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Thrombus formation is an initiate event that occurs when there is an injury on the blood vessel
wall to keep the hemostasis. Circulating platelets are recruited to the site of injury, where they
become a major component of the developing thrombus; blood coagulation, initiated by tissue
factor, culminates in the generation of thrombin and fibrin. When pathologic processes
overwhelm the regulatory mechanisms of hemostasis, excessive quantities of thrombin form,
initiating thrombosis.[1] Thrombosis is a critical event in the arterial diseases associated with
myocardial infarction and stroke, and venous thromboembolic disorders account for considerable
morbidity and mortality.[1,2]
Atherothrombosis describes a disease process that includes atherosclerosis and thrombosis in the
artery.[3] Atherothrombotic diseases are a major healthcare problem and are responsible for >25%
of all deaths worldwide. World Health Organization statistics have highlighted the true global
impact of this disease, with ~80% of the worlds deaths from atherothrombosis occurring in lowand middle-income countries. The development of a clot in the coronary or cerebral circulation
(causing acute myocardial infarction or ischemic stroke, respectively) is now the single most
common cause of morbidity and mortality globally, and the prevalence of these diseases
continues to rise, particularly in developing nations.[2]
Arterial thrombosis generally develops as a result of underlying vascular abnormalities, typically
atherosclerotic vascular disease and less frequently in individuals with vasculitis. Atherosclerosis
is a disease affecting medium and large sized arteries and is rarely found in arteries smaller than
500 microns in diameter.[4] Arterial narrowing due to atherosclerosis limits blood flow and causes
ischemic symptoms when the oxygen requirements are increased by exercise. [5] The clots formed
in arterial thrombosis are called white clots due to their composition of fibrin and platelets.[4]
Effect of therapies on mortality rates has remained disappointingly small, with less than one in
four individuals taking antithrombotic therapies avoiding a fatal thrombotic event. Obesity,
diabetes, and the metabolic syndrome rapidly are the conditions that typically more resistant to

the benefits of antithrombotic therapy.[2] The most effective means of preventing arterial
thrombosis is to prevent atherosclerosis. The proven risk factors for atherosclerosis are
hypercholesterolemia, hypertension, cigarette smoking, obesity, physical inactivity, age, family
history, diabetes, and male sex. The first five of these risk factors are potentially reversible, and
there is evidence that their reversal reduces the complications of atherosclerosis.[5]



2.1 Arterial Thrombus Formation

Rupturing or erosion of an unstable atherosclerotic plague is the most common cause of arterial
thrombosis. This thrombosis is primarily composed of aggregated platelets because of their
ability to adhere to injured vessels and other activated platelets in rapid blood flow conditions. [11]
Upon rupture of the atherosclerotic plaque, its lipid core is exposed to the circulating blood of
the arterial system. The core area contains tissue factor and fragments of collagen that are highly
thrombogenic.[12] Thus, upon vascular injury, subendothelial matrix protein becomes exposed to
blood. Among them are von Willebrand factor (vWF), fibrillar collagens, fibronectins, and
laminin. All of these proteins support the platelet adhesion through binding with specific
Within the high shear pressure of the arterial blood flow, initial platelet adhesion is triggered by
interaction of vWF and platelet receptor complex glycoprotein (GP) Ib/V/IX. [13] This bond
between GP Ib and vWF does not support stable adhesion due to its rapid off rate. As a result,
platelets must translocate over vWF and adhere through more stable interactions of collagen,
fibronectin or laminin. Stable platelet adhesion occurs through binding of platelet GPVI with
fibrilar collagen as well as ligation of multiple B1 integrins with collagen and fibronectin. After
adhering stable within the arterial lumen, platelets induce integrin IIb3 activation which
induces high affinity interaction with adhesion proteins.[11]
A soon as the platelets adhere to the vessel wall, they initiate morphological and biochemical
changes that results in release of platelets granule and up regulation of the adhesive function of
integrin IIb3. The components released within the platelets activation include thromboxane A2
and dense-granular ADP, these two substances act to potentiate platelet activation through
specific G protein-coupled receptors. ADP binds to the P2y1 and p2y12 receptor, while
thromboxane acts on the TP and TP. Both substances stimulate platelets to enhance thrombus
formation.[11] The integrin IIb3, upon activation increases recruitments of platelets to the
thrombus as well as interplatelet interaction. Activation of platelets occurs in a subgroup of

