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Epidemiology, Pathophysiology, Stratification, and Natural History of Pulmonary Embolism
Epidemiology, Pathophysiology, Stratification, and Natural History of Pulmonary Embolism Nicholas J. Giordano, MA,* Paul S. Jansson, MD, MS,†,‡,§ Michael N. Young, MD,|| Kaitlin A. Hagan, ScD, MPH,¶ and Christopher Kabrhel, MD, MPH*,¶ Pulmonary embolism (PE) is a common and potentially fatal form of venous thromboembolism that can be challenging to diagnose and manage. PE occurs when there is obstruction of the pulmonary vasculature and is a common cause of morbidity and mortality in the United States. A combination of acquired and inherited factors may contribute to the development of this disease and should be considered, since they have implications for both susceptibility to PE and treatment. Patients with suspected PE should be evaluated efficiently to diagnose and administer therapy as soon as possible, but the presentation of PE is variable and nonspecific so diagnosis is challenging. PE can range from small, asymptomatic blood clots to large emboli that can occlude the pulmonary arteries causing sudden cardiovascular collapse and death. Thus, risk stratification is critical to both the prognosis and management of acute PE. In this review, we discuss the epidemiology, risk factors, pathophysiology, and natural history of PE and deep vein thrombosis. Tech Vasc Interventional Rad 20:135-140 C 2017 Published by Elsevier Inc. KEYWORDS PE, DVT, Natural History, VTE
Introduction Pulmonary embolism (PE) is a life-threatening manifestation of venous thromboembolism (VTE) that can be challenging to diagnose and manage. VTE is a spectrum of disease that encompasses both PE and deep vein thrombosis (DVT). In DVT, a blood clot forms in the deep veins of the extremities, most commonly in the leg. PE occurs when a portion of the clot from a DVT breaks off, travels through the right heart, and eventually lodges in *Department of Emergency Medicine, Center for Vascular Emergencies, Massachusetts General Hospital, Boston, MA. †Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA. ‡Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA. §Department of Emergency Medicine, Harvard Medical School, Boston, MA. ||Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA. ¶Channing Division of Network Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA. Address reprint requests to Nicholas J. Giordano, MA, Department of Emergency Medicine, Center for Vascular Emergencies, Massachusetts General Hospital, Boston, MA. E-mail: [email protected] 1089-2516/14/$ - see front matter & 2017 Published by Elsevier Inc. http://dx.doi.org/10.1053/j.tvir.2017.07.002
the pulmonary vasculature. More than 50% of patients with DVT in the lower extremity proximal veins (iliac, femoral, and popliteal) present with a concurrent PE.1-3 Although the vast majority of patients with VTE survive, VTE can be fatal. The clinical presentation and severity of both PE and DVT is variable, ranging from the minimally symptomatic to cardiopulmonary arrest requiring immediate intervention. In this review, we discuss the epidemiology, risk factors, pathophysiology, and natural history of PE and DVT.
Epidemiology VTE is a common disorder. In the United States, as many as 2 million people are diagnosed with DVT every year and 500,000-600,000 have PE.4 The estimated incidence of PE is 100-200 cases per 100,000 people.5-8 Males are slightly more likely to develop a VTE than females with an estimated incidence rate of 56 males and 48 females per 100,000 people.9-11 In recent years, as the population of the United States has grown older and the technology used to diagnose PE has become more accessible and sensitive, multiple studies have reported a rising incidence of PE.5-8 135
136 Currently, PE is estimated to be responsible for 100,000 annual deaths in the United States and VTE remains the third most common cause of cardiovascular death in the United States.9,12,13 There are multiple risk factors that may increase the likelihood of developing VTE (Fig. 1). Risk factors can be divided into 2 main categories: inherited and acquired. Acquired risk factors can be further subdivided into provoking or nonprovoking. The nature of provoking risk factors is that, while present, they increase the risk of PE during a finite time period, after which the risk returns to baseline. In contrast, with nonprovoking risk factors the VTE risk remains elevated over time. The distinction between provoking and nonprovoking factors is important, as this may inform the long-term management strategy such as duration of oral anticoagulation, although the distinction between provoking and nonprovoking is often unclear.
Risk Factors Inherited Risk Factors Several genetic risk factors are known to increase VTE risk and typically involve disorders in clotting factor
A
B
Figure 1 The combination of acquired and inherited risk factors can lead to a pulmonary embolism. It is important to recognize that some acquired risk factors blur the line between provoked and nonprovoked factors and can be classified as either. Additionally, when provoking and nonprovoking risk factors are combined they result in an increased risk of VTE that is higher than either individual component factor. (Color version of the figure available online.)
