Pulmonary embolism

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; The APEX Trial Investigators; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

Pulmonary embolism (PE) is an acute obstruction of the pulmonary artery (or one of its branches). The obstruction in the pulmonary artery that causes a PE can be due to thrombus, air, tumor, or fat. Most often, this is due to a venous thrombosis (blood clot from a vein), which has been dislodged from its site of formation in the lower extremities. It has then embolized to the arterial blood supply of one of the lungs. This process is termed thromboembolism. PE is a potentially lethal condition. The patient can present with a range of signs and symptoms, including dyspnea, chest pain while breathing, and in more severe cases collapse, shock, and cardiac arrest. PE treatment requires rapid and accurate risk stratification before the development of hemodynamic collapse and cardiogenic shock. Treatment consists of an anticoagulant medication, such as heparin or warfarin, and in severe cases, thrombolysis or surgery. Pulmonary embolism can be classified based on the time course of symptom presentation (acute and chronic) and the overall severity of disease (stratified based upon three levels of risk: massive, submassive, and low-risk).

Throughout history, many renowned researchers and health care professionals have contributed to the understanding, definition, and treatment of pulmonary embolism. Though the first documented case of pulmonary embolism occurred in 1837, historical record of thrombotic disease dates as far back as the 7th century BCE.^[1]

PE can be classified based on the time course of symptom presentation (acute and chronic) and the overall severity of disease (stratified based upon three levels of risk: massive, submassive, and low-risk). Massive PE is characterised by the presence of either sustained hypotension, or pulselessness, or bradycardia. Submassive PE is characterized by the presence of either right ventricular dysfunction or myocardial necrosis in the absence of hypotension. In low risk PE, there is absence of hypotension, shock, right ventricular dysfunction and myocardial necrosis.^[2]

PE occurs when there is an acute obstruction of the pulmonary artery or one of its branches. It is commonly caused by a venous thrombus that has dislodged from its site of formation and embolized to the arterial blood supply of one of the lungs. The process of clot formation and embolization is termed thromboembolism. PE results in the elevation of the pulmonary vessel resistance as a consequence of not only mechanical obstruction of the capillary by the embolism, but also due to pulmonary vasoconstriction. When pulmonary vascular resistance occurs following an acute PE, the rapid increase in the right ventricular afterload might lead to the dilatation of the right ventricular wall and subsequent right heart failure.^[3][4]

Pulmonary embolism (PE) is the acute obstruction of the pulmonary artery or one of its branches by a thrombus, air, tumor, or fat. Most often, PE is due to a venous thrombus which has been dislodged from its site of formation in the deep veins of the lower extremities, a process referred to as venous thromboembolism.

Pulmonary embolism must be distinguished from other life-threatening causes of chest pain including acute myocardial infarction, aortic dissection, and pericardial tamponade, as well as a large list of non-life-threatening causes of chest discomfort and shortness of breath.

The precise number of people affected by venous thromboembolism (VTE), that is either deep vein thrombosis, PE, or both, is unknown, but estimates range from 300,000 to 600,000 (1 to 2 per 1,000, and in those over 80 years of age, as high as 1 in 100) each year in the United States. Approximately 5 to 8% of the U.S. population has one of several genetic risk factors, also known as inherited thrombophilias in which a genetic defect can be identified that increases the risk for thrombosis.^[5][6]

The most common sources of PE are proximal leg deep venous thromboses (DVTs) or pelvic vein thromboses; therefore, any risk factor for DVT also increases the risk of PE. Approximately 15% of patients with a DVT will develop a PE. In these chapters on venous thromboembolism (VTE), the word risk factors refers to those epidemiologic and genetic variables that expose someone to a higher risk of developing venous thrombosis. The word triggers refer to those factors in the patients immediate history or environment that may have lead to the occurrence of the venous thrombosis. The risk factors for VTE are a constellation of predisposing conditions which stem from the three principles of Virchow’s triad: stasis of the blood flow, damage to the vascular endothelial cells, and hypercoagulability. Approximately 5 to 8% of the U.S. population has one of several genetic risk factors, also known as inherited thrombophilias in which a genetic defect can be identified that increases the risk for thrombosis.^[7][6] The risk factors for VTE can be classified as temporary, modifiable and non-modifiable. It is suggested that venous thrombosis also shares risk factors with arterial thrombosis, such as obesity, hypertension, smoking, and diabetes mellitus.^[8]

The triggers of VTE include injury to a deep vein from surgery, a fracture, or other trauma, especially a paralytic spinal cord injury.^[9] Another trigger for VTE is prolonged immobilization that causes stasis in the deep veins which may occur after surgery, prolonged bed-rest, or prolonged seating during travel.

PE can be acutely complicated by the development of cardiogenic shock, pulseless electrical activity and sudden cardiac death and chronically by the development of pulmonary hypertension. The medical management of PE often requires the administration of potent parenteral anticoagulants and fibrinolytics and massive bleeding can be a complication of their administration. If left untreated almost one-third of patients with PE die, typically from recurrent PE. However, with prompt diagnosis and treatment, the mortality rate is approximately 2–8%. The true mortality associated with PE may be underestimated as two-thirds of all PE cases are diagnosed by autopsy. Estimates suggest that 60,000-100,000 Americans die of VTE, 10 to 30% of which will die within one month of diagnosis. Sudden death is the first symptom in about one-quarter (25%) of people who have a PE. One-third (about 33%) of people with VTE will have a recurrence within 10 years.^[10][6]

When a patient presents with the cardinal symptoms of PE, such as sudden onset of dyspnea, pleuritic chest pain, tachypnea, and/or tachycardia, the initial step is to stratify the patient into high risk or non-high risk depending on their hemodynamic status. Patients who are suspected to have PE and who are hemodynamically unstable should be administered anticoagulants and should undergo a CT scan or echocardiography if CT scan is unavailable. Among patients who are hemodynamically stable, the pretest probability of PE should be estimated using one of the available scoring systems, the most used of which is the Wells score. Patients who have a low or intermediate pretest probability of PE should undergo D-dimer testing as the initial test, whereas those who have a high pretest probability of PE should undergo a CT scan without a D-dimer test. Patients at intermediate or high pretest probability of PE should be administered anticoagulation therapy before the completion of the diagnostic testing.

The diagnosis of PE is based primarily on the clinical assessment of the pretest probability of PE combined with diagnostic modalities such as spiral CT, V/Q scan, use of the D-dimer, and lower extremity ultrasound. Clinical prediction rules for PE include: the Wells score, the Geneva score and the PE rule-out criteria (PERC).

Venous thromboembolism (VTE) consists of deep vein thrombosis (DVT), pulmonary embolism (PE), or both. VTE is a disease associated with morbidity and mortality; therefore, VTE prophylaxis is indicated among specific categories of patients at elevated risk for VTE. Several scores have been developed for the assessment of risk of subsequent VTE such as the Padua prediction score and the IMPROVE score among hospitalized medically ill patients, and Roger’s score and Caprini score among surgical patients.

A proper history and physical exam is crucial to establish an accurate diagnosis of PE. The symptoms of PE depend on the severity of the disease, ranging from mild dyspnea, chest pain, and cough, to sustained hypotension and shock.^[11][12] A PE may also be an incidental finding in so far as many patients are asymptomatic.^[12][13] Sudden death can be the initial presentation of PE. One of the first steps in the management of PE is the determination of the Wells score for PE, whose criteria can be ascertained solely on the basis of history and physical exam. Symptoms of DVT of the lower extremity may be present.

PE is associated with the presence of tachycardia and tachypnea. Signs of right ventricular failure include jugular venous distension, a right sided S3, and a parasternal lift. These signs are often present in cases of massive and submassive pulmonary emboli, also known as intermediate-risk and high-risk respectively.^[11][14] Since PE most commonly occurs as a complication of deep vein thrombosis (DVT), the physical examination should include an assessment of the lower extremities for erythema, tenderness, and/or swelling.

The results of routine laboratory tests including arterial blood gas analysis are non-specific in making the diagnosis of PE. These laboratory studies can be obtained to rule-out other cause of chest discomfort and tachypnea. In patients with acute PE, non-specific lab findings include: leukocytosis, elevated ESR with an elevated serum LDH and serum transaminase (especially AST or SGOT). A negative D-dimer in a patient with low to intermediate probability of PE strongly suggests PE is not present.

