Pulmonary Embolism

Background

Pulmonary embolism is a common and potentially lethal condition. Most patients who succumb to pulmonary embolism do so within the first few hours of the event. Despite diagnostic advances, delays in pulmonary embolism diagnosis are common and represent an important issue. [6] As a cause of sudden death, massive pulmonary embolism is second only to sudden cardiac death.

In patients who survive a pulmonary embolism, recurrent embolism and death can be prevented with prompt diagnosis and therapy. Unfortunately, the diagnosis is often missed because patients with pulmonary embolism present with nonspecific signs and symptoms. If left untreated, approximately one third of patients who survive an initial pulmonary embolism die from a subsequent embolic episode. (See Prognosis.)

When a pulmonary embolism is identified, it is characterized as acute or chronic. In terms of pathologic diagnosis, an embolus is acute if it is situated centrally within the vascular lumen or if it occludes a vessel (vessel cutoff sign) (see the first image below). Acute pulmonary embolism commonly causes distention of the involved vessel. An embolus is chronic if it is eccentric and contiguous with the vessel wall (see the second image below), it reduces the arterial diameter by more than 50%, evidence of recanalization within the thrombus is present, and an arterial web is present.

Computed tomography angiogram in a 53-year-old man with acute pulmonary embolism. This image shows an intraluminal filling defect that occludes the anterior basal segmental artery of the right lower lobe. Also present is an infarction of the corresponding lung, which is indicated by a triangular, pleura-based consolidation (Hampton hump).

Computed tomography angiography in a young man who experienced acute chest pain and shortness of breath after a transcontinental flight. This image demonstrates a clot in the anterior segmental artery in the left upper lung (LA2) and a clot in the anterior segmental artery in the right upper lung (RA2).

A pulmonary embolism is also characterized as central or peripheral, depending on the location or the arterial branch involved. Central vascular zones include the main pulmonary artery, the left and right main pulmonary arteries, the anterior trunk, the right and left interlobar arteries, the left upper lobe trunk, the right middle lobe artery, and the right and left lower lobe arteries. A pulmonary embolus is characterized as massive when it involves both pulmonary arteries or when it results in hemodynamic compromise. Peripheral vascular zones include the segmental and subsegmental arteries of the right upper lobe, the right middle lobe, the right lower lobe, the left upper lobe, the lingula, and the left lower lobe. (See Physical Examination.)

The variability of presentation sets the patient and clinician up for potentially missing the diagnosis. The challenge is that the "classic" presentation with abrupt onset of pleuritic chest pain, shortness of breath, and hypoxia is rarely seen. Studies of patients who died unexpectedly of pulmonary embolism revealed that the patients had complained of nagging symptoms, often for weeks, before dying. Forty percent of these patients had been seen by a physician in the weeks prior to their death. [7] (See the images below.)

A large pulmonary artery thrombus in a hospitalized patient who died suddenly.

Pulmonary embolism was identified as the cause of death in a patient who developed shortness of breath while hospitalized for hip joint surgery. This is a close-up view.

The most important conceptual advance regarding pulmonary embolism over the last several decades has been the realization that pulmonary embolism is not a disease; rather, pulmonary embolism is a complication of venous thromboembolism, most commonly deep venous thrombosis (DVT; shown in the image below). Virtually every physician who is involved in patient care encounters patients who are at risk for venous thromboembolism, and therefore at risk for pulmonary embolism.

Computed tomography venograms in a 65-year-old man with possible pulmonary embolism. This image shows acute deep venous thrombosis with intraluminal filling defects in the bilateral superficial femoral veins.

Clinical signs and symptoms for pulmonary embolism are nonspecific; therefore, patients suspected of having pulmonary embolism—because of unexplained dyspnea, tachypnea, or chest pain or the presence of risk factors for pulmonary embolism—must undergo diagnostic tests until the diagnosis is ascertained or eliminated or an alternative diagnosis is confirmed. Further, routine laboratory findings are nonspecific and are not helpful in pulmonary embolism, although they may suggest another diagnosis. Pulmonary angiography historically was the criterion standard for the diagnosis of pulmonary embolism, but with the improved sensitivity and specificity of CT angiography, it is now rarely performed. (See Workup.)

Immediate full anticoagulation is mandatory for all patients suspected to have DVT or pulmonary embolism. Diagnostic investigations should not delay empirical anticoagulant therapy. (See Treatment.)

Long-term anticoagulation is critical to the prevention of recurrence of DVT or pulmonary embolism. The general consensus is that a significant reduction in recurrence is associated with 3-6 months of anticoagulation.

Anatomy

Knowledge of bronchovascular anatomy (seen in the image below) is the key to the accurate interpretation of CT scans obtained for the evaluation of pulmonary embolism. A systematic approach in identifying all vessels is important. The bronchovascular anatomy has been described on the basis of the segmental anatomy of lungs. The segmental arteries are seen near the accompanying branches of the bronchial tree and are situated either medially (in the upper lobes) or laterally (in the lower lobes, lingula, and right middle lobe).

Pulmonary thromboembolism is not a disease in and of itself. Rather, it is a complication of underlying venous thrombosis. Under normal conditions, microthrombi (tiny aggregates of red cells, platelets, and fibrin) are formed and lysed continually within the venous circulatory system. This dynamic equilibrium ensures local hemostasis in response to injury without permitting uncontrolled propagation of clot.

Pathophysiology

There are both respiratory and hemodynamic consequences associated with pulmonary embolism.

Respiratory consequences

Acute respiratory consequences of pulmonary embolism include the following:

• Increased alveolar dead space

• Hypoxemia

• Hyperventilation

Additional consequences that may occur include regional loss of surfactant and pulmonary infarction (see the image below). Arterial hypoxemia is a frequent, but not universal, finding in patients with acute embolism. The mechanisms of hypoxemia include ventilation-perfusion mismatch, intrapulmonary shunts, reduced cardiac output, and intracardiac shunt via a patent foramen ovale. Pulmonary infarction is an uncommon consequence because of the bronchial arterial collateral circulation.

Lung infarction secondary to pulmonary embolism occurs rarely.

Lung infarction secondary to pulmonary embolism occurs rarely.

Hemodynamic consequences

Pulmonary embolism reduces the cross-sectional area of the pulmonary vascular bed, resulting in an increment in pulmonary vascular resistance, which, in turn, increases the right ventricular afterload. If the afterload is increased severely, right ventricular failure may ensue. In addition, the humoral and reflex mechanisms contribute to the pulmonary arterial constriction. Following the initiation of anticoagulant therapy, the resolution of emboli usually occurs rapidly during the first 2 weeks of therapy; however, it can persist on chest imaging studies for months to years. Chronic pulmonary hypertension may occur with failure of the initial embolus to undergo lyses or in the setting of recurrent thromboemboli.

Etiology

Three primary influences predispose a patient to thrombus formation; these form the so-called Virchow triad, which consists of the following [8, 9, 10] :

• Endothelial injury

• Stasis or turbulence of blood flow

• Blood hypercoagulability

Thrombosis usually originates as a platelet nidus on valves in the veins of the lower extremities. Further growth occurs by accretion of platelets and fibrin and progression to red fibrin thrombus, which may either break off and embolize or result in total occlusion of the vein. The endogenous thrombolytic system leads to partial dissolution; then, the thrombus becomes organized and is incorporated into the venous wall.

Pulmonary emboli usually arise from thrombi originating in the deep venous system of the lower extremities; however, they may rarely originate in the pelvic, renal, or upper extremity veins or the right heart chambers. After traveling to the lung, large thrombi can lodge at the bifurcation of the main pulmonary artery or the lobar branches and cause hemodynamic compromise. Smaller thrombi typically travel more distally, occluding smaller vessels in the lung periphery. These are more likely to produce pleuritic chest pain by initiating an inflammatory response adjacent to the parietal pleura. Most pulmonary emboli are multiple, and the lower lobes are involved more commonly than the upper lobes.

The causes for pulmonary embolism are multifactorial and are not readily apparent in many cases. The causes described in the literature include the following:

• Venous stasis

• Hypercoagulable states

• Immobilization

• Surgery and trauma

• Pregnancy

• Oral contraceptives and estrogen replacement

• Malignancy

• Hereditary factors

• Acute medical illness

A study by Malek et al confirmed the hypothesis that individuals with HIV infection are more likely to have clinically detected thromboembolic disease. [11]The risk of developing a pulmonary embolism or DVT is increased 40% in these individuals.

Venous stasis

Venous stasis leads to accumulation of platelets and thrombin in veins. Increased viscosity may occur due to polycythemia and dehydration, immobility, raised venous pressure in cardiac failure, or compression of a vein by a tumor.

Hypercoagulable states

The complex and delicate balance between coagulation and anticoagulation is altered by many diseases, by obesity, or by trauma. It can also occur after surgery.

Concomitant hypercoagulability may be present in disease states where prolonged venous stasis or injury to veins occurs.

Hypercoagulable states may be acquired or congenital. Factor V Leiden mutation causing resistance to activated protein C is the most common risk factor. Factor V Leiden mutation is present in up to 5% of the normal population and is the most common cause of familial thromboembolism.

