the
tissue lining the back inside of your eye), or smaller side veins,
stops blood from draining from your eye. The blood leaks out and
can lead to serious vision problems, like glaucoma or a detached
retina.
74
9.2. PERSPECTIVES
May-Thurner Syndrome
13
Your right iliac artery carries blood to your right leg. Your left iliac
vein brings blood from your left leg back to your heart. These two
blood vessels cross in your pelvis. Normally, that's not a problem.
But in someone with May-Thurner syndrome, the artery squeezes
the vein against the spine, making a clot in your left leg more
likely. It's something to consider when a young woman has
sudden swelling in their lower body.
75
Portal Vein Thrombosis

14
The portal vein carries blood from your digestive tract and spleen
to your liver. People with cirrhosis or who are prone to clots could
get one in it. A small clot usually doesn't cause symptoms, and
your doctor might not treat it. But if pressure builds up in the vein
behind the clot, you could get an enlarged spleen, swollen belly,
and bleeding. Your doctor will treat these symptoms and may try
to stop the clot from getting bigger.
76
9.2. PERSPECTIVES
Budd-Chiari Syndrome
15
A blood clot narrows or blocks the veins that carry blood from
your liver to your heart. It's not the same as portal vein
thrombosis, but it has some of the same symptoms, including a
large spleen, swollen belly, and bleeding. The main problem is
with your liver. It doesn't work as well as it should. If it's very
damaged, you could need a liver transplant.
77
Renal Vein Thrombosis

16
A kidney disease called nephrotic syndrome can cause a clot in

either of the veins that carry blood away from your kidneys. You
might not have symptoms with a slow-growing clot. A clot that
happens suddenly can give you low back pain and blood in your
pee. When you have only one kidney or clots in both veins, your
kidneys could stop working.
78
79
4 BLOOD DISORDERS
Different Blood Disorders
Disorders and diseases of the blood can impair the many

functions that blood performs.
Some common blood disorders are:
 Anemia: This happens when low red blood cell or

hemoglobin levels mean the cells do not transport oxygen
effectively, leading to fatigue, pale skin, and other
symptoms.
 Blood clotting: Clotting helps wounds and injuries heal,

but blood clots that form inside a blood vessel can create a
blockage, which can be life threatening. If clots become
dislodged and move through the heart to the lungs,
a pulmonary embolism can form.
80
 Blood cancers: Cancers such as leukemia, myeloma,
and lymphoma occur when blood cells start to divide
9.2. PERSPECTIVES
uncontrollably without dying off at the end of their life
cycle.
 Hemophilia: If a person has low levels of clotting factors in

the blood, they can bruise or bleedTrusted Source very
easily. They may bleed for too long after a minor injury or
surgery, or during menstruation. It affects around 18,000
people in the U.S.
 Sickle cell disease: An inherited trait causes red blood cells

to take on a crescent shape. It affects over 100,000 people
in the U.S., mostly Black Americans. It can severely impact
how blood functions and can be life threatening.
 Thalassemia: This is also a type of inherited anemia in

which the body produces an unusual form of hemoglobin.
It affected around 1000 people in the U.S. in 2008 and is
most common in people from around the Mediterranean
and parts of Asia.
If symptoms suggest a person may have a blood disorder, they

should seek medical advice. A doctor may refer them to a
specialist in blood disorders, known as a hematologist.
Blood is essential for maintaining the health and life of the human
body. It has many functions, including delivering nutrients and
81
oxygen. The four main components of blood are red blood cells,
white blood cells, plasma, and platelets.
82
83
5 HOME REMEDIES AND NATURAL TREATMENT
There are certain home remedies for DVT that can be used to
reduce the symptoms of DVT

1. Ginger
Apart from being an execellent healing spice, ginger plays an

important role in trating deep vein thrombosis. It is an effective
medicine to break down the fibrins that cause DVT and further
helps in smooth movement of blood. According to Nutritionist
Sagar, drink ginger tea at least two to three times a day. It can
help prevent high cholesterol that causes plaque buildup further
inhibiting blood circulation.
84
9.2. PERSPECTIVES
It is an effective medicine to break down the fibrins that cause DVT
2. Vitamin E rich foods Vitamin E rich foods like walnuts, spinach,

sunflower seeds, olive oil, bell peppers and kiwis help the blood to
flow smoothly. Vitamin K is known to thicken the blood promoting
the formation of clots; hence, vitamin E acts as anti-coagulant for
the veins. Include more green leafy vegetables, spinach, mustard
greens, fish, liver, eggs and cereals in your diet.)
Vitamin K is known to thicken the blood promoting the formation of clots
85
3. Cayenne pepper

Cayenne pepper is known to be a natural blood thinner that helps
in treating DVT. The compound capsaicin present in cayenne
promotes smooth blood circulation and helps prevent blood clots.
Apart from this, it also helps normalize blood pressure and
reduces cholesterol levels that may be a cause of blood clots.
Make sure you do not eat cayenne pepper without
consultation.
Cayenne pepper is known to be a natural blood thinner that helps in treating DVT
4. Garlic Cloves
Garlic is a known ingredient that promotes blood circulation and

helps you get rid of all the effects of DVT. According to Nutritionist
86
Sagar, one clove a day can actually help reduce the signs of DVT. It
is9.2. PERSPECTIVES
known to be anti-thrombotic, which helps in preventing blood
clots in patients at the risk of clots. Eating raw garlic first thing in
the morning is said to be quite effective for many people.

Garlic is a known ingredient that promotes blood circulation
5. Cinnamon

Cinnamon has a natural anticoagulant called coumarin that helps
in lowering blood pressure as well acts as a blood thinner
promoting blood circulation and preventing blood clots.
Cinnamon's blood thinning properties can help deep vein
thrombosis patients manage blood clotting by acting as an anti-
clotting agent. Drinking cinnamon water is super beneficial for
87
over all, as per various health experts. Do not regard this as a sole
measure for alternative healing in blood clotting.

Cinnamon has a natural anticoagulant called coumarin
While all the natural remedies and treatments for DVT are
effective, you shouldn’t completely rely on them. Consult a doctor
before switching to the natural remedies. Also it is imperative to
exercise regularly, at least for 15-30 minutes to ensure regular
movement of the body and good blood circulation.
88
89
6 BLOOD COAGULATION
6.1 Blood coagulation
The injury of the endothelial tissue always triggers an appropriate

blood clotting response. In the process of hemostasis, tissue
factor (TF) is exposed to the bloodstream which initiates a chain
of biochemical reactions that ultimately culminates in the
production of the fibrin clot. Platelets accelerate the coagulation
process and reinforce the clot by adhering to the injury site and
forming an aggregate. Under
some conditions, the coagulability of blood can be altered
resulting in a blood clotting abnormality. In this section, we will
describe each of the physiological mechanisms regulating blood
coagulation and provide some of the mathematical models that
were developed in order to understand it.
6.1.1 The coagulation cascade
Biological background
Blood coagulation is the process by which blood changes from a

liquid to a gel, forming a blood clot. The coagulation cascade plays
a vital role in this process characterized by the formation of fibrin
polymer. This cascade consists of a network of biochemical
reactions where blood clotting factors are successively activated
resulting in the conversion of fibrinogen ntofibrin, a loose mesh of
strands that entangles platelets and red blood cells (Fig. 1.1). The
concept of the coagulation cascade was first introduced by
Davie, Ratnoff and Macfarlane in the 1960’s [1]. They described
the ‘Y’-shaped path ways where the intrinsic and the extrinsic
pathways come together into a common pathway leading to the
production of thrombin and the subsequent generation of the
90
fibrin mesh. The coagulation cascade consists of the three main
phases regulated by different mechanisms [2].
9.2. PERSPECTIVES
The activation phase.

The coagulation process can be initiated by different pathways.
The most common one is the extrinsic pathway, also known as the
tissue factor pathway, where tissue factor (TF) is exposed to the
bloodstream and activates FVII. The active form of the later forms
a complex with TF (TF/FVIIa) and generates an initial
concentration of the factors FIXa and FXa. These two active
factors convert prothrombin into thrombin which triggers the
clotting process. Another possible mechanism of the coagulation
process activation is the contact pathway. In this mechanism, FXII
is activated upon the contact with any foreign material. FXIIa then
converts both FIX and FX into their active form resulting in the
generation of an initial amount of thrombin (FIIa). The coagulation
process can also be activated
BLOOD COAGULATION
TF
FVII FVIIa TF:FVIIa
FIX FIXa FXIIIa FXIII
APC PC
FX
FIXa
FXa
FXIIIa FXIII
FVa FV
FII FII
FIXa:FXIIIa
FXa:FVa ATIII FIIa:TM
FXII FXIIa
FXI FXIa
Foreign material
FII FIIa
FI FIa TMFibrin polymer
91
Figure 1.1: Schematic representation of the coagulation cascade.

directly by the thrombin expressed at the surface of platelets. In
this mechanism, thrombin directly
activates factors of the intrinsic pathway which leads to a further
conversion of prothrombin (FII) into
thrombin.
The elongation phase.

The generated concentration of thrombin activates blood
clotting factors such as FV, FVIII, and FXI which further converts
more prothrombin into thrombin through a feedback
process. This phase is only triggered when a threshold of
generated thrombin is reached [3]. The
elongation phase is characterised by the amplification of the
thrombin generation and the subsequent
growth of the clot. In this phase, FIXa and FVIIIa come together to
form an intrinsic tenase complex
which further activates FX. The active form of the later forms the
prothrombinase complex with FVa
that converts prothrombin into thrombin. The termination phase.
There exist various mechanisms that prevent excessive blood
clotting such as antithrombin, tissue factor pathway inhibitor
(TFPI), and activated protein C (APC). Antithrombin is a small
protein that inactivates several factors in the coagulation system.
It binds to thrombin and FXa which disables their action in the
clotting process and ultimately results in blood clotting arrest.
TFPI is another protein that plays an anticoagulant role during the
coagulation process especially when initiated by the extrinsic
pathway. TFPI is considered as a dual inhibitor because it binds to
both the TF/FVIIa
complex as well as FXa. In this context, FXa exerts a negative
feedback on its own production by forming a complex with TFPI
(TFPI/FXa) which further inhibits FXa and TF/FVIIa. Another
possible mechanism of the clot growth arrest involves protein C
(PC) and thrombomodulin (TM). PC is a vitamin- K dependent
protein that circulates in the blood plasma. TM is a membrane
92
protein expressed on the surface of intact endothelial cells. It
forms a complex with thrombin which activates PC. Subsequently,
9.2. PERSPECTIVES
activated protein C (APC) inactivates clotting factors of the

intrinsic pathway such as FVIIa and FXIIIa which inhibits the
amplification of thrombin generation.
Mathematical modelling
Different mathematical modelling
approaches were used to describe the
coagulation cascade. The most widely used
technique consists in representing the
biochemical reactions of the cascade by a
system of
ordinary differential equations (ODEs). In
such models, the concentration of each
blood clotting factor is described by an ODE
where the production and the degradation
terms depend on the concentrations
6.1.1. BLOOD COAGULATION

of other clotting factors. In this context, Hockin et al. developed
an important deterministic model of the coagulation cascade that
is able to reproduce clinical data [4]. The model is able to simulate
the experimental results in the case of normal, excessive and
insufficient thrombin generation. It is considered to be one of the
most complete models devoted to the modelling of the extrinsic
pathway as it includes 34 ODEs with nonlinear terms. As a result,
it was used in other works as a basis to develop
more realistic models that study the spatial clot growth dynamics
and include blood flow and platelets.
However, one of the important limitations of this model is the lack

of the intrinsic pathway. This feature was overcome in more
93
recent works [5, 6]. These models also include platelets and many
details of the coagulation cascade providing the possibility of
studying different blood clotting disorders. There are several
other works devoted to the modelling of the coagulation cascade
using a deterministic approach [7, 8, 9, 10]. Stability results of a
mathematical model of the coagulation cascade were presented
in another study [11] Deterministic models of blood coagulation
are usually studied using numerical simulations. How- ever, due to
the complexity of such model, it becomes difficult to explore them
using mathematical analysis tools. Fortunately, the numerical
simulation of such models is usually computationally cheap and
requires a short time. As a result, sensitivity analysis becomes an
essential tool to test the reliability of the predictions made by
these models. In this context, a Monte Carlo study was used by
Luan et al. to determine the most sensitive parameters that affect
thrombin generations [5]. Ultimately, they show that the
concentrations of FX and FII are the most sensitive parameters
and this is what makes them a
therapeutic target to prevent excessive clotting.
Another possible application of sensitivity analyses consists in

determining the appropriate rate constants that reproduce the
most accurate results. The difference in the experimental
conditions where these constants are measured gives rise to
divergent model outputs. Hence, the same mathematical model
can have two different results when two parameter sets are used
as demonstrated in a recent study [12]. An exhaustive sensitivity
analysis devoted to the impact of the parameter uncertainty on
thrombin generation was performed in another work [13].
Another possible odelling methodology that is used to describe
the coagulation cascade is the stochastic models. One of the most
important works in this area of research is the model developed
by Lo et al. [14]. In this study, a kinetic Monte Carlo simulation
method was used to capture the stochastic variability in the
clotting process.
94
6.1.2 Blood clotting abnormalities
9.2. PERSPECTIVES
There are many abnormalities that are associated with the blood
clotting system. These abnormalities can be divided into two
families depending on the blood clotting scenario: excessive
clotting (thrombosis) and insufficient clotting (bleeding) (Fig. 1.2).
In this section, we present some disorders of blood coagulation
and provide the corresponding mathematical models developed
to study them.
Pathological conditions associated with thrombosis
Thrombosis occurs when an upregulation in the coagulability of

blood results in the formation of a blood clot. These clots, also
known as thrombi, can become calcified which results in the
complete or partial occlusion of the vessel. Alternatively, they can
detach and migrate with the flow causing the occlusion of smaller
vessels in the circulatory system. This is a serious medical
condition known as embolism and can potentially lead to
dangerous complications such as ischemia or a necrosis of some
part of the
system (e.g. stroke). There are many causes and medical
conditions that provoke thrombosis.
Deep venous thrombosis.
Deep venous thrombosis (DVT) is a condition characterized by the

formation of a blood clot within a deep vein, most commonly
located in the legs. DVT has many symptoms such as the swelling,
redness, warmness, and engorged superficial veins. It is
associated with a dangerous complication where a part of the clot
detaches and migrates with the flow to the lungs provoking a
pulmonary embolism (PE). The combination of DVT and PE gives
birth to a medical condition as the
venous thrombo-embolism (VTE). According to Virchow, the
interaction between three processes is be-
95
hind the development of DVTs. These processes include the

immobility of flow, the hypercoagulability
1.1. BLOOD COAGULATION 14
Excessive
clotting
(thrombosis)
Deep venous thrombosis

Arterial thrombosis
Pulmonary embolism
Vessel occlusion
Cancer-associated
thrombosis
Inflammatory disease
thrombosis
Blood
clotting
disorders
Insufficient
clotting
thrombosis
Inflammatory disease
Hemophilia
Anticoagulant therapy
Figure 1.2: Classification of the main blood clotting abnormalities.
of blood, and changes in the vessel wall [15]. Hence, the severity
of DVT differs from one individual to another. In order to quantify
the coagulability of blood in DVT patients, researchers
incorporated the blood characteristics of such patients into
existing mathematical models of the coagulation cascade.
In this context, Brummel-Ziedins et al. have used the model

developed by Hockin et al. [4] in order to compute the thrombin
and FXa generation curves belonging to blood samples of DVT
patients [16]. A more realistic model of the coagulation cascade
was developed by including other details of the coagulation
96
cascade such as protein C [7]. These models show how individual
9.2. PERSPECTIVES
plasma compositions can lead to different results of thrombin
generation and quantify the effect of different clotting factors on
the blood coagulability. In the future, they can help the clinicians
to determine the coagulation cascade components that should be
targeted by the new anticoagulant drugs. They can also be used to
assess the effectiveness and safety of the existing therapies.
Cancer-associated thrombosis. Cancer is a group of malignancies
that involve the excessive growth of a type of cells that invade the
neighboring tissues and potentially the other organs. These
aggressive cancer cells are usually eliminated using a type of
treatments known as chemotherapy. Venous thromboembolism is
not only a common complication of cancer, but also a an
important side effect of chemotherapy [17]. It is estimated that
20% of cancer patients develop VTE during their treatment
period. There are many mechanisms involved in the formation of
blood clots due to cancer. First, cancer cells secrete procoagulant
cytokines such as interleukin 1β (IL-1β ), tumor necrosis factor-α
(TNF-α), and vascular endothelial growth factor (VEGF). These
factors have different effects on the endothelial cells. For
example, they can up regulate the expression of tissue factor on
these cells. They can also decrease the expression of
thrombomodulin. Furthermore, they also promote the adhesion
of leukocytes and platelets to the endothelial tissue which
increases the chances of thrombosis formation [18]. Another
mechanism by which cancer provokes thrombosis is through the
expression of tissue factor by cancer cells themselves. It was
reported that many types of cells express tissue factor in various
cancers such as breast, colon, pancreas, lung, brain [19].
Circulating tumor cells (CTCs) aggregate platelets and leukocytes
to create tissue factor-bearing micro particles that promote
thrombi formation in different areas of the circulatory system.
97
Chemotherapy has also several prothrombotic effects which

makes it an independent risk factor of VTE [20]. A clinical study
has shown an incidence rate of VTE in patients undergoing
chemotherapy estimated at 10.9% [21]. Chemotherapy induces
thrombosis by increasing the expression of TF in endothelial
tissues, activating platelets and altering the concentration of
clotting factors in the plasma. Both tumor cells and chemotherapy
stimulate development of vascular networks which in turns
stimulates the formation of blood clots. The modeling of the
interaction between vascular networks remodeling and blood
flow was conducted using a systems biology method [22]. Another
work describes the fields of blood clotting factors generated by
mobile CTCs in flow [23]. Thrombosis in inflammatory diseases.
Inflammation is a mechanism of innate immunity. It is

characterized by the progressive destruction of tissues by harmful
stimulus to compromise the survival of the organism. There are
many disorders which induce abnormal inflammation such as
atherosclerosis, rheumatoid arthritis, HIV, in addition to some
types of cancers. There exist complex interactions between blood
coagulation and inflammation [24]. These interactions involve the
secretion of procoagulant cytokines and chemokines by inflamed
tissues, the up regulation of tissue factor expression by
endothelial cells, and the activation of platelets and endothelial
cells. Atherosclerosis is an inflammatory disease that has an
elevated number of prothrombotic complications. In this disease,
white blood cells invade an artery wall causing it to become thick.
As a result, an atheromatous plaque forms and slowly increases
its thickness by cumulating the lipids present in blood which
perturbs the flow inside the vessel. The elevation in the shear rate
of flow ultimately leads to the rupture of the plaque resulting in
the formation of a thrombus overlying the atheroma.
Mathematical models were developed in order to investigate the
initiation of atherosclerosis and how it spreads in tissues [25, 26].
While the interaction between plaque formation and flow was
98
explored using a fluid-structure interaction formalism [27, 28, 29].
9.2. PERSPECTIVES
Psoriatic arthritis (PA) and rheumatoid arthritis (RA) are two other
inflammatory diseases that provoke thrombosis formation.
However, the prothrombotic mechanisms of these two diseases
are different from atherosclerosis. In these diseases, inflamed
tissues secrete procoagulant cytokines, such as interleukin 17 (IL-
17), and tissue necrosis factor α (TNF-α), that upregulates the
expression of TF
and decreases the concentration of TM on endothelial cells. PA
and RA are also known for altering the composition of blood
factors in plasma which increases the coagulability of blood.