N.J. Giordano et al. production or activity. These include, but are not limited to: factor V Leiden, prothrombin gene mutation (20210A), antithrombin deficiency, protein C deficiency, protein S deficiency, and hyperhomocysteinemia. Approximately 20-30 single nucleotide polymorphisms have been associated with VTE risk through candidate gene or highthroughput genotyping methods, although for some mutations, the clinical relevance and underlying pathophysiological mechanism remain unclear.14 Among the most common are factor V Leiden and the prothrombin gene mutation, with estimated prevalences of 4%-5% and 2%-4%, respectively.15,16 Individuals homozygous for Factor V Leiden are even more predisposed to VTE with a nearly 40-fold increase in risk compared to a 2 to 7-fold increase in heterozygous individuals.17 Acquired Risk Factors Acquired risk factors include lifestyle factors, comorbid illnesses, and medical procedures. Some of these factors provoke VTE acutely (provoking factors), while others increase an individual’s lifetime risk of developing VTE (nonprovoking factors). It is important to recognize that any attempt to characterize acquired risk factors will be imperfect and can blur the line between provoked and unprovoked. Common provoking factors include surgery, active cancer, immobilization, pregnancy, initiation of hormone therapy, and indwelling vascular catheters. Common nonprovoking factors include: advanced age, venous insufficiency, obesity, rheumatologic conditions, antiphospholipid antibody syndrome, cardiovascular disease, smoking, and previous VTE. Additionally, when provoking factors are combined with nonprovoking risk factors, the resulting increased risk of VTE is higher than each component factor alone.18 Provoking Acquired Risk Factors Surgery and Trauma VTE risk increases acutely following surgery. Specifically, patients undergoing orthopedic or oncologic surgery have a particularly high risk for VTE following the procedure.19 Surgery can result in direct venous injury, immobilization, and inflammation. Local tissue and vessel trauma also occur in patients with severe burns or upper or lower extremity trauma. Secondary tissue damage from surgery or trauma may lead to the release of inflammatory cytokines, which impair fibrinolysis and down regulate endogenous anticoagulants all of which contribute to an increased risk for VTE. Cancer Active cancer is a major risk factor for VTE. Patients with cancer have twice the incidence of DVT and PE compared to patients without cancer. The highest incidence of VTE is observed during the first year after cancer diagnosis and shortly after initiation of treatment.20 The highest rate of VTE, 4.1%, occurs in the setting of adenocarcinomas.21 Thus, VTE should remain high on the differential in cancer patients presenting with symptoms or signs suggestive of thrombosis. While active malignancy is a major risk factor
Natural history of PE for VTE, it is important to note that a history of cancer that has been treated and remains in remission is not associated with increased VTE risk. Prolonged Immobility Some of the more commonly studied causes of immobility are joint fixation (casting or external fixation), hospitalization, and prolonged travel. Among patients with joint fixation, the incidence of VTE has been found to increase to approximately twice that of a control after 72 hours of immobility.22 This risk applies to discharged medical and surgical patients as well. One study investigating community-acquired VTE found that 36% of patients had been hospitalized and 23% had undergone surgery in the 3 months before diagnosis. Most VTE patients had their event occur within 1 month of being hospitalized.23 Overall, long-haul travel increases the risk of VTE by nearly 3-fold and studies have shown that there is a doseresponse relationship between travel duration and VTE risk. For every 2-hour incremental increase in travel duration, individuals are 18% more likely to develop a VTE.24 However, despite the relative risk associated with travel, the absolute risk of VTE for any given traveler is relatively low. A study at Charles de Gaulle Airport found that for travelers flying over 10,000 km, only 4.8 cases of PE per million were reported.25 Therefore, the greatest risk of VTE from limb immobility comes from recently hospitalized patients. Estrogen Use and Pregnancy VTE is associated with estrogen-containing oral contraceptives, pregnancy, and postmenopausal hormone replacement therapy. When actively using oral contraceptives, especially those containing desogestrel or gestodene, the risk of VTE increases by 3 to 4-fold.26 Prior studies have estimated that postmenopausal hormone replacement therapy increases the risk of VTE 2 to 3-fold compared to controls, and the risk of VTE seems to be the greatest during the first year of hormone use.27 VTE risk during pregnancy begins in the first trimester and continues into the postpartum period where within 2 weeks of delivery approximately 70% of pregnancy related VTE occurs.28 In the United States, VTE occurred in 1.72 of 1000 deliveries with 1.1 deaths estimated per 100,000.29 Indwelling Catheters Vessel wall damage is believed to be one of the major contributing factors to formation of VTE related to an indwelling catheter. In vivo, this foreign object might prompt the fibrin and coagulation factors to attach to the vessel wall and propagate.30 For patients with symptomatic VTE, indwelling catheters have been found to be associated with a 15%-25% increase in risk for PE.30 Although an indwelling catheter is associated with an increased risk for PE, most of the patients that require indwelling catheters for prolonged periods of time, such as critically ill intensive care unit or cancer patients, often are already at high risk for VTE.31