Primary or acquired deficiencies in protein C, protein S, and antithrombin III are other risk factors. The deficiency of these natural anticoagulants is responsible for 10% of venous thrombosis in younger people.

Immobilization

Immobilization leads to local venous stasis by accumulation of clotting factors and fibrin, resulting in thrombus formation. The risk of pulmonary embolism increases with prolonged bed rest or immobilization of a limb in a cast.

In the Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) study, immobilization (usually because of surgery) was the risk factor most commonly found in patients with pulmonary embolism.

Surgery and trauma

A prospective study by Geerts and colleagues indicated that major trauma was associated with a 58% incidence of DVT in the lower extremities and an 18% incidence in proximal veins. [12]

Surgical and accidental traumas predispose patients to venous thromboembolism by activating clotting factors and causing immobility. Pulmonary embolism may account for 15% of all postoperative deaths. Leg amputations and hip, pelvic, and spinal surgery are associated with the highest risk.

Fractures of the femur and tibia are associated with the highest risk of fracture-related pulmonary embolism, followed by pelvic, spinal, and other fractures. Severe burns also carry a high risk of DVT or pulmonary embolism.

Pregnancy

The incidence of thromboembolic disease in pregnancy has been reported to range from 1 case in 200 deliveries to 1 case in 1400 deliveries (see Epidemiology). Fatal events are rare, with 1-2 cases occurring per 100,000 pregnancies.

Oral contraceptives and estrogen replacement

Estrogen-containing birth control pills have increased the occurrence of venous thromboembolism in healthy women. The risk is proportional to the estrogen content and is increased in postmenopausal women on hormonal replacement therapy. The relative risk is 3-fold, but the absolute risk is 20-30 cases per 100,000 persons per year.

Malignancy

Malignancy has been identified in 17% of patients with venous thromboembolism. Pulmonary emboli have been reported to occur in association with solid tumors, leukemias, and lymphomas. This is probably independent of the indwelling catheters often used in such patients. [13] The neoplasms most commonly associated with pulmonary embolism, in descending order of frequency, are pancreatic carcinoma; bronchogenic carcinoma; and carcinomas of the genitourinary tract, colon, stomach, and breast.

Hereditary factors

Hereditary factors associated with the development of pulmonary embolism include the following:

• Antithrombin III deficiency

• Protein C deficiency

• Protein S deficiency

• Factor V Leiden (most common genetic risk factor for thrombophilia)

• Plasminogen abnormality

• Plasminogen activator abnormality

• Fibrinogen abnormality

• Resistance to activated protein C

Acute medical illness

Acute medical illnesses associated with the development of pulmonary embolism include the following:

• AIDS (lupus anticoagulant)

• Behçet disease

• Congestive heart failure (CHF)

• Myocardial infarction

• Polycythemia

• Systemic lupus erythematosus

• Ulcerative colitis

Additional risk factors

Risk factors for pulmonary embolism also include the following:

• Drug abuse (intravenous [IV] drugs)

• Drug-induced lupus anticoagulant

• Hemolytic anemias

• Heparin-associated thrombocytopenia

• Homocystinemia

• Homocystinuria

• Hyperlipidemias

• Phenothiazines

• Thrombocytosis

• Varicose veins

• Venography

• Venous pacemakers

• Venous stasis

• Warfarin (first few days of therapy)

• Inflammatory bowel disease

• Sleep-disordered breathing [14]

In the PIOPED II study, 94% of patients with pulmonary embolism had 1 or more of the following risk factors [15] :

• Immobilization

• Travel of 4 hours or more in the past month

• Surgery within the last 3 months

• Malignancy, especially lung cancer

• Current or past history of thrombophlebitis

• Trauma to the lower extremities and pelvis during the past 3 months

• Smoking

• Central venous instrumentation within the past 3 months

• Stroke, paresis, or paralysis

• Prior pulmonary embolism

• Heart failure

• Chronic obstructive pulmonary disease

Pulmonary embolism in children

In contrast to adults, most children (98%) diagnosed with pulmonary emboli have an identifiable risk factor or a serious underlying disorder (see Epidemiology).

In 1993, David et al reported that 21% of children with DVT and/or pulmonary emboli had an indwelling central venous catheter. [16] Additional series have reported the presence of central lines in as many as 36% of patients. [17] A clot may form as a fibrin sleeve that encases the catheter. When the catheter is removed, the fibrin sleeve is often dislodged, releasing a nidus for embolus formation. In another scenario, a thrombus may adhere to the vessel wall adjacent to the catheter.

David and colleagues also reported that 5-10% of children with venous thromboembolic disease have inherited disorders of coagulation, such as antithrombin III, protein C, or protein S deficiency. [16] In 1997, Nuss et al reported that 70% of children with a diagnosis of pulmonary embolism have antiphospholipid antibodies or coagulation-regulatory protein abnormalities. [18]However, this was a small study in a population with clinically recognized pulmonary emboli; hence, its applicability to the broader pediatric population is uncertain.

A study reported that major thrombosis or pulmonary embolism was present in more than 33% of children treated with long-term hyperalimentation and that pulmonary embolism was the major cause of death in 30% of these children. Fat embolization may exacerbate this clinical picture. [19]

Dehydration, especially hyperosmolar dehydration, is typically observed in younger infants with pulmonary emboli.

Epidemiology

United States statistics

The incidence of pulmonary embolism in the United States is estimated to be 1 case per 1000 persons per year. [20] Studies from 2008 suggest that the increasing use of computed tomography (CT) scanning for assessing patients with possible pulmonary embolism has led to an increase in the reported incidence of pulmonary embolism. [21, 22]

From 1979-1998, the age-adjusted death rate for pulmonary embolism in the United States decreased from 191 deaths per million population to 94 deaths per million population. [20] Regional studies covering the years after 1998 found either a slight decrease in the incidence of mortality or no change in the frequency. [21, 22]

Pulmonary embolism is present in 60-80% of patients with DVT, even though more than half these patients are asymptomatic. Pulmonary embolism is the third most common cause of death in hospitalized patients, with at least 650,000 cases occurring annually. Autopsy studies have shown that approximately 60% of patients who have died in the hospital had pulmonary embolism, with the diagnosis having been missed in up to 70% of the cases. Prospective studies have demonstrated DVT in 10-13% of all medical patients placed on bed rest for 1 week, 29-33% of all patients in medical intensive care units, 20-26% of patients with pulmonary diseases who are given bed rest for 3 or more days, 27-33% of patients admitted to a critical care unit after a myocardial infarction, and 48% of patients who are asymptomatic after a coronary artery bypass graft.

Venous thromboembolism is a major health problem. The average annual incidence of venous thromboembolism in the United States is 1 person per 1000 population, [3, 23, 24] with about 250,000 incident cases occurring annually.

A challenge in understanding the real disease has been that autopsy studies have found an equal number of patients diagnosed with pulmonary embolism at autopsy was were initially diagnosed by clinicians. [23, 25] This has led to estimates of between 650,000 to 900,000 fatal and nonfatal venous thromboembolic events occurring in the US annually. The incidence of venous thromboembolism has not changed significantly over the last 25 years. [23]Capturing the true incidence going forward will be challenging because of the decreasing rate of autopsy. In a longitudinal, 25-year prospective study from 1966-1990, autopsy rates dropped from 55% to 30% over the study period. [23]Current trends would suggest a continued decline in autopsy rate.

International statistics

The incidence of pulmonary embolism may differ substantially from country to country; observed variation is likely due to differences in the accuracy of diagnosis rather than in the actual incidence.

Canadian data derived from 15 tertiary care centers showed a frequency of 0.86 events per 10,000 pediatric hospital admissions for patients aged 1 month to 1 year. [26] Frequency of pulmonary embolism in developed countries has been increasing when compared with historical data. This increase in frequency is linked with the increased use of central venous lines in the pediatric population.[27] The overall frequency in children is still considerably less than that in adults.

Association between sex and pulmonary embolism

Data are conflicting as to whether male sex is a risk factor for pulmonary embolism; however, an analysis of national mortality data found that death rates from pulmonary embolism were 20-30% higher among men than among women. [20] The incidence of venous thromboembolic events in the older population is greater among men than women. In patients younger than 55 years, the incidence of pulmonary is higher in females. The overall age- and sex-adjusted annual incidence of venous thromboembolism is reported to be 117 cases per 100,000 people (DVT, 48 cases per 100,000; pulmonary embolism, 69 cases per 100,000). [23]

A prospective cohort study of female nurses found an association between idiopathic pulmonary embolism and hours spent sitting each week. Women who reported in both 1988 and 1990 that they sat more than 40 hours per week had more than twice the risk of pulmonary embolism compared with women who reported both years that they sat less than 10hours per week. [28]

Association between race and pulmonary embolism

The incidence of pulmonary embolism appears to be significantly higher in blacks than in whites. [29] Mortality rates from pulmonary embolism for blacks have been 50% higher than those for whites, and those for whites have been 50% higher than those for people of other races (eg, Asians, Native Americans).[20] Asian/Pacific Islanders/American Indian patients have a markedly lower risk of thromboembolism. [20, 30]

Pulmonary embolism in elderly persons

Pulmonary embolism is increasingly prevalent among elderly patients, yet the diagnosis is missed more often in these patients than in younger ones because respiratory symptoms often are dismissed as being chronic. Even when the diagnosis is made, appropriate therapy frequently is inappropriately withheld because of bleeding concerns. An appropriate diagnostic workup and therapeutic anticoagulation with a careful risk-to-benefit assessment is recommended in this patient population.