Thrombin generation curves of RA patients were simulated using
a coagulation cascade model by Undas et al. [30]. Another

inflammatory disease with prothrombotic complications is sepsis.
It is a life-threatening condition usually triggered by
lipopolysaccharides (LPS), also known as endotoxins. These are
molecules present on the outer membrane of the Gram-negative
bacteria. They provoke an endothelial inflammatory response
chacaterised by the expression of high concentrations of TF which
initiates the coagulation cascade. In addition, LPS also increase
the number of TF-bearing monocytes that also express pro-
inflammatory cytokines on their surface. To our knowledge, there
is no mathematical model studying the coagulation
cascade dynamics during sepsis. However, several mathematical
models were developed to simulate the concentrations of
procoagulant and pro-inflammatory cytokines during the
progression of the dis-
ease [31, 32]. These models can be combined with the models of
the coagulation cascade dynamics to
estimate the risk of VTE during sepsis.
Thrombosis due to antithrombin deficiency. Antithrombin is a
99
protein that is necessary for clot growth arrest. It is present in

blood plasma and binds to several blood clotting factors, such
thrombin and FXa, in order to inactivate them. The deficiency of
ATIII results in the hypercoagulability of blood which favors the
formation of blood clots. There are two types of ATIII deficiencies.
The first is inherited and observed in one person out of two to five
hundred in the normal population. The second is acquired and
involves the decrease of antithrombin following a major surgery,
liver dysfunction, or in the proteinuria nephrotic syndrome.
Antithrombin deficiency not only reduces the necessary time for
blood clotting, but
also increases the maximal size reached by the thrombus as
shown in a mathematical modelling study [33].
HIV-associated thrombosis.
The human immunodeficiency virus (HIV) is considered to be one
of the risk factors of thrombosis. HIV infects the vital cells such as
CD4+ T-cells, macrophages, and dendritic cells. Once infected, the
cell becomes unable to function normally, and represents a target
to
6.1.2. THROMBUS DEVELOPMENT UNDER BLOOD FLOW

proteins that have different functions. These proteins involve
clotting factors, hormones, globulins, glucose, oxygen, and carbon
dioxide. Each of these has a fundamental role in the normal
functioning of the body. Blood also contains several types of cells
that are also known as hematopoietic cells because they are a
product of hematopoiesis. It is the process by which
hematopoietic stem cells give rise to different types of cells after a
series of cell differentiations. Blood cells fall into three basic
categories:
red blood cells (erythrocytes), platelets (thrombocytes), and white
blood cells (leukocytes).
Red blood cells (RBCs) are the cells that carry oxygen (O2 ) to the
different organs of the body.
100
The process by which these cells are produced in the bone
9.2. PERSPECTIVES
marrow is called erythropoiesis. In this process, colony-forming
unit and pro-erythroblast (CFU/ProEB) differentiate into
reticulocytes after undergoing a process of enucleation. Late
erythroblasts and reticulocytes consume the extracellular iron
that is present in the bone marrow to produce intracellular
hemoglobin, an oxygen-transporting protein metalloprotein. After
losing their nucleus, reticulocytes mature into discoid RBCs and
leave the bone
marrow to bloodstream. There is approximately 4.2-6.1 109 RBCs
per millimeter in blood. Each RBC
remains in blood for around 120 days and then gets recycled by
circulating macrophages. Depending on their hemoglobin

concentration, RBCs bind oxygen and carry it to the different cells
in the body. RBCs are especially known for their effects on blood
rheology. When present in blood flow, RBCs exhibit two
physiological features that have an impact on hemorheology. The

first one is the erythrocyte aggregation observed under low-shear
flow. Under such conditions, RBCs form stacks (rouleaux) due to
their discoid shape [37] which increases the overall viscosity of
blood. The other mechanical property of RBCs is their
deformability, which becomes particularly important under higher
shear flows and has an adverse effect
on hemorheology than erythrocyte aggregation. Because of these
two conflicting mechanical properties, blood behaves as a non-
Newtonian flow. RBCs and fibrin are the main components of
venous thrombus. For this reason, we refer to these thrombi as
red clots due to the red color of erythrocytes. Furthermore, RBCs
contribute to thrombosis by marginating platelets toward the
endothelium. They also express phosphatidylserine on their
surface which promotes thrombin generation [38]. Platelets, also
101
known as thrombocytes, are another type of cells that is present

in the bloodstream and play an important role in blood
coagulation. These smaller cells are fragments of the large bone
marrow cells called megakaryocytes after they get divided. They
have a diameter of 2-3 μm and can be found
in unactivated and activated forms. While unactivated, platelets
have a lens-shaped structure. Once activated, they become round
and extend filaments in order to cover the wound region and
aggregate other platelets. The aggregation of platelets is an
important process in blood coagulation whose main role is to
prevent bleeding. In this process, platelets are the first to react to
an endothelial injury by attaching to the subendothelium. Next,
these platelets become activated and express procoagulant
factors on their surfaces such as TF, ADP, and thrombin which
initiates the blood clotting system. Due to their round shape and
their filaments, activated platelets recruit the neighboring
unactivated platelets in flow and progressively form the platelet
plug. Platelets can also be activated by other mechanisms such as
physical damage, lack of oxygen, or under high-shear flow.
The third type of cells that can be found in blood is the white
blood cells or leukocytes. These cells protect the body from the
infectious diseases and foreign invaders and participate in the
immune response. There are different subtypes of white blood
cells, such as neutrophils, basophils, lymphocytes, and monocytes,
with a specific role for each one. Most of these cells are not
directly involved in the blood clotting process except monocytes.
Some of these large cells can express procoagulant factors on
their surface when exposed to TF or inflammatory cytokines
which results in the formation of microparticles that contribute to
the development of blood clots [39]. Blood is also an important
component of the circulatory system which is composed of
several organs.In this system, blood is transported through vessels
known as arteries and veins. When it leaves the heart, blood goes
through the aorta, then the arteries until it reaches smaller
microvessels called the arterioles, and then the capillaries. It
102
returns to the heart by moving through the venules and then the
9.2. PERSPECTIVES
veins. Blood flow exhibits different velocities and characteristics
as it circulates through each of these vessel types.
In this context, venous flow is generally low-shear laminar flow,

while arterial flow can be unsteady especially in curves and
branches [40]. Furthermore, the circulation of flow throughout
the vascular network is pressure driven across a branched
network of vessels. The arterial flow is pulsatile with an
amplitude that decreases as the distance of the artery from the
heart increases. It was observed that this
flow is affected by flow obstructions in other parts of the
circulatory system [41].
6.2. THROMBUS DEVELOPMENT UNDER BLOOD FLOW
Mathematical-modelling
Mathematical modelling is used to study several questions that
are essential to properly describe the

dynamics of blood. These questions involve the rheology of blood,
mechanical modelling of erythrocytes, 1D models of flow
netwoks, modelling the distribution of cells in flow among others
[42]. To capture the dynamics of blood flow inside blood vessels,
researchers typically use continuous models that are based on the
Navier-Stokes equations. There exist two subtypes of these
models: Newtonian and non-Newtonian viscosity models. The
Newtonian approximation of blood viscosity is only valid when
shear rate does not exceed a critical value. In this case, we can
assume that the viscosity of blood depends on the hematocrit
[43]. Each of the Newtonian models suggested a specific formula
103
for the viscosity which depends on various characteristic of the

flow such as the interaction between cells and their migration [44,
45, 46]. The second subtype of blood flow continuous models is
the non-Newtonian viscosity models. These models include the
shear thinning behavior of blood through an equation that defines
the relationship between the viscosity and shear rate [47, 48, 49].
These models can be either time independent or time dependent

because shear rate changes during the cardiac cycle. They usually
use experimental data on viscosity to determine the used
constants. These are commonly used in Computational Fluid
Dynamics (CFD) studies of blood flow. In this context, viscoeslatic
models represent one of the most accurate rheological
description of blood flow. Another approach that is used to model
blood flow consists in describing flow using particle methods.
These Lagrangian methods involve Smoothed-Particle
Hydrodynamics (SPH), Lattice Boltzmann Method (LBM),
Dissipative Particle Dynamics (DPD), Molecular Dynamics (MD),
and Cellular Potts Methods (CPM). By suggesting a Boltzmann Bi-
viscosity model, Liu was able to develop a validated LBM model of
blood flow [50]. In SPH, MD and DPD, the plasma is divided to a
set of elements called particles whose dynamics are governed by
different forces. Although these methods can be more
computationally expensive than the classical CFD methods, they
are certainly better adapted to the modelling of complex fluids
cases such as blood flow in patient-specific vessels. In this context,
SPH was used to computationally describe blood flow in CT-
reconstructed arteries [51]. The DPD method was successfully
used to provide a realistic representation of blood flow including
erythrocytes and platelets [52]. The same model was able to
explain the magination of platelets by red blood cells.
The development of the thrombus under flow
Biological background
In thrombosis, the formation of the fibrin clot takes place in a
104
medium of circulating blood. Hence, it is normal for blood flow to
9.2. PERSPECTIVES
affect the dynamics of clot growth. While low-shear flow
stimulates clot growth by transporting the platelets and the
procoagulant factors to the thrombus, high-shear flow limits clot
growth by detaching platelets and washing away the same
factors. In this context, experimental studies have shown that for
low-shear flow, the rate of clot growth rate increases as the shear
rate increases until
it reaches a critical value. Then, the rate of clot growth starts
decreasing until it reaches a constant value [53]. On one hand, it is
important for blood flow to be steady and fast for a normal
hemostatic response to take place. On the other hand, alterations
in blood flow are considered to be a factor that contributes to the
pathogenesis of thrombosi. In this context, the factors leading to
the development of venous thrombosis belong to three
categories: the hypercoagulability of blood, the endothelial injury,
and the stasis of blood flow. These three broad categories form
what is called the Virchow’s triad of venous thrombosis [54] (Fig.
1.3). Hence, the study of hemodynamic changes is of paramount
important for researchers who try to understand the
pathophysiology of thrombosis. There are many conditions that
can potentially lead to the stasis and stagnation of venous flow.
For instance, prolonged periods of immobility and paralysis of the
lower limbs are sufficient to decrease the rate and velocity of

blood flow in deep veins and increase the risk of DVT. Varicose
veins are another important risk factor of DVT. In this condition,
veins become enlarged and twisted due to diseased valves that
cannot prevent the flow from going backwards anymore. Reduced
flow velocity can also result from the perturbation of flow in other
areas of the vascular network. Overall, the stasis of blood flow
facilitates the interaction between blood factors, platelets, and
105
the vessel wall. Furthermore, it
6.2. THROMBUS DEVELOPMENT UNDER BLOOD FLOW

Hypercoagulability of blood
Cancer, thrombophilia,
inflammatory disease...
Virchow’s triad
of thrombosis
Stasis of blood
Immobility, varicose
veins, venous
obstruction...
Vessel wall injury
Surgery, chemical
irritation,
inflammation...
Figure 1.3: The Virchow’s triad of risk factors for venous
thrombosis.
deprives the endothelial tissues of oxygen resulting in their
hypoxia. This results in the expression of TF and P-selectin on the
surface of these cells which leads to the activation of the
coagulation process [55]. Hence, reduced flow does not only
increase the coagulability of blood, but also provoke a change in
the endothelial wall which confirms the hypothesis that the
categories of the Virchow’s triad are interlinked. If the speed at
which blood circulates is sufficiently high, then it does not only
delay the formation of the clot, but can also completely stop it.
For this reason, fast steady blood flow is considered to be a
fundamental condition for a healthy hemostatic response. If blood
flow changes the dynamics of thrombosis development, the latter
have various effects on the hemodynamical properties of blood.
Venous thrombi are composed mainly of fibrin polymer and red
blood cells which makes them a dense porous medium. It was
shown in in vitro experimental studies that the permeability of
blood clots depends on the densities of fibrin polymer and
platelets [56]
106
Therefore, exaggerated clot formation can either perturb or
9.2. PERSPECTIVES
completely block the circulation of blood.
For this reason, venous thrombosis can be occlusive when the

thrombus completely obstructs blood flow. Otherwise, it is
considered to be non-occlusive as the clot perturbs blood flow but
does not completely stop it. In this case, the rate of blood flow
and its velocity can still be reduced because it is driven by a
constant pressure difference.
Blood coagulation is a complex process whose complexity further

increases when the interaction with blood flow is considered.
Hence, mathematical modelling becomes an important tool that
can provide new insights into the complex puzzle of clot growth in
flow. Before incorporating blood flow, the de-terministic ODEs
models are extended to PDEs by including the spatial aspect of
clot growth such as diffusion and advection in most cases.

However, it is possible to include blood flow directly to ODEs by
considering a term of removal by flow [57, 58, 59]. While these
models use a simple treatment for blood flow and do not consider
hemodynamical changes during clot growth, they represent a
simple way to introduce flow effects on clot growth.The rest of
the model considers a spatiotemporal representation of clot
formation usually inside a blood vessel. These models simulate
both flow dynamics and clot growth in the same domain. The first
approach that is used in this regard consists in considering a

continuous model for both blood flow and the blood coagulation
factors. This approach is especially efficient because it allows to
couple both models and to solve them in the same numerical
107
mesh. Usually, the Navier-Stokes equations are used
6.3. CLINICAL APPLICATIONS OF BLOOD COAGULATION

MODELLING
To describe blood flow while advection-diffusion-reaction

equations are solved to capture the concentrations of clotting
factors and fibrin polymer. As a first approximation, some
researchers considered that fibrin polymer does not affect blood
flow dynamics [60]. Others preferred using a generalized
Newtonian model for blood flow where the viscosity depends on
the concentration of fibrin [61, 62]. Another type of continuous
models considers blood clot to be solid and use a fluid-structure
approach to cap-
ture its growth under the flow [63]. More recent models consider
the fibrin clot to be a porous medium whose permeability directly
affects the flow through a resistance term incorporated into the
Navier-Stokes equations [64, 65]. This method is particularly
important because we can track the development of the
thrombus as well as the hemodynamical changes in the same
domain without recomputing the computational mesh at each
time step.
Other types of modelling approach of thrombus formation under

flow include the hybrid models.These models combine both the
continuous and discrete description of blood flow, cells, and
clotting factors to achieve a realistic representation of the
coagulation process. Some of these models use a continuous
approach to describe both blood flow and the clotting factors and
a discrete one to track the motion of blood cells [66, 67, 68].
Other researchers opt for a particle representation of blood flow
using methods such as DPD coupled with continuous approach to
describe the distributions of blood clotting factors [69, 70].
Clinical applications of blood coagulation modelling

