VENOUS THROMBOEMBOLISM

SGD B06

Kevin Kusuman 1402005135

Wardatun Nugraheni 1402005158

Nabila Putri Rachmawati 1402005005

Merlynda Ayu Rara D 1402005142

Maya Paramita Wijaya 1402005017

Christian Nurtanto P. 1402005139

I B G Tirta Yoga Y. 1402005240

William Abraham S. 1402005150

Sieny Veronica 1402005105

Tan Beng Hong 1400205174

Vaideshwari Marimuthu 1402005184

Diviya Batumalay 1402005171

Fakultas Kedokteran

Universitas Udayana

2017

I
 CONTENT
Cover .................................................................................................................................... i

Content ...............................................................................................................................ii

CHAPTER I Introduction ...................................................................................................... 1

CHAPTER II .......................................................................................................................... 3

2.1 Definition and epidemiology ............................................................................. 3

2.2 etiology .............................................................................................................. 4

2.3 Pathophysiology ................................................................................................. 5

2.4 Clinical Manifestation ...................................................................................... 10

2.5 Diagnosis .......................................................................................................... 11

2.6 Differential Diagnosis........................................................................................ 17

2.7 Management .................................................................................................... 18

2.8 Prognosis.......................................................................................................... 22

CHAPTER III Summary ...................................................................................................... 23

References ....................................................................................................................... 25

II
 CHAPTER I
INTRODUCTION

Vein thromboembolism is one of the most common cardiovascular disease

in community. Vein thrombosis occurs when red blood cells, fibrin and, to a
lesser extent, platelets, and leucocytes form a mass within an intact vein.
Historically, a consensus view proposed a triad of factors that cause thrombosis;
alterations in blood flow (stasis and turbulence), vascular endothelial injury, or
alterations in the blood coagulation. These components are commonly described
as Virchows triad.[1,2]

Vein thromboembolism had been causing 60.000 deaths in UK. The

incidence of vein thromboembolism rises with increasing age. There are 0.5-1
incidence per 1.000 per year in the general population while there are about 5
incidences per 1000 per year among over 70 years of age while. Its incidence also
rises in people who had hospitalization, malignancy, major trauma, and
prolonged immobility but not as significant as the increasing age as the main risk
factor.[1,2]

Vein thromboembolism (VTE) includes deep vein thrombosis (DVT) and

pulmonary embolism (PE). Without proper treatment, both DVT and PE can lead
to complication. Post-thrombotic syndrome (PTS) commonly occurs to 20-50% of
DVT patient. Chronic thromboembolic pulmonary hypertension (CTEPH) can
occurs as complication in 2-4% PE patients. Patient with PTS will have chronic leg
pain and swelling and in minority patient can progress to venous ulcers. In the
other hand, patient with CTEPH will have dyspnea and exercise intolerance.
Therefore, both PTS and CTEPH will cause significant disability and reducing the
patients quality of life. [1,2]

DVT and PE also associated with significant 30 days-mortality rate in

patient without proper treatment. The mortality rate in the absence of proper

1
treatment is about 3% in the DVT patient and for PE patient is about 31%. In
order to decrease the mortality and morbidity caused by vein thromboembolism,
proper screening and knowledge is needed for prevention, early detection, and
treatment of the patient. However, the clinical sign and symptoms of the vein
thromboembolism is not specific and the sensitivity and specificity of screening
test in asymptomatic patients is also low so the physician must assess the patient
in detail, especially the risk factor that might be associated with vein
thromboembolism.[1,2]

2
 CHAPTER II
CONTENT

2.1. Definition and Epidemiology

Vein thromboembolism is a blood clot that starts in a vein. A number of acquired
etiologic risk factors (predispositions) are associated with a tendency to develop VTE.
These include increasing age, immobilization, surgery, trauma, hospital or nursing home
confinement, malignancy, neurologic disease with extremity paresis, as well as certain
types of oral contraception and hormone replacement therapy. In addition, a variety of
genetic risk factors, such as factor V Leiden, protein S or C deficiency have also been
identified. The pathogenic conditions for VTE comprise a triad of factors and include (1)
venous stasis, (2) hypercoagulable states, and (3) vascular endothelium injury.[3]

Deep vein thrombosis and pulmonary embolism are distinct but related aspects of
the same dynamic disease process known as vein thromboembolism.[4] Deep vein
thrombosis and pulmonary embolism are distinct but related aspects of the same
dynamic disease process known as vein thromboembolism. Pulmonary embolism and
deep vein thrombosis together constitute one of the big three cardiovascular
diseases, the other two being myocardial infarction (MI) and stroke. It is the third
leading vascular diagnosis after heart attack and stroke.