recruited platelets, while the remaining platelets are associated with the thrombus but not
undergo activation. [14]
The next step of arterial thrombosis is the initiation of coagulation. Platelets have an important
function to support the assembly of coagulation complex on their plasma membrane. Their role
is to provide localization of a thrombin generation and fibrin formation. [11] The coagulation
process initiates within cells that express tissue factor (TF). Upon binding with factor VIIa, the
TF-factor VIIa then activates small amounts of factor IX and factor X. Factor Xa then activates
factor V on the TF-bearing cells and forms complex with factor Va. This reaction will convert a
small amount of prothrombin (factorII) to thrombin. [12] The process continues to amplification
process, during this process the thrombin generated activates factor VII,V, and XI, leading to a
burst of thrombin-generating potential. In addition, the thrombin also activates platelets. [14]
Within the surface of activated platelets, factor XIa activates factor IX. Factor IXa from both the
surface of activated platelets and the TF-factor VIIa complex, form the tenase complex with
factor VIIIa. Finally, the factor IXa-factor VIIIa complex activates factor X, which in turn forms
the prothrombinase complex with factor Va and produces a burst of thrombin generation. The
thrombins generated in turn cleaves soluble fibrinogen into insoluble fibrin.[11]
Both platelet activation and blood coagulation are important for the formation of arterial
thrombus. Spatial and temporal regulation of these events influence the outcome of the process.
For example, in regions of high shear and distributed flow, platelet recruitment preferentially
occurs. This leads to formation of predominately white thrombi over the site of injury. In
reverse, maximal fibrin generations occurs in regions of low flow, leading to the development of
fibrin rich thrombus tail.[11]

2.2 Atherosclerotic Plaque Formation

Atherosclerosis is a multifocal, smoldering, immunoinflammatory disease of medium-sized and
large arteries fuelled by lipids.[6] It is characterized mainly by patchy intramural thickening of the
sub intima that encroaches on the arterial lumen. Many cells are involved in the formation of an
atherosclerotic plaque. The first components are predominantly smooth muscle cells and
macrophage. The second component consists of connective tissue matrix and extracellular lipid.

The third component is intracellular lipid that accumulates within macrophages, thereby
converting them into foam cells.[7] The main pathogenesis involves imbalance lipid metabolism
and maladaptive immune response causing a chronic inflammation of the arterial wall.[8]
The initial stage of atherosclerosis occurs when endothelial cells begin to dysfunction. This
process is initiated by risk factors such as hiperlipoproteinemia, hypertension, and cigarette
smoking.[9] The endothelial dysfunction is also accompanied by structural alterations, including
absence of confluent luminal elastin layer and exposure of proteoglycans. All of these factors in
turn permit accumulation of low-density lipoprotein (LDL). LDL binding to extracellular matrix
leads to retention of LDL particles in the intima, making them susceptible to oxidative
modification by reactive oxygen species or enzymes such as myeloperoxidase or lipogenases.[8]
Oxidized lipids and LDL (oxLDL) trigger expression of adhesion molecules and secretion of
chemokines by endothelial cells. This process drives intimal immune cell infiltration that recruits
inflammatory leukocytes.[8] Some example of adhesion molecules include; vascularcell
adhesionmolecule1 (VCAM-1) and monocyte chemo-attractant protein-1 (MCP-1). As their
name implies, VCAM-1 increase the recruitment of monocytes and T-cells to sites of endothelial
injury, while MCP-1 magnifies the inflammatory cascade by recruiting additional leukocytes,
activating leukocytes in the media and proliferation of smooth muscle. [7] Chemokines have an
even more complex inflammatory recruitment function as adhesion molecules, except that they
can also function as cell hemostasis.[8]
The recruited monocytes, under the influence of monocyte colony stimulating factor transforms
into macrophage.[7] They eventually express scavenger receptors that bind modified lipoproteins.
Upon binding with lipoproteins these macrophages become lipid laden foam cells. Hence,
conglomerates of foam cells form fatty streaks, yellow patches visible in the arterial wall. [9] The
process above is also accompanied by proliferation and migration of smooth muscle cells
towards the arterial lumen. It is initiated by secretion of small peptides that regulate cell growth
by both smooth muscle and endothelial cells. These peptides include; platelet-derived growth
factor (PDGF), interleukin-1 (IL-1), and tumor necrosis factor (TNF). Relocation of smooth
muscle cells and accumulation of new matrix, results in the formation of a fibrous cap that
covers the lipid pool. This concludes the creation of a mature atherosclerotic plaque.[10]