Developing mathematical models of blood coagulation is essential
in understanding the pathogenesis of
108
blood clotting abnormalities such as thrombosis, hemophilia, etc.
9.2. PERSPECTIVES
Usually, the developed models are
firstly built in order to describe the dynamics of healthy blood
coagulation. However, it is sufficient to
change some parameters associated with a coagulation disorder
to describe pathological blood coagula-
tion. The ultimate goal of these models is to study the action of
treatments on the coagulation process.
Despite the wide range of mathematical methods used in the
development of PK-PD hemostasis models,
the modellers are faced with numerous challenges due to the
complexity of the blood clotting system.
Below, we present a state of the art of the approaches used in the
mathematical modelling of blood
clotting disorders and their treatment.
1.3.1 The characterization of individual patients
Developing individual profiles of the blood clotting response is
important to bridge the clinical data with
the outputs of mathematical models. There are several diagnostic
tests that are used by clinicians in

order to assess the blood coagulability of individual patients. The
most commonly used diagnostic test
is the prothrombin time (PT) which describes the necessary time
for thrombin generation after adding
an amount of tissue factor to blood plasma. This test is mainly
used to evaluate the functioning of
the tissue .
Blood coagulation The injury of the endothelial tissue always

triggers an appropriate blood clotting response. In the process of
hemostasis, tissue factor (TF) is exposed to the bloodstream
109
which initiates a chain of biochemical reactions that ultimately

culminates in the production of the fibrin clot. Platelets accelerate
the coagulation process and reinforce the clot by adhering to the
injury site and forming an aggregate. Under some conditions, the
coagulability of blood can be altered resulting in a blood clotting
abnormality. In this section, we will describe each of the
physiological mechanisms regulating blood coagulation and
provide some of the mathematical models that were developed in
order to understand it.
The coagulation cascade Biological background Blood

coagulation is the process by which blood changes from a liquid to
a gel, forming a blood clot. The coagulation cascade plays a vital
role in this process characterized by the formation of fibrin
polymer. This cascade consists of a network of biochemical
reactions where blood clotting factors are successively activated
resulting in the conversion of fibrinogen into fibrin, a loose mesh
of strands that entangles platelets and red blood cells (Fig. 1.1).
The concept of the coagulation cascade was first introduced by
Davie, Ratnoff and Macfarlane in the 1960’s [1]. They described
the ‘Y’-shaped pathways where the intrinsic and the extrinsic
pathways come together into a common pathway leading to the
production of thrombin and the subsequent generation of the
fibrin mesh. The coagulation cascade consists of the three main
phases regulated by different mechanisms [2]. The activation
phase. The coagulation process can be initiated by different
pathways. The most common one is the extrinsic pathway, also
known as the tissue factor pathway, where tissue factor (TF) is
exposed to the bloodstream and activates FVII. The active form of
the later forms a complex with TF (TF/FVIIa) and generates an
initial concentration of the factors FIXa and FXa. These two active
factors converts prothrombin into thrombin which triggers the
clotting process. Another possible mechanism of the coagulation
process activation is the contact pathway. In this mechanism, FXII
is activated upon the contact with any foreign material. FXIIa then
converts both FIX and FX into their active form resulting in the
110
9.2. PERSPECTIVES
generation of an initial amount of thrombin (FIIa). The
coagulation process can also be activated 11 1.1. BLOOD
COAGULATION 12 TF FVII FVIIa TF:FVIIa FIX FIXa FXIIIa FXIII APC PC
FX FXa FVa FV FII FII FIXa:FXIIIa FXa:FVa ATIII FIIa:TM FXII FXIIa FXI
FXIa Foreign material FII FIIa FI FIa Fibrin polymer TM Figure 1.1:
Schematic representation of the coagulation cascade. directly by
the thrombin expressed at the surface of platelets. In this
mechanism, thrombin directly activates factors of the intrinsic
pathway which leads to a further conversion of prothrombin (FII)
into thrombin. The elongation phase. The generated
concentration of thrombin activates blood clotting factors such as
FV, FVIII, and FXI which further converts more prothrombin into
thrombin through a feedback process. This phase is only triggered
when a threshold of generated thrombin is reached [3]. The
elongation phase is characterised by the amplification of the
thrombin generation and the subsequent growth of the clot. In
this phase, FIXa and FVIIIa come together to form an intrinsic
tenase complex which further activates FX. The active form of the
later forms the prothrombinase complex with FVa that converts
prothrombin into thrombin. The termination phase. There exist
various mechanisms that prevent excessive blood clotting such as
antithrombin, tissue factor pathway inhibitor (TFPI), and activated
protein C (APC). Antithrombin is a small protein that inactivates
several factors in the coagulation system. It binds to thrombin and
FXa which disables their action in the clotting process and
ultimately results in blood clotting arrest. TFPI is another protein
that plays an anticoagulant role during the coagulation process
especially when initiated by the extrinsic pathway. TFPI is
considered as a dual inhibitor because it binds to both the
TF/FVIIa complex as well as FXa. In this context, FXa exerts a
negative feedback on its own production by forming a complex
with TFPI (TFPI/FXa) which further inhibits FXa and TF/FVIIa.
Another possible mechanism of the clot growth arrest involves
protein C (PC) and thrombomodulin (TM). PC is a vitaminK
111
dependent protein that circulates in the blood plasma. TM is a

membrane protein expressed on the surface of intact endothelial
cells. It forms a complex with thrombin which activates PC.
Subsequently, activated protein C (APC) inactivates clotting
factors of the intrinsic pathway such as FVIIa and FXIIIa which
inhibits the amplification of thrombin generation. Mathematical
modelling Different mathematical modelling approaches were
used to describe the coagulation cascade. The most widely used
technique consists in representing the biochemical reactions of
the cascade by a system of ordinary differential equations (ODEs).
In such models, the concentration of each blood clotting factor is
described by an ODE where the production and the degradation
terms depend on the concentrations
BLOOD COAGULATION of other clotting factors. In this context,

Hockin et al. developed an important deterministic model of the
coagulation cascade that is able to reproduce clinical data [4]. The
model is able to simulate the experimental results in the case of
normal, excessive and insufficient thrombin generation. It is
considered to be one of the most complete models devoted to
the modelling of the extrinsic pathway as it includes 34 ODEs with
nonlinear terms. As a result, it was used in other works as a basis
to develop more realistic models that study the spatial clot
growth dynamics and include blood flow and platelets. However,
one of the important limitations of this model is the lack of the
intrinsic pathway. This feature was overcome in more recent
works [5, 6]. These models also include platelets and many details
of the coagulation cascade providing the possibility of studying
different blood clotting disorders. There are several other works
devoted to the modelling of the coagulation cascade using a
deterministic approach [7, 8, 9, 10]. Stability results of a
mathematical model of the coagulation cascade were presented
in another study [11] Deterministic models of blood coagulation
are usually studied using numerical simulations. However, due to
the complexity of such model, it becomes difficult to explore
112
9.2. PERSPECTIVES
them using mathematical analysis tools. Fortunately, the
numerical simulation of such models is usually computationally
cheap and requires a short time. As a result, sensitivity analysis
becomes an essential tool to test the reliability of the predictions
made by these models. In this context, a Monte Carlo study was
used by Luan et al. to determine the most sensitive parameters
that affect thrombin generations [5]. Ultimately, they show that
the concentrations of FX and FII are the most sensitive parameters
and this is what makes them a therapeutic target to prevent
excessive clotting. Another possible application of sensitivity
analyses consists in determining the appropriate rate constants
that reproduce the most accurate results. The difference in the
experimental conditions where these constants are measured
gives rise to divergent model outputs. Hence, the same
mathematical model can have two different results when two
parameter sets are used as demonstrated in a recent study [12].
An exhaustive sensitivity analysis devoted to the impact of the
parameter uncertainty on thrombin generation was performed in
another work [13]. Another possible modelling methodology that
is used to describe the coagulation cascade is the stochastic
models. One of the most important works in this area of research
is the model developed by Lo et al. [14]. In this study, a kinetic

Monte Carlo simulation method was used to capture the
stochastic variability in the clotting process.
Blood clotting abnormalities There are many abnormalities

that are associated with the blood clotting system. These
abnormalities can be divided into two families depending on the
blood clotting scenario: excessive clotting (thrombosis) and
insufficient clotting (bleeding) (Fig. 1.2). In this section, we present
some disorders of blood coagulation and provide the
corresponding mathematical models developed to study them.
113
Pathological conditions associated with thrombosis Thrombosis

occurs when an upregulation in the coagulability of blood results
in the formation of a blood clot. These clots, also known as
thrombi, can become calcified which results in the complete or
partial occlusion of the vessel. Alternatively, they can detach and
migrate with the flow causing the occlusion of smaller vessels

in the circulatory system. This is a serious medical condition
known as embolism and can potentially lead to dangerous
complications such as ischemia or a necrosis of some part of the
system (e.g. stroke). There are many causes and medical
conditions that provoke thrombosis. Deep venous thrombosis.
Deep venous thrombosis (DVT) is a condition characterized by the
formation of a blood clot within a deep vein, most commonly
located in the legs. DVT has many symptoms such as the swelling,
redness, warmness, and engorged superficial veins. It is
associated with a dangerous complication where a part of the clot
detaches and migrates with the flow to the lungs provoking a
pulmonary embolism (PE). The combination of DVT and PE gives
birth to a medical condition as the venous thrombo-embolism
(VTE). According to Virchow, the interaction between three
processes is behind the development of DVTs. These processes
include the immobility of flow, the hypercoagulability 1.1. BLOOD
COAGULATION 14 Excessive clotting (thrombosis) Deep venous
thrombosis Arterial thrombosis Pulmonary embolism Vessel
occlusion Cancer-associated thrombosis Inflammatory disease
thrombosis Blood clotting disorders Insufficient clotting
thrombosis Inflammatory disease Hemophilia Anticoagulant
therapy Figure 1.2: Classification of the main blood clotting
abnormalities. of blood, and changes in the vessel wall [15].
Hence, the severity of DVT differs from one individual to another.
In order to quantify the coagulability of blood in DVT patients,
researchers incorporated the blood characteristics of such
patients into existing mathematical models of the coagulation
cascade. In this context, Brummel-Ziedins et al. have used the
model developed by Hockin et al. [4] in order to compute the
114
thrombin and FXa generation curves belonging to blood
9.2. PERSPECTIVES
samples of DVT patients [16]. A more realistic model of the
coagulation cascade was developed by including other details of
the coagulation cascade such as protein C [7]. These models show
how individual plasma compositions can lead to different results
of thrombin generation and quantify the effect of different
clotting factors on the blood coagulability. In the future, they can
help the clinicians to determine the coagulation cascade
components that should be targeted by the new anticoagulant
drugs. They can also be used to assess the effectiveness and
safety of the existing therapies. Cancer-associated thrombosis.
Cancer is a group of malignancies that involve the excessive
growth of a type of cells that invade the neighboring tissues and
potentially the other organs. These aggressive cancer cells are
usually eliminated using a type of treatments known as
chemotherapy. Venous thromboembolism is not only a common
complication of cancer, but also a an important side effect of
chemotherapy [17]. It is estimated that 20% of cancer patients
develop VTE during their treatment period. There are many
mechanisms involved in the formation of blood clots due to
cancer. First, cancer cells secrete procoagulant cytokines such as
interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α), and
vascular endothelial growth factor (VEGF). These factors have
different effects on the endothelial cells. For example, they can
upregulate the expression of tissue factor on these cells. They can
also decrease the expression of thrombomodulin. Furthermore,
they also promote the adhesion of leukocytes and platelets to the
endothelial tissue which increases the chances of thrombosis
formation [18]. Another mechanism by which cancer provokes
thrombosis is through the expression of tissue factor by cancer
cells themselves. It was reported that many types of cells express
tissue factor in various cancers such as breast, colon, pancreas,
lung, brain [19]. Circulating tumor cells (CTCs) aggregate platelets
and leukocytes to create tissue factor-bearing microparticles that
promote thrombi formation in different areas of the circulatory
115
system. Chemotherapy has also several prothrombotic effects

which makes it an independent risk factor of 1.1. BLOOD
COAGULATION 15 VTE [20]. A clinical study has shown an
incidence rate of VTE in patients undergoing chemotherapy
estimated at 10.9% [21]. Chemotherapy induces thrombosis by
increasing the expression of TF in endothelial tissues, activating
Platelets and altering the concentration of clotting factors in

the plasma. Both tumor cells and chemotherapy stimulate
development of vascular networks which in turns stimulates the
formation of blood clots. The modeling of the interaction between
vascular networks remodeling and blood flow was conducted
using a systems biology method [22]. Another work describes the
fields of blood clotting factors generated by mobile CTCs in flow
[23]. Thrombosis is inflammatory diseases. Inflammation is a
mechanism of innate immunity. It is characterized by the
progressive destruction of tissues by harmful stimulus to
compromise the survival of the organism. There are many
disorders which induce abnormal inflammation such as
atherosclerosis, rheumatoid arthritis, HIV, in addition to some
types of cancers. There exist complex interactions between blood
coagulation and inflammation [24]. These interactions involve the
secretion of procoagulant cytokines and chemokines by inflamed
tissues, the upregulation of tissue factor expression by endothelial
cells, and the activation of platelets and endothelial cells.
Atherosclerosis is an inflammatory disease that has an elevated
number of prothrombotic complications. In this disease, white
blood cells invade an artery wall causing it to become thick. As a
result, an atheromatous plaque forms and slowly increases its
thickness by cumulating the lipids present in blood which perturbs
the flow inside the vessel. The elevation in the shear rate of flow
ultimately leads to the rupture of the plaque resulting in the
formation of a thrombus overlying the atheroma. Mathematical
models were developed in order to investigate the initiation of
atherosclerosis and how it spreads in tissues [25, 26]. While the
interaction between plaque formation and flow was explored
116
9.2. PERSPECTIVES
using fluid structure interaction formalism [27, 28, and 29].
Psoriatic arthritis (PA) and rheumatoid arthritis (RA) are two other
inflammatory diseases that provoke thrombosis formation.
However, the prothrombotic mechanisms of these two diseases
are different from atherosclerosis. In these diseases, inflamed
tissues secrete procoagulant cytokines, such as interleukin 17 (IL-
17), and tissue necrosis factor α (TNF-α), that upregulates the
expression of TF and decreases the concentration of TM on
endothelial cells. PA and RA are also known for altering the
composition of blood factors in plasma which increases the
coagulability of blood. Thrombin generation curves of RA patients
were simulated using a coagulation cascade model by Undas et al.
[30]. Another inflammatory disease with prothrombotic
complications is sepsis. It is a life-threatening condition usually
triggered by lipopolysaccharides (LPS), also known as endotoxins.
These are molecules present on the outer membrane of the
Gram-negative bacteria. They provoke an endothelial
inflammatory response characterized by the expression of high
concentrations of TF which initiates the coagulation cascade. In
addition, LPS also increase the number of TF-bearing monocytes
that also express pro-inflammatory cytokines on their surface. To
our knowledge, there is no mathematical model studying the
coagulation cascade dynamics during sepsis. However, several
mathematical models were developed to simulate the
concentrations of procoagulant and pro-inflammatory cytokines
during the progression of the disease [31, 32]. These models can
be combined with the models of the coagulation cascade
dynamics to estimate the risk of VTE during sepsis. Thrombosis is
due to antithrombin deficiency. Antithrombin is a protein that is
necessary for clot growth arrest. It is present in blood plasma and
binds to several blood clotting factors, such thrombin and FXa, in
order to inactivate them. The deficiency of ATIII results in the
hypercoagulability of blood which favors the formation of blood
clots. There are two types of ATIII deficiencies. The first is
117
inherited and observed in one person out of two to five hundred

in the normal population. The second is acquired and involves the
decrease of antithrombin following a major surgery, liver
dysfunction, or in the proteinuria nephrotic syndrome.
Antithrombin deficiency not only reduces the necessary time for
blood clotting, but also increases the maximal size reached by the
thrombus as shown in a mathematical modeling study [33].
HIV-associated thrombosis.
The human immunodeficiency virus (HIV) is considered to be

one of the risk factors of thrombosis. HIV infects the vital cells
such as CD4+ T-cells, macrophages, and dendritic cells. Once
infected, the cell becomes unable to function normally, and
represents a target to CD8+ T-cells. The virus can also induce the
death of the infected cell by cytotoxicity. As a result, the immune
response system is impaired and the body becomes vulnerable to
any infection. HIV has many procoagulant effects on the blood
clotting system. First, infected CD4+ T-cells secrete inflammatory
cytokines such as IL-6, IL-17, and TNF-α that upregulates the
concentration of P-selectin in endothelial cells. It is a protein that
is responsible for cell recruitment and adhesion which activates
endothelial cells. HIV also increases the number of monocytes and
micro particles expressing TF in blood [34]. Then, HIV also causes
the deficiency of various anticoagulant factors such as PC and
ATIII. The mechanisms by which HIV down regulates these factors
are still unknown to this day [35]. To our knowledge, there is no
mathematical model that quantifies the effects of HIV on the
coagulation process.
Pathological conditions associated with bleeding
Bleeding is the condition where the thrombus does not form

properly due to insufficient blood clotting. While excessive clotting
can induce dangerous complications such as DVT and strokes,
underclotting can provoke equally dangerous conditions such as
hemorrhages. Bleeding can lead to other dangerous conditions
such as anemia and hematoma. An insufficient blood
118
9.2. PERSPECTIVES
clotting response can be both inherited and acquired. Below
we present some of the most common conditions inducing under-
clotting. Hemophilia. Hemophilia is a rare inherited blood clotting
disorder characterized by the lack of a procoagulant factor in
blood. There are three types of hemophilia depending on which
clotting factor is lacking: FVIII in type A, FIX in type B, and FXI in
type C. The deficiency of these factors prevents the generation of
thrombin and the subsequent formation of the blood clot.
Mathematical modelling can be used to estimate the response of
the hemostatic response in patients with hemophilia. In this
context, thrombin wave curves of hemophilia B patients were
compared with healthy counterparts [36]. As expected,
hemophilia B not only reduce the time of clotting but also the size
of the clot. Bleeding incidence during anticoagulant therapy.
Anticoagulant drugs are usually prescribed to prevent the
incidence of thrombosis. However, when administrated in higher
doses, the same drugs can potentially provoke bleeding.
Mathematical modelling can be used to assess the safety of these
drugs and determine the therapeutic window for every individual
patient. We present a review of the main works that attempt to
determine the bleeding and thrombosis risk for numerous
anticoagulant drugs in
Thrombus development under blood flow Under the real in

