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INTRODUCTION
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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
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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.
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
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.
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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.
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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.
9
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.
10
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.
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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
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
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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
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
16
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.
17
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