Pulmonary embolism: Epidemiology and pathogenesis in adults

INTRODUCTION — 

Acute pulmonary embolism (PE) is a form of venous thromboembolism that is common and sometimes fatal.

The definition, classification, epidemiology, and pathophysiology of PE are discussed in detail in this topic. Details regarding the diagnosis and treatment of PE are provided separately.

●(See "Clinical presentation and diagnostic evaluation of the nonpregnant adult with suspected acute pulmonary embolism".)

●(See "Acute pulmonary embolism in adults: Treatment overview and prognosis".)

●(See "Acute pulmonary embolism in adults: Thrombolytic therapy in intermediate- and high-risk patients".)

●(See "Venous thromboembolism: Initiation of anticoagulation".)

●(See "Venous thromboembolism: Anticoagulation after initial management".)

DEFINITION — 

PE refers to obstruction of the pulmonary artery or one or more of its branches by material (eg, thrombus, tumor, air, or fat) that originated elsewhere in the body. This topic focuses on PE due to thrombus. Tumor, air, and fat embolisms are discussed separately.

●(See "Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Diagnostic evaluation and management".)

●(See "Air embolism".)

●(See "Fat embolism syndrome".)

CLASSIFICATION — 

PE can be classified by the risk of death from PE (low, intermediate, or high), the temporal pattern of presentation (acute, subacute, or chronic), the anatomic location (saddle, main, lobar, segmental, or subsegmental), and the presence or absence of symptoms (symptomatic or asymptomatic).

The risk of death from PE — While in the past PE was classified as stable or unstable, it is now preferred that it be classified according to the risk of death from PE (low, intermediate [subcategories: intermediate-low and intermediate-high], or high). The definition of these categories is provided in the table (table 1). This distinction is important since patients with high-risk PE are more likely to die from obstructive shock in the first two hours of presentation and therefore benefit from more aggressive treatment. Further details regarding these categories and how they are used to choose therapy are provided separately. (See "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Assess mortality risk (low, intermediate, high)'.)

The temporal pattern of presentation — Patients with PE can present acutely, subacutely, or chronically:

●Acute – Patients with acute PE typically develop symptoms and signs immediately after obstruction of pulmonary vessels.

●Subacute – Some patients with PE present subacutely within days or weeks following the initial event.

●Chronic – Patients with chronic PE slowly develop symptoms of pulmonary hypertension over many years following an acute or subacute event, which may have been symptomatic or asymptomatic (ie, chronic thromboembolic pulmonary hypertension [CTEPH]). CTEPH is discussed separately. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension" and "Chronic thromboembolic pulmonary hypertension: Initial management and evaluation for pulmonary artery thromboendarterectomy".)

The anatomic location

●Saddle PE – Saddle PE sits at the bifurcation of the main pulmonary artery, often extending into the right and left main pulmonary arteries; once one pulmonary artery is obstructed, a "tail" grows towards the remaining artery to obstruct it too. Approximately 3 to 6 percent of patients with PE present with a saddle embolus [1,2]. Traditionally, saddle PE was thought to be associated with hemodynamic instability and death. However, retrospective studies suggest that among those diagnosed with a saddle embolus, only 22 percent are hemodynamically unstable, with an associated mortality of 5 percent [1,2].

●Main, lobar, segmental, or subsegmental PE – Most PEs move beyond the bifurcation of the main pulmonary artery to lodge distally in the main, lobar, segmental, or subsegmental branches of the pulmonary artery. They can be bilateral or unilateral. Smaller thrombi that are located in the peripheral segmental or subsegmental branches are more likely to cause pulmonary infarction and pleuritis (image 1). (See 'Infarction' below.)

●Clot-in-transit – A clot that is "in transit" through the heart is often classified as a form of PE, even though the thrombus has not yet lodged in a pulmonary artery. Clot-in-transit is associated with high mortality (up to 40 percent). (See "Acute pulmonary embolism in adults: Thrombolytic therapy in intermediate- and high-risk patients", section on 'Clot-in-transit'.)