vivo conditions, blood coagulation is usually affected by
hemodynamics since it occurs inside blood vessels. Hence, it is
particularly important to understand the properties and the
dynamics of blood flow before moving to more complex questions
such as the interplay between clot growth and the flow. One of
the challenges facing the modellers is studying the effect of the
different flow conditions on the formation of the clot. After
exploring the different conditions of blood flow that can be found
in the circulatory system, we will study the dynamics of blood
clotting in flow. Then, we will present a state of the art of the
119
computational and mathematical modelling studies devoted to

hemodynamics and thrombus development in flow. 1.2.1 Blood
flow Biological background Blood is a body fluid that is present in
humans and other animals. The average volume of blood in a
human adult is 5 liters. Its main role consists in transporting
oxygen and nutrients to the different organs and tissue and move
metabolic waste away from the same cells. It is mainly composed
of blood plasma and numerous types of cells. Blood plasma is a
Newtonian yellow colored liquid that makes up about 55% of the
body blood and consists mostly of water (up to 95% of mass).
THROMBUS DEVELOPMENT UNDER BLOOD FLOW
proteins that have different functions. These proteins involve

clotting factors, hormones, globulins, glucose, oxygen, and carbon
dioxide. Each of these has a fundamental role in the normal
functioning of the body. Blood also contains several types of cells
that are also known as hematopoietic cells because they are a
product of hematopoiesis. It is the process by which
hematopoietic stem cells give rise to different types of cells after a
series of cell differentiations. Blood cells fall into three basic
categories: red blood cells (erythrocytes), platelets
(thrombocytes), and white blood cells (leukocytes). Red blood
cells (RBCs) are the cells that carry oxygen (O2) to the different
organs of the body. The process by which these cells are produced
in the bone marrow is called erythropoiesis. In this process,
colony-forming unit and pro-erythroblast (CFU/ProEB)
differentiate into reticulocytes after undergoing a process of
enucleation. Late erythroblasts and reticulocytes consume the
extracellular iron that is present in the bone marrow to produce
intracellular hemoglobin, an oxygen-transporting protein
metalloprotein. After losing their nucleus, reticulocytes mature
into discoid RBCs and leave the bone marrow to bloodstream.
There is approximately 4.2-6.1 109 RBCs per millimeter in blood.
Each RBC remains in blood for around 120 days and then gets
recycled by circulating macrophages. Depending on their
hemoglobin concentration, RBCs bind oxygen and carry it to the
120
9.2. PERSPECTIVES
different cells in the body. RBCs are especially known for their
effects on blood rheology. When present in blood flow, RBCs
exhibit two physiological features that have an impact on
hemorheology. The first one is the erythrocyte aggregation
observed under low-shear flow. Under such conditions, RBCs form
stacks (rouleaux) due to their discoid shape [37] which increases
the overall viscosity of blood. The other mechanical property of
RBCs is their deformability, which becomes particularly important
under higher shear flows and has an adverse effect on
hemorheology than erythrocyte aggregation. Because of these
two conflicting mechanical properties, blood behaves as a non-
Newtonian flow. RBCs and fibrin are the main components of
venous thrombus. For this reason, we refer to these thrombi as
red clots due to the red color of erythrocytes. Furthermore, RBCs
contribute to thrombosis by marginating platelets toward the
endothelium. They also express phosphatidylserine on their
surface which promotes thrombin generation [38]. Platelets, also
known as thrombocytes, are another type of cells that is present
in the bloodstream and play an important role in blood
coagulation. These smaller cells are fragments of the large bone
marrow cells called megakaryocytes after they get divided. They
have a diameter of 2-3 μm and can be found in unactivated and
activated forms. While unactivated, platelets have a lens-shaped
structure. Once activated, they become round and extend
filaments in order to cover the wound region and aggregate other
platelets. The aggregation of platelets is an important process in
blood coagulation whose main role is to prevent bleeding. In this
process, platelets are the first to react to an endothelial injury by
attaching to the subendothelium. Next, these platelets become
activated and express procoagulant factors on their surfaces such
as TF, ADP, and thrombin which initiates the blood clotting
system. Due to their round shape and their filaments, activated
platelets recruit the neighboring unactivated platelets in flow and
progressively form the platelet plug. Platelets can also be
121
activated by other mechanisms such as physical damage, lack of

oxygen, or under high-shear flow. The third type of cells that can
be found in blood is the white blood cells or leukocytes. These
cells protect the body from the infectious diseases and foreign
invaders and participate in the immune response. There are
different subtypes of white blood cells, such as neutrophils,
basophils, lymphocytes, and monocytes, with a specific role for
each one. Most of these cells are not directly involved in the
blood clotting process except monocytes. Some of these large
cells can express procoagulant factors on their surface when
exposed to TF or inflammatory cytokines which results in the
formation of microparticles that contribute to the development of
blood clots [39]. Blood is also an important component of the
circulatory system which is composed of several organs. In this

system, blood is transported through vessels known as arteries
and veins. When it leaves the heart, blood goes through the aorta,
then the arteries until it reaches smaller micro vessels called the
arterioles, and then the capillaries. It returns to the heart by
moving through the venules and then the veins. Blood flow
exhibits different velocities and characteristics as it circulates
through each of these vessel types. In this context, venous flow is
generally low-shear laminar flow, while arterial flow can be
unsteady especially in curves and branches [40]. Furthermore, the
circulation of flow throughout the vascular network is pressure
driven across a branched network of vessels. The arterial flow is
pulsatile with amplitude that decreases as the distance of the
artery from the heart increases. It was observed that this flow is
affected by flow obstructions in other parts of the circulatory
system [41].
Mathematical modeling Mathematical modeling is used to

study several questions that are essential to properly describe the
dynamics of blood. These questions involve the rheology of blood,
mechanical modeling of erythrocytes, 1D model of flow networks,
modeling the distribution of cells in flow among others [42]. To
122
9.2. PERSPECTIVES
capture the dynamics of blood flow inside blood vessels,
researchers typically use continuous models that are based on the
Navier-Stokes equations. There exist two subtypes of these
models: Newtonian and non-Newtonian viscosity models. The
Newtonian approximation of blood viscosity is only valid when
shear rate does not exceed a critical value. In this case, we can
assume that the viscosity of blood depends on the hematocrit
[43]. Each of the Newtonian models suggested a specific formula
for the viscosity which depends on various characteristic of the
flow such as the interaction between cells and their migration [44,
45, 46]. The second subtype of blood flow continuous models is
the non-Newtonian viscosity models. These models include the
shear thinning behavior of blood through an equation that defines
the relationship between the viscosity and shear rate [47, 48, and
49]. These models can be either time independent or time
dependent because shear rate changes during the cardiac cycle.
They usually use experimental data on viscosity to determine the
used constants. These are commonly used in Computational Fluid
Dynamics (CFD) studies of blood flow. In this context, viscoelasatic
models represent one of the most accurate rheological
description of blood flow. Another approach that is used to model
blood flow consists in describing flow using particle methods.
These Lagrangian methods involve Smoothed-Particle
Hydrodynamics (SPH), Lattice Boltzmann (LBM), Dissipative

Particle Dynamics (DPD), Molecular Dynamics (MD), and Cellular
Potts Methods (CPM). By suggesting a Boltzmann Bi-viscosity
model, Liu was able to develop a validated LBM model of blood
flow [50]. In SPH, MD and DPD, the plasma is divided to a set of
elements called particles whose dynamics are governed by
different forces. Although these methods can be more
computationally expensive than the classical CFD methods, they
are certainly better adapted to the modelling of complex fluids
123
cases such as blood flow in patient-specific vessels. In this context,

SPH was used to computationally describe blood flow in CT-
reconstructed arteries [51]. The DPD method was successfully
used to provide a realistic representation of blood flow including
erythrocytes and platelets [52]. The same model was able to
explain the magination of platelets by red blood
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of Fluid Mechanics, 29(1), 399-434.
[41] Wootton, D. M., & Ku, D. N. (1999). Fluid

mechanics of vascular systems, diseases,
and thrombosis. Annual review of
biomedical engineering, 1(1), 299-329.
[42] Bessonov, N., Sequeira, A., Simakov, S.,

Vassilevskii, Y., & Volpert, V. (2016).
Methods of blood flow modelling.
Phenomena, 11(1), 1-25.
[43] Crowley, T. A., & Pizziconi, V. (2005).

Isolation of plasma from whole blood
using planar micro- filters for lab-on-a-
chip applications. Lab on a Chip, 5(9),
922-929.
[44] Einstein, A. (1911). Berichtigung zu

meiner Arbeit:„Eine neue Bestimmung
der Molek´’uldimensionen”. Annalen der
Physik, 339(3), 591-592.
[45] Lee, S. W., & Steinman, D. A. (2007). On

the relative importance of rheology for
image-based CFD models of the carotid
bifurcation. Journal of biomechanical
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[46] Phillips, R. J., Armstrong, R. C., Brown,

R. A., Graham, A. L., & Abbott, J. R.
(1992). A con- stitutive equation for
concentrated suspensions that accounts for
shear-induced particle migration. Physics
of Fluids A: Fluid Dynamics, 4(1), 30-40.
[47] Johnston, B. M., Johnston, P. R., Corney,

S., & Kilpatrick, D. (2004). Non-Newtonian
blood flow in human right coronary
arteries: steady state simulations. Journal
of biomechanics, 37(5), 709-720.
[48] Malkin, A. I. (1994). Rheology fundamentals. ChemTec

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semisolid foods: principles and
applications. Springer Sci- ence &
Business Media.
132
133
7 MATHEMATICAL MODEL FOR COAGULATION
The development of the thrombus under flow Biological

background In thrombosis, the formation of the fibrin clot takes
place in a medium of circulating blood. Hence, it is normal for
blood flow to affect the dynamics of clot growth. While low-shear
flow stimulates clot growth by transporting the platelets and the
procoagulant factors to the thrombus, high-shear flow limits clot
growth by detaching platelets and washing away the same
factors. In this context, experimental studies have shown that for
low-shear flow, the rate of clot growth rate increases as the shear
rate increases until it reaches a critical value. Then, the rate of clot
growth starts decreasing until it reaches a constant value [53]. On
one hand, it is important for blood flow to be steady and fast for a
normal hemostatic response to take place. On the other hand,
alterations in blood flow are considered to be a factor that
contributes to the pathogenesis of thrombosi. In this context, the
factors leading to the development of venous thrombosis belong
to three categories: the hypercoagulability of blood, the
endothelial injury, and the stasis of blood flow. These three broad
categories form what is called the Virchow’s triad of venous
thrombosis [54] (Fig. 1.3). Hence, the study of hemodynamic
changes is of paramount important for researchers who try to
understand the pathophysiology of thrombosis. There are many
conditions that can potentially lead to the stasis and stagnation of
venous flow. For instance, prolonged periods of immobility and
paralysis of the lower limbs are sufficient to decrease the rate and
velocity of blood flow in deep veins and increase the risk of DVT.
134
Varicose veins are another important risk factor of DVT. In this
condition, veins become enlarged and twisted due to diseased
9.2. PERSPECTIVES
valves that cannot prevent the flow from going backwards
anymore. Reduced flow velocity can also result from the
perturbation of flow in other areas of the vascular network.
Overall, the stasis of blood flow facilitates the interaction
between blood factors, platelets, and the vessel wall.
Furthermore, it 1.2. THROMBUS DEVELOPMENT UNDER BLOOD
FLOW 19 Hypercoagulability of blood Cancer, thrombophilia,
inflammatory disease… Virchow’s triad of thrombosis Stasis of
blood Immobility, varicose veins, venous obstruction… Vessel wall
injury Surgery, chemical irritation, inflammation… Figure 1.3: The
Virchow’s triad of risk factors for venous thrombosis. deprives the
endothelial tissues of oxygen resulting in their hypoxia. This
results in the expression of TF and P-selectin on the surface of
these cells which leads to the activation of the coagulation
process [55]. Hence, reduced flow does not only increase the
coagulability of blood, but also provoke a change in the
endothelial wall which confirms the hypothesis that the
categories of the Virchow’s triad are interlinked. If the speed at
which blood circulates is sufficiently high, then it does not only
delay the formation of the clot, but can also completely stop it.
For this reason, fast steady blood flow is considered to be a
fundamental condition for a healthy hemostatic response. If blood
flow changes the dynamics of thrombosis development, the latter
have various effects on the hemodynamical properties of blood.
Venous thrombi are composed mainly of fibrin polymer and red
blood cells which makes them a dense porous medium. It was
shown in in vitro experimental studies that the permeability of
blood clots depends on the densities of fibrin polymer and
platelets [56]. Therefore, exaggerated clot formation can either
perturb or completely block the circulation of blood. For this
reason, venous thrombosis can be occlusive when the thrombus
completely obstructs blood flow. Otherwise, it is considered to be
non-occlusive as the clot perturbs blood flow but does not
135
completely stop it. In this case, the rate of blood flow and its
velocity can still be reduced because it is driven by a constant
pressure difference. Mathematical modelling Blood coagulation is

a complex process whose complexity further increases when the
interaction with blood flow is considered. Hence, mathematical
modelling becomes an important tool that can provide new
insights into the complex puzzle of clot growth in flow. Before
incorporating blood flow, the deterministic ODEs(Ordinary
differential equations) models are extended to PDEs(Partial
differential equations) by including the spatial aspect of clot
growth such as diffusion and advection in most cases. However, it
is possible to include blood flow directly to ODEs by considering a
term of removal by flow [57, 58, 59]. While these models use a
simple treatment for blood flow and do not consider
hemodynamical(blood dynamics) changes during clot growth,
they represent a simple way to introduce flow effects on clot
growth. The rest of the model considers a spatio-temporal
representation of clot formation usually inside a blood vessel.
These models simulate both flow dynamics and clot growth in the
same domain. The first approach that is used in this regard
consists in considering a continuous model for both blood flow
and the blood coagulation factors. This approach is especially
efficient because it allows to couple both models and to solve
them in the same numerical mesh. Usually, the Navier-Stokes
equations are used
CLINICAL APPLICATIONS OF BLOOD COAGULATION MODEL
Thrombin
∂T/ ∂t +∇.(vT) = DΔT + k1φc +k2Ba + k3T3 /(1+k10Ca )P−k4AT, (7.1)
Factors IXa, Xa
∂Ba/ ∂t +∇.(vBa) = DΔB−k5ABa, (7.2)
136
APC
9.2. PERSPECTIVES
∂Ca /∂t +∇.(vC) = DΔC, (7.3)
Antithrombin
∂A/ ∂t +∇.(vA) = DΔA−k4AT −k5AB, (7.4)
Fibrinogen
∂Fg/ ∂t +∇.(vFg) = DΔFg − k6TFg /(K6 +Fg ), (7.5)
Fibrin
∂F /∂t +∇.(vF) = DΔF + k6T Fg/( K6 +Fg) −k7F, (7.6)
Fibrin polymer
∂Fp/ ∂t = k7F. (7.7)
We considered the following equations for the concentrations of

prothrombin P, thrombin T, antithrombin A, factors IX and X with their
total concentration denoted by B and their active form Ba, protein C
denoted by C and its active form Ca, fibrinogen Fg, fibrin F and fibrin
polymer Fp:
Prothrombin
∂P /∂t +∇.(vP) = DΔP− (k1φc +k2Ba + k3T3/( 1+k8Ca) )P,

(7.8)
137
138
9.2. PERSPECTIVES
8 ANTICOAGULANT MODEL
Clot Growth Dynamics in Antithrombin Deficiency and

Inflammation: insights from mathematical modelling
The effect of antithrombin deficiency on clot growth
Biological background Blood coagulation is a complex process

whose main function is preventing blood loss in case of the blood
vessel damage. As the result, under the normal conditions a fibrin
clot is formed on the injury site preventing the vessel from
leaking. The reaction of fibrinogen conversion to fibrin is catalyzed
by the key enzyme of the coagulation cascade called thrombin. In
case of the vessel damage some amount of thrombin is formed
near the vessel wall through the tissue factor pathway. If this
amount reaches the threshold value, thrombin launches a cascade
of activation reactions resulting in the self-sustained bulk
production of thrombin whose concentration propagates from the
damaged vessel wall to the vascular lumen . Thrombin wave
propagation is controlled by the anticoagulant system that
incorporates different plasma inhibitors suppressing the
activation processes. The most important inhibitor of thrombin is
antithrombin that forms a stable complex with thrombin
decreasing its activity in the blood flow . Furthermore,
antithrombin also binds to other factors participating as activators
in the coagulation cascade and thus has a crucial influence on the
139
clotting dynamics. If the thrombin propagation becomes intensive

enough the additional anticoagulant mechanisms such as
activation of protein C pathway are launched. Nevertheless, the

role of antithrombin during the initiation phase of coagulation
cascade is predominant and it determines whether the
propagation of thrombin wave will take place.
Mathematical model of blood clotting initiated by the intrinsec

pathway We consider the following model of the intrinsic
pathway of coagulation cascade:
THE EFFECT OF ANTITHROMBIN DEFICIENCY ON CLOT GROWTH
∂T/∂t = DΔT + ( k2U10 +k2 (k510/h510) U10U5) P/ P0 −h2T,
∂P/∂t = DΔP+ (k2U10 −k2 (k510/h510) U10U5 ) P /P0 ,