Hypoxemia, hypocapnia, increased alveolar-arterial gradient, and respiratory alkalosis are the typical findings that may be observed in patients with PE. The absence of the typical results of the arterial blood gas (ABG) analysis, however, does not exclude PE.^[15] ABG analysis results do not contribute reliably to tailoring the management of the patients among whom PE is suspected.^[16]

D-dimer is used in the diagnosis of deep vein thrombosis and pulmonary embolism among patients with low or unlikely probability of venous thromboembolism.^[17][18] While 500 ng/mL has long been the most commonly used cut off value for abnormal D-dimer concentration, recent studies suggest the use of an age adjusted cut-off concentration of D-dimer. The age adjusted cut-off value of D-dimer is 500 ng/mL for subjects whose age is less than 50 years, and the age multiplied by 10 for subjects older than 50 years.^[19][20][21]

Although the usefulness of brain natriuretic peptide (BNP) concentrations to diagnose PE is limited,^[22] elevated BNP and pro-BNP levels are associated with right ventricular dysfunction and increased mortality, and are therefore useful prognostic markers.^[12] The evaluation of troponin concentration also serves as a useful prognostic marker to identify myocardial necrosis^[23][24] and mortality associated with acute PE.^[25]

The electrocardiogram (ECG) in the cases of PE is often abnormal; however, the ECG abnormalities are neither sensitive nor specific.^[26][27] Some of the most common ECG abnormalities in PE include T wave inversion in the anterior leads and sinus tachycardia.^[28][29][27] The ECG abnormalities reported in PE are also present in a variety of other conditions rendering the utility of ECG for the diagnosis of PE limited. Nevertheless, an ECG is routinely performed in all patients with suspected PE in order to rule out other differential diagnoses such as myocardial infarction.

The majority of chest X-rays (CXR) of patients with PE are abnormal; however, CXR findings are of limited value to establish a diagnosis of a pulmonary embolus (PE).^[30] The importance of a CXR obtained in patients with shortness of breath or chest pain suspected to have a PE is to rule out alternative diagnoses such as pneumonia, congestive heart failure, and rib fracture.^[31] The most common findings reported among patients with PE include atelectasis and/or increased opacity in parenchymal areas^[32] and cardiomegaly.^[33]

A ventilation/perfusion scan (otherwise known as V/Q scan or lung scintigraphy) is a study which shows whether an area of the lung is being ventilated with oxygen and perfused with blood. In the setting of a PE, perfusion can be obstructed due to the formation of a clot. The ventilation/perfusion scan is less commonly used due to the more widespread availability of computed tomography (CT) technology, however it may be useful in patients who have an allergy to iodinated contrast. It may also be useful in pregnant patients in an attempt to minimize radiation exposure. The diagnostic value of the results of the V/Q scan is improved when combined with the clinical pretest probability of PE. A high probability scan coupled with a high clinical pretest probability of PE is diagnostic for PE, while a normal scan regardless of the clinical pretest probability excludes PE. For the majority of the cases of suspected PE, however, the ventilation/perfusion scan does not establish the diagnosis nor exclude PE and further tests are required.^[34]

Routine echocardiography in patients with suspected pulmonary embolism (PE) is not required.^[35] In fact, the majority of patients with PE have a normal echocardiography.^[35] However if elevations in the cardiac troponins or brain natriuretic peptide are present, then acute right ventricular (RV) dysfunction may be present and echocardiography is warranted.^[36] Echocardiography is also valuable for the evaluation of hemodynamically unstable patients with acute dyspnea, right heart failure, or syncope who are suspected to have PE.^[35] The presence of right ventricular dysfunction is a predictor of early death among patients with PE.^[37] When evidence of RV dysfunction is present, PE is risk stratified into submassive PE or massive PE depending on the absence or presence of hypotension respectively.^[2][38]

Compression ultrasonography of the legs is used to evaluate the presence of deep venous thrombosis (DVT) in the lower extremities, which can lead to the development of a PE. The presence of a DVT demonstrated by ultrasonography is enough to warrant anticoagulation without a V/Q or spiral CT scans. The decision to administer anticoagulation therapy to a patient with a positive compression ultrasound is due to the strong association between DVT and subsequent PE. Compression ultrasonography is not the routine initial method of evaluation in a suspected PE during pregnancy unless the patient has coexisting symptoms and signs of DVT.^[39] In case the compression ultrasound is negative for DVT and there is persistent clinical suspicion of PE, the negative ultrasound does not rule out PE and additional imaging tests are required.^[39]

CT pulmonary angiography (CTPA) is the recommended first line diagnostic imaging test in most people. A negative CT pulmonary angiogram excludes a clinically important pulmonary embolism.^[40] Multi-Detector Computed Tomography (MDCT) has rapidly replaced the use of pulmonary angiography in the clinical setting because MDCT is less invasive and easier to perform. Therefore, pulmonary angiography should only be performed first if MDCTA is unavailable or contraindicated.

Magnetic resonance pulmonary angiography should be considered in the setting of a pulmonary embolism only at centers that routinely perform it well and only for patients for whom standard tests are contraindicated. MRA has a sensitivity and specificity of 78% and 99% respectively.^[41]

Pulmonary angiography is the gold standard for diagnosing a PE. The pulmonary angiogram has a sensitivity and specificity of >95% in diagnosing a PE. The estimated false-negative rate is 0.5% – 1.7%. Pulmonary angiography is presently used less frequently in the diagnosis of pulmonary embolism due to wider acceptance of CT scans, which are non-invasive. CT pulmonary angiography is the recommended first line diagnostic imaging test in most people. A negative CT pulmonary angiogram excludes a clinically important pulmonary embolism.^[40] Multi-Detector Computed Tomography (MDCTA) has rapidly replaced the use of pulmonary angiography in the clinical setting because MDCT is less invasive and easier to perform. Therefore, pulmonary angiography should only be performed first if MDCTA is unavailable or contraindicated.

Prompt recognition, diagnosis and treatment of pulmonary embolism is critical. Anticoagulant therapy is the mainstay of treatment for patients who are hemodynamically stable. If hemodynamic compromise is present, then fibrinolytic therapy is recommended.

Medical therapy for PE includes anticoagulation therapy and fibrinolytic therapy. Parenteral anticoagulation therapy with either unfractionated heparin, low molecular weight heparin (LMWH), or fondaparinux is indicated in the initial treatment of patients with PE who do not have any contraindications for anticoagulation. Initial parenteral anticoagulation therapy should be started before the completion of the diagnostic workup among patients who have a high pretest probability of PE as well as among those with intermediate pretest probability of PE and an expected delay in the diagnostic results of more than 4 hours.^[42] Thrombolytic therapy is indicated for the treatment of massive PE, also known as high-risk PE.^[43] Patients with PE require long term anticoagulation therapy with agents such as vitamin K antagonists, LMWH, dabigatran, or rivaroxaban.

Inferior vena cava (IVC) filter is not indicated for the treatment of pulmonary embolism unless the patient has contraindications to anticoagulation therapy due to an elevated risk of bleeding. Anticoagulation therapy should be initiated when the bleeding risk subsides.^[43][2][14]

In thoracic surgery, a pulmonary thrombectomy, is an emergency procedure that removes clotted blood (thrombus) from the pulmonary arteries. There are two types of pulmonary embolectomy: surgical pulmonary embolectomy and percutaneous catheter embolectomy. Pulmonary embolectomy is indicated for the treatment of PE in patients with massive PE among whom fibrinolytic therapy is contraindicated or who fail to improve after initial treatment with fibrinolytic therapy. In addition, pulmonary embolectomy is indicated in patients with submassive PE who fail to improve on the initial treatment and have contraindications to fibrinolytic therapy.^[43][2][14]

In thoracic surgery, a pulmonary thromboendarterectomy, is an operation that removes organized clotted blood (thrombus) from the pulmonary arteries. PTE is a treatment for chronic thromboembolic pulmonary hypertension (pulmonary hypertension induced by recurrent/chronic pulmonary emboli).^[44][45]

While hospital admission is necessary for patients who have a massive or submassive pulmonary embolism (PE), patients with low risk PE who have no evidence of hypotension, right ventricular dysfunction, or myocardial necrosis can be discharged early on and put on an outpatient treatment regimen.^[12] The long term management of PE depends on whether the episode is the first one or not, whether it is provoked or unprovoked, and on the risk of bleeding of the patient. Among non cancer patients, the first line therapy for long term outpatient anticoagulation therapy is vitamin K antagonists (VKA); whereas the first line treatment among cancer patients is low molecular weight heparin (LMWH).