The presence or absence of symptoms — Symptomatic PE refers to the presence of symptoms in association with radiologically confirmed PE. Asymptomatic PE refers to the incidental finding of PE on imaging (eg, contrast-enhanced computed tomography [CT]) performed for another reason (eg, follow-up of an abnormality). (See "Clinical presentation and diagnostic evaluation of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Diagnostic imaging'.)

EPIDEMIOLOGY

General population

Incidence — Estimates of the incidence of PE in the general population increased following the introduction of D-dimer testing and CT pulmonary angiography in the 1990s and vary considerably depending on the population studied [3-9]. However, studies since then have reported stable rates [8,10]. As examples:

●One Canadian study, reported an age- and sex-adjusted incidence rate of 0.38 per 1000 person-years, which remained stable between 2002 and 2012 [8].

●A 2023 American Heart Association report estimated an annual incidence of 393,000 cases of PE in the United States [11].

●A modelling study estimated the annual PE incidence in six countries in Europe as 296,000 cases (total population 310.4 million) [12]. In Asia, PE rates are estimated to be lower than Europe and the US while little is known about PE rates in Africa [13].

●The overall lifetime risk of PE and/or deep venous thrombosis at age 45 is estimated to be 8.1 percent and is higher in Black individuals (11.5 percent) and individuals with obesity (10.9 percent) [14].

Among older patients ≥90 years of age, one report described a rising incidence in PE diagnoses from 57 percent in 2004 to 2008 to 69 percent in 2019 to 2023 [15].

The use of statins, exercising regularly, and a low body mass index may reduce the incidence of PE [16].

PE is slightly more common in males than females. The incidence rises with increasing age and several other factors and conditions, which are discussed below. (See 'Special populations' below.)

Mortality — PE accounts for approximately 110,000 annual deaths in the United States [17-19] while it accounts for 300,000 annual deaths in Europe [20].

An analysis from the National Center for Health Statistics reported a total of 109,992 PE-related annual deaths in the US between 2006 and 2019; females constituted 54.7 percent [17]. The overall age-adjusted mortality rate per 100,000 was unchanged during the study period (2.84 in 2006 to 2.81 in 2019) but increased for males and Black individuals. Mortality rates were also higher in rural areas than in micropolitan and large metropolitan areas.

In an analysis of data from five European countries, the majority of venous thromboembolism (VTE)-related deaths were due to hospital-acquired PE and most were diagnosed antemortem [12]. However, many sudden cardiac deaths are thought to be secondary to PE, so the actual mortality attributable to PE is difficult to estimate.

In a review of death certificates in the Multiple-Cause Mortality Files compiled by the National Center for Health Statistics from 1979 to 1998, age-adjusted mortality rates were 50 percent higher in African American adults compared with White American adults; compared with other groups (eg, Asian American, American Indian), mortality rates in White Americans were 50 percent higher [18].

In a cohort of 15,531 patients with PE discharged from a hospital between 2000 and 2002, Black patients had a 30 percent higher mortality relative to White patients. However, in a separate analysis of 8473 hospitalizations for acute PE from 2012 to 2019, Black race was not associated with mortality when adjusting for the greater severity of PE among Black patients [21].

Among older adults, the incidence of fatal PE declined (4 percent in 2004–2008 to 2 percent in 2019–2023) [15]. Whether the use of DOACs correlates with this decline is unclear.

Special populations — The incidence of VTE in select populations is discussed in the following sections:

●Patients with malignancy (see "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Incidence and risk factors' and "Supportive care for locally advanced or metastatic exocrine pancreatic cancer", section on 'Venous thromboembolism')

●Patients who are pregnant (See "Venous thromboembolism in pregnancy: Epidemiology, pathogenesis, and risk factors", section on 'Epidemiology'.)