Pulmonary embolism in pediatric patients

DVT and pulmonary embolism are rare in pediatric practice. In 1993, David et al identified 308 children reported in the medical literature from 1975-1993 with DVT of an extremity and/or pulmonary embolism. [16] In 1986, Bernstein reported 78 episodes of pulmonary embolism per 100,000 hospitalized adolescents. [31]Unselected autopsy studies in children estimate the incidence of pulmonary embolism from 0.05-3.7%.

However, among pediatric patients in whom DVT or pulmonary emboli do occur, these conditions are associated with significant morbidity and mortality. Various authors suggest that pulmonary embolism contributes to the death of affected children in approximately 30% of cases. [32] (Others, however, have reported pulmonary embolism as a cause of death in fewer than 5% of affected children.[33] )

Thromboembolic disease in pregnancy

A population-based study covering the years 1966-1995 collated the cases of DVT or pulmonary embolism in women during pregnancy or postpartum. The relative risk was 4.29, and the overall incidence of venous thromboembolism (absolute risk) was 199.7 incidents per 100,000 woman-years. Among postpartum women, the annual incidence was 5 times higher than in pregnant women (511.2 vs 95.8 incidents per 100,000 women, respectively).

The incidence of DVT was 3 times higher than that of pulmonary embolism (151.8 vs 47.9 incidents, respectively, per 100,000 women). Pulmonary embolism was relatively less common during pregnancy than in the postpartum period (10.6 vs 159.7 incidents, respectively, per 100,000 women, respectively). [24] A national review of severe obstetric complications from 1998-2005 found a significant increase in the rate of pulmonary embolism associated with the increasing rate of cesarean delivery. [34]

Pulmonary embolism and postoperative mortality

Pulmonary embolism may account for 15% of all postoperative deaths. Leg amputations and hip, pelvic, and spinal surgery are associated with the highest risk.

Practice Essentials

Pulmonary emboli usually arise from thrombi that originate in the deep venous system of the lower extremities; however, they rarely also originate in the pelvic, renal, upper extremity veins, or the right heart chambers (see the image below). After traveling to the lung, large thrombi can lodge at the bifurcation of the main pulmonary artery or the lobar branches and cause hemodynamic compromise.

38722

The pathophysiology of pulmonary embolism. Although pulmonary embolism can arise from anywhere in the body, most commonly it arises from the calf veins. The venous thrombi predominately originate in venous valve pockets (inset) and at other sites of presumed venous stasis. To reach the lungs, thromboemboli travel through the right side of the heart. RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle.

Pulmonary thromboembolism is not a disease in and of itself. Rather, it is a complication of underlying venous thrombosis. Under normal conditions, microthrombi (tiny aggregates of red cells, platelets, and fibrin) are formed and lysed continually within the venous circulatory system.

Signs and symptoms

The classic presentation of pulmonary embolism is the abrupt onset of pleuritic chest pain, shortness of breath, and hypoxia. However, most patients with pulmonary embolism have no obvious symptoms at presentation. Rather, symptoms may vary from sudden catastrophic hemodynamic collapse to gradually progressive dyspnea. The diagnosis of pulmonary embolism should be suspected in patients with respiratory symptoms unexplained by an alternative diagnosis.

Patients with pulmonary embolism may present with atypical symptoms, such as the following:

• Seizures

• Syncope

• Abdominal pain

• Fever

• Productive cough

• Wheezing

• Decreasing level of consciousness

• New onset of atrial fibrillation

• Hemoptysis

• Flank pain [1]

• Delirium (in elderly patients) [2]

History

The challenge in dealing with pulmonary embolism is that patients rarely display the classic presentation of this problem, that is, the abrupt onset of pleuritic chest pain, shortness of breath, and hypoxia. Studies of patients who died unexpectedly from pulmonary embolism have revealed that often these individuals complained of nagging symptoms for weeks before death. Forty percent of these patients had been seen by a physician in the weeks prior to their death. [7]

The following risk factors can be indications for the presence of pulmonary embolism:

• Venous stasis

• Hypercoagulable states

• Immobilization

• Surgery and trauma

• Pregnancy

• Oral contraceptives and estrogen replacement

• Malignancy

• Hereditary factors resulting in a hypercoagulable state

• Acute medical illness

• Drug abuse (intravenous [IV] drugs)

• Drug-induced lupus anticoagulant

• Hemolytic anemias

• Heparin-associated thrombocytopenia

• Homocystinemia

• Homocystinuria

• Hyperlipidemias

• Phenothiazines

• Thrombocytosis

• Varicose veins

• Venography

• Venous pacemakers

• Warfarin (first few days of therapy)

• Inflammatory bowel disease

The PIOPED II study listed the following indicators for pulmonary embolism:

• Travel of 4 hours or more in the past month

• Surgery within the last 3 months

• Malignancy, especially lung cancer

• Current or past history of thrombophlebitis

• Trauma to the lower extremities and pelvis during the past 3 months

• Smoking

• Central venous instrumentation within the past 3 months

• Stroke, paresis, or paralysis

• Prior pulmonary embolism

• Heart failure

• Chronic obstructive pulmonary disease

Physical Examination

Physical examination findings are quite variable in pulmonary embolism and, for convenience, may be grouped into four categories as follows:

• Massive pulmonary embolism

• Acute pulmonary infarction

• Acute embolism without infarction

• Multiple pulmonary emboli or thrombi

The presentation of pulmonary embolism may vary from sudden catastrophic hemodynamic collapse to gradually progressive dyspnea. (Prior poor cardiopulmonary status of the patient is an important factor leading to hemodynamic collapse.) Most patients with pulmonary embolism have no obvious symptoms at presentation. In contrast, patients with symptomatic DVT commonly have pulmonary embolism confirmed on diagnostic studies in the absence of pulmonary symptoms. Sickle cell disease often creates a diagnostic difficulty with regard to pulmonary embolism. A chest infection is often the presenting symptom.

Patients with pulmonary embolism may present with atypical symptoms. In such cases, strong suspicion of pulmonary embolism based on the presence of risk factors can lead to consideration of pulmonary embolism in the differential diagnosis. These symptoms include the following:

• Seizures

• Syncope

• Abdominal pain

• Fever

• Productive cough

• Wheezing

• Decreasing level of consciousness

• New onset of atrial fibrillation

• Flank pain [1]

• Delirium (in elderly patients) [2]

The diagnosis of pulmonary embolism should be sought actively in patients with respiratory symptoms unexplained by an alternative diagnosis. The symptoms of pulmonary embolism are nonspecific; therefore, a high index of suspicion is required, particularly when a patient has risk factors for the condition.

Acute respiratory consequences of pulmonary embolism include the following:

• Increased alveolar dead space

• Hypoxemia

• Hyperventilation

In patients with recognized pulmonary embolism, the incidence of physical signs has been reported as follows:

• Tachypnea (respiratory rate >16/min) - 96%

• Rales - 58%

• Accentuated second heart sound - 53%

• Tachycardia (heart rate >100/min) - 44%

• Fever (temperature >37.8°C [100.04ºF]) - 43%

• Diaphoresis - 36%

• S3 or S4 gallop - 34%

• Clinical signs and symptoms suggesting thrombophlebitis - 32%

• Lower extremity edema - 24%

• Cardiac murmur - 23%

• Cyanosis - 19%

The PIOPED study reported the following incidence of common symptoms of pulmonary embolism [35] :

• Dyspnea (73%)

• Pleuritic chest pain (66%)

• Cough (37%)

• Hemoptysis (13%)

Fever of less than 39°C (102.2ºF) may be present in 14% of patients; however, temperature higher than 39.5°C (103.1º) Fis not from pulmonary embolism. Chest wall tenderness upon palpation, without a history of trauma, may be the sole physical finding in rare cases.

Pleuritic chest pain without other symptoms or risk factors may be a presentation of pulmonary embolism. Pleuritic or respirophasic chest pain is a particularly worrisome symptom. Pleuritic chest pain is reported to occur in as many as 84% of patients with pulmonary emboli. Its presence suggests that the embolus is located more peripherally and thus may be smaller.

Pulmonary embolism has been diagnosed in 21% of young, active patients who come to emergency departments (EDs) complaining only of pleuritic chest pain. These patients usually lack any other classical signs, symptoms, or known risk factors for pulmonary thromboembolism. Such patients often are dismissed inappropriately with an inadequate workup and a nonspecific diagnosis, such as musculoskeletal chest pain or pleurisy.

Massive pulmonary embolism

Patients with massive pulmonary embolism are in shock. They have systemic hypotension, poor perfusion of the extremities, tachycardia, and tachypnea. In addition, patients appear weak, pale, sweaty, and oliguric and develop impaired mentation.

Signs of pulmonary hypertension, such as palpable impulse over the second left intercostal space, loud P2, right ventricular S3 gallop, and a systolic murmur louder on inspiration at left sternal border (tricuspid regurgitation), may be present.