The plaque could protrude into the lumen, eventually obstructing the artery. This plaque
obstruction in turn leads to clinical symptoms such as angina pectoris or intermittent
claudication.[10] In other settings, the fibrous cap could rupture at point of weakening, providing
access for coagulation factors in the blood to thrombogenic tissue factor-containing lipid core.
Depending on the prothrombotic and fibrinolytic mechanism, at the region, an occlusive
thrombus causing coronary syndrome may occur.[19]
Figure 1.

2.3 Etiology of an Acute Arterial Thrombosis, Virchows Triad

The result of the thrombotic process is lies in the development of a highly organized mass of
blood cells, such as platelets, red blood cells, white blood cells and other elements caught in a
mesh of cross-linked fibrin. The predisposition factors leading to thrombus development are
summarized in the so-called Virchow triad. The basics of Virchows triad are the following:
Endothelial damage in arterial circulation there are three main causes of endothelial damage;
the first is due to physiological hemodynamic stress during systolic inflation of the vessel and
immediate diastolic deflation the elasticity of the vessel puts a high demand on endothelial
cells that kind wear down after a period of time. An increase in systemic blood pressure increases
the hemodynamic stress on endothelial cells; the second cause of endothelial damage is
atherosclerosis and the third one is direct trauma. Changes in blood flow the most frequent
changes observed are stasis and turbulence within the vessel (switch from a laminar flow to a
turbulent one). Normally (laminar flow), there is a little or no contact between the endothelial
membrane and circulating blood cells. However, a change in the charge of elements may play a
role in the establishment of a continuous pathological insult. Positive charging of the endothelial
surface starts to attract platelets and the so called opsonization of the endothelium commences. A
decrease in blood flow may have two main causes: heart failure and increase in blood viscosity.
Activation of coagulation is actually the least frequent cause of thrombosis. It starts due to a
prothrombotic or thrombophilic condition of the patient. Moreover, systemic coagulation is
activated following excessive burn injuries, heart failure, disseminated metastatic disease and
long term estrogen medication, either pre-menopausal or in oral contraceptives. [15]

2.4 Clinical Presentation

Atherosclerosis usually doesn't cause signs and symptoms until it severely narrows or totally
blocks an artery. Many people don't know they have the disease until they have a medical
emergency, such as a heart attack or stroke. Some people may have clinical manifestation of the
disease. It will depend on which arteries are affected. [24]

Coronary Arteries
The coronary arteries supply oxygen-rich blood to the heart. If plaque narrows or blocks
these arteries (a disease called coronary heart disease, or CHD), a common symptom is
angina. Angina is chest pain or discomfort that occurs when the heart muscle doesn't get
enough oxygen-rich blood. [24]
Angina may feel like pressure or squeezing in the chest. It also may feel it in shoulders,
arms, neck, jaw, or back. Angina pain may even feel like indigestion. The pain tends to
get worse with activity and go away with rest. Emotional stress also can trigger the pain.

