CHAPTER I

INTRODUCTION

A pulmonary embolism is a blockage in one of the blood vessels in the lungs.

It happens when part, or all, of a blood clot blocks the blood supply to your lungs. A
pulmonary embolism is a serious, potentially life-threatening, condition. Blood clots
that develop in a vein are known as venous thrombosis. Pulmonary embolism is a form
of venous thromboembolism (VTE), which means a blood clot in the vein. Most cases
of pulmonary embolism develop when part, or all, of the blood clot travels in the
bloodstream from the deep veins in your leg and up into your lungs. Having deep vein
thrombosis (DVT) puts you at greater risk of developing a pulmonary embolism. DVT
occurs when a blood clot forms in one of the veins in your leg.1
Every year, one in every 1,000 people develops DVT, and around one in 10
people with untreated DVT will develop a pulmonary embolism. The incidence of
pulmonary embolism may differ substantially from country to country; observed
variation is likely due to differences in the accuracy of diagnosis rather than in the
actual incidence. The incidence of pulmonary embolism in the United States is
estimated to be 1 case per 1000 persons per year. Studies from 2008 suggest that the
increasing use of computed tomography (CT) scanning for assessing patients with
possible pulmonary embolism has led to an increase in the reported incidence of
pulmonary embolism.1
Pulmonary embolism is present in 60-80% of patients with DVT, even though
more than half these patients are asymptomatic. Pulmonary embolism is the third most
common cause of death in hospitalized patients, with at least 650,000 cases occurring
annually. Autopsy studies have shown that approximately 60% of patients who have
died in the hospital had pulmonary embolism, with the diagnosis having been missed
in up to 70% of the cases. Prospective studies have demonstrated DVT in 10-13% of
all medical patients placed on bed rest for 1 week, 29-33% of all patients in medical
intensive care units, 20-26% of patients with pulmonary diseases who are given bed
rest for 3 or more days, 27-33% of patients admitted to a critical care unit after a

1
myocardial infarction, and 48% of patients who are asymptomatic after a coronary
artery bypass graft. Venous thromboembolism is a major health problem. The average
annual incidence of venous thromboembolism in the United States is 1 person per 1000
population, with about 250,000 incident cases occurring annually.1

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 CHAPTER II
CONTENTS

2.1 Definition of Pulmonary Embolism

Pulmonary embolism (PE) is a common life-threatening cardiovascular
illness. Confirmed PE can be defined as a probability of PE high enough to indicate
the need for PE-specific treatment while excluded PE can be defined as a
probability of PE low enough to justify withholding PE-specific treatment with an
acceptable low risk.2 The prognosis and treatment of people diagnosed with acute
PE are related to the initial hemodynamic status. High-risk PE (massive PE) is
defined by the presence of the systemic arterial hypotension, cardiogenic shock and
severe dyspnea. Intermediate-risk (or sub massive PE) is defined by the presence
of right ventricular dysfunction or injury in the absence of arterial hypotension.
Meanwhile, non-high-risk PE (non-massive PE) is defined by the absence of
hypotension and od markers of right ventricular dysfunction or injury.3,4

2.2 Etiology and Pathophysiology of Pulmonary Embolism

Pulmonary embolism (PE) is a dramatic and life-threatening complication of
deep venous thrombosis (DVT). Pulmonary embolism (PE) usually results from a
lower extremity deep venous thrombosis (DVT), within or proximal to the popliteal
vein .5 Pulmonary embolism (PE) is a condition due to blockage of the pulmonary
artery or one of its branches and can cause death in all age. Emboli can be formed
by material other than a blood clot, such as air, fat, tumor cells, and amniotic fluid.6
2.2.1 Etiology of Pulmonary Embolism
In 1856, Rudolf Virchow described three factors leading to
intravascular coagulation (Virchow’s triad) those are:5
a. Local injury to the vessel wall
Local trauma, vasculitis and previous thrombosis can cause
damage to the endothelium of the vessel wall. Damage to the vessel wall

3
 disrupts endothelial function and prevents normal inhibition of
coagulation and fibrinolysis.
b. Hypercoagulability
This condition can be caused by certain medications therapy
including oral contraceptives, hormone replacement therapy and
steroids. Besides that, acquired or congenital thrombophilias can
promote hypercoagulability. It also influenced by polycythemia,
malignant cancers especially adenocarcinoma.
c. Venous stasis
Venous stasis due to obstruction or immobilization (e.g.,
hospitalization, prolonged bed rest) decreases dilution and clearance of
activated clotting factors. This condition also influenced by advanced
age, post-operative period, post-infarction period, heart failure, obesity,
pregnancy and other factors.