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Nonprovoking Acquired Risk Factors Age With advancing age, the production of circulating anticoagulants like protein C and S decreases at a faster rate than procoagulation factors, thus leading to a progressively prothrombotic state in the elderly. Numerous other VTE risk factors coincide with aging, and few studies investigate the confounding variables associated with age.32 However, the incidence of VTE clearly increases with age. One study found that among individuals 40-49 years old the incidence of DVT was 17 per 100,000 persons/year whereas the incidence was 232 per 100,000 persons/year among individuals 70-79 years of age.33 Venous Insufficiency Venous insufficiency due to venous dilation and venous valvular dysfunction is commonly found in the elderly and is associated with increased risk of VTE.34 Venous dilation results in venous stasis and this stagnate, pooling blood increases the risk of clot formation. Obesity Obesity has long been identified as a risk factor for VTE, and a recent prospective cohort study demonstrated a linear relationship between body mass index (BMI) and VTE35 In this study, severe obesity (BMI 4 35) predisposed individuals to a VTE risk 6 times that of normal weight (BMI o 25) cohorts.35 Rheumatologic Disease The severity of an underlying rheumatologic condition is associated with an additive risk of VTE.36 Inflammatory rheumatologic diseases such as inflammatory bowel disease or lupus, especially when poorly controlled, have an increased risk for VTE compared to well-managed patients.37 Arterial Cardiovascular Disease and Risk Factors There may be some shared pathophysiology between the development of arterial and venous disease. Independent studies looking at the relationship between venous and arterial disease have indicated that known risk factors for cardiovascular disease such as smoking, hypertension, and obesity may increase the risk of idiopathic PE.35 For instance, a Canadian study found that in patients who had an unprovoked VTE, their risk of suffering a myocardial infarction within the subsequent 10 years was 4 times higher than that of controls.38 Although a causal relationship between arterial and venous disease has yet to be elucidated, there is growing evidence to suggest that these 2 broad categories of vascular disease are interconnected. Previous VTE One of the strongest risk factors for VTE is a history of prior VTE, even in patients who are actively being treated with anticoagulation.39 Patients become more likely to have a recurrent VTE with increasing durations of time.
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One study found that after 2 years, there was a 17.5% chance of recurrent VTE, after 5 years a 24.6% chance, and after 8 years a 30.3% chance of recurrent VTE.39 Antiphospholipid Antibody Syndrome Patients with lupus anticoagulant or anti-β2-glycoprotein-I antibodies are prone to a hypercoagulable state. In otherwise healthy patients, rates of VTE are 5%-8% greater in patients who carry these antibodies.40
Pathophysiology PEs most frequently arise from a dislodged thrombus in the veins of the lower extremities. However, PE may also result from non-thrombotic material such as fat, tumor, or air. In 1856, Rudolf Virchow postulated a triad of events that could cause a thrombus-related VTE: (1) venous stasis, (2) hypercoagulability, and (3) local trauma to the vessel wall. Although Virchow’s triad is antiquated, contemporary research shows that many patients with VTE fulfill Virchow’s triad.41-43 Thrombosis occurs when the balance between blood coagulation and the natural anticoagulant or fibrinolytic mechanisms becomes disrupted. Venous thrombi are composed predominantly of fibrin, red blood cells, and platelets. They usually arise at sites of vessel damage or areas of stasis, such as in venous sinuses, or a valve cusp. Some small DVT undergo spontaneous lysis, but others many extend into more proximal veins. When DVT detach, they follow the natural course of venous blood flow by traversing the vena cava to the right heart chambers and ultimately, a pulmonary artery where they lodge to become a PE. Approximately one-half of patients with PE do not have evidence of DVT when tested, hypothetically because the venous clot has fully embolized. DVTs cause vascular congestion, and therefore, present symptomatically as swelling and pain, though these symptoms can be quite subtle or even nonexistent. In the short term, the lack of blood flow increases venous stasis and further exacerbates thrombus formation. More proximal, larger clots are more likely to embolize than isolated distal clots.44 When venous obstruction persists over time, patients can experience ongoing discomfort, swelling, and chronic skin changes due to stasis, such as hyperpigmentation and ulceration. The morbid postthrombotic syndrome that develops from inadequate collateral drainage results in chronic leg or arm swelling, pressure, and pain. Postthrombotic syndrome is characterized by chronic venous insufficiency and affects approximately one-half of patients with DVT, with up to 5% continuing on to venous ulceration. PE occurs when a DVT dislodges and obstructs a pulmonary artery resulting in some degree of vascular occlusion. PE can range in size from small thrombi, which may only obstruct segmental or subsegmental arteries, to large emboli which straddle the bifurcation of the pulmonary arteries (also known as a saddle PE) or obstruct nearly the entire pulmonary outflow tract (Fig. 2). Small PE frequently lyse spontaneously and may be clinically
Figure 2 Computed tomographic pulmonary angiography of 2 pulmonary embolisms. Image A is a saddle PE with red arrows pointing to the occlusion of both the left and right pulmonary artery. Image B shows a bilateral subsegmental PE in which the red arrows highlight the pulmonary occlusion. (Color version of the figure available online.)