●Patients with stroke (see "Prevention and treatment of venous thromboembolism in patients with acute stroke", section on 'Pulmonary embolism')

●Hospitalized medical patients (see "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'General medical patients')

●Hospitalized surgical patients (including those undergoing orthopedic surgery) (see "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients", section on 'Baseline thrombosis risk' and "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement", section on 'Risk of thrombosis' and "Prevention of venous thromboembolism (VTE) in adults with non-major extremity orthopedic injury with or without surgical repair", section on 'Risk of thrombosis')

●Hospitalized gynecologic patients (see "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Incidence and risk factors')

●Patients with nephrotic syndrome (see "Hypercoagulability in nephrotic syndrome", section on 'Epidemiology')

●Patients with acute traumatic spinal cord injury (see "Acute traumatic spinal cord injury")

●Patients with inherited thrombotic disorders (see "Overview of the causes of venous thrombosis in adults", section on 'Inherited thrombophilia')

●Patients with sickle cell trait or disease (see "Sickle cell trait", section on 'Venous thromboembolism' and "Overview of the clinical manifestations of sickle cell disease", section on 'Venous thromboembolism')

●Patients with coronavirus disease 2019 (COVID-19) (see "COVID-19: Hypercoagulability")

An extensive review of the causes of VTE is provided separately. (See "Overview of the causes of venous thrombosis in adults".)

PATHOGENESIS AND PATHOPHYSIOLOGY

Risk factors — The few studies that have specifically examined risk factors for PE alone confirm that they are similar to those for venous thromboembolism (VTE) in general (table 2) [22-28]. Risk factors for VTE are discussed in detail separately. (See "Overview of the causes of venous thrombosis in adults".)

Source — Most emboli are thought to arise from lower extremity proximal veins (iliac, femoral, and popliteal; ie, veins with low flow) (table 3). More than 50 percent of patients with proximal vein deep venous thrombosis (DVT) have concurrent PE at presentation [29-33]. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".)

Distal (also known as calf vein) DVT rarely embolizes to the lung [34-43]. Typically, more than two-thirds of distal DVT resolve spontaneously after detection. However, if untreated, thrombus that extends into the proximal veins results in a greater potential to embolize. Distinguishing calf vein DVT that is at higher risk of embolizing is discussed separately. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Distal DVT'.)

PE can also arise from veins with high venous flow, including the inferior vena cava and the pelvic veins, and from non-lower-extremity veins, including the renal vein and upper extremity veins, although embolization from renal and upper extremity veins is less common. (See "Hypercoagulability in nephrotic syndrome" and "Overview of thoracic central venous obstruction".)

Pathophysiologic response to PE — PEs are typically multiple, with the lower lobes being involved in the majority of cases [44]. Once thrombus lodges in the lung, a series of pathophysiologic responses can occur, including infarction, abnormal gas exchange, and cardiovascular compromise. However, these responses are not always clinically evident.

Infarction — In about 10 percent of patients, thrombi obstruct segmental and subsegmental vessels resulting in pulmonary infarction [45]. An intense inflammatory response in the lung and adjacent visceral and parietal pleura often results in the classic triad of pleuritic chest pain, hemoptysis, and pleural effusion (which may be bloody).

Abnormal gas exchange — Impaired gas exchange is common in PE (although not always present). (See "Clinical presentation and diagnostic evaluation of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Laboratory tests' and "Measures of oxygenation and mechanisms of hypoxemia".)

●Hypoxemia – Hypoxemia is the most common form of gas exchange abnormality in PE and is due to the following [46]:

•Ventilation/perfusion (V/Q) mismatch due to redistribution of blood from obstructed vascular regions to nonobstructed vascular regions. This leads to high V/Q units in the obstructed regions and low V/Q in the nonobstructed regions where there is over perfusion.

•Inflammation results in surfactant dysfunction and atelectasis, which can cause very low V/Q lung units or functional intrapulmonary shunting.

•A low mixed venous oxygen tension from low cardiac output and/or increased oxygen consumption.