Vein thromboembolism occurs for the first time in 100 persons per 100,000 each
year in the United States, and rises exponentially from <5 cases per 100,000 persons <15
years old to 500 cases (0.5%) per 100,000 persons at age 80 years. Approximately one
third of patients with symptomatic VTE manifest pulmonary embolism, whereas two
thirds manifest deep vein thrombosis alone.[5]

DVT/ PE disproportionately affect the elderly. The incidence among children

(under the age of 14) is quite low, at less than 1 per 100,000 measured in person-years.
Incidence rates rise relatively slowly until the age of 50, then accelerate dramatically,
reaching 1,000 per 100,000 person-years by the age of 85. Women have a higher
incidence of DVT during their child-bearing years although this risk is still relatively low
compared to risk levels for older men and women. However, after the age of 50, men
are at greater risk than women.[4]

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2.2. Etiology
Vein thromboembolism, refers to the diseases deep vein thrombosis of the
leg and pulmonary embolism, as well as rarer manifestations, such as cerebral
venous thrombosis (CVT), upper limb vein thrombosis and splanchnic vein
thrombosis (SVT). The etiology of VTE can be divided in two main groups:
hereditary or acquired, but there are not sufficient studies about incidence of
each of them published.[6]
In about 50% of cases of VTE, no direct known cause can be identified. In
the other 50%, certain risk factors can be identified that increase the risk of VTE.
For most of these risk factors, a direct interaction with one or more of elements
in Virchows triad. The three elements currently known to contribute to the
pathologies of VTE, i.e., stasis (interruption of the blood stream), endothelial
injury (irritation of the vessel wall), and hypercoagulability (changes in blood
constituents), are attributed to the German physician Rudolf Virchow (1856), and
have been adopted as Virchows triad.[6]
Risk factor for VTE can be categorized as inherited, acquired, or a
combination of both. Inherited risk factor are known as thrombophilia; there are
3 known genetic deficiencies of a natural anticoagulatant (heterozygous
deficiency of protein C, protein S or antithrombin), and 3 genetic prothrombotic
factors (Factor V Leiden mutation, prothrombin G20210A mutation, and blood
group non-O). The addition of hyperhomocysteinemia, that also can be caused
by a genetic disorder (metabolism of homocysteine is affected) or by deficiency
of vitamins B6 or B12 or folic acid, renal failure, hypothyroidism, etc, to one of
these factors increases dramatically the risk of DVT. Although these
thrombophilic factors are associated with an increased risk of a first DVT or PE,
recent studies have indicated that testing for these factors only serves a limited
purpose, as there is no markedly increased association with recurrent VTE.
Acquired risk factors are more common and include older age,
immobilization (due to illness, surgery or fractures), use of oral contraceptives,

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pregnancy or the postpartum period, infection, cancer, and cancer treatment
(Table.1).[6,7]
(Table.1) Risk factors for VTE.[6,7]

Most of the DVT start in the calf veins and resolve spontaneosly. The
presence of symptoms are associated with the extent and location of the
thrombosis. Most symptomatic patients have occlusive proximal thrombosis at
the time of presentation. It is important to emphasize that VTE is a dynamic
process, and that the balance between progression and resolution of the process
may change, resulting in clinical manifestations of remissions or exacerbations.[7]

2.3. Pathophysiology
2.3.1 Deep Vein Thrombosis
Thrombosis is the homeostatic mechanism on the body where blood
coagulates that crucial for the establishment of hemostasis after a wound. It can
be initiated from several pathways. It started from cascading activation of
enzymes that magnify the effect of an initial trigger event until creation of similar

5
complex of events results in fibrinolysis or the dissolution of thrombi.
Microscopic thrombus formation and thrombolysis (dissolution) are continuous
events. The beginning of vein thrombosis starts with tissue factor, which leads to
conversion from prothrombin to thrombin, followed by fibrin deposition. [8] Red
blood cells and fibrin are the main component in thrombosis. Normally, the fibrin
always attaches to the blood vessel wall or endothelium to induce clotting in the
blood vessel. But in DVT cases, the fibrin happens to have a deposition causing
coagulation even with or without injury on the vessel.[9]
Under normal circumstances, a physiologic balance is present between
factors that promote and retard coagulation. A disturbance in this equilibrium
may result in the coagulation process occurring at an inopportune time or
location or in an excessive manor. Alternatively, failure of the normal coagulation
mechanisms may lead to hemorrhage. Rudolf Virchow invented the Virchow
triad that has been used for factors that comply with development of vein
thrombosis. Virchow triad is (1) venous static (2) activation of blood coagulation
(3) vein damage. [9]
Venous static can be caused by anything that slows or obstructs the flow of
venous blood that will result in creation of microthrombi causing increase in
blood viscosity that cant be washed away by blood fluid movement. Therefore,
microthrombi can grow larger and propagate causing obstruction in blood vessel.
Endothelial damage in blood vessel can be intrinsic or secondary to external
trauma on blood vessel. It is usually caused by accidental injury or surgical insult.
Hypercoagulable state can occur due to unbalance biochemical and circulating
factor, combined with a decrease in circulating plasma antithrombin and
fibrinolysis. Decreased vein wall contractility and vein valve dysfunction can also
contribute to the development of chronic venous insufficiency. The rise in
ambulatory venous pressure causes a variety of clinical symptoms of varicose
veins, lower extremity edema, and venous ulceration. [9,10]
Thrombus usually forms behind valve cusps or at venous branch points,
most of which begin in the calf. thrombin may disrupt the endothelial cell barrier