Other symptoms of CHD are shortness of breath and arrhythmias. Arrhythmias are
problems with the rate or rhythm of the heartbeat. [24]
Plaque also can form in the heart's smallest arteries. This disease is called coronary
microvascular disease (MVD). Symptoms of coronary MVD include angina, shortness of
breath, sleep problems, fatigue (tiredness), and lack of energy. [24]
Carotid Arteries
The carotid arteries supply oxygen-rich blood to the brain. If plaque narrows or blocks
these arteries (a disease called carotid artery disease), the patients may have symptoms of
a stroke. These symptoms may include: [24]

Sudden weakness

Paralysis (an inability to move) or numbness of the face, arms, or legs, especially
on one side of the body


Trouble speaking or understanding speech

Trouble seeing in one or both eyes

Problems breathing

Dizziness, trouble walking, loss of balance or coordination, and unexplained falls

Loss of consciousness

Sudden and severe headache

Peripheral Arteries
Plaque also can build up in the major arteries that supply oxygen-rich blood to the legs,
arms, and pelvis (a disease called peripheral arterial disease). If these major arteries are
narrowed or blocked, the patients may have numbness, pain, and, sometimes, dangerous
infections. [24]
Renal Arteries
The renal arteries supply oxygen-rich blood to kidneys. If plaque builds up in these
arteries, the patients may develop chronic kidney disease. Over time, chronic kidney
disease causes a slow loss of kidney function. [24]
Early kidney disease often has no signs or symptoms. As the disease gets worse it can
cause tiredness, changes in how you urinate (more often or less often), loss of appetite,
nausea (feeling sick to the stomach), swelling in the hands or feet, itchiness or numbness,
and trouble concentrating. [24]

2.5 Clinical Diagnostic

Primary data obtained from a patient should be based on individual history and major symptoms.
Physical examination and primary vascular examination is still widely regarded as an important
first step for establishing proper and early diagnosis. Inspection of color, followed by close
monitoring of any skin efflorescence, as well as drop in local temperature may help in the exact
localization of vascular occlusions. Peripheral pulse palpation is another method of targeting the

source of the problem. Auscultation may aid in finding murmurs, especially in the upper femoral
region. [16]
As another step, methods of diagnostic imaging should be utilized, not only for exact localization, but also for assistance in deciding upon treatment options. Basic ultrasonography, using a
two-dimensional picture along with Doppler Effect measurement is currently used in clinical
practice. Angiography is another method that can be used. Digital subtractional contrast
angiography (DSA) is widely regarded as the gold standard for thorough examination of
vascular damage. It enables exact visualization of the inner surface of the vessel and can outline
both major and minor irregularities of the vessel wall. Magnetic Resonance Angiography (MRA)
and CT-guided contrast angiography are other methods of choice for vascular imaging of lower
extremities. Both methods are non-invasive and use contrast media for good visualization of
arterial circulation with extremely high resolution. With the development of new workstations
for CT scanning and magnetic resonance imaging, along with duplex sonography, these methods
have become more and more useful as first-choice options in vascular diagnostic imaging. [16]
Sometimes, the justification for specific advanced diagnostic methods becomes an issue. An
exact indication should come after detailed history was obtained and thorough physical examination performed. In most cases, no specific rules or guidelines exist and the steps to be followed
are case-specific and depend, more or less, on the possibilities of the actual diagnostic imaging
department. Moreover, many methods of imaging are complimentary and their utilization often
helps in establishing a proper diagnosis. In any case, the critical consideration must always be to
avoid any delay, especially in cases when there is a risk of limb amputation or exitus. In patients
suffering from excessive damage or gangrene (or both) there is no need for in-depth examination
and life-saving (or limb-saving) procedures should follow. In such cases, immediate MRA or
angiography should be performed without any delay. Generally, the most accurate information
comes from MRA or digital subtractional angiography and all patients, especially those
scheduled for surgical revascularization should undergo one of these treatments. [16]