Venous thromboembolism (VTE) is a disease associated with morbidity and mortality; therefore, VTE prophylaxis is indicated among specific categories of patients at elevated risk for VTE. VTE prophylaxis can be either pharmacological through the administration of medications such as low molecular weight heparin (LMWH) or fondaparinux among others, or mechanical through intermittent pneumatic compression or elastic stockings. The decision to administer VTE prophylaxis, the duration of the prophylaxis treatment and the choice of the modality depend on the reason for hospitalization such as medical illness, non orthopedic surgery or orthopedic surgery, as well as on the estimated risk of subsequent VTE and the estimated risk of bleeding.

When indicated, early discharge and outpatient treatment for pulmonary embolism is more cost effective than inpatient treatment.^[46] The inpatient treatment with low molecular weight heparin has been reported to be more cost effective than that with unfractionated heparin.^[46]

There are several ongoing studies on future therapies for the prevention of venous thromboembolism (VTE). The APEX study is a multicenter, randomized, active-controlled efficacy and safety study comparing extended duration betrixaban with standard of care enoxaparin for the prevention of VTE in acute medically ill patients.[3] MARINER is a randomized, double-blind, placebo-controlled, event-driven, multicenter study in patients who are hospitalized for a specific acute medical illness and have other risk factors for VTE, which aims to evaluate rivaroxaban in the prevention of symptomatic VTE events and VTE-related deaths for a period of 45 days post-hospital discharge.[4]

In a support group, members provide each other with various types of nonprofessional, nonmaterial help to pulmonary embolism patients. The help may take the form of providing relevant information, relating personal experiences, listening to others’ experiences, providing sympathetic understanding, and establishing social networks. A support group may also provide ancillary support, such as serving as a voice for the public or engaging in advocacy.

When anticoagulation is indicated for the prevention or treatment of venous thromboembolism in pregnancy, low molecular weight heparin (LMWH) should be administered instead of vitamin K antagonists (VKA).^[47] In fact, VKA can cross the placenta and lead to embryopathy as well as fetal loss. Some of the teratogenic effect of VKA include midfacial hypoplasia, stippled epiphysis, and limb hypoplasia.^[47][48][49] The teratogenic effect of VKA is particularly important during the first trimester of pregnancy.^[47]

Cancer patients who have an episode of pulmonary embolism should receive an extended anticoagulation therapy for at least 3 months. The first line long term anticoagulation therapy for venous thromboembolism (VTE) in cancer patients is vitamin K antagonist (VKA) over low molecular weight heparin (LMWH). Outpatient cancer patients with no additional risk factors for VTE should not receive any routine VTE prophylaxis.^[50]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The APEX Trial Investigators

Throughout history, many renowned researchers and health care professionals have contributed to the understanding, definition, and treatment of pulmonary embolism. Though the first documented case of pulmonary embolism occurred in 1837, historical record of thrombotic disease dates as far back as the 7th century BCE.^[1]

Year	Event
600-1000 BCE	Ayurveda physician and surgeon, Sushruta, makes the first written reference to thrombotic disease in a patient. He notes the patient’s condition as having had a “swollen and painful leg which was difficult to treat”.
1837	French pathologist Jean Cruveilhier documents the first case report on pulmonary embolism.
1922	Researchers publish a description of pulmonary embolism characteristics visible within a chest x-ray.
Prior to 1930	The practicing consensus viewed a pulmonary embolism as universally fatal. They believed surgery was the only treatment despite an operative mortality of 100%.
1935	Researchers begin to utilize heparin in clinical trials aimed at treating pulmonary embolisms.
1940	Researchers, Hampton and Castleman, describe the radiographic appearance of pulmonary embolisms and pulmonary infarctions. These observations are later referred to as Hampton’s hump.
1960	Barritt et al demonstrate that anticoagulant therapy reduces death and recurrent venous thromboembolism in patients with pulmonary embolism.[2]
1977	Physician Eugene Robin published a landmark article recommending the use of pulmonary angiography as an approach to diagnosing pulmonary embolism.[3]
1995	Goodman et al. compared Helical CT angiography (CTA) with pulmonary angiography in patients with unresolved suspicion for pulmonary thromboembolism.[4]
2005	CT replaced scintigraphy as the noninvasive test of choice for suspected pulmonary thromboembolism.[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The APEX Trial Investigators; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

Pulmonary embolism (PE) can be classified based on the time course of symptom presentation (acute and chronic) and the overall severity of disease (stratified based upon three levels of risk: massive, submassive, and low-risk). Massive PE is characterised by the presence of either sustained hypotension, or pulselessness, or bradycardia. Submassive PE is characterized by the presence of either right ventricular dysfunction or myocardial necrosis in the absence of hypotension. In low risk PE, there is absence of hypotension, shock, right ventricular dysfunction and myocardial necrosis.^[1]

Acute PE is the sudden obstruction of the pulmonary arteries by an embolism, which may result in the immediate occurrence of symptoms. Acute PE can be either silent, symptomatic, or fatal. Acute PE can also classified by its severity (as discussed below) as massive PE, submassive PE, or low-risk PE.

Chronic PE, referred to as chronic thromboembolic pulmonary hypertension, is the presence of persistent pulmonary hypertension for at least 6 months following acute PE.^[2] The episode of acute PE preceding the chronic thromboembolic pulmonary hypertension can be either symptomatic or asymptomatic.^[3]

In addition to the time of presentation and the size of the embolus, a PE can also be classified based on the severity of disease. PE can be classified into three types based on the severity: massive (5-10% of cases), submassive (20-25% of cases), and low-risk (70% of cases).

Classification of PE by Severity	Criteria[1]
Massive PE (also known as high risk PE)	– Sustained hypotension (systolic blood pressure <90 mm Hg), not due to arrhythmia, hypovolemia, sepsis, or left ventricular dysfunction, and either lasting for at least 15 minutes or necessitating the administration of inotropes OR – Pulselessness OR – Persistent profound bradycardia (heart rate < 40 bpm) plus findings of shock
Submassive PE (also known as intermediate risk PE)	– Right ventricular dysfunction OR myocardial necrosis AND – Absence of systemic hypotension (systolic blood pressure >90 mm Hg)
Low risk PE	– Absence of hypotension, shock, right ventricular dysfunction and myocardial necrosis

• Massive PE accounts for 5-10% of pulmonary emboli.
• Massive PE falls under the category “high risk patients” in the European guidelines. High risk PE patients have a risk of PE-related early mortality of > 15%.^[4]

• According to the American Heart Association, massive PE is characterized by the presence of:

Sustained hypotension (systolic blood pressure <90 mm Hg), not due to arrhythmia, hypovolemia, sepsis, or left ventricular dysfunction, and either lasting for at least 15 minutes or necessitating the administration of inotropes
OR
Pulselessness
OR
Persistent profound bradycardia (heart rate < 40 bpm) plus findings of shock^[1]

• Submassive PE accounts for 20-25% of pulmonary emboli.

• Submassive PE falls under the category “intermediate risk patients” in the European guidelines. Intermediate risk PE patients have a risk of PE-related early mortality ranging between 3 and 15%.^[4]
  

• According to the American Heart Association, submassive PE is characterized by:

Right ventricular dysfunction OR myocardial necrosis
AND
Absence of systemic hypotension (systolic blood pressure >90 mm Hg)^[1][5]

• Submassive PE patients share the following characteristics:^[6][7]
  • A significantly higher rate of in-hospital complications.
  • A higher potential for long-term pulmonary hypertension and cardiopulmonary disease.