2.2.2 Pathophysiology of Pulmonary Embolism

Blood clot is a collection of platelets to repair damage of blood vessels,
which form tissue with red blood cells and fibrin. In normal condition, clot
formed to stop bleeding, but sometimes clot arises without any injuries. Blood
clots that form in venous called thrombus, whereas blood clot loose and move
to other parts of the body causing embolism. Sometimes other material such
as a tumor, fat, air can get into the bloodstream and cause emboli that blocks
arteries. Most blood clot originating from the knee to the upper leg and pelvis.
Clot of the deep veins can migrate through the bloodstream to the right heart,
and then into the pulmonary artery.5
When venous thrombus separated from the place where they formed,
these embolus will follow the flow of the venous system that will enter the
pulmonary arterial circulation. If embolus is large enough, it will be able to
occupy the bifurcation of the pulmonary arteries and form a saddle embolus.
Not infrequently this condition causes the pulmonary veins blocked.5 This

4
situation will lead to an increase in pulmonary artery pressure that will release
vasoconstrictor substances such as serotonin, vasoconstriction reflex of the
pulmonary arteries and hypoxemia that will ultimately lead to pulmonary
arterial hypertension.6,7

Figure 2.1. Pathophysiology of the effect of pulmonary embolism on the pulmonary and
systemic circulation.5 IVS–interventricular septum; LV–left ventricle; PA–pulmonary
artery;RV-right ventricle.
Increased of pulmonary arterial pressure will increase the right ventricle
pressure followed by dilatation and dysfunction of right ventricle as
consequence, which will lead to depressed interventricular septum to the left
side by the impact of disruptions ventricular filling and a decrease in
diastolic distention. Then, the systemic cardiac output will decrease then
reduce coronary perfusion and cause myocardial ischaemia. Elevation of
right ventricular pressure followed by a massive pulmonary embolism would
lower right coronary flow and causing an increased in oxygen demand of the
right ventricle which in turn lead to ischemia and cardiogenic shock. This

5
 cycle can lead to right ventricular infarction, collapse circulation and
death.6,7

2.3 Clinical Manifestation of Pulmonary Embolism

Most of Patient with Pulmonary Embolism has unexplained shortness of breath
and/ or chest paint with dyspnoea, presyncope or syncope, and/ heaemoptysis.8
Arterial hypotension and shock are rare but important clinical presentations. Chest
pain is a frequent symptom of pulmonary embolism and is usually cause by pleural
irritation due to distal emboli causing pulmonary infarction.9 In patient with pre
exiting heart failure or pulmonary disease, worsening dyspnoea may be the only
symptom indicate Pulmonary embolism.9 Some individuals may also experience
uncommon symptoms such as dizziness, back pain or wheezing. 8
Because the clinical symptom is non specific, Pulmonary Embolism has been
called “the Great Masquerader”. It can be like pneumonia, congestive heart failure,
and an illness known as pleurisy.8

Table 2.1 Cinical Characteristic of Patient with Suspected PE in the emergency departement 10
Feature PE confirmed PE not confirmed
(n=1880) (n=528)
Dyspnoea 50% 51%
Pleuritic chest pain 39% 28%
Cough 23% 23%
Substernal chest pain 15% 17%
Fever 10% 10%
Haemoptysis 8% 4%
Syncope 6% 6%
Unilateral leg pain 6% 5%
Sign of Deep pain 24% 18%
thrombosis ( unilateral
extremity swelling)