∂U11/ ∂t = DΔU11 +k11T −h11U11,
∂U10/ ∂t = DΔU10 +k10U9 +k10 k89 /h89 U9U8 −h10U10,
∂U9/ ∂t = DΔU9 +k9U11 −h9U9,
∂U8/ ∂t = DΔU8 +k8T −h8U8,
∂U5/ ∂t = DΔU5 +k5T −h5U5,

∂Fg/ ∂t = DΔFg −k1T Fg,
∂F /∂t = DΔF +k1T Fg − kF,
∂Fp/ ∂t = kF. Here Ui are the concentrations of the activated
forms of i-th factors; P,T,Fg,F,Fp are the concentrations of
prothrombin, thrombin, fibrinogen, fibrin and fibrin polymer
respectively; D is the diffusion coefficient considered to be the
same for all factors; ki, ki and hi are the rates of factor i activation
and inhibition respectively; ki j, hi j are the rates of formation and
inhibition of the complexes of factors i and j. As compared to
140
these models, in the current study we take into account the role
of blood flow in clot formation. To reflect the mechanical
9.2. PERSPECTIVES
properties of the clot we introduce the variables of fibrinogen,

fibrin and fibrin polymer concentrations. Fibrin polymer forms the
clot scaffold and is not transported by the blood flow but affects
the flow dynamics. Finally, we take the rate of thrombin inhibition
to be proportional to antithrombin concentration (A): h2 = α∗A.
We consider a 2D computational domain corresponding to the
vessel cross-section with blood flow moving along the x axis (Fig.
4.1). As prothrombin and fibrinogen are abundantly present in
blood plasma, we prescribe the Dirichlet conditions
P(x,0,t) = P0, Fg(x,0,t) = F0
on the bottom vessel wall and also use P0 and F0 as initial
concentrations for prothrombin and fibrinogen respectively. We
also prescribe Dirichlet condition T(x,0,t) = T 0 and U11(x,0,t) = U0
for x ∈ [x1, x2] supposing that the initial concentration of
thrombin is already formed in the proximity of the injury site due
to the reactions on the vessel surface. For all the other factors we
prescribe zero-flux boundary conditions and zero concentrations
as the initial condition.
141
142
9.2. PERSPECTIVES
9 THROMBOSIS MODEL AND SIMULATION
Modelling and Simulation of Clot Formation and Platelet

Aggregation Under Flow
9.1 Thrombus development modelling under flow
In this section we formulate the model of blood coagulation and

clot growth in a 2D rectangular domain. We use reaction-diffusion
equations with convection terms to describe blood factor
concentrations in plasma. Navier-Stokes equations are used to
simulate blood flow. Clot is considered as a porous medium where
flow velocity is described with the Navier-Stokes equations with
additional terms depending on the clot porosity. This approach
allows us to describe blood flow and clot growth by the same
model without tracking the clot geometry. The model is based on
several biological assumptions as it is devoted to the study of
microvascular thrombosis under specific conditions. The first
assumption concerns the blood flow. In order to mimic the in vivo
143
condition where a pressure gradient drives the flow through the

microvessels, we impose a constant pressure difference between
the inlet and the outlet. Next, we only consider in situ
thrombus formation following the injury of a part of the vessel

wall. Other clotting initiation mechanisms such as thrombin
activation by ADP are not included in the model. Among the other
simplifying assumptions is reducing the study to the fibrin-rich
microvascular clots which are known as “red" thrombi. These
microvascular thrombi usually develop in microvessels such as
arteriols, venules and capillaries. Platelets aggregation is less
important in the dynamics of the formation of these clots. Thus,
we do not consider platelets, red blood cells and their role in the
coagulation process in this model. We will introduce platelets in
the future developments of the model. Concerning the role of red
blood cells, we note that thrombus growth rates are similar in the
normal blood and in the platelet rich plasma [120]. This result
suggests that erythrocytes do not affect thrombus growth rates.
Their effect is limited to delaying the onset of clot growth through
hindering platelets adhesion. Hence, in the absence of platelets,
red blood cells have no effect on clot growth dynamics. In
continuous models of blood coagulation, red blood cells are taken
into account implicitly through hemodynamics (viscosity, rheology
of blood flow). The influence of individual erythrocytes can be
considered in cell based models where blood flow is modeled as a
heterogeneous fluid which consists of plasma and blood cells.
Such models become very complex and computationally
expensive. They are developed for blood flows with platelets and
erythrocytes but without blood coagulation and with platelets and
blood coagulation but without erythrocytes. To the best of our
knowledge, the works taking into account all three of these
factors do not yet exist due to the extreme complexity of such
modeling. The Von Willebrand factor and its role in carrying factor
VIII in the plasma not included in the model either. To further
simplify the study, we restricted the described coagulation
144
cascade to the most important proteins participating in the
clotting process. Although a more detailed description of the
9.2. PERSPECTIVES
clotting cascade will improve the model, the resulting complexity

will make the interpretation of the obtained results more difficult.
Furthermore, we consider the vessel walls to be rigid and not
deformed neither by changes in
9.1. THROMBUS DEVELOPMENT MODELLING UNDER FLOW
blood flow nor by thrombus development. Finally, although the

model can be used for 3D modelling of thrombosis development,
the present work is limited to 2D study case. We expect the main
conclusion to be qualitatively similar though they can be different
quantitatively in the 3D case. 3.1.1 Exhaustive spatiotemporal
model of clot growth Blood factors concentrations. The clotting
cascade is initiated following the activation of factors IX and X by
the complex of tissue factor and factor VII. The latter is present
along a damaged portion of the vessel wall. The concentration of
tissue factor at the damaged wall is considered to be constant.
After their activation, factors IX and X convert an initial amount of
prothrombin into thrombin. This is known as the initiation phase.
When the concentration of the generated thrombin is sufficiently
high, it activates some factors of the amplification phase such as
factor V, VIII and XI. These factors further convert more
prothrombin into its active form. As the result, a positive feedback
loop of thrombin generation is sustained. This loop can be
inhibited by activated protein C. It is an anticoagulant protein
which is activated by the complex of thrombin and
thrombomodulin formed at the intact tissues. Another important
anticoagulant protein present in the model is antithrombin. It
inactivates several factors in the coagulation cascade. In our
model, we will restrict the role of antithrombin to the direct
inhibition of the thrombin. The part of the clotting cascade
described in our model is shown in Fig. 4.1 a. We consider a two-
145
dimensional rectangular domain that corresponds to a section of

blood vessel (Fig. 4.1 b). Blood flow crosses it along the axial
direction. The computational domain corresponds to vessels with
50 μm diameters. This allows us to model the conditions observed
in the experiments conducted in [122] and [53]. Clot development
in microvessels with different heights can be studied with the
same model. We consider the following model of clot formation
whose formulation was presented in the previous Chapter:
prothrombin
∂P/ ∂t +∇.(vP) = DΔP− k1φc +k2Ba + k3T3/(1+k8Ca) P, (9.1.1)

thrombin
∂T/∂t +∇.(vT) = DΔT + k1φc +k2Ba + k3T3/ (1+k10Ca)P−k4AT, (9.1.2)
factors IXa, Xa
∂Ba/∂t +∇.(vBa) = DΔBa −k5ABa, (9.1.3)
APC ∂Ca/∂t +∇.(vCa) = DΔCa −kcCa, (9.1.4)
antithrombin ∂A/ ∂t +∇.(vA) = DΔA−k4AT −k5AB, (9.1.5)
fibrinogen ∂Fg/∂t +∇.(vFg) = DΔFg − k6T Fg K6 +Fg , (9.1.6)
fibrin ∂F/∂t +∇.(vF) = DΔF + k6T Fg K6 +Fg −k7F, (9.1.7)
fibrin polymer ∂Fp/ ∂t = k7F. (3.1.8)
Boundary conditions. In order to describe the generation of

thrombin in the initiation phase at the damaged endothelial wall,
we consider the complex T∗ f formed by the tissue factor and
factor VII. Factors IX and X interact with this complex due to a
surface reaction. They come from the bulk solution being inactive,
form a complex [T∗ f B] with T∗ f and return to the solution in the
active form. The reaction rate for the surface concentration of this
146
complex can be written as follows:
9.2. PERSPECTIVES
∂ [T∗ f B]/ ∂n = k+ f B(T∗ f −[T∗ f B])−k− f [T∗ f B], where the first
term in the right-hand side of this equation describes the flux of B
to the surface, the second term describes the flux from the
surface. Assuming that this reaction is fast, we can use the
detailed equilibrium
k+ f B(T∗ f −[T∗ f B]) = k− f [T∗ f B].

Then [T∗ f B] = kf BT∗ f 1+k f B, (9.1.9) where kf = k+ f /k− f . The
boundary conditions for the variables B and Ba at the damaged
surface are as follows:
∂B /∂n = −k+ f B(T∗ f −[T∗ f B]),

∂Ba/ ∂n = k− f [T∗ f B],
We prescribe the zero flux condition at the intact surface. In order

to simplify the boundary conditions, let us introduce the variable
z = B+Ba. From equations (9.1.3) and the boundary conditions for
B and Ba we get:
∂ z /∂t +∇.(vz) = DΔz−kbz,
∂ z/ ∂n = 0. (9.1.10)
Assuming that initially B + Ba = B0, where B0 is the initial

concentration of factors IX and X, we conclude that the solution of
problem (9.1.10) is identically constant, B + Ba = B0. Hence we can
exclude the variable B from the equations and from the boundary
condition:
(∂Ba /∂n) Γd = α1(B0 −Ba) 1+β1(B0 −Ba) , (9.1.11)
where α1 = k− f kf T∗ f and β1 = kf . Protein C is activated by the
complex of thrombin-thrombomodulin. The fluxes of protein C at
the surface in its active and intactive forms are given as follows:
∂C/ ∂n = −k+ c C((T Tm)−(CTTm)),
∂Ca/∂n = k− c (CTTm). Here Tm is the concentration of
147
thrombomodulin present at the undamaged surface. Protein C

arrives next to thrombin and thrombomodulin and forms the
complex (CTTm). Here k+ 8 is the reaction rate constant of protein
C activation by the complex of thrombin thrombomodulin, k− c is
the rate of the inverse reaction. Again using the detailed
equilibrium, we obtain the condition of APC production on
undamaged walls:
(∂Ca/∂n ) Γu = α2(C0 −C)[T Tm] 1+β2(C0 −Ca) , (9.1.12)

[T Tm] = kT T Tm 1+kT T Tm , (9.1.13)
where α2 = k− c kc and β2 = kc, [T Tm] is the complex thrombin
thrombomodulin that activates protein C present in blood plasma.
We consider the no-flux boundary conditions for these
concentrations at the other parts of the boundary and also for
other concentrations. In the case of nonzero flow velocity, the
concentrations of prothrombin, fibrinogen and antithrombin at
the entrance of the domain (x = 0) are kept constant .
Blood flow model.
We use the Navier-Stokes equations to describe the blood flow.

Non-Newtonian properties of blood are not taken into account.
We model clot as a porous medium with the porosity depending
on the concentration of fibrin polymer . The flow through the clot
is modelled by the Navier-Stokes equations with additional terms
which describe the fluid deceleration by the porous medium. The
advantage of this approach is that we use the same model in the
whole computational domain. We do not need to determine the
clot geometry and to solve Navier-Stokes equations in the outer
(with respect to the clot) domain. We have the following
equations for the incompressible fluid flow:
ρ ∂u/∂t +u∇u = −∇p+ μΔu− μ Kf(x) u, (9.1.14)

∇u = 0,
where u = (ux,uy) is the velocity vector, p is the pressure, ρ the
148
desnity of blood, μ the viscosity, H the height of the vessel. In this
9.2. PERSPECTIVES
work we consider laminar incompressible flow. Kf is the hydraulic
permeability of fibrin polymer :
Kf(x) = 1/16 α2 Fp(x) 1.5(1+56Fp(x) 3). (9.1.15)
Here α is the fiber radius. We prescribe the no-slip boundary

conditions for the velocity at the upper and lower walls, and
periodic boundary conditions in the axial direction. The periodic
boundary conditions for the velocity are convenient since they
allow us to study steady state flows where the velocity at the
entrance and at the exit of the flow are not fixed and can vary in
time. Blood flow is driven by the pressure difference. Therefore,
we use periodic boundary conditions for velocity coupled with
constant pressure difference condition: pin = pout +Δp, (9.1.16)
where pin is the pressure at the inlet, pout is the outlet pressure
and Δp is the pressure difference which is considered as an
imposed constant. Contrary to the condition of fixed inlet velocity,
this imposed pressure difference condition allows the clot to
completely occlude the vessel and obstruct the flow. This
condition is verified in experimental settings as well as in some
areas of the circulatory system such as capillary networks. It is not
verified for large arteries where wall shear rate is high. Numerical
implementation. Reaction-diffusion system of equation is solved
numerically with a finite difference method and an upwinding
scheme in discretizing convective terms in order to avoid
numerical instabilities in the convection dominated cases. A
regular 2000 × 400 mesh is used in the numerical simulations.
Accuracy of the results was controlled by decreasing the time and
space steps. Numerical implementation of the Navier-Stokes
equations is carried out with the projection method , and
Successive Over Relaxation (SOR) method is used to solve the
pressure Poisson problem. Finally, we introduce a simplified
model of pressure driven Poiseuille flow and describe the exact
conditions for blood flow to stop thrombin wave propagation.
149
Thrombin is the most important enzyme of the coagulation

cascade. The formation of the fibrin clot is always preceded by the
propagation of a thrombin wave. The behavior of this wave
depends on the local concentrations of the clotting factors as well
as the perturbations caused by the flow. The propagation of
thrombin wave can only occur if the characteristic reaction time is
lower than the characteristic convection time. To mathematically
capture the dynamics of the thrombin wave propagation, we

derive a simplified analytical model of thrombin distribution from
the system . The model describes the evolution the thrombin
wave front and admits mathematical investigation.We replace the
concentrations of factors IXa, IXa distribution (Ba) by their steady
state values obtained as stationary solutions of equations .
Furthermore, the model does not take into account neither
prothrombin nor antithrombin consumption. The concentrations
of these two proteins are introduced as constants. Let us consider
the 1D model describing the thrombin distribution in the vertical
cross section of the 2D model:
∂T/ ∂t = D ∂ 2T/ ∂ y2 +Φ(T, y), (9.1.17)

where Φ(T, y)=(k2Ba(y) +k+ 3 T3)(P0 −T)−σ(y)T, D is the diffusion
coefficient, P0 is the prothrombin concentration initially present in
blood flow, k1 and k2 are kinetic coefficients. The function Ba(y)
expresses the initiation of thrombin generation by factors IXa and
Xa. It corresponds to a stationary solution of the equation (9.1.3),
Ba(y) = λe−y/σ . The coefficient σ represents inhibition of
thrombin production by antithrombin and blood flow. We set σ =
k4A0 + av(y), where A is the antithrombin concentration supposed
to be constant, and v(y) is blood flow velocity in the horizontal
direction. Inhibition by APC can be taken into account in the
nonlinear reaction term. For simplicity, we do not consider it here.
Equations are decoupled, and the corresponding concentrations
do not directly influence thrombin production. The flow velocity is
replaced by an approximate solution of the Navier-Stokes
150
equations specified below. If k3 = α2 = 0, then the function Φ does
9.2. PERSPECTIVES
not depend on y, and (9.2.27) is an autonomous reactiondiffusion
equation. It has a traveling wave solution T(y,t) = W(y − ct), where
c is the speed of wave propagation . This function satisfies the
equation W+cW+Φ(W) = 0 (dependence of the function Φ on y is
omitted here) considered on the whole axis with the limits at
infinity W(−∞) = T∗,W(∞) = 0, where T∗ is the maximal solution of
the equation Φ(T) = 0. Solution of equation (9.2.27) converges to
the travelling wave solution if the initial condition is sufficiently
large. The speed of the wave is positive if and only if the following
condition is satisfied [115]:
T∗ 0 Φ(T, y)dT > 0. (9.1.18) Only positive velocity of thrombin

wave propagation corresponds to the regime clot growth.
Condition (9.1.18) also implies that thrombin production exceeds
its loss due to its inhibition by antithrombin and blood flow. Let us
then consider the case of nonzero coefficients k 3 and k4 and
function Φ depending on y. If we assume that this dependence is
weak, that is the derivative ∂Φ/∂ y is sufficiently small, we can use
inequality (9.1.18) for each fixed value of y. Let us take the value
of y equal to zero that corresponds to the coordinate of the cell
wall and then increase it considering the thrombin concentration
on some positive distance from the wall. At some moment the
inequality (9.1.18) will be no more satisfied and the critical value
of y will give an approximation of the maximal clot height. We
specify the conditions of the thrombin wave propagation (9.1.18)
for the exact expression of function Φ . At y = 0, we have Ba(0) = λ
and v(0) = 0, hence from (3.1.18) we get: A0 < 1 k4 2k2λ P0 T∗
−k2λ +k+ 3 (T∗)2P0 2 −2k+ 3 (T∗)3 5 . (3.1.19)
Figure 3.1: The final height of the clot for different damaged area
widths. Simulations were run for 10 minutes and the stable clot
heights were reached after 2 - 3 minutes of simulations time in
agreement with expermental data. : a) in quiescent plasma, b) in
151
pressure driven flow with an initial parabolic flow v(y) where