inconsequential. Whereas large emboli can cause obstruction of the pulmonary vasculature, increase strain on the right heart, and possibly lead to hypotension and death. In general, the extent of pulmonary vascular occlusion predicts the development of right heart strain. However, the correlation between clot size and symptoms or physiology is variable.45 Clots are physiologically active, and the release of vasoactive mediators also increases pulmonary vascular resistance and pulmonary pressures. Like DVT, large PE may organize over time; chronic thromboembolic pulmonary hypertension has implications on exercise capacity, quality of life, and life expectancy.
Natural History And Risk Stratification Anticoagulation therapy has been the mainstay treatment of PE for decades, with essentially all patients, except those with absolute contraindications, receiving therapy. As a result, the natural history of untreated PE is difficult to assess. Mortality estimates range from 5%-30%.8,46 However, these estimates are extrapolated from autopsy studies performed before the current diagnostic and therapeutic era, or studies of selected patients who were not treated for specific reasons (eg, contraindications and distal clots).47,48 Therefore, the true mortality associated with untreated PE is not known. Among treated patients, the natural history of PE varies widely. Some patients are asymptomatic, whereas others suffer sudden death. Outcomes depend both on the
Natural history of PE severity of disease and the treatment strategy. Therefore, risk stratification of patients with PE is of paramount importance. Risk stratification identifies patients at risk for both short- and long-term morbidity and mortality, and guides treatment. The main determinants of VTE severity are hemodynamic instability, the presence of right heart strain (typically measured on echocardiogram or computed tomography), and myocardial necrosis based on cardiac biomarker elevation. In the United States, PE is classified into low-risk, submassive, and massive with the latter 2 categories defined by the presence of right heart strain and hemodynamic instability, respectively. Similar categories in Europe are called low risk, intermediate risk, and high risk.49,50 The mortality associated with low risk PE is less than 1%, with 1-year survival 4 95%.51 Mortality is higher in patients with active cancer and heart failure; however, because of the high mortality associated with these diseases, it is unclear how much PE contributes to the overall mortality rate in these cases. The presence of residual DVT, especially proximal DVT, should also raise concern for subsequent embolism following a low-risk PE diagnosis.52 Because the mortality of low-risk PE is low, anticoagulation remains the mainstay of therapy. Thrombolysis or other advanced therapies are generally not indicated in this low-risk category. Intermediate-risk, or submassive PE, is defined predominately by the presence of right heart strain. The presence of large PE with right heart strain on echocardiography is associated with a 5%-15% risk of short-term death.50 Moderate or severe right ventricular hypokinesis, elevated right ventricular systolic pressure (acute cor pulmonale or pulmonary hypertension), and free-floating thrombus in the right atrium are particularly associated with short-term death or clinical deterioration. Modern techniques such as catheter-directed thrombolysis have shown promise in acutely reducing arterial pressure, but have not demonstrated decreased mortality.53,54 Despite the elevated risk of intermediate-risk or submassive PE, thrombolytic therapy remains controversial for these patients due to the high rate of associated major bleeding, including the particularly feared complication of intracranial bleeding.55 High risk, or massive PE presents with hemodynamic instability and have a mortality rate of up to 50%, even with anticoagulation.56 Rapid assessment, resuscitation, and treatment are critical for this patient population. In these patients, treatment with systemic thrombolysis is associated with a clear survival benefit. The recent development of advanced clot removal techniques (eg, catheterdirected thrombolysis and surgical thrombectomy) in combination with PE response teams (PERTs) to deliver these therapies is changing the treatment landscape for these patients.57
Conclusion PE is a common and potentially fatal form of VTE. There are many factors that increase the risk of PE. These risk
139 factors are categorized as inherited and acquired. Acquired risk factors can be further subdivided into provoking or nonprovoking in nature. These distinctions have implications for both PE risk and treatment. PE range from small, asymptomatic obstruction of segmental or subsegmental arteries up to large emboli that may present with sudden cardiovascular collapse and death. The natural history of PE depends on the extent and physiologic reaction to the embolized clot. Risk stratification is therefore critical to the prognosis and management of acute PE.