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2.4 Diagnosis of Pulmonary Embolism
Clinical signs and symptoms for pulmonary embolism are nonspecific;
therefore, patients suspected of having pulmonary embolism—because of
unexplained dyspnea, tachypnea, or chest pain or the presence of risk factors for
pulmonary embolism—must undergo diagnostic tests until the diagnosis is
ascertained or eliminated or an alternative diagnosis is confirmed. Further, routine
laboratory findings are nonspecific and are not helpful in pulmonary embolism,
although they may suggest another diagnosis.
A hypercoagulation workup should be performed if no obvious cause for
embolic disease is apparent. This may include screening for conditions such as the
following:
 Antithrombin III deficiency
 Protein C or protein S deficiency
 Lupus anticoagulant
 Homocystinuria
 Occult neoplasm
 Connective tissue disorders
More clinical studies are needed to evaluate the utility of new approaches to the
condition’s diagnosis. The availability of diagnostic tests, as well as cost-
effectiveness analysis, local traditions, and the expertise of radiologists involved
in the diagnosis, are considerations in the workup of a patient in whom pulmonary
embolism is suspected.

2.4.1 Clinical Scoring Systems

In 2015, pulmonary embolism guidelines were released by the
American College of Physicians and are summarized as follows:11
 Plasma D-dimer tests are more appropriate for those at
intermediate risk for a pulmonary embolism, and no testing may
be necessary for some patients at low risk.

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  Use either the Wells or Geneva rules to choose tests based on a
patient's risk for pulmonary embolism.
 If the patient is at low risk, clinicians should use the eight PERC;
if a patient meets all eight criteria, the risks of testing are greater
than the risk for embolism, and no testing is needed.
 For patients at intermediate risk, or for those at low risk who do
not meet all of the rule-out criteria, use a high-sensitivity plasma
D-dimer test as the initial test.
 In patients older than 50 years, use an age-adjusted threshold (age
×10 ng/mL, rather than a blanket 500 ng/mL), because normal D-
dimer levels increase with age.
 Patients with a D-dimer level below the age-adjusted cutoff should
not receive any imaging studies.
 Patients with elevated D-dimer levels should then receive
imaging.
 Patients at high risk should skip the D-dimer test and proceed to
CT pulmonary angiography, because a negative D-dimer test will
not eliminate the need for imaging in these patients.
 Clinicians should only obtain ventilation-perfusion scans in
patients with a contraindication to CT pulmonary angiography or
if CT pulmonary angiography is unavailable.
 Clinicians should use validated clinical prediction rules to
estimate pretest probability in patients in whom acute PE is being
considered.

2.4.2 D-Dimer Follow-Up on Low-to-Moderate Pretest Probability

When clinical prediction rule results indicate that the patient has a
low or moderate pretest probability of pulmonary embolism, D-dimer
testing may be the next step.12 D-Dimer, a degradation product
produced by plasmin-mediated proteases of cross-linked fibrin, is

8
measured by a variety of assay types, including quantitative,
semiquantitative, and qualitative rapid enzyme-linked immunosorbent
assays (ELISAs); quantitative and semiquantitative latex; and whole-
blood assays. A systematic review of prospective studies of high
methodologic quality concluded that the ELISAs—especially the
quantitative rapid ELISA—dominate the comparative ranking among
the D-dimer assays for sensitivity and negative likelihood ratio. The
quantitative rapid ELISA has a sensitivity of 0.95 and negative
likelihood ratio of 0.13; the latter is similar to that for a normal to near-
normal lung scan in patients with suspected pulmonary embolism.
Negative results on a high-sensitivity D-dimer test in a patient with a
low pretest probability of pulmonary embolism indicate a low
likelihood of venous thromboembolism and reliably exclude pulmonary
embolism. A large, prospective, randomized trial found that in patients
with a low probability of pulmonary embolism who had negative D-
dimer results, forgoing additional diagnostic testing was not associated
with an increased frequency of symptomatic venous thromboembolism
during the subsequent 6 months. In a 2012 prospective cohort study, a
Wells score of ≤4 combined with a negative qualitative D-dimer test
was shown to safely exclude pulmonary embolism in primary care
patients.13
D-dimer testing is most reliable for excluding pulmonary embolism
in younger patients who have no associated comorbidity or history of
venous thromboembolism and whose symptoms are of short duration.
However, it is of questionable value in patients who are older than 80
years, who are hospitalized, who have cancer, or who are pregnant,
because nonspecific elevation of D-dimer concentrations is common in
such patients. D-dimer testing should not be used when the clinical
probability of pulmonary embolism is high, because the test has low
negative predictive value in such cases.