The mechanisms of hypoxemia are discussed separately. (See "Measures of oxygenation and mechanisms of hypoxemia".)

●Hypocapnia – Inflammation and pain are thought to stimulate respiratory drive, resulting in hypocapnia and respiratory alkalosis.

●Hypercapnia – Hypercapnia and acidosis are unusual in PE unless shock is present. (See "Mechanisms, causes, and effects of hypercapnia".)

Cardiovascular compromise — Hypotension from PE is due to diminished stroke volume and cardiac output. In patients with PE, pulmonary vascular resistance (PVR) is increased due to physical obstruction of the vascular bed with thrombus as well as hypoxic and metabolically mediated vasoconstriction within the pulmonary arterial system. Increased PVR, in turn, impedes right ventricular (RV) outflow and causes RV dilation and flattening or bowing of the intraventricular septum. Together, these changes reduce left ventricular (LV) preload and LV volume, resulting in reduced cardiac output and hypotension. When severe, this results in obstructive shock. (See "Definition, classification, etiology, and pathophysiology of shock in adults", section on 'Obstructive'.)

As an example, when obstruction of the pulmonary vascular bed approaches 75 percent, the RV must generate a systolic pressure in excess of 50 mmHg to preserve adequate pulmonary artery flow [47]. When the RV fails to accomplish this, hypotension ensues. Thus, in patients without underlying cardiopulmonary disease, multiple large thrombi are generally responsible for hypotension via this mechanism. In contrast, in patients with underlying cardiopulmonary disease, especially those with pre-existing elevations in PVR, hypotension can be induced by smaller emboli, likely due to a substantial vasoconstrictive response and/or an inability of the RV to generate sufficient pressure to combat high PVR.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Superficial vein thrombosis, deep vein thrombosis, and pulmonary embolism".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Pulmonary embolism (blood clot in the lung) (The Basics)")

●Beyond the Basics topics (see "Patient education: Pulmonary embolism (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Pulmonary embolism (PE) is a common and sometimes fatal disease. It is due to obstruction of a pulmonary artery or one or more of its branches by material (eg, thrombus, tumor, air, or fat) that originated elsewhere in the body. This topic discusses PE due to thrombus. (See 'Definition' above.)

●Classification – PE can be classified according to the following (see 'Classification' above):

-The risk of death from PE (low, intermediate, or high) (table 1)

-The temporal pattern of presentation (acute, subacute, or chronic)

-The anatomic location (saddle, main, lobar, segmental, or subsegmental)

-The presence or absence of symptoms (symptomatic or asymptomatic)

Determining the risk of death is important since patients with high-risk PE are more likely to die from obstructive shock in the first two hours of presentation and therefore benefit from more aggressive treatment. Further details on the management of PE are provided separately. (See "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Assess mortality risk (low, intermediate, high)'.)

●Epidemiology – PE rates vary. Annual rates are estimated at 393,000 in the United States and 296,000 in Europe. PE is slightly more common in males than females and incidence increases with age. Annual deaths from PE are approximately 110,000 in the United States and 300,000 annual deaths in Europe. Mortality appears to be higher in Black patients compared with White patients. Both the incidence and mortality of PE have stabilized. (See 'Epidemiology' above.)

●Pathogenesis – Proximal vein deep venous thrombosis (DVT) in the legs is the source of most PE (figure 1). Distal leg DVT rarely embolizes to the lung. However, if left untreated, up to one-third (typically 10 to 15 percent) extend into the proximal veins, where they may embolize. DVT in non-lower-extremity veins (eg, renal and upper extremity thrombosis) is an uncommon source of PE. Once thrombus lodges in the lung, a series of pathophysiologic responses can occur, including infarction, abnormal gas exchange, and cardiovascular compromise. However, these responses are not always clinically evident. (See "Overview of the causes of venous thrombosis in adults" and 'Pathogenesis and pathophysiology' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Charles Hales, MD, who contributed to earlier versions of this topic review.