6
by inducing F-actin Fillament in endothelial cell and expose the
subendothelium.[11] Platelets adhere to the subendothelial surface by means of
von Willebrand factor or fibrinogen in the vessel wall. Neutrophils and platelets
are activated, releasing procoagulant and inflammatory mediators. Neutrophils
also adhere to the basement membrane and migrate into the subendothelium.
Complexes form of the surface of platelets and increase the rate of thrombin
generation and fibrin formation. Stimulated leukocytes irreversibly bind to
endothelial receptors and extravasate into the vein wall by means of mural
chemotaxis. Because mature thrombus composed of platelets, leukocytes and
fibrin develops, and an active thrombotic and inflammatory process occurs at the
inner surface of the vein, and an active inflammatory response occurs in the wall
of the vein.[9,10,11]
Over time, thrombus organization begins with the infiltration of
inflammatory cells into the clot results in a fibroelastic intimal thickening at the
site of thrombus attachment and a fibrous synechiae in up to 11% cases. This
interaction between vessel wall and thrombus leads to valvular dysfunction and
overall vein wall fibrosis. Histological examination of vein wall remodeling after
vein thrombosis has demonstrated an imbalance in connective tissue matrix
regulation and a loss of regulatory venous contractility that contributes to the
development of chronic venous insufficiency.[9,12]
Over a few months, most acute DVTs evolve to complete or partial
recanalization, and collaterals. Although blood flow may be restored, residual
evidence of thrombus or stenosis is observed in half the patients after 1 year.
Furthermore, the damage to the underlying valves and those compromised by
peripheral dilation and insufficiency usually persists and may progress. Venous
stasis, venous reflux, and chronic edema are common in patients who have had a
large DVT.[9,13]
Deep vein thrombosis can occur in the upper or lower extremities. Deep
vein thrombosis more often develop in the lower extremities. Lower extremities
DVT is much more likely to cause pulmonary embolism, that caused by the higher

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clot burden. Based on its location, DVT in lower extremities can be divided into 2
parts, distal (from genu to lower parts of leg) and proximal (from genu to inguinal
parts of the body). The superficial femoral and popliteal veins are most
commonly affected on lower extremities. Anatomical characteristic of the soleal
vein play a major role in the occurrence, propagation, and embolic risk of vein
thrombus in the lower extremities.[14]
For most cases lower extremity DVT can occur caused by impaired venous
return such as immobilized patients, endothelia injury or dysfunction or tissue
factor such as after leg fractures, and hypercoagubility. For upper extremities
DVT can occur caused by Endothelial injury due to central venous catheters,
pacemakers, or injection of drug. DVT usually begins in venous valve cusps.
Thrombi consist of thrombin, fibrin, red blood cells and few platelets, without
treatment thrombi may propagate proximally to the lung. [14]

2.3.2 Pulmonary Embolism

Thrombotic pulmonary embolism is not a sole isolated disease of the chest
but rather a complication of vein thrombosis. In many case, patient with vein
thromboembolism usually develop both Deep Venous Thromboembolism (DVT)
and Pulmonary Embolism (PE). Evidence of leg DVT is found in about 70% of
patients who have sustained a pulmonary embolism. In most of the remainder, it
is assumed that the whole thrombus has already become detached and
embolised. As pulmonary embolism is preceded by DVT, the factors predisposing
to the two conditions are the same and broadly fit Virchows triad of venous
stasis, injury to the vein wall and enhanced coagulability of the blood.[15]

The manifestation of the embolus depends on : the extent to which it

obstructs the pulmonary circulation, the duration over which that obstruction
accumulates, and the pre-existing state of the patient which has been defined
only imprecisely. Some humoral mediators (for example, serotonin or
thromboxane from activated platelets) can probably produce vasospasm in non-
embolised segments of the lung. As a result, a degree of pulmonary hypertension

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may develop disproportionate to the amount of vasculature that is mechanically
occluded where most emboli are multiple.[16]

Once deep vein thrombosis develops, clots may dislodge and travel
through the vein system and the right side of the heart to lodge in the pulmonary
arteries, where they partially or completely occlude one or more vessels. The
consequences depend on the size and number of emboli, the underlying
condition of the lungs, how well the right ventricle (RV) is functioning, and the
ability of the bodys intrinsic thrombolytic system to dissolve the clots. Death
occurs due to right ventricular failure.[15,16]