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 Combining D-dimer results with measurement of the exhaled end-
tidal ratio of carbon dioxide to oxygen (etCO2/O2) can be useful for
diagnosis of pulmonary embolism. Kline et al found that, in moderate-
risk patients with a positive D-dimer (>499 ng/mL), an etCO2/O2 <
0.28 significantly increased the probability of finding segmental or
larger pulmonary embolism on computed tomography multidetector-
row pulmonary angiography, while an etCO2/O2) >0.45 predicted the
absence of segmental or larger pulmonary embolism.

2.4.3 Ischemia-Modified Albumin levels

A potential alternative to D-dimer testing is assessment of the
ischemia-modified albumin (IMA) level, which data suggest is 93%
sensitive and 75% specific for pulmonary embolism. Notably, in a
study comparing the prognostic value of IMA to D-dimer testing, IMA
assessment in combination with Wells and Geneva probability scores
appeared to positively impact overall sensitivity and negative predictive
value. The positive predictive value of IMA, in particular, is better than
D-dimer. However, it should not be used alone.

2.4.4 Computed Tomography Scanning

Technical advances in CT scanning, including the development of
multidetector-array scanners, have led to the emergence of CT
scanning as an important diagnostic technique in suspected pulmonary
embolism. Contrast-enhanced CT scanning is increasingly used as the
initial radiologic study in the diagnosis of pulmonary embolism,
especially in patients with abnormal chest radiographs in whom
scintigraphic results are more likely to be nondiagnostic.
Computed tomography angiography (CTA) is the initial imaging
modality of choice for stable patients with suspected pulmonary
embolism. The American College of Radiology (ACR) considers chest

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 CTA to be the current standard of care for the detection of pulmonary
embolism.15 A study by Ward et al determined that a selective strategy
in which CTA is used after compression ultrasonography is cost-
effective for patients with a high pretest probability of pulmonary
embolism. This strategy may reduce the need for CTA and help
eliminate adverse effects associated with CTA.

2.5 Differential Diagnosis of Pulmonary Embolism

The differential diagnosis of pulmonary embolism (PE) includes asthma,
chronic obstructive pulmonary disease (COPD), atelectasis, pneumonia,
hypovolemia, etc., as well as in patients who are on mechanical ventilation with
positive end-expiratory pressure.16 These conditions are seen as false positive on
lung perfusion scan and can be ruled out by undergoing lung angiography. Acute
left-heart insufficiency, acute coronary syndrome with heart failure, and acute
exacerbation of COPD can also be the differential diagnosis of PE due to the
presence of the most typical feature of PE which is dyspnea, when accompanied
with chest pain.7 The elevated levels of D-dimers with the ELISA method on PE
are also found in other diseases including myocardial infarction, pneumonia, heart
failure, cancer, post-surgery, and trauma, and thus can be differentiated by
undergoing compression ultrasonography (CUS) and Spiral computed
tomography (CT).5
The initial discrimination of patients’ conditions to make the correct
diagnosis of PE is critical in order to determine the appropriate therapeutic
procedures for this condition and thus can furthermore benefit the patients’ goal
to heal better from their disease.

2.6 Treatment of Pulmonary Embolism

Management of pulmonary embolism (PE) is depend on risk stratification
that based from hemodynamic instability, RV dysfunction on echocardiography,

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 RV enlargement on chest CT, or elevation of the troponin level due to RV
microinfarction.16

Fig 2.2. Algorithm for PE management. It shows that management of PE divided into three categories.16

2.6.1 Anticoagulation
Effective anticoagulation is the foundation for successful treatment PE.
There are three options: [1] the conventional strategy of parenteral therapy
“bridged” to warfarin, [2] parenteral therapy “bridged” to a novel oral
anticoagulant such as dabigatran (a direct thrombin inhibitor) or edoxaban
(an anti-Xa agent), or [3] oral anticoagulation with rivaroxaban or apixaban
(both are anti-Xa agents) with a loading dose followed by a maintenance
dose as monotherapy without parenteral anticoagulation. The three heparin-
based parenteral anticoagulants are [1] unfractionated heparin (UFH), [2]
low-molecular-weight heparin (LMWH), and [3] fondaparinux.16
Unfractionated heparin (UFH)
UFH role as anticoagulation by binding to and accelerating the
activity of antithrombin. UFH will preventing additional thrombus
formation which it dosed to achieve a target activated partial
thromboplastin time (aPTT) of 60–80 s. UFH uses an initial bolus of 80
U/kg, followed by an initial infusion rate of 18 U/kg per h. The major