• Though patients with submassive pulmonary emboli may initially appear hemodynamically and clinically stable, there is potential to undergo a cycle of progressive right ventricular failure. A submassive PE requires continuous monitoring to prevent irreversible damage and death.^[5]

Right ventricular (RV) dysfunction is characterized by the presence of AT LEAST ONE of the following:^[1][5]

• Echocardiography findings:
  • RV dilation (ratio of apical 4-chamber RV diameter to left ventricle (LV) diameter > 0.9)
  • RV systolic dysfunction
• CT findings: RV dilation (ratio of 4-chamber RV diameter to LV diameter > 0.9)
• BNP > 90 pg/mL
• N-terminal pro-BNP >500 pg/mL
• EKG findings:
  • New complete or incomplete right bundle-branch block
  • Anteroseptal ST elevation or ST depression
  • Anteroseptal T-wave inversion

Myocardial necrosis is defined as the presence of:^[1][5]

• Elevation of troponin I (>0.4 ng/mL)

OR

• Elevation of troponin T (>0.1 ng/mL)

• Low risk PE accounts for 70% of pulmonary emboli.
• Low risk PE patients have a risk of PE-related early mortality of <1%.^[4] According to the American Heart Association, low risk PE is characterized by the absence of hypotension, shock, right ventricular dysfunction and myocardial necrosis.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The APEX Trial Investigators; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

Pulmonary embolism (PE) occurs when there is an acute obstruction of the pulmonary artery or one of its branches. It is commonly caused by a venous thrombus that has dislodged from its site of formation and embolized to the arterial blood supply of one of the lungs. The process of clot formation and embolization is termed thromboembolism. PE results in the elevation of the pulmonary vessel resistance as a consequence of not only mechanical obstruction of the capillary by the embolism, but also due to pulmonary vasoconstriction. When pulmonary vascular resistance occurs following an acute PE, the rapid increase in the right ventricular afterload might lead to the dilatation of the right ventricular wall and subsequent right heart failure.^[1][2]

• Most PE commonly originate from a thrombus that has formed in the iliofemoral vein, deep within the vasculature of the lower extremity.
• Less commonly, a PE may also arise from a thrombus in the upper extremity veins, renal veins, or pelvic veins.
• The development of thrombosis is classically due to a group of conditions referred to as Virchow’s triad. Virchow’s triad includes alterations in blood flow, factors in the vessel wall, and factors affecting the properties of the blood. It is common for more than one risk factor to be present. Shown below is an image depicting Virchow’s triad.

• After its formation, a thrombus might dislodge from the site of origin and circulate through the inferior vena cava, into the right ventricle, and into the pulmonary vasculature.^[3]

• Hemodynamic complications and the nature of the clinical manifestations of a PE depend on a number of factors:^[4]
  • The size of the embolus and the degree to which it occludes the vascular tree and its subsequent branches
  • The presence of any preexisting cardiopulmonary conditions
  • The role of chemical vasoconstriction as it is insinuated by platelets releasing serotonin and thromboxane in addition to other vasoconstrictors
  • The presence of pulmonary artery dilatation and subsequent reflex vasoconstriction

• PE results in the elevation of the pulmonary vessel resistance as a consequence of not only mechanical obstruction of the capillary by the embolism, but also due to pulmonary vasoconstriction. Pulmonary vasoconstriction can be either biochemically mediated, hypoxia induced, or reflex-induced.^[5][6]

• Several mediators are involved the pulmonary vasoconstriction that occurs in the setting of acute PE, such as:
  • Thromboxane A2 (end product of arachidonic acid metabolism)^[6]
  • Serotonin (vasoconstrictor in the pulmonary circulation and vasodilator in the systemic circulation)^[6]
  • Endothelin 1^[6]
  • Prostaglandin F2α^[6]
  • Thrombin^[7]
  • Histamine^[7]

• While serotonin and thromboxane A2 are mainly produced by activated platelets, the vascular wall and pulmonary neuroendocrine cells might also be the source of some vasoconstrictors.^[6]

• Prostacyclin is a vasodilator produced by the endothelial cells in response to the hemodynamic changes induced by the acute PE.^[6]

• When pulmonary vascular resistance occurs following an acute PE, the rapid increase in the right ventricular afterload might lead to the dilatation of the right ventricular wall and subsequent right heart failure. In addition, the elevated pulmonary vascular resistance causes a decrease in the left ventricular preload and consequently leads to systemic hypotension.^[1][2] In patients with underlying cardiopulmonary disease, the cardiac output suffers substantial deterioration in overall output as compared to otherwise healthy individuals.

• Right heart failure, as well as systemic hypotension, can attenuate coronary perfusion and contribute to subsequent coronary ischemia.^[1][2]

• In summary, the hemodynamic consequences of PE include:
  • Pulmonary hypertension
  • Right ventricular strain
  • Right heart failure
  • Systemic hypotension

• In PE, hypoxemia occurs mainly due to the ventilation perfusion mismatch.^[7] In fact, in the setting of an acute PE, the ventilation to perfusion ratio (V/Q) increases and the dead space enlarges.^[8]

• In addition, the occurrence of right to left shunt also contributes to the hypoxemia among patients with PE. When right to left shunt occurs, the administration of oxygen to the patient fails to correct the hypoxemia.^[7]

• Hypocapnia occurs among patients with PE secondary to a compensatory increase in the minute ventilation.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The APEX Trial Investigators; Associate Editor(s)-in-Chief: Ogheneochuko Ajari, MB.BS, MS [2]

Pulmonary embolism (PE) is the acute obstruction of the pulmonary artery or one of its branches by a thrombus, air, tumor, or fat. Most often, PE is due to a venous thrombus which has been dislodged from its site of formation in the deep veins of the lower extremities, a process referred to as venous thromboembolism.

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. Pulmonary embolism is a life-threatening condition and must be treated as such irrespective of the underlying cause.

• The most common cause of PE is a venous thrombus which has been dislodged from its site of formation in the deep veins of the lower extremities.
  • Deep vein thrombosis

• Non-thrombotic causes of PE are:
  • Cancer
  • Fat
  • Infection
  • Amniotic fluid

Cardiovascular	Antithrombin III deficiency, deep vein thrombosis, dyslipidemia, embolism, fat, heart failure, hypercholesterolemia, hypertension, May-Thurner syndrome, Meadows syndrome, Paget-Schroetter disease, pelvic vein thrombosis, plasminogen deficiency, thromboembolism, thrombosis
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	Behcet’s disease
Drug Side Effect	Asparaginase Erwinia chrysanthemi,axitinib, bevacizumab, clomifene, crizotinib, desogestrel and ethinyl estradiol, epirubicin , Estropipate, Ethacrynic Acid, ethynodiol diacetate and ethinyl estradiol, etonogestrel, fibrinogen,glucocorticoids, goserelin, hormone replacement therapy, idursulfase, interferon gamma, lenalidomide, letrozole, medroxyprogesterone, meropenem, oral contraceptives, ospemifene, palbociclib, pergolide, polidocanol, pramipexole, progesterone, romidepsin, tamoxifen, testosterone, thalidomide, toremifene, trametinib, transdermal contraceptive, vorinostat
Ear Nose Throat	No underlying causes
Endocrine	Polycystic ovary syndrome
Environmental	No underlying causes
Gastroenterologic	Colorectal cancer, inflammatory bowel disease, liver disease, Paget-Schroetter disease
Genetic	Paroxysmal nocturnal hemoglobinuria, protein C deficiency, protein S deficiency
Hematologic	Antiphospholipid syndrome, antithrombin III deficiency, deep vein thrombosis, embolism, essential thrombocythemia, essential thrombocytosis, factor V Leiden mutation, factor XII deficiency, familial dysfibrinogenemia, heparin cofactor II deficiency, heparin-induced thrombocytopenia, hyperviscosity, paroxysmal nocturnal hemoglobinuria, pelvic vein thrombosis, plasminogen deficiency, polycythemia vera, protein C deficiency, protein S deficiency, thromboembolism, thrombosis
Iatrogenic	Cancer surgery, neurosurgery, orthopedic surgery, presence of central venous catheter, vascular surgery
Infectious Disease	Infection, tuberculosis
Musculoskeletal/Orthopedic	Bone fractures
Neurologic	Corticobasal degeneration
Nutritional/Metabolic	Dyslipidemia, hypercholesterolemia, hyperhomocysteinemia
Obstetric/Gynecologic	Amniotic fluid, antiphospholipid syndrome, hormone replacement therapy, Meadows syndrome, oral contraceptives, ovarian hyperstimulation syndrome, polycystic ovary syndrome, pregnancy, transdermal contraceptive
Oncologic	Cancer, colorectal cancer, lung cancer, malignancy, pancreatic cancer, polycythemia vera, prostate cancer, renal cell carcinoma
Ophthalmologic	No underlying causes
Overdose/Toxicity	heparin-induced thrombocytopenia, neuroleptic malignant syndrome
Psychiatric	Corticobasal degeneration, neuroleptic malignant syndrome
Pulmonary	Asthma, lung cancer, thrombosis
Renal/Electrolyte	Chronic renal disease, nephrotic syndrome, renal cell carcinoma
Rheumatology/Immunology/Allergy	Antiphospholipid syndrome, Behcet’s disease, Hughes-Stovin syndrome, prothrombin gene mutation G20210A, rheumatoid arthritis
Sexual	No underlying causes
Trauma	Injury, intravenous drug use, surgery, trauma
Urologic	Prostate cancer
Miscellaneous	Cancer surgery, immobilization, neurosurgery, orthopedic surgery, renal transplantation, vascular surgery