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Introduction Pulmonary embolism (PE) is a life-threatening manifestation of venous thromboembolism (VTE) that can be challenging to diagnose and manage. VTE is a spectrum of disease that encompasses both PE and deep vein thrombosis (DVT). In DVT, a blood clot forms in the deep veins of the extremities, most commonly in the leg. PE occurs when a portion of the clot from a DVT breaks off, travels through the right heart, and eventually lodges in *Department of Emergency Medicine, Center for Vascular Emergencies, Massachusetts General Hospital, Boston, MA. †Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA. ‡Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA. §Department of Emergency Medicine, Harvard Medical School, Boston, MA. ||Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA. ¶Channing Division of Network Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA. Address reprint requests to Nicholas J. Giordano, MA, Department of Emergency Medicine, Center for Vascular Emergencies, Massachusetts General Hospital, Boston, MA. E-mail: [email protected] 1089-2516/14/$ - see front matter & 2017 Published by Elsevier Inc. http://dx.doi.org/10.1053/j.tvir.2017.07.002
the pulmonary vasculature. More than 50% of patients with DVT in the lower extremity proximal veins (iliac, femoral, and popliteal) present with a concurrent PE.1-3 Although the vast majority of patients with VTE survive, VTE can be fatal. The clinical presentation and severity of both PE and DVT is variable, ranging from the minimally symptomatic to cardiopulmonary arrest requiring immediate intervention. In this review, we discuss the epidemiology, risk factors, pathophysiology, and natural history of PE and DVT.
Epidemiology VTE is a common disorder. In the United States, as many as 2 million people are diagnosed with DVT every year and 500,000-600,000 have PE.4 The estimated incidence of PE is 100-200 cases per 100,000 people.5-8 Males are slightly more likely to develop a VTE than females with an estimated incidence rate of 56 males and 48 females per 100,000 people.9-11 In recent years, as the population of the United States has grown older and the technology used to diagnose PE has become more accessible and sensitive, multiple studies have reported a rising incidence of PE.5-8 135
136 Currently, PE is estimated to be responsible for 100,000 annual deaths in the United States and VTE remains the third most common cause of cardiovascular death in the United States.9,12,13 There are multiple risk factors that may increase the likelihood of developing VTE (Fig. 1). Risk factors can be divided into 2 main categories: inherited and acquired. Acquired risk factors can be further subdivided into provoking or nonprovoking. The nature of provoking risk factors is that, while present, they increase the risk of PE during a finite time period, after which the risk returns to baseline. In contrast, with nonprovoking risk factors the VTE risk remains elevated over time. The distinction between provoking and nonprovoking factors is important, as this may inform the long-term management strategy such as duration of oral anticoagulation, although the distinction between provoking and nonprovoking is often unclear.
Risk Factors Inherited Risk Factors Several genetic risk factors are known to increase VTE risk and typically involve disorders in clotting factor
A
B
Figure 1 The combination of acquired and inherited risk factors can lead to a pulmonary embolism. It is important to recognize that some acquired risk factors blur the line between provoked and nonprovoked factors and can be classified as either. Additionally, when provoking and nonprovoking risk factors are combined they result in an increased risk of VTE that is higher than either individual component factor. (Color version of the figure available online.)