2.6 Treatment
There are two main types of treatment for arterial thrombosis:

If a patient has a heart attack, they may be offered thrombolytic drugs or clot busters.
These are given as an intravenous injection that breaks down the clot in the coronary
artery, opens up the artery and allows blood to flow again. For example, such as alteplase,
which can help dissolve clots and restore the flow of the blood to the brain or heart. [27]
Another treatment of established arterial thrombosis includes the use of Antiplatelet
drugs. Antiplatelet drugs alter the platelet activation at the site of vascular damage crucial
to the development of arterial thrombosis.[18]

Irreversibly inhibits the enzyme COX, resulting in reduced platelet
production of TXA2 (thromboxane - powerful vasoconstrictor which

lowers cyclic AMP and initiates the platelet release reaction).

Inhibits platelet phosphodiesterase, causing an increase in cyclic AMP
with potentiation of the action of PGI2 opposes actions of TXA2.
Affects the ADP-dependent activation of IIb/IIIa complex.
Glycoprotein IIb/IIIa receptor antagonists[18]
Block a receptor on the platelet for fibrinogen and von Willebrand factor.
3 classes:

o Murine-human chimeric antibodies (e.g. abciximab)

o Synthetic peptides (e.g. eptifibatide)
o Synthetic non-peptides (e.g. tirofiban)
Is a prostacyclin which is used to inhibit platelet aggregation during renal
dialysis (with or without heparin) and is also used in primary pulmonary


Thrombolytic therapy is used in myocardial infarction, cerebral infarction and occasionally in

massive pulmonary embolism. The main risk is bleeding. Treatment should not be given to
patients who have had recent bleeding, uncontrolled hypertension or a hemorrhagic stroke, or
surgery or other invasive procedures within the previous 10 days.[18]


Forms a complex with plasminogen, resulting in a conformational change which activates
other plasminogen molecules to form plasmin.
Plasminogen activators (PA) [18]
Tissue-type plasminogen activators (alteplase, tenecteplase) are produced by recombinant
Where the affected artery is either unblocked or the blood flow is re-routed past the point
of the blockage.

The type of surgery which offered it depends on the location and severity of the arterial
Heart surgery
Heart surgery is needed if the blood clot is in an artery that supplies blood to your heart. A
coronary angioplasty is the most common type of surgery for a heart attack. A hollow metal tube
called a stent is inserted to widen the artery and stop it from becoming blocked again.
Sometimes, a coronary artery bypass graft may be carried out after a heart attack. This is where a
blood vessel that is taken from another part of the body is used to bypass the point of the
Carotid endarterectomy
Another type of surgery for arterial thrombosis is called carotid endarterectomy, which may have
if had a blood clot in an artery in the neck which cause a stroke. The surgeon makes a cut in the
neck to open up the artery and remove the fatty deposits.[17]
2.7 Prognosis and Complication


Arterial thrombosis is associated with the main cause of death on a world-wide scale. It leads to
many complications of cardiovascular events. The frequent complications of arterial thrombosis
are cardiovascular death, myocardiac infarct, stroke, and cardiovascular hospitalization. All
causes mortality was 2,58% in one year followed up study and 12,81% patients experienced
complications. There are 1,65% patients experienced cardiovascular death, 1,14% myocardiac
infarct, and 1,66% stroke. In 4 years followed up study, there were 12,12% patients experienced
complication that included 5,12% cardiovascular death, 2,72% myocardial infarction, 4,2%
stroke, and 0,09% with both myocardial infarction and stroke. [30] Patients who experienced
cardiovascular hospitalization were caused by unstable angina, which was the most frequent,
congestive heart failure, transient ischemic attack, other ischemic arterial event, worsening of
claudication and hospitalization, bleeding, and new diagnosis of claudication and hospitalization.