v(H/2) = vm = 400 μm/s and A0 = 0.4. In both cases there is a
sharp transition from the partial occlusion regime to the complete
occlusion as the clot width exceeds some critical value. This
critical value is much larger for blood coagulation in flow. If this
condition is satisfied, then the initial quantity of thrombin
produced near the vessel wall is sufficiently large to initiate clot
growth. Otherwise the clot will not form. From the
pathophysiological point of view this situation corresponds to
bleeding, and it can occur for example in case of hemophilia or

treatments with anticoagulant drugs.
The regimes of microvessel occlusion Blood flow influences clot

growth in multiple ways. It brings fibrinogen and inactivated blood
factors to the growing clot accelerating chemical reactions. At the
same time blood flow removes thrombin and thus prevents
thrombin accumulation due to the positive feedback loops of the
coagulation cascade and thus slows down clot growth. Finally,
blood flow transports APC generated at the intact surface to the
wound region thus contributing to the downregulation of the
thrombin production. At the same time, growing clot modifies the
blood flow dynamics. In our computational model this influence
depends significantly on the conditions imposed on the flow
velocity at the boundaries of the considered domain. Let us
consider first the case where the fluid velocity at the entrance of
the computational domain is time independent. Since fluid
velocity decreases inside the clot, then the velocity would
increase in the part of the cross section of the vessel without clot
according to the mass conservation law. The resulting high fluid
velocity prevents clot growth removing thrombin and other blood
factors participating in coagulation reactions. If we consider the
limiting case where the clot has zero porosity and the fluid
velocity inside the clot is zero, then complete vessel occlusion is
not possible since fluid should leave the computational domain.
152
The situation is different in the case of a pressure driven flow
9.2. PERSPECTIVES
where the fluid velocity at the entrance is not fixed and the total
flow rate can decrease due to the hydrodynamic resistance
exerted by the clot. For a given pressure difference, the fluid
velocity can decrease and the total vessel occlusion becomes
possible. In this case there are two competing factors determining
the blood flow dynamics. Flow velocity increases in the narrow
part of the vessel, and the total flow rate decreases because of
the clot resistance. It appears that the first factor is more
important in the case where the width of the clot is small, while
the second one becomes more important in case of large clot. To
better understand the dynamics of clot growth in blood flow, we
calculate the dimensionless Damköhler number (Da). This number
represents the degree of conversion that can be achieved by a
reaction. It corresponds to the division of the reaction rate by the
convection rate. In order to estimate the Damköhler number for
prothrombin conversion, we proceed with the
nondimensionalization of the reaction-diffusion system .
Considering the concentrations to be already nondimensional, we
define other nondimensional variables denoted by:
x∗ = x H ,
∇ = ∇∗ 1/H ,
Δ = Δ∗ 1/H2 ,
v = v∗ v0 ,
t ∗ = t H/v0 . where v0 and H are the characteristic flow velocity
and length which is also the vessel diameter. We also consider
transformations for the kinetic rate constants of the system: k∗ i =
ki k0 i = 1,..,9 k∗ a = ka k0 a , where k0 is the characteristic kinetic
rate of the system. With these nondimensional variables,
equation (9.1.2) becomes:
∂T /∂t∗ +∇∗.(v∗T) = D v0H Δ∗T + H v0 (Φ∗(T,Ba,Ca)P−k∗ 4AT),

(9.1.20)
where Φ∗(T,Ba,Ca) = k∗ 2Ba + k∗ 3T3/( 1+k∗ 8Ca ). Under these
153
conditions, we define the Damköhler number at the front where

Ba = 0 and Ca = 0 and considering that for t >> 0, thrombin
concentration at the bottom boundary equals P0. We give its
expression as follows:
Da = H v0 k∗ 3P40 −k∗ 4A0P0 . (9.1.21) The final height of the clot
in case of different values of the initial blood flow velocity. a):
numerical simulations for three different values of antithrombin
concentration in plasma (A0). b): numerical (solid line) and
analytical (dashed line) solutions of the simplified model for A0 =
0.4. For the exhaustive and simplified models we observe
complete occlusion for low flow velocities and partial occlusion
for high velocities with a sharp transition between these two

regimes. The dependence of the final clot size on the initial flow
velocity . The complete vessel occlusion occurs only if the flow
velocity is small enough. If the flow velocity is sufficiently large,
then the size of the clot remains bounded (partial occlusion). We
again observe a sharp transition between these two regimes for
our model. Thus, the observed three regimes of clot growth:
initiation without propagation, initiation with limited propagation
(partial occlusion), and initiation with unlimited propagation
(complete occlusion) are qualitatively similar for the clot growth
in quiescent plasma and in the blood flow. In the next section we
will determine the conditions of the existence of each of these
three regimes on the basis of the simplified theoretical model.
The quantification of the procoagulant effects of platelets on clot
growth .
We use a previously developed model of clot growth dynamics

already presented . The model consists of reaction-advection-
diffusion equations describing the spatiotemporal distributions of
blood coagulation factors during thrombus development:
platelets in flow
154
9.2. PERSPECTIVES
∂ φf /∂t +∇.(k(φc)vφf) = k(φc)DpΔ(φf)−k9Tφf −k10φf φc, (9.1.22)
platelets in clot
∂φc/ ∂t +∇.(k(φc)vφc) = k(φc)DpΔ(φc) +k9Tφf +k10φf φc, (9.1.23)
Here v is the flow velocity, D is the diffusion coefficient that is

taken the same for all proteins and k(φc)Dp is the effective
diffusion coefficient for platelets,
where k(φc) = tanh(π(1− φc+φf φmax )) a decreasing function.

Fibrin polymer forms a solid clot, it does not diffuse and it is not
transported by flow.
9.2. THE QUANTIFICATION OF THE PROCOAGULANT EFFECTS OF

PLATELETS ON CLOT GROWTH
To incorporate the action of blood flow on clot growth, we use

the Navier-Stokes equations to describe the dynamics of blood
flow in the vessel.
ρ ∂u /∂t +u∇u = −∇p+ μΔu− μ /Kf(x) u, (9.2.24)
∇u = 0, where u = (ux,uy) is the velocity vector, p is the pressure, ρ

the desnity of blood, ν the kinematic viscosity, H the height of the
vessel. In this work we consider laminar incompressible flow. Kf is
the hydraulic permeability of fibrin polymer :
1 Kf(x) = 1/16 α2 Fp 1.5 (1+56F¯ p(x) 3) 1+φ¯ c(x) 1−φ¯ c(x) .
(9.2.25) Here F¯ p and φ¯ c are the normalized concentration of
fibrin polymer and density of platelets in the clot respectively, α is
the fiber radius. We prescribe the no-slip boundary conditions for
the velocity at the upper and lower walls, and periodic boundary
conditions in the axial direction. Blood flow is driven by the
155
pressure difference. Therefore, we use periodic boundary

conditions for velocity coupled with constant pressure difference
condition:
pin = pout +Δp, (9.2.26) where pin is the pressure at the inlet, p out is
the outlet pressure and Δp is the pressure difference which is
considered as an imposed constant. Contrary to the condition of
fixed inlet velocity, this imposed pressure difference condition
allows the clot to completely occlude the vessel and obstruct the
flow. 3.2.2 Quantitative study of platelets procoagulant effects on
thrombus development We consider the following reduced
thrombin distribution model:
∂T /∂t = D ∂2T /∂ y2 +Φ(T, y), (9.2.27)
where Φ(T, y)=(k1φ0 +k2Ba(y) +k+ 3 T3)(P0 −T)−γ(y)T, D is the

diffusion coefficient, P0 is the prothrombin concentration initially
present in blood flow, k1, k2, and k+ 3 are kinetic coefficients. The
function γ(y) = k4A0T +aγT shows the influence of antithrombin
and of shear rate in the downregulation of thrombin production.
Here H is the width of the vessel, vm is the maximal flow velocity
at its axis. This means that we neglect the boundary effects of clot
initiation and the blood flow (quiescent plasma). If P 3 0 <
(27k4A0)/(4k∗ 3), then this function has three zeros, T = 0 and
T1,T2, where T0 < T1 < T2. The equilibria T0 = 0 and T = T2 are
stable as solutions of the corresponding ODE, while T = T1 is
unstable. Thus, we obtain a classical reaction-diffusion equation in
the bistable case. If it is considered on the whole axis, it has
travelling wave solutions, that is solutions of the form T(x,t) = W(x
− ct), where W is a solution of the equation DW+cW +Φ0(W) = 0,
W(−∞) = T2, W(∞) = 0, and c is the speed of propagation. In the
case of a positive speed c, such solution describes clot growth. It is
known that the wave speed is positive if and only if T2 T0 Φ0(T)dT
> 0 (9.2.28)
156
9.2. PERSPECTIVES
Thus, the condition on shear rate for thrombin propagation is as
follows:
γ > 1 aT2/2 k1(φ0P0T2/2−φ0T2 2 /3) +k2(BaP0 −BaT2/2) +k+ 3 (P0T3

2 /4−T4 2 /5)−k4A0T2/2−av(y)T2/2 . (9.2.29)
Let us denote the shear rate threshold by γ∗ = 1 aT2/2

k1(φ0P0T2/2−φ0T2 2 /3) +k2(BaP0 −BaT2/2) +k+ 3 (P 0T3 2 /4−T4 2
/5)−k4A0T2/2−av(y)T2/2
Thrombus development modelling under flow In this section we

formulate the model of blood coagulation and clot growth in a 2D
rectangular domain. We use reaction-diffusion equations with
convection terms to describe blood factor concentrations in
plasma. Navier-Stokes equations are used to simulate blood flow.
Clot is considered as a porous medium where flow velocity is
described with the Navier-Stokes equations with additional terms
depending on the clot porosity. This approach allows us to
describe blood flow and clot growth by the same model without
tracking the clot geometry. The model is based on several
biological assumptions as it is devoted to the study of
microvascular thrombosis under specific conditions. The first
assumption concerns the blood flow. In order to mimic the in vivo
condition where a pressure gradient drives the flow through the
microvessels, we impose a constant pressure difference between
the inlet and the outlet. Next, we only consider in situ thrombus
formation following the injury of a part of the vessel wall. Other
clotting initiation mechanisms such as thrombin activation by ADP
are not included in the model. Among the other simplifying
assumptions is reducing the study to the fibrin-rich microvascular
clots which are known as “red" thrombi. These microvascular
thrombi usually develop in microvessels such as arteriols, venules
and capillaries. Platelets aggregation is less important in the
157
dynamics of the formation of these clots. Thus, we do not

consider platelets, red blood cells and their role in the coagulation
process in this model. We will introduce platelets in the future
developments of the model. Concerning the role of red blood
cells, we note that thrombus growth rates are similar in the
normal blood and in the platelet rich plasma [120]. This result
suggests that erythrocytes do not affect thrombus growth rates.
Their effect is limited to delaying the onset of clot growth through
hindering platelets adhesion. Hence, in the absence of platelets,
red is were considered to be rigid and not deformable by the flow.
Although our model encompasses the main
features of injury-induced blood clotting, it
does not include platelets and their role in the
coagulation process. Platelets increase the
strength of the clot by aggregating and

forming a plug . They detach when exposed
to high shear stress and migrate with blood
flow leading to embolisms. They may
stimulate clot growth to a certain level. Still,
they are affected by blood flow similarly to
thrombin and the other factors. Hence,
considering blood clotting without platelets is
still valid for an initial approach. We will
include the effect of platelets aggregation in
a more complete model of coagulation in a
forthcoming work and the study the action of
combined anticoagulant and antiplatelet
treatments. Another limitation of our model is
the considered vitamin-K dependent factors.
In order to use mathematical investigations,
we assumed that warfarin only reduces the
concentrations of factors IX, X and
prothrombin. In reality, warfarin treatment
down- regulates the synthesis of other factors
158
such as protein C and S as well as factor VII.
9.2. PERSPECTIVES
The reduction of the anti-coagulant
proteins C and S in bloodstream is observed
only the first three days of the treatment
(hypercoagulation phase) . Then, the
reduction of procoagulant factors IX, X and
prothrombin overshadows the decrease in the
anticoagulant proteins. Lastly, in our model,
the role of antithrombin was reduced to the
direct inhibition of thrombin. In reality,
antithrombin also inhibits factors of the
initiation phase such as factors IX, X and XI .
We have studied the direct inhibition of
thrombin by antithrombin since it is exclusively
present in the real in vivo blood clotting and
not considered in INR tests.
Our results not only explain the persistence
of reccurent thrombosis and bleeding during
warfarin treatment, but can also serve as a
basis for individualized INR prediction. This
methodology can be used by clinicians to
adjust the administrated warfarin dose,
especially for those with an embolic risk higher
than 3. We suggest that the current test for INR
should be accompagned with venous pressure
as well as antithrombin measurements. Our
computational models can be used then to
predict the appropriate INR that should be
targeted during warfarin therapy.
159
160
9.2. PERSPECTIVES
10 PRECAUTION FOR THROMBOSIS
DIAGNOSIS AND TESTS
How is it diagnosed?
A diagnosis of thrombosis usually happens in a hospital. However,

healthcare providers may start suspecting it in a healthcare
setting like a doctor’s office or an urgent care-type clinic. If it
happens outside a hospital, medical professionals will likely treat
your case as a medical emergency because of the risk of heart
attack, stroke or pulmonary embolism, all of which are life-
threatening.
A healthcare provider diagnoses thrombosis based on a

combination of your medical history, questions they ask you, a
physical examination, laboratory tests, imaging tests and other
diagnostic methods. The tests they use may vary greatly
depending on the conditions they suspect or are possible.
What tests will be done to diagnose this condition?
The following test types are most likely when a healthcare

provider suspects thrombosis:
161
Physical exam
A physical exam is where a doctor looks at different areas on your

body for visible signs of a problem. They’ll also feel areas of
concern (for problems like swelling, tissue changes or
temperature changes), and listen to your heart, breathing and
digestive system.
In cases where they suspect thrombosis in your arms or legs, they

might listen to the sound of your pulses in your affected limb.
That can help them figure out the approximate location of a clot.
Imaging tests
Healthcare providers will use a wide range of imaging tests to let

them “see” inside your body, too. These tests help with
diagnosing and locating blood clots, as well as guide treatment.
Some of the possible tests include the following methods:
 X-rays. This also includes computed tomography (CT)

scans, which use a computer to assemble X-ray images
into a 3D picture of the inside of your body. These
methods may also involve substances that a healthcare
provider injects into your body. These substances are
highly visible depending on the imaging method, which
can help highlight any areas where blood isn’t circulating.
 Ultrasound. Tests that use this involve ultra-high-
frequency sound waves that help generate a picture of the
inside of your body. The sound waves bounce off different
areas inside of your body, much like how dolphins and
bats use sonar to “see” in places where there’s no light.
 Magnetic resonance imaging (MRI). This imaging method
uses a very powerful magnet and computer processing to
create a high-resolution picture of the inside of your body.
162
Laboratory tests
9.2. PERSPECTIVES
Because clotting is something your blood does naturally, lab tests
on your blood can help analyze and determine if your blood clots
too easily. These tests can also help discover why your blood is
clotting and can help decide on possible treatments.
These tests usually look for the following:
 Blood components. This includes several tests that

measure certain types of blood cells like platelets and
chemical compounds, especially ones that affect clotting.
 Clot-formation markers. These are chemicals that typically
only show up in your blood if you have a clot at the time.
They can help healthcare providers confirm or rule out an
active clot as the source of a blockage.
 Heart damage markers. An example of this is troponin, a
protein found in muscle cells. Your heart muscle cells
contain a very specific type of troponin that doesn’t occur
elsewhere in your body. Damage to your heart cells, such
as from a heart attack, causes troponin to leak out of those
cells and into your blood. Tests that detect troponin can
help confirm or rule out heart attacks, which often happen
because of thrombosis.
MANAGEMENT AND TREATMENT
How is it treated?
Treatment of thrombosis depends strongly on why it’s happening

and what parts of your body it affects. In some cases, such as
when it’s happening because of a genetic or inherited condition,
thrombosis is potentially treatable but not curable.
Treatment of thrombosis can take several different forms. It can

involve medication, surgery, minimally invasive catheter
163
procedures and more. In many cases, thrombosis treatment starts

with prevention, keeping clots from forming and becoming a
danger.
What medications or treatments are possible for thrombosis?
Treatment of thrombosis can involve any — including various

combinations — of the following:
Preventive medications
Preventive treatments for thrombosis typically involve a few

different classes of medications. These usually include one or
more of the following:
 Blood-thinners. These medications keep your blood from

clotting too easily. There are different types of blood-
thinners, including antiplatelet, anticoagulant and
fibrinolytic drugs.
 Blood pressure-lowering medications. Over time, high
blood pressure puts too much stress and wear on the
inside of your blood vessels. This kind of wear and tear can
make it easier for blood clots to form and grow on your
vessel walls. Blood pressure medications prevent clots by
not giving them new places to form.
 Cholesterol-lowering medications. Your cholesterol levels
directly influence the buildup of plaque on the inside of
your blood vessels. Lowering your cholesterol limits that
buildup.
Acute medications
Acute blood clots (meaning they started very recently) are also
treatable with medications. These medications usually include the
following:
164
 Blood-thinners (for the same reasons mentioned under
“Preventive treatments” above).
9.2.
 PERSPECTIVES
Clot-busting drugs. These drugs break down existing clots,
which is especially helpful when a clot is in a critical area.
Drugs like this are common in the treatment of heart
attack, stroke and other thrombosis-related conditions.
Healthcare providers may also prescribe other medications, such