The acutely developing pulmonary hypertension in PE leads to an increase

in RV afterload, presenting as right ventricular (RV) dilation and may eventually
cause right-heart failure. Once pulmonary vascular resistance has risen to a level
that the RV is unable to tolerate, PE can result in sudden death through pulseless
electrical activity (formerly electromechanical dissociation) or asystole. A less
sudden drop in RV cardiac output results in decreasing left ventricular (LV) filling,
deteriorated diastolic LV function due to RV dilation (ventricular
interdependence) and interventricular septal bulging. These events can lead to a
fall in blood pressure and present as syncope, hypotension or cardiogenic shock.
RV overload and reduction in coronary flow secondary to high RV pressure in the
presence of massive PE can lead to subendocardial RV ischemia or infarction,
with a potential contribution of coronary atherosclerosis. Patients surviving the
initial episode of right-heart failure develop compensatory mechanisms via
activation of the sympathetic nervous system. Inotropic and chronotropic
stimulation, together with the Frank-Starling mechanism, results in the
development of pulmonary hypertension crucial for maintaining pulmonary
artery flow and, hence, systemic circulation. Together with systemic
vasoconstriction, these mechanisms can preserve systemic blood pressure and
organ function. It is believed that the RV of a healthy man exposed to acute

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overload will not generate more than 40 mmHg of mean pulmonary artery
pressure.[16]

Small emboli may have no acute physiologic effects and may begin to lyse
immediately and resolve within hours or days. Larger emboli can cause a reflex
increase in ventilation (tachypnea), hypoxemia due to ventilation/perfusion
(V/Q) mismatch, and low mixed venous oxygen content as a result of low cardiac
output, atelectasis due to alveolar hypocapnia and abnormalities in surfactant,
and an increase in pulmonary vascular resistance caused by mechanical
obstruction and vasoconstriction. Endogenous lysis reduces most emboli, even
those of moderate size, and physiologic alterations decrease over hours or days.
Some emboli resist lysis and may organize and persist.[15,16]

2.4. Clinical Features

Vein thromboembolism (VTE) is a blood clot that starts in a vein. It is the third
leading vascular diagnosis after heart attack and stroke, affecting about 300,000
600,000 Americans each year. There are two types which is deep vein thrombosis (DVT)
is a clot in a deep vein, usually in the leg, but sometimes in the arm or other
veins.Pulmonary embolism (PE) occurs when a DVT clot breaks free from a vein wall,
travels to the lungs and blocks some or all of the blood supply. Blood clots in the thigh
are more likely to break off and travel to the lungs than blood clots in the lower leg or
other parts of the body.[17]

The clinical manifestation of deep vein thrombosis are related to the degree of
venous outflow obstruction and inflammation of the vessel wall.The patients may be
asymptomatic but may present with unilateral leg swelling associated with
tenderness,warmth and redness and prominent superficial veins.Pulmonary embolism
may be the primary clinical presentation in 10 percent of patients without clinical
evidence of deep vein thrombosis. Some patients with deep vein thrombosis describe
calf pain.This is non specific and may only be present on forced upwards flexing of the
foot which is regarded as an unrealible sign.Superficial thrombophlebitis may be seen
and a low-grade fever is not uncommon.Complete occulusion of the ileofemoral vessels
can lead to severe unilateral limb oedema with cyanotic discolouration and if the
femoral artery is compressed the limb may become ischaemic.It must be remembered

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that alternative diagnoses are found in 70 per cent patients with clinically suspected
deep vein thrombosis.[17,18]

The clinical manifestation of pulmonary embolism are often non-specific and vary
in frequency and intensity, depending on the extent of vascular occlusion and the
degree of underlying cardio-respiratory disease. Patients classically present with acute
onset chest pain, dyspnea and haemoptysis but all three of these symptoms are only
seen in 20 percent of patients. Other symptoms are include cough, wheeze, abdominal
pain, anxiety, cardiac arrhythmias and syncope.Due to the difficulty in diagnosing
pulmonary embolism it should be considered in any patient presenting with unexplained
respiratory smptoms.Patients may have signs of underlying deep vein thrombosis.If the
emboli are small and occur over a longer period of time ,these may not be noticed until
the insidious onset of cor pulmonale.[17,18]

2.5. Diagnosis
Vein thromboembolism, including deep vein thrombosis (DVT) and
pulmonary embolism (PE), is the third most common cardiovascular disorder.[19]
The essential element of a clinical diagnostic evaluation include history taking,
physical examination and supporting investigation.