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advantage of UFH is its short half-life, which is especially useful in
patients in whom hour-to-hour control of the intensity of
anticoagulation is desired.16

Low-molecular-weight heparin (LMWH)

Low-molecular-weight heparin (LMWH) fragments of UFH exhibit
less binding to plasma proteins and endothelial cells which
consequently have greater bioavailability, a more predictable dose
response, and a longer half-life than does UFH. No monitoring or dose
adjustment is needed unless the patient is markedly obese or has chronic
kidney disease.16

Fondaparinux
Fondaparinux, an anti-Xa pentasaccharide. Fondaparinux is
administered as a weight-based once-daily subcutaneous injection in a
prefilled syringe. No laboratory monitoring is required. Fondaparinux
is synthesized in a laboratory and, unlike LMWH or UFH, is not derived
from animal products. It does not cause heparin-induced
thrombocytopenia. The dose must be adjusted downward for patients
with renal dysfunction.16

Warfarin
This vitamin K antagonist prevents carboxylation activation of
coagulation factors II, VII, IX, and X. The full effect of warfarin
requires at least 5 days, even if the prothrombin time used for
monitoring, becomes elevated more rapidly. If warfarin is initiated as
monotherapy during an acute thrombotic illness, a paradoxical
exacerbation of hypercoagulability increases the likelihood of
thrombosis. In an average-size adult, warfarin is often initiated in a dose
of 5 mg. The target of prothrombin time is usually 2.5, with a range of

13
 2.0–3.0 with standardized by calculating the international normalized
ratio (INR).16
The most serious adverse effect of anticoagulation is hemorrhage.
For life-threatening or intracranial hemorrhage due to heparin or
LMWH, protamine sulfate can be administered. Heparin-induced
thrombocytopenia is less common with LMWH than with UFH. There
is no specific reversal agent for bleeding caused by fondaparinux, direct
thrombin inhibitors, or factor Xa inhibitors. Major bleeding from
warfarin is best managed with prothrombin complex concentrate. With
serious but non–life-threatening bleeding, fresh-frozen plasma or
intravenous vitamin K can be used. Recombinant human coagulation
factor VIIa (rFVIIa) is an off-label option to manage catastrophic
bleeding from warfarin, but prothrombin complex concentrate is a better
choice. Oral vitamin K is effective for managing minor bleeding or an
excessively high INR in the absence of bleeding. For an initial episode
of PE, 3 to 6 months of anticoagulation are considered sufficient. An
alternative approach after the first 6 months of anticoagulation is to
reduce the intensity of anticoagulation and to lower the target INR range
to between 1.5 and 2.16

2.6.2 Thrombolysis
Randomized trials have consistently shown that thrombolytic
therapy of pulmonary embolism effectively resolves thrombo-embolic
obstruction and promptly reduces pulmonary artery pressure and resistance
with a concomitant increase in cardiac output.17 The greatest benefit is
observed when treatment is initiated within 48 h of symptom onset, but
thrombolysis can still be useful in patients who have had symptoms for 6–
14 days.17 Epidemiological study which include more than 2.000.000
patients discharged between 1998 and 2008 with the diagnosis of PE,
support the efficacy and safety of thrombolysis in haemodynamically