Massive pulmonary embolism has been defined by hemodynamic parameters and evidence of myocardial injury rather than anatomic findings because the former is associated with adverse outcomes. [42] Although previous studies of CT scans in the diagnosis of pulmonary embolus suggested that central obstruction was not associated with adverse outcomes, a new multicenter study clarifies this observation. Vedovati et al found no association between central obstruction and death or clinical deterioration in 579 patients with pulmonary embolus. [43] However, when a subset of 516 patients who were hemodynamically stable was assessed, central localization of emboli was found to be an independent mortality risk factor while distal localization was inversely associated with adverse events. Thus, anatomic findings by CT scan may be important in assessing risk in hemodynamically stable patients with pulmonary embolus.

Acute pulmonary infarction

Approximately 10% of patients have peripheral occlusion of a pulmonary artery, causing parenchymal infarction. These patients present with acute onset of pleuritic chest pain, breathlessness, and hemoptysis. Although the chest pain may be clinically indistinguishable from ischemic myocardial pain, normal ECG findings and no response to nitroglycerin rules out myocardial pain. Patients with acute pulmonary infarction have decreased excursion of the involved hemithorax, palpable or audible pleural friction rub, and even localized tenderness. Signs of pleural effusion, such as dullness to percussion and diminished breath sounds, may be present.

Acute embolism without infarction

Patients with acute embolism without infarction have nonspecific physical signs that may easily be secondary to another disease process. Tachypnea and tachycardia frequently are detected, pleuritic pain sometimes may be present, crackles may be heard in the area of embolization, and local wheeze may be heard rarely.

Multiple pulmonary emboli or thrombi

Patients with pulmonary emboli and thrombi have physical signs of pulmonary hypertension and cor pulmonale. Patients may have elevated jugular venous pressure, right ventricular heave, palpable impulse in the left second intercostal space, right ventricular S3 gallop, systolic murmur over the left sternal border that is louder during inspiration, hepatomegaly, ascites, and dependent pitting edema. These findings are not specific for pulmonary embolism and require a high index of suspicion for pursuing appropriate diagnostic studies.

Pulmonary embolism in children

Many physical findings are typically less marked in children than they are in adults, presumably because children have greater hemodynamic reserve and, thus, are better able to tolerate the significant hemodynamic and pulmonary changes.

Because of the rarity of pulmonary emboli in children, these patients are probably underdiagnosed. For the same reason, much of the information pertaining to diagnosis and management of pulmonary embolism has been derived from adult practice.

Cough is present in approximately 50% of children with pulmonary emboli; tachypnea occurs with the same frequency. Hemoptysis is a feature in a minority of children with pulmonary emboli, occurring in about 30% of cases. Crackles are heard in a minority of cases.

Cyanosis and hypoxemia are not prominent features of pulmonary embolism. If present, cyanosis suggests a massive embolism leading to a marked ventilation-perfusion (V/Q) mismatch and systemic hypoxemia. Some case reports have described massive pediatric pulmonary embolism with normal saturation.

A pleural rub is often associated with pleuritic chest pain and indicates an embolism in a peripheral location in the pulmonary vasculature. Signs that indicate pulmonary hypertension and right ventricular failure include a loud pulmonary component of the second heart sound, right ventricular lift, distended neck veins, and hypotension. An increase in pulmonary artery pressure is reportedly not evident until at least 60% of the vascular bed has been occluded.

A gallop rhythm signifies ventricular failure, while peripheral edema is a sign of congestive heart failure. Various heart murmurs may be audible, including a tricuspid regurgitant murmur signifying pulmonary hypertension.

Fever is an unusual sign that is nonspecific, and diaphoresis is a manifestation of sympathetic arousal. Signs of other organ involvement in patients with sickle cell disease would be elicited, such as sequestration crisis, priapism, anemia, and stroke.

Complications

Complications of pulmonary embolism include the following:

• Sudden cardiac death

• Obstructive shock

• Pulseless electrical activity

• Atrial or ventricular arrhythmias

• Secondary pulmonary arterial hypertension

• Cor pulmonale

• Severe hypoxemia

• Right-to-left intracardiac shunt

• Lung infarction

• Pleural effusion

• Paradoxical embolism

• Heparin-induced thrombocytopenia

• Thrombophlebitis

Diagnosis

Evidence-based literature supports the practice of using clinical scoring systems to determine the clinical probability of pulmonary embolism before proceeding with testing. [3] Validated clinical prediction rules should be used to estimate pretest probability of pulmonary embolism and to interpret test results. [4]

Physical signs of pulmonary embolism include the following:

• Tachypnea (respiratory rate >16/min): 96%

• Rales: 58%

• Accentuated second heart sound: 53%

• Tachycardia (heart rate >100/min): 44%

• Fever (temperature >37.8°C [100.04°F]): 43%

• Diaphoresis: 36%

• S3 or S4 gallop: 34%

• Clinical signs and symptoms suggesting thrombophlebitis: 32%

• Lower extremity edema: 24%

• Cardiac murmur: 23%

• Cyanosis: 19%

Testing

Perform diagnostic testing on symptomatic patients with suspected pulmonary embolism to confirm or exclude the diagnosis or until an alternative diagnosis is found. Routine laboratory findings are nonspecific and are not helpful in pulmonary embolism, although they may suggest another diagnosis.

A hypercoagulation workup should be performed if no obvious cause for embolic disease is apparent, including screening for conditions such as the following:

• Antithrombin III deficiency

• Protein C or protein S deficiency

• Lupus anticoagulant

• Homocystinuria

• Occult neoplasm

• Connective tissue disorders

Potentially useful laboratory tests in patients with suspected pulmonary embolism include the following:

• D-dimer testing

• Ischemia-modified albumin level

• White blood cell count

• Arterial blood gases:

• Serum troponin levels

• Brain natriuretic peptide

Imaging studies

Imaging studies that aid in the diagnosis of pulmonary embolism include the following:

• Computed tomography angiography (CTA): Multidetector-row CTA (MDCTA) is the criterion standard for diagnosing pulmonary embolism

• Pulmonary angiography: Criterion standard for diagnosing pulmonary embolism when MDCTA is not available

• Chest radiography: Abnormal in most cases of pulmonary embolism, but nonspecific

• V/Q scanning: When CT scanning is not available or is contraindicated

• ECG: Most common abnormalities are tachycardia and nonspecific ST-T wave abnormalities

• MRI: Using standard or gated spin-echo techniques, pulmonary emboli demonstrate increased signal intensity within the pulmonary artery

• Echocardiography: Transesophageal echocardiography may identify central pulmonary embolism

• Venography: Criterion standard for diagnosing DVT

• Duplex ultrasonography: Noninvasive diagnosis of pulmonary embolism by demonstrating the presence of a DVT at any site

Diagnostic Considerations

The variability of presentation for pulmonary embolism sets the patient and clinician up for potentially missing the diagnosis. Such missed diagnoses occur in approximately 400,000 patients in the United States per year; approximately 100,000 deaths could be prevented with proper diagnosis and treatment.

The diagnostic challenge is that the "classic" presentation of the condition, with abrupt onset of pleuritic chest pain, shortness of breath, and hypoxia, is rarely seen. Studies of patients who died unexpectedly from pulmonary embolism have revealed that the patients complained of nagging symptoms, often for weeks, before dying. Forty percent of these patients had been seen by a physician in the weeks prior to their death. [7]

The differential diagnoses are extensive, and they should be considered carefully with any patient thought to have pulmonary embolism. These patients also should have an alternative diagnosis confirmed, or pulmonary embolism should be excluded, before discontinuing the workup. Additional problems to be considered include the following:

• Musculoskeletal pain

• Pleuritis

• Pericarditis

• Salicylate intoxication

• Hyperventilation

• Silicone pulmonary embolism [44]

• Lung trauma

• Mediastinitis, acute

Sickle cell disease

Sickle cell disease often creates a diagnostic difficulty with regard to pulmonary embolism. A chest infection is often the presenting symptom. Hypoxemia, dehydration, and fever lead to intravascular sludging within pulmonary (among others) vasculature. This promotes a vicious cycle, further exacerbating local hypoxemia, ultimately leading to local tissue infarction. This process is further worsened by bone marrow infarction, which may cause release of fat emboli that lodge in the pulmonary circulation. [45]

Differential Diagnoses

• Acute Coronary Syndrome

• Acute Pericarditis

• Acute Respiratory Distress Syndrome

• Angina Pectoris

• Anxiety Disorders

• Aortic Stenosis

• Atrial Fibrillation

• Cardiogenic Shock

• Cor Pulmonale

• Dilated Cardiomyopathy

• Emphysema

• Fat Embolism

• Hypersensitivity Pneumonitis

• Mitral Stenosis

• Myocardial Infarction

• Pneumothorax Imaging

• Idiopathic Pulmonary Arterial Hypertension

• Pulmonary Arteriovenous Fistulae

• Restrictive Cardiomyopathy

• Pulmonary Arterial Hypertension

• Sudden Cardiac Death

• Superior Vena Cava Syndrome in Emergency Medicine

• Syncope

Management

Anticoagulation and thrombolysis

Immediate full anticoagulation is mandatory for all patients suspected of having DVT or pulmonary embolism. [5] Diagnostic investigations should not delay empirical anticoagulant therapy.