2.5.1 Diagnosis of Deep Vein Thrombosis

Common symptoms of DVT are unilateral calf or thigh pain, leg swelling,
redness and skin discoloration (phlegmasia alba dolens / milk leg and phlegmasia
cerulea dolens / blue leg).[19,20] The Wells Clinical Score for DVT is a useful tool to
help with the clinical diagnosis. It stratifies patients into high, moderate, or low
risk groups (Figure.1).[21]

2.5.1.1 History and Physical Examination

A history and physical examination itself can be used for the initial workup
diagnosis to approach patients with suspected thrombosis. Using basic 4 and
sacred 7 would establish history match with the cases. Previous diseases history

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and family history is one of the known risk factors that often take part in
development of DVT.
DVT alone cant be diagnosed using only history and physical examination
because of the clinical symptoms that are not specific or sensitive in each cases.
But using Well's rule combination with non-invasive test, the results are
expected to improve, thus reducing the need for further investigation. In Wells
rules, score of 0 or less, suggesting the possibility of DVT is low, a score of 1 or 2
indicates the possibility of DVT being, and scores of 3 or more indicates a high
probability of DVT.[20]
2.5.1.2 Laboratory Tests
Increasing levels of D-dimer and decreased antithrombin (AT) are one of
the most expected result when diagnosing a DVT. D-dimer itself is a fibrin
degradation products. Examination of D-dimer can be done by using ELISA or
latex agglutination assay. D-dimer <0.5 mg / mL would mean definite diagnosis of
DVT. This examination is sensitive but not specific, so a negative result is very
useful for the exclusion of DVT, whereas positive values are not specific to DVT,
so it cannot be used as a single test for the diagnosis of DVT.[20]
2.5.1.3 Imaging Tests
Imaging testing is important in diagnose DVT. Several types of imaging tests
that can be used for diagnosis of DVT, included:[20]
Venography
Angiography (venography or flebography) is the most significant basic
examination (gold standard) in DVT. The principle of the examination is to
inject a contrast agent into venous system, soon a picture of the venous
system in the calf, thigh, inguinal up to the proximal iliaca veins could be seen.
Venography is used on suspicion of DVT cases that was failed to identified
using a non-invasive examination. Venography is the most accurate
examination for diagnosing DVT. Sensitivity and specificity approaching 100%,
thus becoming the gold standard DVT diagnosis. However, it is rarely used

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 because of an invasive, painful, expensive, radiation exposure, and the risk of
various complications.
Flestimografi Impedance
The principle of this inspection is to monitor changes in blood volume leg. This
examination is more sensitive to the femoral vein thrombosis and iliaca
compared veins in the leg.
Ultrasonography (USG) Doppler
Until now ultrasound is often used in diagnosing DVT because of its
advantage where it is non-invasive. Ultrasound has a sensitivity 97% and
specificity of 96% in patients suspected of suffering from symptomatic DVT
and is located in the proximal region.
Magnetic Resonance Venography
The principle of this investigation was to compare the magnetic resonance
between local and venous blood flow smoothly blocked with blood clots. This
examination has high sensitivity and specificity, but has not been widely used.

(Figure.1) CPTP Wells DVT Score.[21]

2.5.2 Diagnosis of Pulmonary Embolism

PE is usually can be suspected when patient came with dyspnea and
pleuritic chest pain either single or combination of both symptoms.[19] The Wells

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Clinical Score for PE is a useful tool to help with the clinical diagnosis (Figure
2).[21]
A classification of pulmonary thromboembolism can be made based on the
stage (acute or chronic) and the size of the emboli (massive or submassive).
Classification pulmonary embolism can be divided into three main types (Table 2).[15]
The first and most common presentation is dyspnoea with or without pleuritic
pain and haemoptysis (acute minor pulmonary embolism). The second
presentation is haemodynamic instability, which is associated with acute massive
pulmonary embolism. The third and least common presentation mimics heart
failure or indolent pneumonia, especially in the elderly (subacute massive
pulmonary embolism).[15]
(Table.2) Clinical Forms of PE.[15]

2.5.2.1 History and Physical Examinations

Risk factor assessment for vein thromboembolic disease plays a crucial role
in determining the pretest probability of PE. Risk factors include previous history
of VTE, recent surgery, immobilization, paresis, personal or family history of
inheritable thrombophilic disorder or personal history of acquired thrombophilia
(e.g., antiphospholipid antibody, cancer, estrogen, pregnancy or
myeloproliferative disorder).[21]
2.5.2.2 Laboratory Tests
Arterial oxygen saturation (PaO2) may be reduced in patients with PE but
this finding is non-specific and seen in other repiratory conditions so it cant be
used to help differentiate PE from the other disease. A normal PaO2 is seen in at