as pain medications or blood pressure medications, which will
ease your symptoms and improve blood flow.
Surgery and catheter procedures
Depending on the location and size of the clot, healthcare

providers may be able to go in and remove the clot directly. This
kind of clot removal, known as thrombectomy, can happen in a
few different ways:
 Surgery. One of the most direct ways to remove a clot is

for a surgeon to access it directly and remove it. In some
cases, they may also use surgery to do a bypass, where the
surgeon takes a section of blood vessel from elsewhere in
your body and uses it to construct a bypass, or detour,
around an area of another blood vessel that’s very narrow.
This restores blood flow to the affected parts of your body.
 Catheter procedures. These types of procedures use a
long, thin, tube-like device called a catheter. A healthcare
provider inserts this device into a major blood vessel
somewhere on your body and steers the catheter through
your blood vessels to the blocked area. Once there, they
can use devices on the tip of the catheter to break apart
and suck up the clot fragments (rheolytic thrombectomy),
and/or inflate a small balloon on the tip of the catheter to
widen narrow sections of a blood vessel. They can also
sometimes place a stent, a scaffold-like device, which acts
as a support to hold your blood vessel open.
165
Complications/side effects of the treatment
The possible complications from thrombosis depend strongly on

the location of the clot(s), why they formed and treatments used.
Your healthcare provider is the best person to explain the
potential complications and side effects, as well as any potential
risks.
How to take care of myself/manage symptoms?
You should only manage a thrombosis according to guidance from

your healthcare provider. Thrombosis is a very dangerous
condition, and your healthcare provider is the best person to
determine how to safely and effectively treat a clot.
How soon after treatment will I feel better, and how long does it
take to recover from treatment?
Most people who receive treatment for thrombosis feel better as

they’re treated, especially with restoration of blood flow to
previously blocked areas. That can happen in minutes or hours,
depending on the location and size of the clot and the specific
treatments.
In cases where you had severe effects from a clot, especially ones
that caused a life-threatening event like a heart attack or stroke, it
may be a few days before you start feeling better. That’s
especially true if you need surgery or more intensive procedures
and care.
Your healthcare provider is the person who bests understands

your case. They can tell you more about what to expect, especially
regarding your specific circumstances, and answer any questions
you might have.
PREVENTION
166
How can I reduce my risk?
9.2. PERSPECTIVES
There are several circumstances or health conditions that can
increase your risk for this condition. Managing them can help
reduce your chance of developing thrombosis and the dangerous
conditions that can follow. The circumstances you can influence
include:
 Blood pressure.
 Cholesterol.
 Obesity.
 Diabetes.
 Kidney problems.
 Liver problems.
 Your level of physical activity.
 Smoking (or other forms of tobacco use).
How can I prevent this?
When you know you’re at risk for clots, prevention is much easier.
The best way to know about your risk is to get an annual physical
(wellness visit or checkup). Many conditions that increase your
risk for thrombosis are detectable during a checkup long before
clots ever form. If your healthcare provider finds any conditions or
concerns that increase your risk, they can guide you on what to do
to care for yourself.
Other ways to prevent clots from forming include:
 Move around. Sitting for long periods can greatly increase

your risk of thrombosis. If you work in a job where you sit
or hold still for long periods, try taking short breaks. Even
standing up and stretching for a couple of minutes can
help. For those who are unable to stand up or move about
because of health conditions or circumstances, your
167
healthcare provider may be able to offer alternative ways

for you to keep your blood moving with activity.
 Quit tobacco or don’t start. Smoking and other forms of
tobacco use (including vaping and smokeless tobacco
products like snuff or chewing tobacco) greatly increase
your risk of thrombosis. Quitting tobacco products or not
starting them at all can make a big difference when it
comes to prevention.
 Manage your weight with diet and exercise. Eating a
healthy diet and getting enough exercise (150 minutes of
moderate-intensity activity per week) can help you lower
your risk of thrombosis.
 Take your medication. If your healthcare provider
prescribes medication, be sure to take it as they instruct,
or ask them about how you can take it. The risk of
dangerous complications increases sharply if you suddenly
stop taking many of the medications that prevent
thrombosis, especially blood-thinners. It’s also dangerous
to take more than the recommended amount, such as
after forgetting to take a dose.
OUTLOOK / PROGNOSIS
What can I expect if I have this condition?
If you have thrombosis, it’s important to get immediate medical

care, such as in a hospital emergency room. That’s because
thrombosis can very easily become one of several extremely
dangerous — and deadly — conditions. The longer thrombosis
continues, the more likely it is that one of those dangerous
conditions will occur.
How long does thrombosis last?
How long thrombosis lasts depends on the underlying cause, the

treatments and how quickly you seek medical attention. In
168
general, the shorter the time you have thrombosis, the better off
you are. That’s why getting medical attention quickly is so critical.
9.2. PERSPECTIVES
While thrombosis may be short-lived (ideally), the dangerous
conditions that cause it can be chronic or even life-long. Some of
them, especially genetic or inherited diseases and conditions, are
ones you have when you’re born.
What’s the outlook for this condition?
Thrombosis is a serious condition, but usually isn’t dangerous on

its own unless it lasts for longer periods. The problem with
thrombosis, though, is that it very easily turns into a dangerous,
life-threatening emergency. But with immediate medical care, it’s
usually possible to avoid serious complications. However, the
longer it takes for that care to start, the greater the danger from
this condition (or the conditions that happen because of it). The
outlook or prognosis with thrombosis also strongly depends on
where it happens and whether or not it affects any other part of
your body. A clot that stays in place is a problem, but is usually
less dangerous than a clot traveling in your bloodstream. The
outlook for this condition can become much worse when a free-
floating clot carried in your bloodstream ends up in a critical
organ like your heart, brain or lungs. If this happens, timing
becomes critical, and minutes may end up deciding whether or
not you have a good outcome.
LIVING WITH
How do I take care of myself?
Because thrombosis is usually a short-lived condition, it’s not

something you’ll likely have to live with for very long. However,
many people have conditions or circumstances that put them at
risk for developing thrombosis, and some of those conditions are
life-long.
169
The best thing you can do if you’re at risk of developing

thrombosis is to prevent it from happening. That means seeing a
healthcare provider regularly, taking prescribed medications,
taking care of your overall health and watching for symptoms that
indicate you have a problem.
When should I seek medical care?
You should seek medical attention anytime you have symptoms of

thrombosis, especially symptoms that show part of your body
isn’t getting enough blood flow.
A note from Cleveland Clinic
Thrombosis is a condition that can very quickly become a life-

threatening emergency. The most important thing you can do is
try to prevent thrombosis, especially if you know you’re at risk for
this condition. While this isn’t always possible, taking actions
ahead of time can make it less severe if it does happen. You can
also greatly improve your chances of a positive outcome if you
don’t delay getting emergency medical care. And, be sure to talk
to your doctor about any concerns, as they are your best source
of information about your specific situation.
Thrombosis is the development of blood clots in the veins or

arteries, most often in the legs. Learn how to define thrombosis,
and then explore its causes, symptoms, the risk factors for it, and
treatment. Clot in this part of your brain stops blood from
draining out.
Symptoms
Thrombosis interrupts blood flow through a blood vessel,
170
9.2. PERSPECTIVES
reducing the amount of blood that reaches the parts of the body
that the vessel supplies. The symptoms of
thrombosis generally stem from a lack of oxygen in the affected
body parts.
DVT
DVT typically develops in the deep veins of the legs, though it can

develop in the pelvis or arms. Symptoms tend to occur in the
affected limb or area and may include:
 swelling
 itchiness
 throbbing, aching, or cramping pain
 skin that is warm to the touch
 skin discoloration or thickening
People with DVT may develop a condition called post-thrombotic
171
syndrome in the following weeks or months. This condition may

cause chronic symptoms in the affected limb or area that may
include:
 cramps
 swelling
 pain
 skin discoloration
PE
Symptoms of this type of embolism include:
 chest pain
 an irregular or rapid heart rate
 sudden shortness of breath or difficulty breathing
 coughing up blood
Without treatment, a PE can cause severe breathing difficulties

and even death. Anyone who may be having symptoms of a PE
should receive emergency medical attention.
Causes
172
Optimal blood flow relies on a balance, or “homeostasis,” among
these
9.2. components of blood:
PERSPECTIVES
 blood cells
 plasma proteins
 coagulation factors, which are proteins that help control

bleeding
 inflammatory cytokines, which are molecules that

promote inflammation
A thrombus may develop as a result of an imbalance in these

components. Or, it may result from issues affecting the blood
vessels. A thrombus can also develop when blood flow slows
significantly due to a long period of immobility.
Some other possible causes of blood clots include:
 fractures
 obesity
 certain medications, such as those that contain estrogen
 disease or injury to the deep veins in the arms, legs, or

pelvis
 autoimmune disorders that promote blood thickening, or
173
coagulation
 certain inherited disorders
Risk factors
Several factors can increase the risk of developing thrombosis.

These include:
 surgery or hospitalization, which accounts for

around 50% of blood clots
 bed rest or long periods of sitting
 traveling for more than 4 hours without moving
 smoking
 pregnancy
 certain medications, such as:
o birth control pills or hormone replacement

therapies that contain estrogen
o chemotherapy drugs
 a family or personal history of blood clots
 a history of stroke or heart attack
Some medical conditions that may increase the risk of blood clots
174
9.2. PERSPECTIVES
include:
 high blood pressure
 high cholesterol
 infections
 obesity
 hardening of the arteries, which is called arteriosclerosis
 genetic clotting disorders
 heart and lung conditions
 autoimmune or inflammatory conditions
 major injuries
 leg paralysis
 cancer
Diagnosis
Before diagnosing thrombosis, a doctor will:
 ask about the person’s symptoms, including when they

began
175
 review the person’s medical history, checking for past

surgeries and current medications
 ask whether there is a family history of thrombosis or
related conditions
If the doctor suspects thrombosis, the following diagnostic tests

can help them detect it:
 blood tests to check for the protein fragment “D-dimer,”

which is present when a blood clot dissolves
 ultrasound scans to check for signs of DVT
 CT scanning with intravenous dye to check for a PE
 Ventilation-perfusion scans, which use radioactive

compounds to show parts of the lungs that, are not
receiving sufficient blood flow.
Treatment
The most common and effective treatments for thrombosis are

medications called anticoagulants. These help prevent the
formation of new blood clots. Usually, a person receives injectable
anticoagulants, such as heparin or low-molecular-weight heparin.
176
These medications begin working within hours.
9.2. PERSPECTIVES
In emergency situations, a person with thrombosis medications
called tissue plasminogen activators. They promote the
production of the enzyme plasmin, which is involved in dissolving
clots.
Long-term treatment for thrombosis typically involves

medications called direct oral anticoagulants. These block parts of
the coagulation process. Examples of these drugs
include warfarin (Coumadin, Jantoven) and rivaroxaban (Xarelto).
People who are unable to take anticoagulant medications may

instead undergo surgery to have a filter placed inside the vena
cava, which is a large vein in the abdomen. The filter prevents any
blood clots from traveling to the heart and lungs.
The doctor may also recommend wearing compression stockings

to encourage blood flow and help reduce the risk of long-term
complications from thrombosis.
Treatment side effects
People taking anticoagulation medications have an increased risk

of excessive bleeding. Signs of this issue include:
 severe or excessive bruising
177
 bleeding gums
 prolonged or frequent nosebleeds
 coughing up or vomiting blood
 increased menstrual bleeding
The following further increase the risk of bleeding complications

in people taking anticoagulants:
 being over 65 years of age
 having liver or kidney failure
 having cancer
People taking anticoagulant medications should receive

emergency medical attention if they experience any of the
following:
 a major injury, such as from a car accident
 a head injury
 bleeding that will not stop
Prevention
178
It is not always possible to prevent thrombosis. However, a
9.2. PERSPECTIVES
person who knows that they have a risk of developing blood clots
can take steps to reduce this risk.
Prevention in at-risk individuals
A doctor can perform a VTE risk assessment, and they should do

this whenever a person is admitted to a hospital.
Anyone at risk of VTE typically receives anticoagulation

medications to help prevent blood clots. They may also need to
use devices that improve blood flow, such as compression
stockings or intermittent pneumatic compression devices, which
are cuffs that intermittently inflate around the legs.
General prevention tips
Other tips for preventing blood clots include:
 moving or exercising the legs, especially:
o after surgery
o when staying in the hospital
179
o when confined to bed
 getting up and walking around every 2–3 hours while

traveling
 avoiding sitting for prolonged periods
 performing gentle exercises when sitting for long periods,

such as:
o raising and lowering the toes with the heels on the

floor
o raising and lowering the heels with the toes on the

floor
o tightening and then relaxing the leg muscles
 wearing loose-fitting, comfortable clothing, especially

while sitting for prolonged periods
 wearing compression clothing
 maintaining a moderate body weight
 getting enough exercise
 treating chronic conditions
 taking anticoagulants, when necessary
Outlook
180
As with most medical conditions, early diagnosis and treatment of
9.2. PERSPECTIVES
thrombosis greatly increases the chances of recovery and reduces

the risk of long-term complications.
Long-term complications
In some cases, thrombosis resolves on its own, as the body breaks

down and removes the thrombus. However, around 33–50% of
people with DVT develop post-thrombotic syndrome. This stems
from damage to the valves within the veins, which help direct
blood flow.
Subsequent blood clots
Most people who develop thrombosis go on to have further or

recurrent blood clots. However, the likelihood of this happening
depends on the factors that caused the initial clot.
If a clot develops due to an injury or surgery, the chances of

developing further clots is fairly low. If a clot develops due to an
underlying health condition, the risk of another clot is fairly high.
181
In general, the risk of developing additional blood clots 6 months

after completing treatment for a clot is 20% within the first 4
years and 30% after 10 years.
Summary
Thrombosis occurs when a blood clot forms inside a blood vessel
and impedes blood flow it. There are two main types of
thrombosis: arterial thrombosis, in which a blood clot blocks an
artery, and venous thrombosis, in which a blood clot blocks a vein.
Thrombosis symptoms stem from a lack of blood and oxygen to

the part of the body that the blocked vessel usually supplies.
Anyone who experiences symptoms of a blood clot should receive

immediate medical attention. Early treatment reduces the risk of
serious complications and improves the outlook.
Anyone at risk of blood clots should discuss preventive measures

with a healthcare professional. These may include staying active,
maintaining a moderate weight, and treating any underlying
182
conditions that increase the risk of thrombosis.
9.2. PERSPECTIVES
183
184
9.2. PERSPECTIVES
11 DIETS FOR THROMBOSIS PATIENTS
The doctors prescribes low calorie and low iron containing

foods ,Basically those food item that contains low vitamin K
content as that leads to blood coagulation which produces
Fibrogen .
Many people associate deep vein thrombosis (also called DVT)

with a lack of activity, such as sitting on an airplane for hours
during an overseas flight. Fewer people realize the role diet plays
in raising or lowering your risk. A DVT is a blood clot that typically
develops in the lower leg. This clot can break apart, travel to the
lungs, and cause a life-threatening event called pulmonary
embolism (PE) that prevents a person from breathing. While
there’s no specific deep vein thrombosis prevention diet, learn
which foods to eat to reduce your risk of developing a DVT.
185
Water
Water is the number one item to consume to help prevent deep

vein thrombosis. Whether tap water or a fancier bottled variety,
water helps naturally thin out your blood and make platelets less
likely to stick together and cause a clot. Drinking pure water does
the trick, with no need to consume sports drinks, vitamin waters,
or other beverages with added ingredients. However, if you’re
following a DVT prevention diet due to heart failure, be sure to
check with your doctor for guidelines on how much fluid is safe to
consume every day.
Olive Oil
Research suggests that eating virgin olive oil may reduce platelet
186
activity, in turn reducing your risk of a dangerous clot in the leg.
Olive oil is a healthy fat that contains substances called phenols
9.2.may
that PERSPECTIVES
make platelets less likely to clump. Incorporating more
virgin olive oil into your diet also might improve your overall heart
health, which is important for reducing DVT risk. Follow the DASH
Diet recommendation to eat two to three servings of healthy fats
like olive oil per day to reduce your risk of DVT.
Fresh Vegetables
Minimally processed vegetables should make any list of deep

vein thrombosis foods. Vegetables add a healthy dose of fiber and
antioxidants to your diet, which can improve your overall heart
health and reduce your risk of developing a DVT. Plain fresh,
frozen, and canned vegetables all pack a nutritional punch. Avoid
vegetables packaged in sauce or covered with cheese. Drained
and rinsed canned beans offer great dietary value in DVT
prevention and are affordable to eat regularly.
Fresh Fruits
187
Consuming a variety of fresh fruits aids heart health, adds fiber to

your diet, and can help prevent DVT. In fact, one study found that
people who consumed five combined servings of fruits and
vegetables per day cut their risk of DVT in half, compared to those
who ate fewer than three servings per day. Whole fruits like
apples, oranges, pears, and grapes make excellent snack foods. If
you take medications for any reason, use caution when
incorporating grapefruit into your diet, as it can affect how your
medications work. Ask your pharmacist for guidance.
Leafy Greens
Leafy greens, like collards, used to be relegated to the “deep vein

thrombosis restrictions” list, especially for those who take the
188
anticoagulant (“blood thinner”) medication warfarin (brand name
Coumadin). Leafy greens contain high concentrations of Vitamin
K,9.2. PERSPECTIVES
which promote blood clotting. Today, however, even people
who take anticoagulants often are told to consume a steady
volume of leafy greens as part of a heart-healthy diet. Leafy
greens contain valuable micronutrients to aid in overall heart
health. If you take an anticoagulant medication, ask your doctor
for guidelines on eating leafy greens.
Lean Proteins
People at risk for a DVT should increase their consumption of fish

and poultry while decreasing their intake of fattier meats like beef
and pork. Eating fattier meats can cause high cholesterol, which
increases your risk of DVT. Eating several servings per day of lean
proteins promotes better heart health, which is important for
preventing DVT. Heart failure and being overweight represent two
major risk factors for deep vein thrombosis, so following a heart-
healthy eating plan like the DASH Diet can help you improve your
cardiovascular health and possibly prevent a DVT.
Not Processed Foods
189
High on the list of foods anyone at risk of DVT should avoid?