N.J. Giordano et al. production or activity. These include, but are not limited to: factor V Leiden, prothrombin gene mutation (20210A), antithrombin deficiency, protein C deficiency, protein S deficiency, and hyperhomocysteinemia. Approximately 20-30 single nucleotide polymorphisms have been associated with VTE risk through candidate gene or highthroughput genotyping methods, although for some mutations, the clinical relevance and underlying pathophysiological mechanism remain unclear.14 Among the most common are factor V Leiden and the prothrombin gene mutation, with estimated prevalences of 4%-5% and 2%-4%, respectively.15,16 Individuals homozygous for Factor V Leiden are even more predisposed to VTE with a nearly 40-fold increase in risk compared to a 2 to 7-fold increase in heterozygous individuals.17 Acquired Risk Factors Acquired risk factors include lifestyle factors, comorbid illnesses, and medical procedures. Some of these factors provoke VTE acutely (provoking factors), while others increase an individual’s lifetime risk of developing VTE (nonprovoking factors). It is important to recognize that any attempt to characterize acquired risk factors will be imperfect and can blur the line between provoked and unprovoked. Common provoking factors include surgery, active cancer, immobilization, pregnancy, initiation of hormone therapy, and indwelling vascular catheters. Common nonprovoking factors include: advanced age, venous insufficiency, obesity, rheumatologic conditions, antiphospholipid antibody syndrome, cardiovascular disease, smoking, and previous VTE. Additionally, when provoking factors are combined with nonprovoking risk factors, the resulting increased risk of VTE is higher than each component factor alone.18 Provoking Acquired Risk Factors Surgery and Trauma VTE risk increases acutely following surgery. Specifically, patients undergoing orthopedic or oncologic surgery have a particularly high risk for VTE following the procedure.19 Surgery can result in direct venous injury, immobilization, and inflammation. Local tissue and vessel trauma also occur in patients with severe burns or upper or lower extremity trauma. Secondary tissue damage from surgery or trauma may lead to the release of inflammatory cytokines, which impair fibrinolysis and down regulate endogenous anticoagulants all of which contribute to an increased risk for VTE. Cancer Active cancer is a major risk factor for VTE. Patients with cancer have twice the incidence of DVT and PE compared to patients without cancer. The highest incidence of VTE is observed during the first year after cancer diagnosis and shortly after initiation of treatment.20 The highest rate of VTE, 4.1%, occurs in the setting of adenocarcinomas.21 Thus, VTE should remain high on the differential in cancer patients presenting with symptoms or signs suggestive of thrombosis. While active malignancy is a major risk factor
Natural history of PE for VTE, it is important to note that a history of cancer that has been treated and remains in remission is not associated with increased VTE risk. Prolonged Immobility Some of the more commonly studied causes of immobility are joint fixation (casting or external fixation), hospitalization, and prolonged travel. Among patients with joint fixation, the incidence of VTE has been found to increase to approximately twice that of a control after 72 hours of immobility.22 This risk applies to discharged medical and surgical patients as well. One study investigating community-acquired VTE found that 36% of patients had been hospitalized and 23% had undergone surgery in the 3 months before diagnosis. Most VTE patients had their event occur within 1 month of being hospitalized.23 Overall, long-haul travel increases the risk of VTE by nearly 3-fold and studies have shown that there is a doseresponse relationship between travel duration and VTE risk. For every 2-hour incremental increase in travel duration, individuals are 18% more likely to develop a VTE.24 However, despite the relative risk associated with travel, the absolute risk of VTE for any given traveler is relatively low. A study at Charles de Gaulle Airport found that for travelers flying over 10,000 km, only 4.8 cases of PE per million were reported.25 Therefore, the greatest risk of VTE from limb immobility comes from recently hospitalized patients. Estrogen Use and Pregnancy VTE is associated with estrogen-containing oral contraceptives, pregnancy, and postmenopausal hormone replacement therapy. When actively using oral contraceptives, especially those containing desogestrel or gestodene, the risk of VTE increases by 3 to 4-fold.26 Prior studies have estimated that postmenopausal hormone replacement therapy increases the risk of VTE 2 to 3-fold compared to controls, and the risk of VTE seems to be the greatest during the first year of hormone use.27 VTE risk during pregnancy begins in the first trimester and continues into the postpartum period where within 2 weeks of delivery approximately 70% of pregnancy related VTE occurs.28 In the United States, VTE occurred in 1.72 of 1000 deliveries with 1.1 deaths estimated per 100,000.29 Indwelling Catheters Vessel wall damage is believed to be one of the major contributing factors to formation of VTE related to an indwelling catheter. In vivo, this foreign object might prompt the fibrin and coagulation factors to attach to the vessel wall and propagate.30 For patients with symptomatic VTE, indwelling catheters have been found to be associated with a 15%-25% increase in risk for PE.30 Although an indwelling catheter is associated with an increased risk for PE, most of the patients that require indwelling catheters for prolonged periods of time, such as critically ill intensive care unit or cancer patients, often are already at high risk for VTE.31