Thrombolytic therapy should be used in patients with acute pulmonary embolism who have hypotension (systolic blood pressure< 90 mm Hg) who do not have a high bleeding risk and in selected patients with acute pulmonary embolism not associated with hypotension who have a low bleeding risk and whose initial clinical presentation or clinical course suggests a high risk of developing hypotension. [5]

Long-term anticoagulation is critical to the prevention of recurrence of DVT or pulmonary embolism, because even in patients who are fully anticoagulated, DVT and pulmonary embolism can and often do recur.

Anticoagulation medications include the following:

• Unfractionated heparin

• Low-molecular-weight heparin

• Factor Xa inhibitors

• Fondaparinux

• Warfarin

Thrombolytic agents used in managing pulmonary embolism include the following:

• Alteplase

• Reteplase

Surgical options

Surgical management options include the following:

• Catheter embolectomy and fragmentation or surgical embolectomy

• Placement of vena cava filters

Approach Considerations

Clinical signs and symptoms for pulmonary embolism are nonspecific; therefore, patients suspected of having pulmonary embolism—because of unexplained dyspnea, tachypnea, or chest pain or the presence of risk factors for pulmonary embolism—must undergo diagnostic tests until the diagnosis is ascertained or eliminated or an alternative diagnosis is confirmed. Further, routine laboratory findings are nonspecific and are not helpful in pulmonary embolism, although they may suggest another diagnosis.

A hypercoagulation workup should be performed if no obvious cause for embolic disease is apparent. This may include screening for conditions such as the following:

• Antithrombin III deficiency

• Protein C or protein S deficiency

• Lupus anticoagulant

• Homocystinuria

• Occult neoplasm

• Connective tissue disorders

More clinical studies are needed to evaluate the utility of new approaches to the condition’s diagnosis. The availability of diagnostic tests, as well as cost-effectiveness analysis, local traditions, and the expertise of radiologists involved in the diagnosis, are considerations in the workup of a patient in whom pulmonary embolism is suspected.

Clinical Scoring Systems

Evidence-based literature supports the practice of determining the clinical probability of pulmonary embolism before proceeding with testing. [3] One study assessed the performance of four4 clinical decision rules in addition to D-dimer testing to exclude acute PE. All four4 rules, Wells rule, simplified Wells rule, revised Geneva score, and simplified revised Geneva score, showed similar performance for excluding acute PE when combined with a normal D-dimer result. [46]

See the Guidelines section and the article Pulmonary Embolism Clinical Scoring Systems.

D-Dimer Follow-Up on Low-to-Moderate Pretest Probability

When clinical prediction rule results indicate that the patient has a low or moderate pretest probability of pulmonary embolism, D-dimer testing may be the next step. [3]

D-Dimer, a degradation product produced by plasmin-mediated proteases of cross-linked fibrin, is measured by a variety of assay types, including quantitative, semiquantitative, and qualitative rapid enzyme-linked immunosorbent assays (ELISAs); quantitative and semiquantitative latex; and whole-blood assays. A systematic review of prospective studies of high methodologic quality concluded that the ELISAs—especially the quantitative rapid ELISA—dominate the comparative ranking among the D-dimer assays for sensitivity and negative likelihood ratio. [47] The quantitative rapid ELISA has a sensitivity of 0.95 and negative likelihood ratio of 0.13; the latter is similar to that for a normal to near-normal lung scan in patients with suspected pulmonary embolism.

Negative results on a high-sensitivity D-dimer test in a patient with a low pretest probability of pulmonary embolism indicate a low likelihood of venous thromboembolism and reliably exclude pulmonary embolism. A large, prospective, randomized trial found that in patients with a low probability of pulmonary embolism who had negative D-dimer results, forgoing additional diagnostic testing was not associated with an increased frequency of symptomatic venous thromboembolism during the subsequent 6 months. [48]

In a 2012 prospective cohort study, a Wells score of 4 or less combined with a negative qualitative D-dimer test was shown to safely exclude pulmonary embolism in primary care patients. [49]

D-dimer testing is most reliable for excluding pulmonary embolism in younger patients who have no associated comorbidity or history of venous thromboembolism and whose symptoms are of short duration. [4] However, it is of questionable value in patients who are older than 80 years, who are hospitalized, who have cancer, or who are pregnant, because nonspecific elevation of D-dimer concentrations is common in such patients.

D-dimer testing should not be used when the clinical probability of pulmonary embolism is high, because the test has low negative predictive value in such cases. [50]

Combining D-dimer results with measurement of the exhaled end-tidal ratio of carbon dioxide to oxygen (etCO2/O2) can be useful for diagnosis of pulmonary embolism. Kline et al found that, in moderate-risk patients with a positive D-dimer (>499 ng/mL), an etCO2/O2< 0.28 significantly increased the probability of finding segmental or larger pulmonary embolism on computed tomography multidetector-row pulmonary angiography, while an etCO2/O2) >0.45 predicted the absence of segmental or larger pulmonary embolism. [51]

Because of the poor specificity, positive D-dimer measurements are not helpful in confirming the diagnosis of venous thromboembolic disease. However, a positive D-dimer measurement may lead to consideration of venous thromboembolic disease in the differential diagnosis in selected patients. In addition, the use of D-dimers in children is not well studied. A small pediatric series reported that D-dimer measurements are negative in 40% of patients. [29]A retrospective series reported an elevated D-dimer in 86% of patients at presentation. [17]

Ischemia-Modified Albumin levels

A potential alternative to D-dimer testing is assessment of the ischemia-modified albumin (IMA) level, which data suggest is 93% sensitive and 75% specific for pulmonary embolism. [52] Notably, in a study comparing the prognostic value of IMA to D-dimer testing, IMA assessment in combination with Wells and Geneva probability scores appeared to positively impact overall sensitivity and negative predictive value. [52] The positive predictive value of IMA, in particular, is better than D-dimer. However, it should not be used alone.[53]

White Blood Cell Count

The white blood cell (WBC) count may be normal or elevated in patients with pulmonary embolism, with a WBC count as high as 20,000 being not uncommon in patients with this condition.

Arterial Blood Gases

Arterial blood gas determinations characteristically reveal hypoxemia, hypocapnia, and respiratory alkalosis; however, the predictive value of hypoxemia is quite low. The PaO2 and the calculation of alveolar-arterial oxygen gradient contribute to the diagnosis in a general population thought to have pulmonary embolism. Nonetheless, in high-risk settings such as patients in postoperative states in whom other respiratory conditions can be ruled out, a low PaO2 in conjunction with dyspnea may have a strong positive predictive value.

The PO2 on arterial blood gases analysis (ABG) has a zero or even negative predictive value in a typical population of patients in whom pulmonary embolism is suspected clinically. This is contrary to what has been taught in many textbooks, and even though it seems counterintuitive, it is demonstrably true. This is because other etiologies that masquerade as pulmonary embolism are more likely to lower the PO2 than pulmonary embolism. In fact, because other diseases that may masquerade as pulmonary embolism (eg, chronic obstructive pulmonary disease [COPD], pneumonia, CHF) affect oxygen exchange more than does pulmonary embolism, the blood oxygen level often has an inverse predictive value for pulmonary embolism.

In most settings, fewer than half of all patients with symptoms suggestive of pulmonary embolism actually turn out to have pulmonary embolism as their diagnosis. In such a population, if any reasonable level of PaO2 is chosen as a dividing line, the incidence of pulmonary embolism will be higher in the group with a PaO2 above the dividing line than in the group whose PaO2 is below the divider. This is a specific example of a general truth that may be demonstrated mathematically for any test finding with a Gaussian distribution and a population incidence of less than 50%.

Conversely, in a patient population with a very high incidence of pulmonary embolism and a lower incidence of other respiratory ailments (eg, postoperative orthopedic patients with sudden onset of shortness of breath), a low PO2 has a strongly positive predictive value for pulmonary embolism.

The discussion above holds true not only for arterial PO2 but also for the alveolar-arterial oxygen gradient and for the oxygen saturation level as measured by pulse oximetry. In particular, pulse oximetry is extremely insensitive, is normal in the majority of patients with pulmonary embolism, and should not be used to direct a diagnostic workup.

Troponin levels

Serum troponin levels can be elevated in up to 50% of patients with a moderate to large pulmonary embolism, presumptively due to acute right ventricular myocardial stretch. [50]

Although troponin assessment is not currently recommended as part of the diagnostic workup, studies have shown that elevated troponin levels in the setting of pulmonary embolism correlate with increased mortality. [54] However, further studies need to be performed to identify subsets of patients with pulmonary embolism who might benefit from this testing.