Processed foods of all types, including lunch meats, snack foods,
and fast food. These products all generally contain high levels of
fat and salt, which are both bad for your heart health. Eating
processed foods increases your chance of developing cholesterol
plaques in your blood vessels, and these plaques can promote the
formation of blood clots. Replace unhealthy processed foods in
your diet with fresh, whole vegetables, fruits, and grains to reduce
your risk of DVT.
What foods can help reduce your risk of thrombosis and

stroke?
1. Lemon
190
We’ve told you about the benefits of lemons countless times.
You’re well aware of the fact that they may help strengthen
9.2. immune
your PERSPECTIVES
system, eliminate toxins, and fight the effects of
free radicals.
But did you know that lemons can be very powerful when it
comes to improving circulation and increasing your production of
red blood cells?
Don’t miss a day of drinking water with lemon juice or adding

a little bit of this juice to your salad dressings.
2. Olive oil
Extra virgin olive oil is a natural gift that’s rich in omega-6 fatty

acids and is ideal for reducing bad cholesterol (LDL) levels in the
bloodstream.
Thanks to olive oil, you can keep your arteries flexible and reduce
the build-up of plaque, which can hinder blood flow and elevate
your risk of thrombosis.
3. Avocado may reduce your risk of thrombosis and stroke
Avocados, when consumed in moderation, aren’t fattening and

are as healthy as or even more so than olive oil itself. Try enjoying
half of an avocado three times a week with your breakfast.
4. A garlic clove a day
191
 Eat at least one garlic clove a day.

 Garlic is rich in allicin, a medicinal enzyme that cares for
the health of your heart, your immune system, and also
has an anti-coagulant effect to keep blood flowing.
5. Artichokes
 Include a cooked artichoke with a little vinegar, olive oil,
and lemon juice in your dining plan. It’s more than just a
healthy choice – it’s amazing!
This vegetable is one of the best choices for helping reduce
your risk of thrombosis and embolisms.
6. Celery
Celery is packed with antioxidants, vitamins, and phyto
192
9.2. PERSPECTIVES
elements that regulate your blood pressure.
 This vegetable may also reduce your blood cortisol levels.

This is a stress hormone that can have a very negative
impact on your cardiovascular health.
 If you consume celery on a regular basis, either raw or in
juices, you may enjoy cleaner, more flexible arteries with
less plaque.
7. Cranberry juice
 One of the best natural options for improving circulation is
cranberry.
 This fruit may improve your circulation thanks to its anti-
coagulant effects.
Drink cranberry juice and buy them dried or even frozen if
they’re out of season.
8. Red wine
193
Drinking one glass of red wine a day may reduce your risk of
having a heart attack or stroke.
 This grape-based beverage is rich in powerful antioxidants,

as well as ethanol, which may help regulate your bad
cholesterol levels.
 Red wine may also delay the formation of plaque in your
arteries and improve your circulation.
9. Carrots
 Everybody loves carrots. They’re refreshing, easy on the
palate, and go with everything. They’re also excellent to
reduce your risk of thrombosis and stroke.
 This is because they’re a great source of beta-carotene, a
194
 substance that may help balance your cholesterol levels.
9.2. PERSPECTIVES
You should definitely increase your consumption of these
nine foods from now on. Your heart will thank you for it!
Food items that should be prohibited/taken in small amount are

as follows
Banana, carrot, Brinjal, Beet root, Legumes such as Ground nuts.
195
196
9.2. PERSPECTIVES
12 HEALTHS AND EXERCISE FOR THROMBOSIS

PATIENTS
General Guidelines for Thrombosis patients
Warm-up 10 minutes
Aerobic 30-60 minutes continuous exercise (use Rating of

Perceived Exertion – see next page)
Weight Training 10-20 minutes
Cool Down 5-10 minutes
Stretching Up to 5 minutes of light stretching
Warm Up Easy/light movement that prepares muscles for aerobic

and/or weight training exercise.
Aerobic done most days of the week.
 Uses large muscle groups working together.
 This should cause an increase in heart rate (HR) and breathing

rate, but you
 Should still be able to carry on a conversation. Weight bearing

exercises (walking) are the suggested type of exercise.
197
 The goal of aerobic activity is to make sure that you keep

moving. Keeping
 Blood moving to all areas of the body helps prevent blood clot
formation. If you cannot exercise continuously for 30-60 minutes,
try shorter bouts of
 Exercise that add up to 30-60 minutes. Preventive Cardiology

Exercise Instructions: Deep Vein Thrombosis - 2 - Weight Training
Aim for high repetitions (reps) with light weights 2-3 days per
week.
 Most training should focus on using your legs (examples: calf

raises or
 squats) Strength training should only be performed after some

form of aerobic
 warm-up. Proper breathing is very important. Be sure to

breathe out on the exertional
 Part of the exercise (when you are contracting the specific

muscle you are training) Note: It is not safe to do isometric
training (pushing or pulling against a fixed object like a wall or bar)
at this time. Cool down Similar to the warm up; light movement to
help bring your heart rate (HR) back to its resting level. Stretching
Decreases muscle soreness and increases flexibility.
 Done after every workout session.
 Hold stretch up to 30 seconds (as tolerated) without moving,

and be sure to
 Keep breathing. PRECAUTIONS your physician should clear you

before you start an exercise program.
198
 Compression stockings may be needed.
9.2. PERSPECTIVES
Exercise may result in fluid loss (dehydration) so drink fluids to

prevent low
Blood pressure after exercise. Patients on fluid restriction should

ask for more specific advice from their physician.
Preventive Cardiology Exercise Instructions:
Deep Vein Thrombosis - This information and/or instructional

materials developed by Michigan Medicine for the typical patient
with your condition. It may include links to online content that
was not created by Michigan Medicine and for which Michigan
Medicine does not assume responsibility. It does not replace
medical advice from your health care provider because your
experience may differ from that of the typical patient. Talk to your
health care provider if you have any questions about this
document, your condition or your treatment plan.
199
Exercise that gets your blood pumping helps guard against

dangerous blood clots.
You know that a sedentary lifestyle can put you at risk

of obesity, diabetes, and heart disease. But there is actually a
more immediate danger — developing deep vein
thrombosis (DVT).
DVT is a clot that forms in a deep vein, typically in the lower leg or
thigh. Left untreated, these clots can break off and travel through
the bloodstream to the lungs, causing a blockage (called a
pulmonary embolism), which can be fatal.
While DVT is often associated with airplane travel, any form of

inactivity can increase your risk of developing a blood clot,
says Rachel Rosovsky, MD, a hematologist at Massachusetts
General Hospital in Boston.
That's because when your legs remain still for hours — whether
you’re binge-watching Netflix or sitting at your desk all day
— your calf muscles don't contract. Without muscle contractions,
which normally help blood, circulate, blood flow slows and
becomes more prone to clotting.
“The more sedentary you are, the higher your risk of developing
DVT,” says Dr. Rosovsky. Being inactive is especially dangerous
200
when combined with other risk factors for the condition, such as
being overweight or having a predisposition to blood clotting.
9.2. PERSPECTIVES
While an estimated 900,000 Americans are affected by DVT each
year, resulting in nearly 100,000 deaths, these dangerous blood
clots can be prevented, say the Centers for Disease Control and
Prevention.
Making certain lifestyle changes, such as quitting

smoking and maintaining a healthy weight can reduce your risk.
Another important way to prevent DVT is simply to move more —
even if it's just working some simple leg exercises and stretches
into your day.
7 Steps to Avoid Deep Vein Thrombosis
201
What Bit Me? How to Identify Common Bug Bites| Everyday

Health
Who Needs to Worry About DVT?
Anyone who is inactive can develop DVT, says Rosovsky, but there
are certain situations and conditions that increase your chances of
forming a dangerous blood clot:
Being older DVT can occur at any age, but your risk increases as
you get older. After age 40, the risk of DVT almost doubles every
10 years, according to the National Heart, Lung, and Blood
Institute (NHLBI).
202
Having a family history of DVT Researchers have found dozens of
genetic changes that can make your blood more likely to clot, per
9.2.
the PERSPECTIVES
NHLBI. An inherited disorder on its own might not cause blood
clots, but it could when combined with one or more other risk
factors.
Taking a hormone-based medication Women who take birth

control pills or get hormone therapy have an increased risk of
clotting. The risk tends to be highest in the first few months after
starting on one of these medications, says the NHLBI.
Being pregnant Pregnancy increases the pressure in the veins in

your pelvis and legs. The risk of blood clots from pregnancy can
continue for up to six weeks after you have your baby, notes
the Mayo Clinic.
Being overweight or obese Carrying extra weight increases the

pressure in the veins in your pelvis and legs, and raises your risk of
forming blood clots, says Rosovsky.
Undergoing surgery Clotting is one of the body’s natural ways to

heal the damage to your blood vessels from surgery, says the
NHLBI. Bed rest and lack of movement can increase the risk of
developing a clot.
Smoking Smoking affects blood clotting and circulation, which can

increase your risk of DVT.
Having other health conditions Some forms of cancer increase

substances in your blood that cause it to clot. Inflammatory bowel
diseases, such as Crohn's disease or ulcerative colitis, also
increase the risk of DVT, according to the Mayo Clinic.
How Do You Know if You Have Deep Vein Thrombosis?
203
Simple Exercises to Help Prevent DVT
Regular activity, ideally daily for at least 30 minutes, can improve

circulation and help keep your body weight in check, both of
which can lower your risk of DVT.
But when travel, a work deadline, or an injury or illness keeps you

stuck in one place for hours at a stretch, these simple strategies
can keep your blood flowing and lower your risk for DVT.
Walking
Even if you’re slammed with work and can't get away from your
desk, try to take mini walks, be it around your home or office or
around the block, every hour or two during the work day,
recommends Rosovsky.
“Not only will this help get the blood pumping and help prevent
blood clots, it will also help your overall mood and give your brain
a break, so you’ll be so much better at getting back to whatever
you’re doing,” she says.
Stuck on a long flight? Take a trip to the restroom or stand up and

stretch whenever possible. On a road trip, stop frequently to walk
and stretch your legs.
If you’re confined to a hospital bed, ask your nurse if it’s okay for
you take walks around the room or down the hall, says Rosovsky,
adding, “Even just moving from your bed to a chair will help your
circulation.”
Chair Exercises
When you can’t get up and walk, try these seated exercises,
advises Eric Robertson, an adjunct associate professor of clinical
204
physical therapy at the University of Southern California in Los
Angeles and a spokesperson for the American Physical Therapy
9.2. PERSPECTIVES
Association.
Aim to do 5 to 10 repetitions of each exercise every half hour.
Foot Pumps Starting with both feet flat on the floor; raise your
toes toward you. Hold for a count of three, and then lower them
back down. Next, raise your heels off the floor, hold for a count of
three, and then lower them back down.
Ankle Circles Raise both feet off the floor and trace circles with
your toes for a count of three. “You could also trace each letter of
the alphabet to keep yourself occupied,” says Robertson.
Leg Raises If you have room in front of you, slowly raise your left
foot off the floor until its parallel with your knee, and then lower
it back down to the floor. Repeat with your right leg. If space is
cramped (say on an airplane), lift your left knee up to your chest,
then bring your foot back to the floor; repeat with your right leg.
Shoulder Rolls Although you’re less likely to form a clot in your

upper body, it doesn’t hurt to keep your blood flowing there.
Simply raise your shoulders and circle them forward, up, back,
and down, then reverse the direction.
Stretching While Lying Down
If you’re stuck in bed due to an illness or injury, or after surgery,

Robertson recommends doing these simple stretches; aim for 5 to
10 repetitions of each about every half hour.
Foot Pumps These are similar to foot pumps done in a chair, just

done lying down. Starting on your back with your legs straight and
heels on the bed, flex your feet and stretch your toes toward your
205
head; hold for a count of three. Next, point your toes away from
your head and hold for a count of three.
Thigh Stretches Starting on your back with your legs straight, raise

your left leg to a 90-degree angle, then use your arms to gently
pull the leg toward you; hold the stretch for 15 to 30 seconds.
Slowly bring your leg back down and repeat with your right leg.
A variation on this stretch: From the same flat starting position,

bring your left knee into your chest and hold it with your arms to
increase the stretch; hold for 15 seconds. Lower your leg back
down to the bed and repeat with your right leg.
THANK YOU
FOR READING
206
207
ABOUT THE AUTHOR
Dr.A.B.Rajib Hazarika, PhD, FRAS, AES ,Assistant Professor and

Head, Dept. of Mathematics, Diphu Govt. College, Diphu.
Gazetted officer -I of Assam Education Service (AES), Govt. of
Assam. MSc (Maths) in 1992 ,
JRF(UGC,NET) ,1993 ,SRF(UGC,NET),PhD(Maths) 1995 ,JNV
University, 1995,Best PhD Thesis award Triple Gold Medal for Best
Mathematics Thesis, Best Science stream Thesis award, Best
Thesis for all stream from Association of Indian Universities, Post
Doctoral Fellow, 1998,Plasma Physics division, IASST, Guwahati as
Research Associate (DST),Govt. of India. Elected Fellow of Royal
Astronomical Society (FRAS), London in 2010. Authored 20 books,
Peer reviewer of 10 Journals. Elected Member of 23 Foreign
professional academies. Guided two scholars for MPhil degree.
208

Drabrh Human Blood and Related Disease Thrombosis by DR A B Rajib Hazarika PHD FRAS AES

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Drabrh Human Blood and Related Disease Thrombosis by DR A B Rajib Hazarika PHD FRAS AES

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HUMAN BLOOD AND

Dr A B RAJIB HAZARIKA PhD

All rights reserved.

ISBN: 9798444523278 (PAPERBACK)

TO MY DOCTORS WHO CURED MY THROMBOSIS

TO MY SO MANY LOVED ONES

Dr.A.B.Rajib Hazarika, PhD, FRAS, AES ,Assistant Professor and

1 Blood, its type composition 2

2 Blood and its composition 23

3 Blood related diseases: Thrombosis 57

5 Home remedies and natural 84

7 Mathematical model for coagulation 126

8 Anticoagulant Model 130

9 Thrombosis model and simulation 138

10 Precautions for Thrombosis 161

11 Diet for thrombosis patients 183

12 Health and exercises for thrombosis 195

I WISH TO acknowledge to all dedicated persons involved in study

1 HUMAN BODY AND BLOOD DISORDERS

Our body consists of muscles, bone, tissues, different organs and

Most common of disorders is thrombosis i.e. blood clotting due

I am interested in presenting the basic model, newly invented

AZADI tablet (Aspirin + Clopidorel+Clavunate) and ABRH-dimer

AZADI tablet is for blood clotting patients, heart and stroke

DR A B RAJIB HAZARIKA PHD FRAS AES

Pronunciation acetylsalicylic acid /əˌsiːtəlˌsælɪˈsɪlɪk/

Trade names Bayer Aspirin, others

Another one ABRH-dimer for blood clotting as well for breathing

Trade names Theolair, Slo-Bid

Exhaustive model consists of a system advection-reaction-

(dFi/ dt) +∇.(vFi) = DΔFi +Ri,

where v is the blood flow velocity, D is the diffusion coefficient,

ρ (∂u/ ∂t) +u(∇.u) = −∇p+ μΔ.u − μ/ K(x) u

What is high blood pressure (hypertension)?

High blood pressure, also known as hypertension, affects nearly a

Blood pressure is assessed using two parameters -- the systolic

sure in those vessels between cardiac contractions. In adults,

What are the most common blood pressure medications?

In terms of dollar sales, there are 5 top high blood pressure

 the angiotensin II receptor blocker valsartan (Diovan) in the lead

 olmesartan and HCTZ (Benicar HCT).

In terms of prescriptions written, here are the top 4 high blood

 the ACE inhibitor lisinopril (Prinivil, Zestril) tops the list,

How to Lower Blood Pressure:

What is the best high blood pressure medication?

Selecting the "best" high blood pressure medication depends on

For example, in a hypertensive patient with asthma, it may be

Certain groups of patients require the use of a specific class of

 The drug of choice for hypertensive, pregnant women is one of

Hypertension in African-Americans tends to occur earlier in life

With age, comes an increased risk for systolic hypertension which

 According to one study, the diuretic chlorthalidone (Hygroton)

High blood pressure medication list

There are several classes of blood pressure medications. Each

Diuretics increase urination which reduces sodium and fluid in the

One side effect of diuretics is a loss of potassium, which is carried

Some diuretics were subsequently developed to address the issue

Finally, there are the combination diuretics, which include a

Salt and sodium are the same

Beta-blockers lower blood pressure by acting directly on the

 Benazepril hydrochloride (Lotensin)

Angiotensin II receptor blockers

The hormone angiotensin narrows blood vessels, but to do its job