14
least 15 % of cases of proven PE. The white blood cell count may be normal or
elevated. Erythrocyte sedimentation rate and lactate dehydrogenase levels are
not uncommon, particularly if pulmonary infarction has occurred. D-dimer levels
may be elevated but this is not sensitve or specific enough to diagnose PE, unlike
in patients with DVT.[17]
2.5.2.3 Imaging Tests
Although many diagnostic imaging tests such as conventional contrast
pulmonary angiography, thoracic ultrasound, and magnetic resonance
angiography are proposed for the diagnosis of PE, ventilation-perfusion (V/Q)
lung scans and computerized tomographic pulmonary angiography (CTPA)
currently are the most widely used and evaluated tests for the diagnosis of PE.[19]
Electrocardiogram (ECG)
The electrocardiogram is usually normal apart from tachycardia. In severe
cases, dilatation of the right side of the heart results in an abnormal ECG,
seen as P-pulmonale (tall, peaked P waves), right axis deviation and right
bundle branch block.[17]
Chest X-ray
Chest x-rays can show atelectasis, pleural based infiltrates or effusions, or,
rarely, engorged central pulmonary artery vasculature associated with a
paucity of peripheral vessels. The initial chest X-ray is often normal in
patients with PE.[21]
Ventilation-perfusion (V/Q) Scanning
V/Q scanning is a technique widely used in the detection of PE. It is helpful in
patients who have normal chest radiography or who are unable to undergo
CTPA (patients with renal insufficiency, contrast allergy, obesity, or
pregnancy). V/Q scan has a very high negative predictive value and should
be used particularly when a low radiation dose is desirable (eg, in young
patients and females).[19]
Computerized Tomographic Pulmonary Angiography (CTPA)

15
 CTPA is the first choice unless a contraindication exists, then V/Q scan would
be preferred. CTPA is an intraluminal filling defect surrounded by contrast.
Other findings suggestive of PE include an expanded, unpacified vessel,
eccentric filling defect, peripheral, wedge-shaped consolidations, and pleural
effusion. CTPA is essentially 100% sensitive and specific for large central
emboli.[17]
Pulmonary Angiography
Pulmonary angiography is performed by injecting contrast media through a
catheter introduces into the main pulmonary artery under X-ray guidance.
Intra-arterial filling defect and complete obstruction of pulmonary arterial
branches may be seen. It is gold standard for diagnosing PE but it is an
invasive and carries significant procedural risks in inexperienced hands with
a mortality rate of up 0,5 %. It has now been superseded by V/Q scan and
CTPA in the majority of cases.[17]
Magnetic resonance angiography (MRA)
MRA may be an alternative to CTPA for the diagnosis of PE in patients who
have contrast allergy or for whom avoidance of radiation exposure is
desired. However, MRA has been reported to be both less sensitive and less
specific and limited by inter-observer variability.[22]

(Figure.2) CPTP Modifies Wells PE Score.[21]

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2.6. Differential Diagnosis
As mentioned before the disease of vein embolism in brief is regard the
obstruction of the lumen of veins by certain substance or fibrils hence induce
those clinical manifestations. However under the similar definition, symptom, or
clinical manifestation there are certain disease that can be taken mistakenly or
confuse with each other in early state of diagnosis, and there is possibilities of
compilation or coexist of such differential diagnosis contributes towards patient
conditions.

Arterial Thrombosis/Thromboembolism, have the same pathogenesis just

like vein thromboembolism pathogenesis.[23,24] Atherosclerosis,
macroangiopathy, endocarditis, atrial fibrillation, postphlebitic syndrome and
mitral stenosis can be the cause of thrombosis and they are having similar
form and presentation by causing restriction in blood flow.[24] Emboli from the
primary thrombus may break away and occlude distal arteries leading to
cerebral thrombosis and transient ischaemic attacks.
Arteriosclerosis, unlike atherosclerosis which can be a specific type of it that
is pathologically similar with embolism, this disease merely giving same
symptom and it most important form is coronary heart disease.[25] In this
disease, the vessel were not clocked but harden primarily in intimal coat. The
vessel wall losing it elasticity due to old age, inflammation, corrosion, or build
up of lipid, ester and cholesterol. As for the clinical manifestation and
progress can be a mild different from embolism since the vessel it self is
harden and weaken hence causing the vessel easier to burst and causing
hemorrhage but rarely having any symptom in early state.[24,25]
Lymphedema, increase of lymph fluid from out-fuss of plasma fluid toward
tissues causing the amount of blood viscosity/component increased hence
creating an situation where blood cannot run through body extremity end or
sometime induce clotting and progress into thrombosis or simply blockage in
blood or lymph vessel.[26,27] This disease can be both the cause of blood clot
and its result, can have similar symptoms.[27] But this disease can gradually

17
 affect immune system. During embolism, clotting can cause up build of
pressure and hence induce the out flow of plasma fluid into tissues but this is
reversible unlike primary lymphedema. Doppler ultrasound,
lymphoscintigraphy, CT and MRI are mainly use in fine diagnosis to rule out
the dd.[27]
The addition example of vena embolism dd that related to thick blood is given
briefly due to it lesser similarities or rareness, hypercoagulation, polycythemia
vera, Hughes Syndrome, pyemia and etc.[28]

2.7. Management
2.7.1 Prevention

Low-fat, high-fiber diets and Weight Control

Some evidence suggests that simultaneously elevated cholesterol and

triglycerides increase this risk. Reducing dietary cholesterol and saturated fat and
increasing dietary fiber have a major effect on blood lipids. low-fat, vegetarian
and vegan diets are particularly effective in achieving this goal. Elevated
fibrinogen levels, which is another risk factor for DVT, are found lower in persons
following vegetarian diets. Obesity can also increase the risk for developing DVT.
The risk may be due to an obesity-related increase in PAI-1, or to associated
elevation of venous pressure for a discussion of weight-control techniques.[29]