A meta-analysis by Jimenez et al suggested that in acute symptomatic pulmonary embolism, elevated troponin levels do not distinguish between patients who are at high risk for death and those who are at low risk. Pooled results from studies including 1366 normotensive patients with acute symptomatic pulmonary embolism showed that elevated troponin levels were associated with a 4.26-fold increased odds of overall mortality (95% confidence interval [CI], 2.13-8.50; heterogeneity chi2 = 12.64; degrees of freedom = 8; P = .125). Summary receiver operating characteristic curve analysis showed a relationship between the sensitivity and specificity of troponin levels to predict overall mortality (Spearman rank correlation coefficient = 0.68; P = .046). Pooled likelihood ratios (LRs) were not extreme (negative LR, 0.59 [95% CI, 0.39-0.88]; positive LR, 2.26 [95% CI,1.66-3.07]). [55]

Serum troponin, although seemingly marginal for purposes of diagnosis of pulmonary embolism, may contribute significantly to the ability to stratify patients by risk for short-term death or adverse outcome events when they reach the ED. In patients with pulmonary embolism and normal blood pressure specifically, elevated serum troponin level has been associated with right ventricular overload. [54, 56, 57, 58]

Leptin is another cardiovascular risk factor that may be associated with outcome in acute pulmonary embolism. Dellas et al conducted a prospective analysis of 264 patients with acute pulmonary embolus and found that serum leptin levels were inversely associated with the risk of adverse outcomes. Further study will be needed to confirm these findings and determine the clinical utility of leptin measurement. [59]

Brain Natriuretic Peptide

Although brain natriuretic peptide (BNP) tests are neither sensitive nor specific, patients with pulmonary embolism tend to have higher BNP levels. BNP testing had a sensitivity and specificity of only 60% and 62%, respectively, in a case-control study of 2213 hemodynamically stable patients with suspected acute pulmonary embolism. [60]

Elevated levels of BNP or of its precursor, N -terminal pro-brain natriuretic peptide (NT-proBNP), do correlate with an increased risk of subsequent complications and mortality in patients with acute pulmonary embolism. One meta-analysis revealed that patients with a BNP level greater than 100 pg/mL or an NT-proBNP level greater than 600 ng/L had an all-cause in-hospital mortality rate 6- and 16-fold higher than those below these cutoffs, respectively. [36] In a second smaller observational study, serum BNP levels greater than 90 pg/mL were associated with a higher rate of complications, such as the need for cardiopulmonary resuscitation, need for mechanical ventilation, need for vasopressor therapy, and death. [61]

BNP testing is not currently recommended as part of the standard evaluation of acute pulmonary embolism, and future studies may aid in defining its role in this setting.

Elevated levels of brain-type natriuretic peptides (BNP) may also provide prognostic information. [57] A meta-analysis demonstrated a significant association between elevated N-terminal–pro-BNP (NT-pro-BNP) and right ventricular function in patients with pulmonary embolism (P< .001), leading to an increased risk for complicated in-hospital course (odds ratio [OR] 6.8; 95% confidence interval [CI], 9.0-13) and 30-day mortality (OR 7.6; 95% CI, 3.4-17). [62]Importantly, increased NT-pro-BNP alone does not justify more invasive treatment.

A recent study by Scherz et al analyzed a large sample of patients hospitalized with acute pulmonary embolism. Hyponatremia at presentation was common and was associated with a higher risk of 30-day mortality and readmission. [63]

Venography

Venography is the criterion standard for diagnosing DVT. With the advent of noninvasive imaging, it has become less common in pediatric and adult practice.

Angiography

Pulmonary angiography is the historical criterion standard for the diagnosis of pulmonary embolism. Following injection of iodinated contrast, anteroposterior, lateral, and oblique studies are performed on each lung. Positive results consist of a filling defect or sharp cutoff of the affected artery (as shown in the image below). Nonocclusive emboli are described as having a tram-track appearance. Abnormal findings on V/Q scans performed prior to angiography guide the operator to focus on abnormal areas. Angiography generally is a safe procedure. The mortality rate for patients undergoing this procedure is less than 0.5%, and the morbidity rate is less than 5%. Patients who have long-standing pulmonary arterial hypertension and right ventricular failure are considered high-risk patients. Negative pulmonary angiogram findings, even if false negative, exclude clinically relevant pulmonary embolism.

A pulmonary angiogram shows the abrupt termination of the ascending branch of the right upper-lobe artery, confirming the diagnosis of pulmonary embolism.

f multidetector-row computed tomography angiography (MDCTA) is unavailable, conduct pulmonary angiography. Long the criterion standard for pulmonary embolism diagnosis, pulmonary angiography is nevertheless more invasive and harder to perform than MDCTA, and for these reasons, it is rapidly being replaced. However, pulmonary angiography remains a useful diagnostic modality when MDCTA cannot be performed.

When pulmonary angiography has been performed carefully and completely, a positive result provides virtually a 100% certainty that an obstruction to pulmonary arterial blood flow exists. A negative pulmonary angiogram provides a greater than 90% certainty for the exclusion of pulmonary embolism.

A positive angiogram is an acceptable endpoint no matter how abbreviated the study. However, a complete negative study requires the visualization of the entire pulmonary tree bilaterally. This is accomplished via selective cannulation of each branch of the pulmonary artery and injection of contrast material into each branch, with multiple views of each area. Even then, emboli in vessels smaller than third order or lobular arteries are not seen.

Small emboli cannot be seen angiographically, yet embolic obstruction of these smaller pulmonary vessels is very common when postmortem examination follows a negative angiogram. These small emboli can produce pleuritic chest pain and a small sterile effusion even though the patient has a normal V/Q scan and a normal pulmonary angiogram.

In most patients, however, pulmonary embolism is a disease of multiple recurrences, with large and small emboli already present by the time the diagnosis is suspected. Under these circumstances, the V/Q scan and the angiogram are likely to detect at least some of the emboli.

Pulmonary angiography demonstrates subsegmental vessels in more detail than does CT scanning, although the superimposition of the small vessels remains a limiting factor. As a result, the interobserver agreement rate for isolated subsegmental pulmonary embolism is only 45%.

The routine use of CT pulmonary angiography for the detection of pulmonary emboli has led to overdiagnosis of the condition, according to a recent study. Overdiagnosing pulmonary embolism has resulted in possible inappropriate treatment with anticoagulation, a leading cause of medication-related death. [64,65]

Between 1998, when CT pulmonary angiography was introduced, and 2006, there was an 80% increase in the incidence of pulmonary embolism but little subsequent drop in deaths, which suggests that many of the extra emboli being detected are not clinically important. During this period, the detection rate rose from 62.1 to 112.3 per 100,000 US adults and US deaths from pulmonary embolism dropped from 12.3 to 11.9 per 100,000. [64, 65]

Computed Tomography Scanning

Technical advances in CT scanning, including the development of multidetector-array scanners, have led to the emergence of CT scanning as an important diagnostic technique in suspected pulmonary embolism. [3, 44] Contrast-enhanced CT scanning is increasingly used as the initial radiologic study in the diagnosis of pulmonary embolism, especially in patients with abnormal chest radiographs in whom scintigraphic results are more likely to be nondiagnostic.

Computed tomography angiography (CTA) is the initial imaging modality of choice for stable patients with suspected pulmonary embolism. [66, 67, 68] The American College of Radiology (ACR) considers chest CTA to be the current standard of care for the detection of pulmonary embolism. [69] A study by Ward et al determined that a selective strategy in which CTA is used after compression ultrasonography is cost-effective for patients with a high pretest probability of pulmonary embolism. [70] This strategy may reduce the need for CTA and help eliminate adverse effects associated with CTA.

Toward a goal of reducing unnecessary CTA and associated radiation exposure, Drescher et al studied the effect of implementing a computerized decision support system for pulmonary embolism evaluation in the ED. Before implementation, the rate of positive pulmonary embolism diagnosis for CTAs performed was 8.3%; after, the positivity rate rose to 12.7%. The positive yield would have been higher (16.7%) had emergency physicians adhered in all cases to the outcome of the decision support system; in 27% of cases they did not. [71]

Like pulmonary angiography, CT scanning shows emboli directly, but it is noninvasive, cheaper than pulmonary angiography, and widely available. CT scanning is the only test that can provide significant additional information related to alternate diagnoses [72] ; spiral (helical) CT scanning results may suggest an alternative diagnosis in up to 57% of patients. This is a clear advantage of CT scanning over pulmonary angiography or scintigraphy.

A study of multidetector computed tomography (MDCTA) for detection of right ventricular dysfunction in 457 patients with acute pulmonary embolism found reasonable correlation with echocardiography, the reference standard. The criterion selected, a right-to-left ventricular dimensional ratio of 0.9 or more at MDCTA, had 92% sensitivity for right ventricular dysfunction. [73] The combination of quantitative assessment of ventricular dimensions by CT and measurement of biomarkers may provide additional diagnostic accuracy for the presence of right ventricular dysfunction. [74]

Chest Radiography

Chest radiographs are abnormal in most cases of pulmonary embolism, but the findings are nonspecific. Common radiographic abnormalities include atelectasis, pleural effusion, parenchymal opacities, and elevation of a hemidiaphragm. The classic radiographic findings of pulmonary infarction include a wedge-shaped, pleura-based triangular opacity with an apex pointing toward the hilus (Hampton hump) or decreased vascularity (Westermark sign). These findings are suggestive of pulmonary embolism but are infrequently observed.