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Nonprovoking Acquired Risk Factors Age With advancing age, the production of circulating anticoagulants like protein C and S decreases at a faster rate than procoagulation factors, thus leading to a progressively prothrombotic state in the elderly. Numerous other VTE risk factors coincide with aging, and few studies investigate the confounding variables associated with age.32 However, the incidence of VTE clearly increases with age. One study found that among individuals 40-49 years old the incidence of DVT was 17 per 100,000 persons/year whereas the incidence was 232 per 100,000 persons/year among individuals 70-79 years of age.33 Venous Insufficiency Venous insufficiency due to venous dilation and venous valvular dysfunction is commonly found in the elderly and is associated with increased risk of VTE.34 Venous dilation results in venous stasis and this stagnate, pooling blood increases the risk of clot formation. Obesity Obesity has long been identified as a risk factor for VTE, and a recent prospective cohort study demonstrated a linear relationship between body mass index (BMI) and VTE35 In this study, severe obesity (BMI 4 35) predisposed individuals to a VTE risk 6 times that of normal weight (BMI o 25) cohorts.35 Rheumatologic Disease The severity of an underlying rheumatologic condition is associated with an additive risk of VTE.36 Inflammatory rheumatologic diseases such as inflammatory bowel disease or lupus, especially when poorly controlled, have an increased risk for VTE compared to well-managed patients.37 Arterial Cardiovascular Disease and Risk Factors There may be some shared pathophysiology between the development of arterial and venous disease. Independent studies looking at the relationship between venous and arterial disease have indicated that known risk factors for cardiovascular disease such as smoking, hypertension, and obesity may increase the risk of idiopathic PE.35 For instance, a Canadian study found that in patients who had an unprovoked VTE, their risk of suffering a myocardial infarction within the subsequent 10 years was 4 times higher than that of controls.38 Although a causal relationship between arterial and venous disease has yet to be elucidated, there is growing evidence to suggest that these 2 broad categories of vascular disease are interconnected. Previous VTE One of the strongest risk factors for VTE is a history of prior VTE, even in patients who are actively being treated with anticoagulation.39 Patients become more likely to have a recurrent VTE with increasing durations of time.
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One study found that after 2 years, there was a 17.5% chance of recurrent VTE, after 5 years a 24.6% chance, and after 8 years a 30.3% chance of recurrent VTE.39 Antiphospholipid Antibody Syndrome Patients with lupus anticoagulant or anti-β2-glycoprotein-I antibodies are prone to a hypercoagulable state. In otherwise healthy patients, rates of VTE are 5%-8% greater in patients who carry these antibodies.40
Pathophysiology PEs most frequently arise from a dislodged thrombus in the veins of the lower extremities. However, PE may also result from non-thrombotic material such as fat, tumor, or air. In 1856, Rudolf Virchow postulated a triad of events that could cause a thrombus-related VTE: (1) venous stasis, (2) hypercoagulability, and (3) local trauma to the vessel wall. Although Virchow’s triad is antiquated, contemporary research shows that many patients with VTE fulfill Virchow’s triad.41-43 Thrombosis occurs when the balance between blood coagulation and the natural anticoagulant or fibrinolytic mechanisms becomes disrupted. Venous thrombi are composed predominantly of fibrin, red blood cells, and platelets. They usually arise at sites of vessel damage or areas of stasis, such as in venous sinuses, or a valve cusp. Some small DVT undergo spontaneous lysis, but others many extend into more proximal veins. When DVT detach, they follow the natural course of venous blood flow by traversing the vena cava to the right heart chambers and ultimately, a pulmonary artery where they lodge to become a PE. Approximately one-half of patients with PE do not have evidence of DVT when tested, hypothetically because the venous clot has fully embolized. DVTs cause vascular congestion, and therefore, present symptomatically as swelling and pain, though these symptoms can be quite subtle or even nonexistent. In the short term, the lack of blood flow increases venous stasis and further exacerbates thrombus formation. More proximal, larger clots are more likely to embolize than isolated distal clots.44 When venous obstruction persists over time, patients can experience ongoing discomfort, swelling, and chronic skin changes due to stasis, such as hyperpigmentation and ulceration. The morbid postthrombotic syndrome that develops from inadequate collateral drainage results in chronic leg or arm swelling, pressure, and pain. Postthrombotic syndrome is characterized by chronic venous insufficiency and affects approximately one-half of patients with DVT, with up to 5% continuing on to venous ulceration. PE occurs when a DVT dislodges and obstructs a pulmonary artery resulting in some degree of vascular occlusion. PE can range in size from small thrombi, which may only obstruct segmental or subsegmental arteries, to large emboli which straddle the bifurcation of the pulmonary arteries (also known as a saddle PE) or obstruct nearly the entire pulmonary outflow tract (Fig. 2). Small PE frequently lyse spontaneously and may be clinically
Figure 2 Computed tomographic pulmonary angiography of 2 pulmonary embolisms. Image A is a saddle PE with red arrows pointing to the occlusion of both the left and right pulmonary artery. Image B shows a bilateral subsegmental PE in which the red arrows highlight the pulmonary occlusion. (Color version of the figure available online.)