Leg Compression Theraphy

There are many forms of compression therapy include elastic and non-
elastic bandages, boots, hosiery or stockings, and pneumatic devices. Graduated
compression stockings are often prescribed and have the advantage of being
more acceptable, relatively easier to put on and less cumbersome than
bandaging and pneumatic devices.[30]

18
 Graduated compression stocking (GCS) work by exerting the greatest
degree of compression at the ankle, with the level of compression gradually
decreasing up the garment. The pressure gradient ensures that blood flows
upward toward the heart instead of refluxing downward to the foot or laterally
into the superficial veins. The application of adequate graduated compression
reduces the diameter of major veins, which increases the velocity and volume of
blood flow. GCS could be used along with other preventions. Graduated
Compression stocking can be used to prevent post thrombotic syndrome (PTS) or
as VTE prevention. Drugs like anticoagulant prevent VTE by suppressing
coagulation, whereas GCS increasing the venous blood flow velocity and
impeding venous stasis in the legs. As a prophylaxis, result of GCS prevention will
be better if combined with anticoagulant, for example, dextran combined with
GCS will have a better result than single use of dextran alone. While for
treatment purpose, GCS is recommended by guidelines to be used for patients
diagnosed with DVT.[30]
2.7.1 Curative
Treatment for Vein Thromboembolism (VTE) and its type mainly to
prevent the extension of thrombus, acute PE, recurrence of thrombosis,
development of late complications such as pulmonary hypertension and post-
thrombotic syndromes. American College of Chest Physicians (ACCP) guidelines
recommend to give initial standart anticoagulation such as subcutaneous low
molecular weight heparin (LMWH) or fondaparinux, or intravenous or subcutan
unfractionated heparin (UFH) with parenteral administrations. Those drug given
at least for 5 days and extended for proximal DVT until 3 month.[31]
Initial treatment also involved vitamin K antagonist such as warfarin and
should be initiated along with 5 days of anticoagulant. LMWH recommended
over UFH for acute DVT because of its efficacy but for patients with severe renal
failure UFH must be chosen since LMWH mainly excreted through kidneys. These
conventional treatment has shown a good result in treating patients but this
treatment need continuous regular coagulation monitoring and dose adjustment

19
to maintain International Normalized Ratio between 2.0 to 3.0, so its will be
hard to monitored home based patients. For this conditions oral anticoagulant
could be administered.[31]
Oral Anticoagulation divided to two grups depends on their site of actions.
rivaroxaban, apixaban and edoxaban targeting Factor Xa and dabigatran
targeting thrombin. Treatment using oral Anticoagulants have more benefits
from conventional anticoagulants such as fixed dose, easy to use, dont need
continuous monitoring, also the efficacy almost the same. Oral anticoagulant
could be used as acute treatment and secondary prevention.[31,32]
(Table.3) List Of Drugs used is VTE Treatment.[31]
Drug Name Acute Treatment Secondary Prevention
Rivaroxaban Rivaroxaban 15 mg bid After completion
for 3 weeks, then 20 mg Rivaroxaban 20 mg od
od for 312 months or for 6 or 12 months or
Placebo for 6 or
12 months
Apixaban Apixaban 10 mg bid for After 612 months of
7 days then 5 mg bid for apixaban or warfarin:
6 months Apixaban 2.5 mg or 5 mg
bid for 12 months
Edoxaban LMWH or UFH for Edoxaban 90 mg od for
5 days then edoxaban 10 days then 60 mg od
60 mg od for 312 (total 90 days)
months or LMWH
Dabigatran LMWH or UFH for After 312 months of
5 days; dabigatran anticoagulant therapy:
150 mg bid for 6 months Dabigatran 150 mg bid
for 636 months

20
Thrombolytic therapy
Trombolytic therapy should be used for patients PE. Thrombolytic
significantly reducing mortality than anticoagulant alone but it also increasing
the risk of bleeding. Thrombolytic therapy increase major bleeding one of them
is intracranial bleeding. Because of that thrombolytic must be used with special
consideration. Thrombolytic therapy can be given to patients associated with
hypotention (systolic 90) or no association but low risk of bleeding.
Thrombolytic agents that could be used are Alteplase, tenecteplase, urokinase,
and streptokinase. The dose for streptokinase is 250,000IU IV bolus followed by
100,000 IU/hr for 24 hours. The dose for tPA is 100mg IV over 2 hours followed
by therapeutic heparin infusion.[32,33]