The abrupt tapering or cutoff of a pulmonary artery secondary to embolus (knuckle sign), cardiomegaly (especially on the right side of the heart), and pulmonary edema are other findings. In the appropriate clinical setting, these findings could be consistent with acute cor pulmonale. A normal-appearing chest radiograph in a patient with severe dyspnea and hypoxemia, but without evidence of bronchospasm or a cardiac shunt, is strongly suggestive of pulmonary embolism.

The ACR recommends chest radiography (see the images below) as the most appropriate study for ruling out other causes of chest pain in patients with suspected pulmonary embolism. [69] Initially, the chest radiographic findings are normal in most cases of pulmonary embolism. However, in later stages, radiographic signs may include a Westermark sign (dilatation of pulmonary vessels and a sharp cutoff), atelectasis, a small pleural effusion, and an elevated diaphragm. Generally, chest radiographs cannot be used to conclusively prove or exclude pulmonary embolism; however, radiography and electrocardiography may be useful for establishing alternative diagnoses. (See Electrocardiography.)

Posteroanterior and lateral chest radiograph findings are normal, which is the usual finding in patients with pulmonary embolism.

A chest radiograph with normal findings in a 64-year-old woman who presented with worsening breathlessness.

A posteroanterior chest radiograph showing a peripheral wedge-shaped infiltrate caused by pulmonary infarction secondary to pulmonary embolism. Hampton hump is a rare and nonspecific finding. Courtesy of Justin Wong, MD

Ventilation-Perfusion Scanning

V/Q scanning of the lungs is an important modality for establishing the diagnosis of pulmonary embolism. V/Q scanning may be used when CT scanning is not available or if the patient has a contraindication to CT scanning or intravenous contrast material. Children generally have a more homogenous perfusion scan; thus, deficits in perfusion are more likely to represent real or significant pulmonary embolism than they are in adults.

The PIOPED II trial provided high-, intermediate-, and low-probability criteria for V/Q scanning diagnosis of pulmonary embolism (see the images of high-probability scans below).

High-probability perfusion lung scan shows segmental perfusion defects in the right upper lobe and subsegmental perfusion defects in right lower lobe, left upper lobe, and left lower lobe.

A normal ventilation scan will make the noted defects in the previous image a mismatch and, hence, a high-probability ventilation-perfusion scan.

Anterior views of perfusion and ventilation scans are shown here. A perfusion defect is present in the left lower lobe, but perfusion to this lobe is intact, making this a high-probability scan.

This perfusion scan shows bilateral perfusion defects. The ventilation scan findings were normal; therefore, these are mismatches, and this is a high-probability scan

The high-probability criteria are as follows:

• Two large (>75% of a segment) segmental perfusion defects without corresponding ventilation or chest radiographic abnormalities

• One large segmental perfusion defect and two moderate (25-75% of a segment) segmental perfusion defects without corresponding ventilation or radiographic abnormalities

• Four moderate segmental perfusion defects without corresponding ventilation or chest radiographic abnormalities

• The intermediate-probability criteria are as follows:

• One moderate to fewer than two large segmental perfusion defects without corresponding ventilation or chest radiographic abnormalities

• Corresponding V/Q defects and radiographic parenchymal opacity in lower lung zone

• Single moderate matched V/Q defects with normal chest radiographic findings

• Corresponding V/Q and chest radiography small pleural effusion

• Difficult to categorize as normal, low, or high probability

Low probability criteria are as follows:

• Multiple matched V/Q defects, regardless of size, with normal chest radiographic findings

• Corresponding V/Q defects and radiographic parenchymal opacity in upper or middle lung zone

• Corresponding V/Q defects and large pleural effusion

• Any perfusion defects with substantially larger radiographic abnormality

• Defects surrounded by normally perfused lung (stripe sign)

• More than three small (< 25% of a segment) segmental perfusion defects with normal chest radiographic findings

• Nonsegmental perfusion defects (cardiomegaly, aortic impression, enlarged hila)

The normal finding is the presence of no perfusion defects and perfusion outlines the shape of the lung seen on a chest radiograph.

The very low–probability criterion is the presence of three small (< 25% of a segment) segmental perfusion defects with normal chest radiographic findings.

In the PIOPED II study, very low–probability V/Q scans in patients whose Wells score indicated low pretest probability of pulmonary embolism reliably excluded pulmonary embolism. [75]

Electrocardiography

The most common ECG abnormalities in the setting of pulmonary embolism are tachycardia and nonspecific ST-T wave abnormalities. The finding of S1 Q3 T3 is nonspecific and insensitive in the absence of clinical suspicion for pulmonary embolism. The classic findings of right heart strain and acute cor pulmonale are tall, peaked P waves in lead II (P pulmonale); right axis deviation; right bundle-branch block; an S1 Q3 T3 pattern; or atrial fibrillation. Unfortunately, only 20% of patients with proven pulmonary embolism have any of these classic electrocardiographic abnormalities. If electrocardiographic abnormalities are present, they may be suggestive of pulmonary embolism, but the absence of such abnormalities has no significant predictive value.

Magnetic Resonance Imaging

With magnetic resonance imaging (MRI), evidence of pulmonary emboli may be detected by using standard or gated spin-echo techniques. Pulmonary emboli demonstrate increased signal intensity within the pulmonary artery. By obtaining a sequence of images, this signal that is originating from slow blood flow may be distinguished from pulmonary embolism. However, this remains a problem in pulmonary hypertension.

Magnetic resonance angiography is performed following intravenous administration of gadolinium. Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or magnetic resonance angiography scans.

NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

MRI has a sensitivity of 85% and specificity of 96% for central, lobar, and segmental emboli; MRI is inadequate for the diagnosis of subsegmental emboli.

Few data are available regarding the use of MRI in children suspected of having a pulmonary embolism. Its use in these patients should be considered investigational at this time.

Few investigators have reported the feasibility of MRI in the evaluation of pulmonary embolism. However, the role of MRI is mostly limited to the evaluation of patients who have impaired renal function or other contraindications for the use of iodinated contrast material. [76, 77] Newer blood-pool contrast agents and respiratory navigators may enhance the role of MRI in the diagnosis of pulmonary embolism.

Echocardiography

This modality generally has limited accuracy in the diagnosis of pulmonary embolism. Transesophageal echocardiography may identify central pulmonary embolism, and the sensitivity for central pulmonary embolism is reported to be 82%. Overall sensitivity and specificity for central and peripheral pulmonary embolism is 59% and 77%.

Echocardiography (ECHO) provides useful information. It may allow diagnosis of other conditions that may be confused with pulmonary embolism, such as pericardial effusion. ECHO allows visualization of the right ventricle and assessment of the pulmonary artery pressure. ECHO serves a prognostic function; the mortality rate is almost 10% in the presence of right ventricular dysfunction and 0% in the absence of right ventricular dysfunction. (Vanni et al reported that a right ventricular strain pattern is associated with a worse short-term outcome. [78] ) ECHO may be used to identify the presence of right-chamber emboli.

The subcostal view is preferred at initial screening for mechanical activity and pericardial fluid and for gross assessment of global and regional abnormalities. To obtain a subcostal view, place the transducer on the left subcostal margin with the beam aimed at the left shoulder.

The parasternal view allows visualization of the aortic valve, proximal ascending aorta, and posterior pericardium and permits determination of left ventricular size. It is particularly helpful when the subcostal view is difficult to obtain. To obtain a parasternal view, place the transducer in the left parasternal area between the second and fourth intercostal spaces. The plane of the beam is parallel to a line drawn from the right shoulder to the left hip.

Several echocardiographic findings have been proposed for noninvasive diagnosis of right ventricular dysfunction at the bedside, including right ventricular enlargement and/or hypokinesis of the free wall, leftward septal shift, and evidence of pulmonary hypertension. If right ventricular dysfunction is seen on cardiac ultrasonography, the diagnosis of acute submassive or massive pulmonary embolism is supported. While the presence of right ventricular dysfunction can be used to support the clinical suspicion of pulmonary embolism, prognostic information can be obtained by assessing the severity of right ventricular dysfunction.

Duplex Ultrasonography

The diagnosis of pulmonary embolism can be proven by demonstrating the presence of a DVT at any site. This may sometimes be accomplished noninvasively by using duplex ultrasonography. To look for DVT using ultrasonography, the ultrasonographic transducer is placed against the skin and pressed inward firmly enough to compress the vein being examined. In an area of normal veins, the veins are easily compressed completely closed, while the muscular arteries are extremely resistant to compression. Where DVT is present, the veins do not collapse completely when pressure is applied using the ultrasonographic probe.

A prospective observational study of 146 patients with suspected or confirmed pulmonary embolism indicates that identification of right ventricular dilatation on bedside echocardiography may aid diagnosis of pulmonary embolism. [79, 80]Bedside echocardiography showed right ventricular dilatation in 15 of the 30 patients who had pulmonary emboli, compared with 2 of the 116 patients without pulmonary emboli.