inconsequential. Whereas large emboli can cause obstruction of the pulmonary vasculature, increase strain on the right heart, and possibly lead to hypotension and death. In general, the extent of pulmonary vascular occlusion predicts the development of right heart strain. However, the correlation between clot size and symptoms or physiology is variable.45 Clots are physiologically active, and the release of vasoactive mediators also increases pulmonary vascular resistance and pulmonary pressures. Like DVT, large PE may organize over time; chronic thromboembolic pulmonary hypertension has implications on exercise capacity, quality of life, and life expectancy.
Natural History And Risk Stratification Anticoagulation therapy has been the mainstay treatment of PE for decades, with essentially all patients, except those with absolute contraindications, receiving therapy. As a result, the natural history of untreated PE is difficult to assess. Mortality estimates range from 5%-30%.8,46 However, these estimates are extrapolated from autopsy studies performed before the current diagnostic and therapeutic era, or studies of selected patients who were not treated for specific reasons (eg, contraindications and distal clots).47,48 Therefore, the true mortality associated with untreated PE is not known. Among treated patients, the natural history of PE varies widely. Some patients are asymptomatic, whereas others suffer sudden death. Outcomes depend both on the
Natural history of PE severity of disease and the treatment strategy. Therefore, risk stratification of patients with PE is of paramount importance. Risk stratification identifies patients at risk for both short- and long-term morbidity and mortality, and guides treatment. The main determinants of VTE severity are hemodynamic instability, the presence of right heart strain (typically measured on echocardiogram or computed tomography), and myocardial necrosis based on cardiac biomarker elevation. In the United States, PE is classified into low-risk, submassive, and massive with the latter 2 categories defined by the presence of right heart strain and hemodynamic instability, respectively. Similar categories in Europe are called low risk, intermediate risk, and high risk.49,50 The mortality associated with low risk PE is less than 1%, with 1-year survival 4 95%.51 Mortality is higher in patients with active cancer and heart failure; however, because of the high mortality associated with these diseases, it is unclear how much PE contributes to the overall mortality rate in these cases. The presence of residual DVT, especially proximal DVT, should also raise concern for subsequent embolism following a low-risk PE diagnosis.52 Because the mortality of low-risk PE is low, anticoagulation remains the mainstay of therapy. Thrombolysis or other advanced therapies are generally not indicated in this low-risk category. Intermediate-risk, or submassive PE, is defined predominately by the presence of right heart strain. The presence of large PE with right heart strain on echocardiography is associated with a 5%-15% risk of short-term death.50 Moderate or severe right ventricular hypokinesis, elevated right ventricular systolic pressure (acute cor pulmonale or pulmonary hypertension), and free-floating thrombus in the right atrium are particularly associated with short-term death or clinical deterioration. Modern techniques such as catheter-directed thrombolysis have shown promise in acutely reducing arterial pressure, but have not demonstrated decreased mortality.53,54 Despite the elevated risk of intermediate-risk or submassive PE, thrombolytic therapy remains controversial for these patients due to the high rate of associated major bleeding, including the particularly feared complication of intracranial bleeding.55 High risk, or massive PE presents with hemodynamic instability and have a mortality rate of up to 50%, even with anticoagulation.56 Rapid assessment, resuscitation, and treatment are critical for this patient population. In these patients, treatment with systemic thrombolysis is associated with a clear survival benefit. The recent development of advanced clot removal techniques (eg, catheterdirected thrombolysis and surgical thrombectomy) in combination with PE response teams (PERTs) to deliver these therapies is changing the treatment landscape for these patients.57
Conclusion PE is a common and potentially fatal form of VTE. There are many factors that increase the risk of PE. These risk
139 factors are categorized as inherited and acquired. Acquired risk factors can be further subdivided into provoking or nonprovoking in nature. These distinctions have implications for both PE risk and treatment. PE range from small, asymptomatic obstruction of segmental or subsegmental arteries up to large emboli that may present with sudden cardiovascular collapse and death. The natural history of PE depends on the extent and physiologic reaction to the embolized clot. Risk stratification is therefore critical to the prognosis and management of acute PE.
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