Embolectomy
Embolectomy is reasonable for patients with massive PE and patients with
contraindication to fibrinolysis. This therapy not recommended ow-risk or
submassive acute pulmonary embolism who have minor right ventricular
dysfunction, minor myocardial necrosis, and no clinical worsening. Patients with
submissive embolism may be considered if patients experiencing adverse
prognosis such as new hemodynamic instability, worsening respiratory failure,
severe right ventricular dysfunction, or major myocardial necrosis. This therapy
doesnt allowed for patient with low risk.[32]

Vena Cava Filters

Vena Cava Filters (VCF) can be used by some indication such as patients
with acute VTE whos on contraindication of using anticoagulant therapy and
patients who have recurrent VTE and some persistent VTE that could not be
treated adequate anticoagulant. Ideal Inverior Vena Cava (IVC) Filter should be
placed using a percutaneous technique and must be able to trap emboli without
causing occlusion.[32]

21
2.8. Prognosis
Most cases of deep venous thrombosis is occult and usually resolves
spontaneously without complication. The principal long-term morbidity from
DVT is postthrombotic syndrome (PTS), which complicates about a quarter of
cases of symptomatic proximal DVT where most cases develop within 2 years
afterward.

Death from DVT is attributed to massive pulmonary embolism (PE), which

causes as many as 300.000 deaths annually in the United States.[34] Patients with
massive PE may present in cardiogenic shock and can die from multisystem
organ failure.[35] PE is the leading cause of preventable in-hospital mortality. The
Longitudinal Investigation of Thromboembolism Etiology (LITE) that combined
data from two prospective cohort studies, the Atherosclerosis Risk in
Communities (ARIC) and the Cardiovascular Health Study (CHS) determined the
incidence of symptomatic DVT and pulmonary embolism in 21,680 participants
aged 45 years or older who were followed for 7.6 years.[36]

Thromboembolism and recurrent thromboembolism appear to be serious

complications of inflammatory bowel disease.4 In study comprising 84 patients
with inflammatory disease and a history of thromboembolism, of whom, 30%
had recurrent thromboembolism, 70 patients (83%) developed vein
thromboembolism (40% of which manifested as DVT and 23% as PE).[37]

22
 CHAPTER III
SUMMARY

Vein thromboembolism (VTE) is a blood clot that starts in a vein. VTE occurs when
red blood cells, fibrin and, to a lesser extent, platelets, and leucocytes form a mass
within an intact vein. Deep vein thrombosis (DVT) and pulmonary embolism (PE) are
distinct but related aspects of the same dynamic disease process known as vein
thromboembolism.

The etiology of VTE can be divided in two main groups: hereditary or acquired.
Risk factors that associated with a tendency to develop VTE are increasing age,
immobilization, surgery, trauma, hospital or nursing home confinement, malignancy,
neurologic disease with extremity paresis, as well as certain types of oral contraception
and hormone replacement therapy.

A triad of factors that cause thrombosis are alterations in blood flow (stasis and
turbulence), vascular endothelial injury, or alterations in the blood coagulation. These
components are commonly described as Virchows triad.

The clinical manifestation of DVT may be asymptomatic but may present with
unilateral leg swelling associated with tenderness, warmth and redness and prominent
superficial veins. Some patients with deep vein thrombosis describe calf pain. While the
clinical manifestations of PE are often non-specific. Patients classically present with
acute onset chest pain, dyspnea and hemoptysis but all three of these symptoms are
only seen in 20% of patients. Other symptoms are include cough, wheeze, abdominal
pain, anxiety, cardiac arrhythmias and syncope.

The essential elements to diagnose VTE are history taking, physical examination,
laboratory test, and imaging test. DVT can be diagnosed with laboratory test by
checking the levels of D-dimer and anti-thrombin (AT). Several types of imaging tests
that can be used for diagnosis of VTE are venography, Flestimografi impedance, Doppler
USG, and magnetic resonance venography. The most widely used and evaluated tests
for the diagnosis of PE are ventilation-perfusion (V/Q) lung scans and computerized
tomographic pulmonary angiography (CTPA). Differential diagnosis for VTE are
thrombosis/thromboembolism, arteriosclerosis and lymphedema.

23
 There are two kinds of therapies known for VTE patient. The first is prevention
therapy by administrating low-fat diets and high-fiber diets. Controling body weight can
also prevent VTE in many cases. The other prevention that is often used in VTE is
compression therapy including elastic and non-elastic bandages, boots, hosiery or
stockings, and pneumatic devices. Graduated compression stockings is the most often
prescribed because of its effectiveness. The last therapy is curative therapy by giving
anticoagulants and vitamin K antagonist, thrombolytic therapy, embolectomy, and vena
cava filters.

Most cases of DVT is occult and usually resolves spontaneously without

complication. The principal long-term morbidity from DVT is post-thrombotic syndrome
(PTS). Death from DVT is attributed to massive pulmonary embolism (PE). Patients with
massive PE may present in cardiogenic shock and can die from multisystem organ
failure. PE is the leading cause of preventable in-hospital mortality. Thromboembolism
and recurrent thromboembolism appear to be serious complications of inflammatory
bowel disease

24
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