14
 unstable patients with acute PE. The case fatality rates attributable to PE
were drastically lower among unstable patients who received (compared
with those who did not receive) thrombolytic treatment.17 Thrombolytic
agents such as tissue plasminogen activator (tPA), streptokinase, and
urokinase more likely effective for spesific groups of patient with PE.18
American College of Chest Physicians (ACCP) guidelines recommended
the use of thrombolytic therapy for patients with an acute symptomatic PE
and hemodynamic instability that do not have major contraindications
owing to bleeding risk, selected high-risk patients without hypotension and
a low risk of bleeding and patients with a submassive acute PE.19 A study
showed that patients who had hypotension (low blood pressure) responded
quickly to streptokinase therapy, and their lung scans returned almost
completely to normal.20 The results of The Urokinase Pulmonary Embolism
Trial (UPET) showed that a 12–h infusion of urokinase followed by heparin
and oral anticoagulants, compared to heparin and oral anticoagulants alone,
increased the resolution rate of pulmonary thromboemboli.20 Recombinant
tissue-type plasminogen activator (rt-PA) indicating its faster action and
greater safety in comparison with Urokinase. A multicentre study showed
that rt-PA decreased mean pulmonary arterial pressure. Results showed that
rt-PA is more effective for acute PE than heparin alone, and that a high dose
of rt-PA leads to rapid improvement in arterial blood gases and lung
perfusion images with no clinical episodes of recurrent PE.20 When one of
these agents is used, the initial intravenous infusion of the thrombolytic
agent is followed by standard anticoagulant therapy.18

2.6.3. Inferior Vena Cava Filter

In some circumstances, treatment of pulmonary embolism involves
placement of a filtering device into the inferior vena cava (IVC), with the
goal of trapping thrombi from the lower extremities en route to the
pulmonary circulation.18 This type of device, is used most frequently if

15
 there are contraindications to anticoagulant therapy (e.g., bleeding
problems), if thromboemboli have recurred despite adequate
anticoagulation, or if the patient already has such limited pulmonary
vascular reserve that an additional clot to the lungs likely would be fatal.18
Observational studies, however, suggest that filters may also benefit
patients with pulmonary embolism and hypotension who do receive
anticoagulants.21 If there is no contraindication, anticoagulation is
continued after the device is in place to decrease the risk of clotting in the
veins distal to the filter. Once in place, some newer filters can be removed
once the need for the filter has resolved.18 Removable filters can be used
in patients with short term contraindications to anticoagulation, but only
about 25% are removed and the long term safety of those that remain is
uncertain.21

2.7 Prognosis of Pulmonary Embolism

The outlook is less good if there is an existing serious illness which helped to
cause the embolism such as advanced cancer. A massive Pulmonary Emboli is more
difficult to treat and is life-threatening. A Pulmonary Emboli is a serious condition
and can have a high risk of death but this is greatly reduced by early treatment in
hospital. The most risky time for complications or death is in the first few hours
after the embolism occurs. Also, there is a high risk of another Pulmonary Emboli
occurring within six weeks of the first one. This is why treatment is needed
immediately and is continued for about three months. We aimed to evaluate the
long-term overall prognosis of patients after acute Pulmonary Embolic.22

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 CHAPTER III
CONCLUSION
Pulmonary embolism is a common life-threatening cardiovascular disease due
to a blockage of part, or all, of a blood clot or other material such as air, fat, tumor cells
and amniotic fluid in one of the blood vessels in the lungs. The incidence of pulmonary
embolism may differ substantially from country to country; observed variation is likely
due to differences in the accuracy of diagnosis rather than in the actual incidence.
Pulmonary embolism (PE) usually results from a lower extremity deep venous
thrombosis (DVT), within or proximal to the popliteal vein. The associating factors
that lead to this intravascular coagulation include local injury to the vessel wall,
hypercoagulability, and venous stasis.
The clinical presentations of pulmonary embolism are non-specific, which is
why this condition has likely been called “The Great Masquerader”. Most patients may
experience unexplained shortness of breath and/ or chest paint with dyspnoea,
presyncope or syncope, and/ heaemoptysis. Arterial hypotension, shock, chest pain,
dizziness, back pain, or wheezing can also present when this condition occurs. Since
the clinical presentations of PE are non-specific, patients with suspected PE should
undergo diagnostic tests to help determining the cause of PE, such as hypercoagulation
tests, plasma D-dimer test, assessment of the ischemia-modified albumin (IMA) level,
and CT scan. These following tests can also help eliminating other differential
diagnosis of PE including asthma, chronic obstructive pulmonary disease (COPD),
atelectasis, pneumonia, acute left-heart insufficiency, and acute coronary syndrome
with heart failure. The management of PE includes anticoagulation, thrombolysis, or
inferior vena cava filter, depending on its risk stratification. The overall prognosis of
patients with PE is amenable if the initial treatment is well-done and the continuous
treatment is maintained as well, but less good if serious illness such as advanced cancer
exists.

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