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The APEX Trial Investigators; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

Pulmonary embolism must be distinguished from other life-threatening causes of chest pain including acute myocardial infarction, aortic dissection, and pericardial tamponade, as well as a large list of non-life-threatening causes of chest discomfort and shortness of breath.

Pulmonary embolism (PE) should be differentiated from other diseases presenting with chest pain, shortness of breath and tachypnea. The differentials include the following:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]}

Diseases	Diagnostic tests			Physical Examination			Symptoms							Past medical history	Other Findings
	CT scan and MRI	EKG	Chest X-ray	Tachypnea	Tachycardia	Fever	Chest Pain	Hemoptysis	Dyspnea on Exertion	Wheezing	Chest Tenderness	Nasalopharyngeal Ulceration	Carotid Bruit
Pulmonary embolism	On CT angiography: Intra-luminal filling defect On MRI: Narrowing of involved vessel No contrast seen distal to obstruction Polo-mint sign (partial filling defect surrounded by contrast)	S1Q3T3 pattern representing acute right heart strain	Fleischner sign (enlarged pulmonary artery), Hampton hump, Westermark’s sign	✔	✔	✔ (Low grade)	✔	✔ (In case of massive PE)	✔	–	–	–	–	Hypercoagulating conditions (Factor V Leiden, thrombophilia, deep vein thrombosis, immobilization, malignancy, pregnancy)	May be associated with metabolic alkalosis and syncope
Congestive heart failure	On CT scan: Mediastinal lymphadenopathy Hazy mediastinal fat On MRI: Abnormality of cardiac chambers (hypertrophy, dilation) Delayed enhancement MRI may help characterize the myocardial tissue (fibrosis) Late enhancement of contrast in conditions such as myocarditis, sarcoidosis, amyloidosis, Anderson-Fabry‘s disease, Chagas disease)	Goldberg’s criteria may aid in diagnosis of left ventricular dysfunction: (High specificity) SV1 or SV2 + RV5 or RV6 ≥3.5 mV Total QRS amplitude in each of the limb leads ≤0.8 mV R/S ratio <1 in lead V4	Cardiomegaly	✔	✔	✔	–	–	✔	–	–	–	–	Previous myocardial infarction Hypertension (systemic and pulmonary) Cardiac arrythmias Viral infections (myocarditis) Congenital heart defects	Right heart failure associated with: Hepatomegaly Positive hepato-jugular reflex Increased jugular venous pressure Peripheral edema Left heart failure associated with: Pulmonary edema Eventual right heart failure
Percarditis	On contrast enhanced CT scan: Enhancement of the pericardium (due to inflammation) Pericardial effusion Pericardial calcification On gadolinium-enhanced fat-saturated T1-weighted MRI: Pericardial enhancement (due to inflammation) Pericardial effusion	ST elevation PR depression	Large collection of fluid inside the pericardial sac (pericardial effusion) Calcification of pericardial sac	✔	✔	✔ (Low grade)	✔ (Relieved by sitting up and leaning forward)	–	✔	–	–	–	–	Infections: Viral (Coxsackie virus, Herpes virus, Mumps virus, HIV) Bacteria (Mycobacterium tuberculosis-common in developing countries) Fungal (Histoplasmosis) Idiopathic in a large number of cases Autoimmune Uremia Malignancy Previous myocardial infarction	May be clinically classified into: Acute (< 6 weeks) Sub-acute (6 weeks – 6 months) Chronic (> 6 months)
Pneumonia	On CT scan: (not generally indicated) Consolidation (alveolar/lobar pneumonia) Peribronchial nodules (bronchopneumonia) Ground-glass opacity (GGO) Abscess Pleural effusion On MRI: Not indicated	Prolonged PR interval Transient T wave inversions	Consolidation (alveolar/lobar pneumonia) Peribronchial nodules (bronchopneumonia) Ground-glass opacity (GGO)	✔	✔	✔	✔	–	✔	✔	–	–	–	Ill-contact Travelling Smoking Diabetic Recent hospitalization Chronic obstructive pulmonary disease	Requires sputum stain and culture for diagnosis Empiric management usually started before culture results
Vasculitis	On CT scan: (Takayasu arteritis) Vessel wall thickening Luminal narrowing of pulmonary artery Masses or nodules (ANCA-associated granulomatous vasculitis) On MRI: Homogeneous, circumferential vessel wall swelling	Right or left bundle-branch block (Churg-Strauss syndrome) Atrial fibrillation (Churg-Strauss syndrome) Non-specific ST segment and T wave changes	Nodules Cavitation	✔	✔	✔	✔	✔	✔	–	✔	✔	✔	Takayasu arteritis usually found in persons aged 4-60 years with a mean of 30 Giant-cell arteritis usually occurrs in persons aged > 60 years Churg-Strauss syndrome may present with asthma, sinusitis, transient pulmonary infiltrates and neuropathy alongwith cardiac involvement Granulomatous vasculitides may present with nephritis and upper airway (nasopharyngeal) destruction
Chronic obstructive pulmonary disease (COPD)	On CT scan: Chronic bronchitis may show bronchial wall thickening, scarring with bronchovascular irregularity, fibrosis Emphysema may show alveolar septal destruction and airspace enlargement (Centrilobular- upper lobe, panlobular- lower lobe) Giant bubbles On MRI: Increased diameter of pulmonary arteries Peripheral pulmonary vasculature attentuation Loss of retrosternal airspace due to right ventricular enlargement Hyperpolarized Helium MRI may show progressively poor ventilation and destruction of lung	Multifocal atrial tachycardia (atleast 3 distinct P wave morphologies)	Enlarged lung shadows (emphysema) Flattening of diaphragm (emphysema)	✔	✔	–	–	–	✔	✔	–	–	–	Smoking Alpha-1 antitrypsin deficiency Increased sputum production (chronic bronchitis) Cough	Alpha 1 antitrypsin deficiency may be associated with hepatomegaly

Life Threatening Differential Diagnosis

• Acute myocardial infarction
• Aortic dissection
• Pericardial tamponade

Common Differential Diagnosis in Outpatients

Among outpatients presenting with dyspnea, <4 % are diagnosed with PE.^[21] Common differential diagnoses include:^[21]

• Acute heart failure
• Pneumonia
• Chronic obstructive pulmonary disease exacerbation

