Pulmonary embolism overview

# Overview
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).

# Historical Perspective
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.

# Classification
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.

# Pathophysiology
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.

# Causes
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.

# Differentiation of Pulmonary Embolism from other Diseases
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.

# Epidemiology and Demographics
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.

# Risk Factors
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. 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.

# Triggers
The triggers of VTE include injury to a deep vein from surgery, a fracture, or other trauma, especially a paralytic spinal cord injury.  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.

# Natural History, Complications and Prognosis
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 28%. 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.

# Diagnosis

## Diagnostic Algorithm
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.

## Assessment of Clinical Probability and Risk Scores
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).

## Assessment of the Probability of Subsequent PE ad Risk Scores
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.

## History and Symptoms
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.  A PE may also be an incidental finding in so far as many patients are asymptomatic.  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.

## Physical Examination
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.  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.

## Laboratory Findings
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.

## Arterial Blood Gas Analysis
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.  ABG analysis results do not contribute reliably to tailoring the management of the patients among whom PE is suspected.

## D-dimer
D-dimer is used in the diagnosis of deep vein thrombosis and pulmonary embolism among patients with low or unlikely probability of venous thromboembolism.  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.

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

## Electrocardiogram
The electrocardiogram (ECG) in the cases of PE is often abnormal; however, the ECG abnormalities are neither sensitive nor specific.  Some of the most common ECG abnormalities in PE include T wave inversion in the anterior leads and sinus tachycardia.  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.

## Chest X Ray
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).  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.  The most common findings reported among patients with PE include atelectasis and/or increased opacity in parenchymal areas and cardiomegaly.

## Ventilation/Perfusion Scan
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.

## Echocardiography
Routine echocardiography in patients with suspected pulmonary embolism (PE) is not required.  In fact, the majority of patients with PE have a normal echocardiography. 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. 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.  The presence of right ventricular dysfunction is a predictor of early death among patients with PE.  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.

## Compression Ultrasonography
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.  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.

## CT
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. 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.

## MRI
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.

## Other Imaging Findings
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. 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.

# Treatment

## Treatment Algorithm
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
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.  Thrombolytic therapy is indicated for the treatment of massive PE, also known as high-risk PE.  Patients with PE require long term anticoagulation therapy with agents such as vitamin K antagonists, LMWH, dabigatran, or rivaroxaban.

## IVC Filter
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.

## Embolectomy
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.

## Thromboendarterectomy
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).

## Discharge Care and Long Term Treatment
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. 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).

## Prevention
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.

## Cost Effectivess of Therapy
When indicated, early discharge and outpatient treatment for pulmonary embolism is more cost effective than inpatient treatment. The inpatient treatment with low molecular weight heparin has been reported to be more cost effective than that with unfractionated heparin.

## Future or Investigational Therapies
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.  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.

## Support Group
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.

# PE in Pregnancy
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).  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.  The teratogenic effect of VKA is particularly important during the first trimester of pregnancy.

# PE in Cancer
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.