Patients who had prior ischemic event at baseline have higher risk than patients with stable

arterial throbosis without prior ischemic event at baseline to experience complications. Patients
with multi risk factors only have the lowest risk to develop complication.[19]

2.8 Prevention
The prevention of arterial thrombosis begins with change in lifestyle like control smoking habit,
increasing physical activity, low fat diet, reducing cholesterol and sodium chloride intake also
high fiber intake.[21]
Many risk factors for cardiovascular and thrombotic diseases are profoundly affected by diet and
thus can be managed or prevented with a nutritional approach.
The quality and quantity of carbohydrate eaten are relevant to changes in plasminogen
activator inhibitor (PAI-1). Hyperglycemia has been associated with activation of protein
kinase C (PKC), which in turn increases PAI-1 and subsequently reduces fibrinolysis. It is
likely that replacing high glycemic index carbohydrate source with low one within the
context of a balanced diet may reduce the risk of thrombogenesis.
Dietary fatty acids[22]


Long chain saturated fatty acids have been shown to increase platelet aggregation, whereas
short and medium chain negatively correlated with platelet aggregation. MUFA may
decrease the prothrombotic environment by modification of platelet adhesion, coagulation
and fibrinolysis.
Few studies have investigated the effects of n-6 long chain PUFA on platelet are to active
cAMP formation and inhibit platelet aggregation. n-3 PUFA may improve cardiovascular
health include antiarrythmic action, improving endothelial function, lowering triglycerides,
and inhibiting platelet aggregation.
Protein and amino acid[22]
Protein deficiency has been shown to increase platelet aggregation, whereas several
peptides from casein, whey proteins, and soy protein have been shown to exert an opposite
effect. One component of animal protein known to cause prothrombotic effects is the
amino acid methionine, which low level of it is the independent risk factor for
thromboembolism. Arginine as precursor for nitric oxide is needed, because low of NO can
lead to endothelial dysfunction and resulting in a prothrombotic state.
Vitamin D[22]
A multicenter randomized controlled trial involving patients with advanced prostate cancer
and supplemented with calcitriol demonstrated a significant reduction of thrombosis.
Vitamin K[22]
Oral administration of this vitamin has been proven safe and effective in patient to prevent
any excessive anticoagulant effect of warfarin. Vitamin K also possesses potent antiplatelet
activity in vitro.
Garlic and onion[22]
Platelet aggregation has been reported to be inhibited by both raw onion and garlic in vitro.
Several compounds have been identified as inhibitors of platelet aggregation; adenosine,
alliin, prostaglandin A1 and thiosulphinates.


Ginger may exert its positive cardiovascular effect through modulation of blood pressure,
hypercholesterolemic effects, antioxidant properties, and inhibition of platelet aggregation.
Ginkgo biloba[22]
The vascular benefit of Ginkgo biloba are attribute to its ability to promote vasodilatation,
improve blood flow, inhibit platelet aggregation, and act as antioxidant.
Tomato exerts cardiovascular benefit through antioxidant effect such as inhibiting LDL
oxidation or non-oxidative mechanisms such as lowering cholesterol or inhibiting platelet
aggregation. In people with diabetes type 2, dietary supplementation with clear tomato
extract resulted in a significant reduction in platelet aggregation.
Flavanols and proanthocyanidins[22]
Flavanols are a type of polyphenol found commonly in plants and plant-derived foods such
as green tea, red wine, grape seeds, and cocoa. Several mechanisms may be involved in the
cardiovascular effects of both flavanols and proanthocyanidins, including inhibition of
LDL oxidation, improvement in endothelial function, and inhibition of platelet activation
and aggregation.
Polyphenol resveratrol found mainly in grapes and thus present in red wine. The biological
effects of resveratrol in platelets include inhibition of platelet adhesion, platelet secretion
and platelet aggregation.
Other than life style changes, there are some risk-reducing agent for prevention;
antihypertensive, antiplatelet, antidiabetic, and lipid-lowering medication. [32] Four major classes
of drugs currently available for treating arterial thrombosis are antiplatelets, statins, ACE
inhibitors, and beta blockers. The highest symptomatic patients with a history of carotid surgery,
CAD, diabetes, or those who were treated by cardiologist usually receiving at least three of four
classes of that drugs.[23]