Complete List of Differential Diagnosis

• Acute coronary syndrome
• Acute heart failure^[21]
• Asthma acute exacerbation
• Acute respiratory distress syndrome
• Anemia
• Angina pectoris
• Anxiety disorders
• Aortic stenosis
• Atrial fibrillation (diagnosis and management)
• Bronchitis
• Cardiogenic shock
• Cardiac tamponade
• Chronic obstructive pulmonary disease exacerbation^[21]
• Community acquired pneumonia^[21]
• Cor pulmonale
• Costochondritis
• Dilated cardiomyopathy
• Distributive shock
• Emphysema
• Fat embolism
• Hemorrhagic shock
• Herpes zoster
• Hyperventilation
• Mediastinitis
• Mitral stenosis
• Musculoskeletal pain
• Myocardial infarction
• Myocardial ischemia
• Myocarditis
• Noncardiogenic pulmonary edema
• Pericarditis
• Pleuritis
• Pneumonia
• Pneumothorax
• Pulmonary hypertension, primary
• Pulmonary hypertension, secondary
• Restrictive cardiomyopathy
• Rib fracture
• Salicylate intoxication
• Septic shock
• Silicone pulmonary embolism^[22]
• Sudden cardiac death
• Superior vena cava syndrome
• Syncope
• Toxic shock syndrome
• Trauma to the chest
• Unstable angina

References

1. ↑ Brenes-Salazar JA (2014). “Westermark’s and Palla’s signs in acute and chronic pulmonary embolism: Still valid in the current computed tomography era”. J Emerg Trauma Shock. 7 (1): 57–8. doi:10.4103/0974-2700.125645. PMC 3912657. PMID 24550636.
2. ↑ “CT Angiography of Pulmonary Embolism: Diagnostic Criteria and Causes of Misdiagnosis | RadioGraphics”.
3. ↑ Bĕlohlávek J, Dytrych V, Linhart A (2013). “Pulmonary embolism, part I: Epidemiology, risk factors and risk stratification, pathophysiology, clinical presentation, diagnosis and nonthrombotic pulmonary embolism”. Exp Clin Cardiol. 18 (2): 129–38. PMC 3718593. PMID 23940438.
4. ↑ “Pulmonary Embolism: Symptoms – National Library of Medicine – PubMed Health”.
5. ↑ Ramani GV, Uber PA, Mehra MR (2010). “Chronic heart failure: contemporary diagnosis and management”. Mayo Clin. Proc. 85 (2): 180–95. doi:10.4065/mcp.2009.0494. PMC 2813829. PMID 20118395.
6. ↑ Blinderman CD, Homel P, Billings JA, Portenoy RK, Tennstedt SL (2008). “Symptom distress and quality of life in patients with advanced congestive heart failure”. J Pain Symptom Manage. 35 (6): 594–603. doi:10.1016/j.jpainsymman.2007.06.007. PMC 2662445. PMID 18215495.
7. ↑ Hawkins NM, Petrie MC, Jhund PS, Chalmers GW, Dunn FG, McMurray JJ (2009). “Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology”. Eur. J. Heart Fail. 11 (2): 130–9. doi:10.1093/eurjhf/hfn013. PMC 2639415. PMID 19168510.
8. ↑ Takasugi JE, Godwin JD (1998). “Radiology of chronic obstructive pulmonary disease”. Radiol. Clin. North Am. 36 (1): 29–55. PMID 9465867.
9. ↑ Wedzicha JA, Donaldson GC (2003). “Exacerbations of chronic obstructive pulmonary disease”. Respir Care. 48 (12): 1204–13, discussion 1213–5. PMID 14651761.
10. ↑ Nakawah MO, Hawkins C, Barbandi F (2013). “Asthma, chronic obstructive pulmonary disease (COPD), and the overlap syndrome”. J Am Board Fam Med. 26 (4): 470–7. doi:10.3122/jabfm.2013.04.120256. PMID 23833163.
11. ↑ Khandaker MH, Espinosa RE, Nishimura RA, Sinak LJ, Hayes SN, Melduni RM, Oh JK (2010). “Pericardial disease: diagnosis and management”. Mayo Clin. Proc. 85 (6): 572–93. doi:10.4065/mcp.2010.0046. PMC 2878263. PMID 20511488.
12. ↑ Bogaert J, Francone M (2013). “Pericardial disease: value of CT and MR imaging”. Radiology. 267 (2): 340–56. doi:10.1148/radiol.13121059. PMID 23610095.
13. ↑ Gharib AM, Stern EJ (2001). “Radiology of pneumonia”. Med. Clin. North Am. 85 (6): 1461–91, x. PMID 11680112.
14. ↑ Schmidt WA (2013). “Imaging in vasculitis”. Best Pract Res Clin Rheumatol. 27 (1): 107–18. doi:10.1016/j.berh.2013.01.001. PMID 23507061.
15. ↑ Suresh E (2006). “Diagnostic approach to patients with suspected vasculitis”. Postgrad Med J. 82 (970): 483–8. doi:10.1136/pgmj.2005.042648. PMC 2585712. PMID 16891436.
16. ↑ Stein PD, Dalen JE, McIntyre KM, Sasahara AA, Wenger NK, Willis PW (1975). “The electrocardiogram in acute pulmonary embolism”. Prog Cardiovasc Dis. 17 (4): 247–57. PMID 123074.
17. ↑ Warnier MJ, Rutten FH, Numans ME, Kors JA, Tan HL, de Boer A, Hoes AW, De Bruin ML (2013). “Electrocardiographic characteristics of patients with chronic obstructive pulmonary disease”. COPD. 10 (1): 62–71. doi:10.3109/15412555.2012.727918. PMID 23413894.
18. ↑ Stein PD, Matta F, Ekkah M, Saleh T, Janjua M, Patel YR, Khadra H (2012). “Electrocardiogram in pneumonia”. Am. J. Cardiol. 110 (12): 1836–40. doi:10.1016/j.amjcard.2012.08.019. PMID 23000104.
19. ↑ Hazebroek MR, Kemna MJ, Schalla S, Sanders-van Wijk S, Gerretsen SC, Dennert R, Merken J, Kuznetsova T, Staessen JA, Brunner-La Rocca HP, van Paassen P, Cohen Tervaert JW, Heymans S (2015). “Prevalence and prognostic relevance of cardiac involvement in ANCA-associated vasculitis: eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis”. Int. J. Cardiol. 199: 170–9. doi:10.1016/j.ijcard.2015.06.087. PMID 26209947.
20. ↑ Dennert RM, van Paassen P, Schalla S, Kuznetsova T, Alzand BS, Staessen JA, Velthuis S, Crijns HJ, Tervaert JW, Heymans S (2010). “Cardiac involvement in Churg-Strauss syndrome”. Arthritis Rheum. 62 (2): 627–34. doi:10.1002/art.27263. PMID 20112390.
21. ↑ ^{21.0 21.1 21.2 21.3 21.4} Squizzato A, Luciani D, Rubboli A, Di Gennaro L, Gennaro LD, Landolfi R; et al. (2013). “Differential diagnosis of pulmonary embolism in outpatients with non-specific cardiopulmonary symptoms”. Intern Emerg Med. 8 (8): 695–702. doi:10.1007/s11739-011-0725-1. PMID 22094406.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
22. ↑ Restrepo CS, Artunduaga M, Carrillo JA, Rivera AL, Ojeda P, Martinez-Jimenez S; et al. (2009). “Silicone pulmonary embolism: report of 10 cases and review of the literature”. J Comput Assist Tomogr. 33 (2): 233–7. doi:10.1097/RCT.0b013e31817ecb4e. PMID 19346851.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The APEX Trial Investigators; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

The precise number of people affected by venous thromboembolism(VTE), that is either deep vein thrombosis, pulmonary embolism (PE), or both, is unknown, but estimates range from 300,000 to 600,000 (1 to 2 per 1,000, and in those over 80 years of age, as high as 1 in 100) each year in the United States. Approximately 5 to 8% of the U.S. population has one of several genetic risk factors, also known as inherited thrombophilias in which a genetic defect can be identified that increases the risk for thrombosis.^[1][2]

• The precise number of people affected by venous thromboembolism (VTE), that is either deep vein thrombosis (DVT), pulmonary embolism (PE), or both, is unknown, but estimates range from 300,000 to 600,000 (1 to 2 per 1,000, and in those over 80 years of age, as high as 1 in 100) each year in the United States.^[1][2]

• In the United States, the annual incidence of VTE is estimated to be approximately 100 per 100,000 persons.^[3]

The incidence of VTE increases with age, ranging from < 5 cases per 100,000 people in childhood to 500 cases per 100,000 people in the elderly.^[3] Subjects who are more than 65 years of age are at three times higher risk for VTE compared to those who are 45-54 years old.^[4]

Studies about differences in the incidence of VTE by gender have mixed results.^[5][6][4][7] In addition, the risk for VTE was reported to consistently increase with age across both genders.^[4]

• There is a significant difference in the incidence of VTE as it relates to race. African Americans characteristically have the highest incidence of VTE and Caucasians rank as the second highest incidence of VTE.^[3]
• Lower thrombosis incidences in non-Caucasians may be related to a lower prevalence of disorders like Factor V Leiden or Prothrombin 20210A mutation.^[8][9]

• As depicted by the figure below, the majority of VTE events is asymptomatic; while some cases present with fatal PE.

• The percentages of the different subtypes of PE are:
  • Massive PE: 5-10%
  • Submassive PE: 20-25%
  • Low-risk PE: ~70%

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The APEX Trial Investigators; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

The most common sources of pulmonary embolism (PE) are proximal leg deep venous thromboses (DVTs) or pelvic vein thromboses; therefore, any risk factor for DVT also increases the risk of PE. Approximately 15% of patients with a DVT will develop a PE. In these chapters on venous thromboembolism (VTE), the word risk factors refers to those epidemiologic and genetic variables that expose someone to a higher risk of developing venous thrombosis. The word triggers refer to those factors in the patients immediate history or environment that may have lead to the occurrence of the venous thrombosis. The risk factors for VTE are a constellation of predisposing conditions which stem from the three principles of Virchow’s triad: stasis of the blood flow, damage to the vascular endothelial cells, and hypercoagulability. Approximately 5 to 8% of the U.S. population has one of several genetic risk factors, also known as inherited thrombophilias in which a genetic defect can be identified that increases the risk for thrombosis.^[1][2] The risk factors for VTE can be classified as temporary, modifiable and non-modifiable. It is suggested that venous thrombosis also shares risk factors with arterial thrombosis, such as obesity, hypertension, smoking, and diabetes mellitus.^[3]

Shown below is a list of predisposing factors for VTE.^[4][5] The risk factors are classified as moderate or weak depending on how strongly they predispose for a VTE.

Moderate risk factors	Weak risk factors
❑ Chemotherapy ❑ Chronic heart failure ❑ Respiratory failure ❑ Hormone replacement therapy ❑ Cancer ❑ Oral contraceptive pills ❑ Stroke ❑ Pregnancy ❑ Postpartum ❑ Prior history of VTE ❑ Thrombophilia	❑ Advanced age ❑ Laparoscopic surgery ❑ Prepartum ❑ Obesity ❑ Varicose veins

The risk factors of VTE can be further classified into modifiable, non-modifiable and temporary.

Modifiable risk factors are reversible based upon lifestyle/behavior modification.

• Obesity: Obesity is defined as a body-mass index (BMI) above 30 kg/m2.^{[6] [7] [8]}

• Smoking:^[6] Smoking significantly increases the risk of DVT, particularly among women who are taking oral contraceptive pills as well as among obese people.

• Use of oral contraceptives^[9]

• Hyperhomocysteinemia:^[10] Hyperhomocysteinemia can be reduced with vitamin B supplementation.

• Advanced age
• Heart failure
• Thrombophilia or hypercoagulable state
  • Factor V Leiden
  • Prothrombin G20210A mutation
  • Protein C deficiency
  • Protein S deficiency
  • Antithrombin deficiency
  • Activated protein C resistance
  • Antithrombin III deficiency
  • Factor VIII mutation
  • Antiphospholipid syndrome
  • Heparin induced thrombocytopenia
  • Nephrotic syndrome
  • Paroxysmal nocturnal hemoglobinuria
• Polycythemia vera

• Pregnancy and the peri-partum period
• Active cancer
• Central venous catheter

Other possible factors associated with VTE include:

• Nutrition low in fish, fruits, and vegetables^[11]
• Psychological stress^[12]
• Cardiovascular risk factors such as diabetes and hypercholesterolemia^[13]
• Acute medical illness
• Drug abuse (intravenous drugs)^[14]
• Sickle cell disease^[15]
• Inflammatory bowel disease^[16]
• Antipsychotic drugs^[17]
• Thrombocytosis^[18]
• Varicose veins^[19][20]

The Nurse’s Health Study (NHS) investigated the risk factors for PE among 112,822 female subjects. The factors that are associated with increased PE in women are obesity, smoking, and hypertension. According to this study the relative risk (RR) and confidence interval (CI) for the occurrence of idiopathic VTE for each of the following factors are:^[21]

• Obesity: RR 2.9 (95% CI, 1.5-5.4)
• Smoking:
  • 25 – 34 cigarettes per day: RR 1.9 (95% CI, 0.9-3.7)
  • More than 35 cigarettes per day: RR 3.3 (95% CI, 1.7-6.5)
• Hypertension: RR 1.9 (95% CI, 1.2-2.8)
• Hypercholesterolemia: 1.1 (95% CI, 0.62-1.8)
• Diabetes: RR 0.7 (95% CI, 0.3-1.9)

In addition, surgery, trauma, cancer and immobilization are associated with provoked PE.

The following factors have been associated with elevated risk of VTE among subjects in the Physicians Health Study. The relative risk for the occurrence of VTE among patients who have these factors compared to those who don’t is provided below.

• Anticardiolipin antibody level above the 95th percentile (RR: 5.3; 95% CI, 1.55 to 18.3; P = 0.01)^[22]
• Factor V Leiden (RR: 2.7; 95% CI, 1.3 to 5.6; P = 0.008)^[23]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The APEX Trial Investigators; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

Venous thromboembolism (VTE) consists of deep vein thrombosis (DVT), pulmonary embolism (PE), or both. In these chapters on VTE, the word risk factors refer to those epidemiologic and genetic variables that expose someone to a higher risk of developing venous thrombosis. The word triggers refer to those factors in the patient’s immediate history or environment that may have lead to the occurrence of the venous thrombosis. The triggers of VTE include injury to a deep vein from surgery, a fracture, or other trauma, especially a paralytic spinal cord injury.^[1] Another trigger for VTE is prolonged immobilization that causes stasis in the deep veins which may occur after surgery, prolonged bed-rest, or prolonged seating during travel.

Shown below is a list of triggers of VTE.^[1][2] The triggers are classified as strong, moderate, or weak depending on how strongly they predispose for a VTE.

Strong triggers	Moderate triggers	Weak triggers
❑ Bone fracture (hip or leg) ❑ Hip replacement surgery ❑ Knee replacement surgery ❑ Major general surgery ❑ Significant trauma ❑ Spinal cord injury	❑ Athroscopic knee surgery ❑ Central venous lines ❑ Chemotherapy	❑ Bed rest for more than 3 days ❑ Prolonged car or air travel ❑ Laparoscopic surgery ❑ Prepartum

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] The APEX Trial Investigators; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [3]

Pulmonary embolism (PE) can be acutely complicated by the development of cardiogenic shock, pulseless electrical activity and sudden cardiac death and chronically by the development of pulmonary hypertension. The medical management of PE often requires the administration of potent parenteral anticoagulants and fibrinolytics and massive bleeding can be a complication of their administration. If left untreated almost one-third of patients with PE die, typically from recurrent PE. However, with prompt diagnosis and treatment, the mortality rate is approximately 2–8%. The true mortality associated with PE may be underestimated as two-thirds of all PE cases are diagnosed by autopsy. Estimates suggest that 60,000-100,000 Americans die of VTE, 10 to 30% of which will die within one month of diagnosis. Sudden death is the first symptom in about one-quarter (25%) of people who have a PE. One-third (about 33%) of people with VTE will have a recurrence within 10 years.^[1][2]

Subsegmental pulmonary emboli may^[3] or may not^[4] have a favorable prognosis.

• Atrial flutter
• Heart failure or shock
• Pulmonary hypertension
• Pulseless electrical activity
• Sudden cardiac death

• Chronic thromboembolic hypertension (rare – 1%)^[5]
• Pulmonary hypertension
• Recurrent pulmonary embolism

• Severe bleeding can occur as a complication of fibrinolytic treatment:

• Major hemorrhage – 10%
• Non major hemorrhage – 20%
• Intracranial hemorrhage – 0.5%

The Pulmonary Embolism Severity Index (PESI) score aims to stratify patients with PE into classes of increasing rate of mortality and adverse outcomes.^[7]

Age, per yr	Age, in yr
Male sex	10
Cancer	30
Heart failure	10
Chronic lung disease	10
Pulse ≥110 beat/min	20
Systolic blood pressure <100 mmHg	30
Respiratory rate ≥30/min	20
Temperature <36	20
Altered mental status	60
Arterial oxygen saturation <90%	20

Class	Score	Class–specific 30-day mortality
Class I, very low risk	≤65	1.1%
Class II, low risk	65-85	3.1%
Class III, intermediate risk	86-105	6.5%
Class IV, high risk	106-125	10.4%
Class V, very high risk	>125	24.5%

The HOPPE risk score contains^[8]:

• Heart rate
• PaO2 (arterial partial pressure of oxygen)
• Systolic blood pressure
• Diastolic blood pressure
• Electrocardiographic score

The HOPPE has not been studied as extensively as PESI; however, initial study suggests it may prove more accurate.^[8]

The Hestia Clinical Decision Rule can help guide the decision for hospitalization.^[9]

• During 2007–2009, an estimated annual average of 547,596 hospitalizations had a diagnosis of VTE for adults aged ≥18 years. Estimates for DVT and PE diagnoses were not mutually exclusive. An estimated annual average of 348,558 adult hospitalizations had a diagnosis of DVT, and 277,549 adult hospitalizations had a diagnosis of PE. An estimated annual average of 78,511 adult hospitalizations (14% of overall VTE hospitalizations) had diagnoses of both DVT and PE.^[10]

• The estimated average annual number of hospitalizations with VTE was successively greater among older age groups: 54,034 for persons aged 18–39 years; 143,354 for persons aged 40–59 years; and 350,208 for persons aged ≥60 years. The estimated average annual number of hospitalizations with VTE was comparable for men (250,973) and women (296,623).^[10] Shown below is an image depicting the estimated average annual number of hospitalization with a diagnosis of DVT, PE, or VTE by age and sex (image courtesy of CDC.gov^[10]).

• The average annual rates of hospitalizations with a discharge diagnosis of DVT, PE, or VTE among adults were 152, 121, and 239 per 100,000 population, respectively. For VTE, the average annual rates were 60 per 100,000 population aged 18–39 years, 143 for persons aged 40–49 years, 200 for persons aged 50–59 years, 391 for persons aged 60–69 years, 727 for persons aged 70–79 years, and 1,134 for persons aged ≥80 years. The rates of hospitalization were similar for men and women, and the point estimates increased for both sexes by age.^[10]

• On average, 28,726 hospitalized adults with a VTE diagnosis died each year. Of these patients, an average of 13,164 had a DVT diagnosis and 19,297 had a PE diagnosis; 3,735 had both DVT and PE diagnoses.^[10]

• There are mixed results regarding the rate of PE recurrence which ranged in the literature from as low as 2 to 50%.^[11][12][13] According to some reports, one-third (about 33%) of people with VTE will have a recurrence within 10 years.^[14][2] A follow up period of 2.2 years of subsequent observation of 265 patients reported that the risk of recurrence of VTE in patients diagnosed with first-time VTE to be around 7-8 percent per year. ^[15]

• Among patients with a first episode of VTE, the risk of recurrence of VTE is elevated in the first 6 to 12 months following the first episode of VTE, particularly in the first week. The risk of recurrent VTE remains up to 10 years, with an estimated cumulative incidence of first overall VTE recurrence of 30 %. Predictors for recurrence of VTE include malignancy, neurological diseases, and paresis.^[16]

• The hospital mortality rates of PE in untreated PE patients and treated PE patients are approximately 30% and 8%, respectively.^[17][18][19] Unfortunately, two-thirds of all PE cases are diagnosed by autopsy. ^[20] Pulmonary embolism causes death in approximately 16% of hospitalized patients.

• A 26% mortality rate associated with untreated PE is often cited based upon a trial published in 1960 by Barrit and Jordan^[21] which compared anti-coagulation against placebo for the management of pulmonary embolism. Barritt and Jordan performed their study in the Bristol Royal Infirmary in 1957. This study is the only placebo controlled trial ever to examine the efficacy of anticoagulants in the treatment of PE. The results of this were so convincing that the trial has not been repeated. On the other hand, the reported mortality rate of 26% in the placebo group may underestimate the true mortality insofar as the sensitivity and specificity of diagnostic technology in 1957 may have only allowed the detection of massive PE.

• Factors that are associated with an elevated rate of mortality in PE are:^[13]
  • Age >60 years
  • Congestive heart failure
  • Pulmonary hypertension
  • Ischemic heart disease
  • Chronic lung disease
  • Cancer
  • Stroke

• The presence of congestive heart failure or cancer are independent correlates of increased mortality in PE.^[13]

• The one year mortality in patients who had an episode of PE was reported to be approximately 24%, only 2.5% of which is due to PE itself (usually within the first two weeks) while the two third of one-year mortality is due to other medical conditions such as heart disease, lung disease, cancer, or sepsis.^[13]

• The rate of PE-related mortality varies according to the severity of PE:
  • Massive PE, also known as high risk PE, is associated with a rate PE-related early mortality of > 15%.^[22]
  • Submassive PE, also known as intermediate risk PE, is associated with a rate of PE-related early mortality ranging from 3 to 15%.^[22]
  • Low risk PE is associated with a rate of PE-related early mortality of <1%.^[22]

• Estimates suggest that 60,000-100,000 Americans die of VTE, 10 to 30% of which will die within one month of diagnosis.^[23][2]

• An analysis of multiple-cause mortality files compiled by the National Center for Health Statistics from 1979 to 1998 reported that out of 42,932,973 deaths that occurred, almost 600,000 patients (approximately 1.5 percent) had been diagnosed with PE. PE might have caused the death of 200,000 of those patients.^[24]

Observational studies such as the International Co-operative Pulmonary Embolism Registry (ICOPER) and the Management and Prognosis in Pulmonary Embolism Trial (MAPPET) have shown that shock and hypotension are principal high risk markers of early death in acute PE.^[25] The MAPPET study demonstrated that systemic shock was associated with mortality of 24.5% whereas hypotension (but not shock) was associated with a mortality of 15.2%.

A post-hoc analysis of the ICOPER study demonstrated that the 90-day all-cause mortality rate was 52.4% (95% CI,43.3–62.1%) among patients with a systolic blood pressure less than 90 mm Hg compared to 14.7% (95% CI, 13.3–16.2%) among patients with a normal blood pressure.^[26]

The presence of right ventricular dysfunction (RVD) on echocardiography has been associated with a higher mortality in the setting of pulmonary embolism.^{[27][28][29][30][31][32]}

In patients with a pulmonary embolism, elevated plasma levels of natriuretic peptides (brain natriuretic peptide and N-terminal pro-brain natriuretic peptide) have been associated with higher mortality.^[33] Levels of N-terminal pro-brain natriuretic peptide greater than 500 ng/L serve as an indicator of the burden of PE and are associated with death.^[34]

Elevated serum troponin levels are associated with an increased risk of death among pulmonary embolism patients. The elevation of troponin in patients with a massive pulmonary embolism does not reflect epicardial coronary artery disease but rather transmural RV infarctions on autopsy.^{[35] [36]}

Hyponatremia at the time of presentation of PE is associated with increased mortality and hospital readmission.^[37]

The electrocardiographic findings in pulmonary embolism lack specificity and sensitivity and their prognostic value is limited. Development of a QR wave in lead V₁ has been identified as an independent risk factor for an adverse prognosis.^[38]

Class I

“1. Initial risk stratification of suspected and/or confirmed PE based on the presence of shock and hypotension is recommended to distinguish between patients with high and non-high-risk of PE-related early mortality. (Level of Evidence: B) ”

Class II

“1. In non-high-risk PE patients, further stratification to an intermediate- or low-risk PE subgroup based on the presence of imaging or biochemical markers of RVD and myocardial injury should be considered.(Level of Evidence: B) ”

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