The presence of right ventricular dilatation on bedside echocardiography had a sensitivity of 50%, specificity of 98%, and positive and negative predictive values of 88% for the diagnosis of pulmonary embolism. [79, 80] Most of the 15 patients with confirmed pulmonary emboli and right ventricular dilatation had proximal clots, while most of those with confirmed pulmonary emboli and a normal right ventricular/left ventricular ratio had more distal clots. [79, 80]

Note that a negative ultrasonographic scan does not rule out DVT, because many DVTs occur in areas that are inaccessible to ultrasonographic examination. Before an ultrasonographic scan can be considered negative, the entire deep venous system must be interrogated using centimeter-by-centimeter compression testing of every vessel. In two thirds of patients with pulmonary embolism, the site of DVT cannot be visualized with ultrasonography, so a negative duplex ultrasonographic scan does not markedly reduce the likelihood of pulmonary embolism.

Ultrasonographic images of thrombi are seen below.

This ultrasonogram shows a thrombus in the distal superficial saphenous vein, which is under the artery.

Longitudinal ultrasound image of partially recanalized thrombus in the femoral vein at mid thigh.

Pulmonary Embolism Treatment & Management

Approach Considerations

Even in patients who are fully anticoagulated, however, DVT and PE can and often do recur. New PE in the hospital can occur in the following patients despite therapeutic anticoagulation:

• Patients who have nonfloating DVT without PE at presentation (3%)

• Patients who present with a floating thrombus but have no PE (13%)

• Patients who present with PE but have no floating thrombus (11%)

• Patients who present with PE who have a floating thrombus visible at venography (39%)

Deciding how to treat a venous thrombosis that may lead to a PE is difficult. A survey of Canadian pediatric intensivists reported the following four patient factors commonly used to determine if a venous thrombosis is clinically important [26] :

• Clinical suspicion of a PE

• Symptoms

• Detection of thrombosis on clinical examination

• Presence of an acute or chronic cardiopulmonary comorbidity that affects the patient's ability to tolerate a PE

Anticoagulants are the treatment of choice in most children with pulmonary emboli. Thrombolytics are rarely used. To date, little data are available regarding the use of LMWH in children with thromboembolic disease.

Thrombolysis

All patients with PE require rapid risk stratification. Thrombolytic therapy should be used in patients with acute PE associated with hypotension (systolic BP< 90 mm HG) who do not have a high bleeding risk. [5] Do not delay thrombolysis in this population because irreversible cardiogenic shock can develop. Thrombolytic therapy is suggested in select patients with acute PE not associated with hypotension and with a low bleeding risk whose initial clinical presentation or clinical course after starting anticoagulation suggests a high risk of developing hypotension. Assessment of pulmonary embolism severity, prognosis, and risk of bleeding dictate whether thrombolytic therapy should be started. Thrombolytic therapy is not recommended for most patients with acute PE not associated with hypotension. [5]

Although most studies demonstrate the superiority of thrombolytic therapy with respect to the resolution of radiographic and hemodynamic abnormalities within the first 24 hours, this advantage disappears 7 days after treatment. Controlled clinical trials have not demonstrated benefits in terms of reduced mortality rates or earlier resolution of symptoms when currently compared with heparin. A large retrospective review suggests that the use of thrombolytic therapy in unstable patients with PE may lead to reduced mortality when compared to anticoagulation therapy alone. Concurrent use of thrombolytic therapy and vena cava filters in such patients may reduce mortality even further. [81, 82]

In a meta-analysis of 16 randomized studies comparing thrombolytic therapy with anticoagulation therapy in patients with pulmonary embolism, including intermediate-risk, hemodynamically stable patients with right ventricular dysfunction, Chatterjee et al found that thrombolytic therapy, as compared with standard anticoagulant therapy, reduced mortality by 47% but was associated with a 2.7-fold increase in major bleeding. [83]

The investigators also found, however, that the rate of major bleeding was not significantly increased with thrombolysis among patients younger than 65 years, whereas it more than tripled in the subgroup of patients older than 65 years. [83]Thrombolytic therapy was associated with a greater risk of intracranial hemorrhage and a lower risk of recurrent pulmonary embolism. [83]

Until randomized clinical trials demonstrate a clear morbidity or mortality benefit, the role of thrombolytic therapy in the management of acute pulmonary embolism will remain controversial (especially in the management of intermediate-risk patients). [84, 85, 86] The currently accepted indications for thrombolytic therapy include hemodynamic instability (systolic BP < 90 mm Hg) or a clinical risk factor assessment that suggests that hypotension is likely to develop.

Anticoagulation

Unfractionated heparin therapy

In patients with acute PE, anticoagulation with IV UFH, LMWH, or fondaparinux is preferred over no anticoagulation. [5] Most patients with acute PE should receive LMWH or fondaparinux instead of IV UFH. In patients with PE, if concerns regarding subcutaneous absorption arise, severe renal failure exists, or if thrombolytic therapy is being considered, IV UFH is the recommended form of initial anticoagulation. [5] Clinicians often choose to use IV UFH in preference to LMWH and fondaparinux in specific clinical circumstances where medical or surgical procedures are likely to be performed and the short half-life of IV UFH allows for temporary cessation of anticoagulation and presumed reduction of bleeding risk during the procedure. Though this strategy has limited supporting evidence, it appears to represent a reasonable practice.

The efficacy of heparin therapy depends on achieving a critical therapeutic level of heparin within the first 24 hours of treatment. The critical therapeutic level of heparin is 1.5 times the baseline control value or the upper limit of normal range of the activated partial thromboplastin time (aPTT).

This level of anticoagulation is expected to correspond to a heparin blood level of 0.2-0.4 U/mL by the protamine sulfate titration assay and 0.3-0.6 by the anti-factor X assay.

Each laboratory should establish the minimal therapeutic level for heparin, as measured by the aPTT, to coincide with a heparin blood level of at least 0.2 U/mL for each batch of thromboplastin reagent being used.

If IV UFH is chosen, an initial bolus of 80 U/kg or 5000 U followed by an infusion of 18 U/kg/h or 1300 U/h should be given, with the goal of rapidly achieving and maintaining the aPTT at levels that correspond to therapeutic heparin levels. Fixed-dose and monitored regimens of subcutaneous UFH are available and are acceptable alternatives.

Low-molecular-weight heparin therapy

Current guidelines for patients with acute PE recommend LMWH over IV UFH (grade 2C) and over SC UFH (grade 2B). [5] In patients being treated with LMWH, once-daily regimens are preferred over twice-daily regimens (grade 2C). The choice between fondaparinux and LMWH should be based on local considerations to include cost, availability, and familiarity of use.

LMWHs have many advantages over UFH. These agents have a greater bioavailability, can be administered by subcutaneous injections, and have a longer duration of anticoagulant effect. A fixed dose of LMWH can be used, and laboratory monitoring of aPTT is not necessary.

Trials comparing LMWH with UFH have shown that LMWH is at least as effective and as safe as UFH. The studies have not pointed to any significant differences in recurrent thromboembolic events, major bleeding, or mortality between the 2 types of heparin.

LMWH can be administered safely in an outpatient setting. This has led to the development of programs in which clinically stable patients with PE are treated at home, at substantial cost savings. The ACCP guidelines suggest that patients with low-risk PE and who have acceptable home circumstances be discharged early from hospital (ie, before the first five days of treatment)(grade 2B).

An international, open-label, randomized trial compared outpatient and inpatient treatment (both using the LMWH enoxaparin as initial therapy) of low-risk patients with acute PE and concluded that outpatient treatment was noninferior to inpatient treatment. [87]

Direct thrombin inhibitors and factor Xa inhibitors

Apixaban, dabigatran, rivaroxaban, and edoxaban are alternatives to warfarin for prophylaxis and treatment of PE. Apixaban, edoxaban, and rivaroxaban inhibit factor Xa, whereas dabigatran is a direct thrombin inhibitor.

Rivaroxaban

Rivaroxaban (Xarelto) is an oral factor Xa inhibitor approved by the FDA in November 2012 for the treatment of DVT or PE, and to reduce risk of recurrent DVT and PE following initial treatment.

Approval for this indication was based on studies totaling 9478 patients with DVT or PE. Participants were randomly assigned to receive rivaroxaban, a combination of enoxaparin and a vitamin K antagonist (VKA) (eg, warfarin), or a placebo. Study endpoints were designed to measure the number of patients who experienced recurrent symptoms of DVT, PE, or death after receiving treatment. [88, 89] Additionally, results from extended treatment demonstrated a reduced risk of recurrent DVT and PE. Approximately 1.3% in the rivaroxaban group experienced recurrent DVT or PE compared with 7.1% in the placebo group. [90, 91]

The results of the Einstein-PE study provide an important advance in the treatment of symptomatic PE. In a prospective, open-label study, 4832 patients were randomized to receive either rivaroxaban or enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. Treatment with a fixed-dose regimen of rivaroxaban was noninferior to standard therapy and had a satisfactory safety profile. [88]

Data from a pooled analysis of the EINSTEIN-PE and EINSTEIN-DVT studies in the treatment of DVT or pulmonary embolism suggest that rivaroxaban is as effective in preventing VTE recurrence as administration of enoxaparin followed by a vitamin-K antagonist. [92, 93] Rivaroxaban may also be associated with less bleeding, particularly in elderly patients and those with moderate renal impairment. [92, 93]

Apixaban

Apixaban was approved for treatment of PE in August 2014. The approval for treatment of PE and prevention of recurrence was based on the outcome of the AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) and AMPLIFY-EXT studies, in which apixaban therapy was compared with enoxaparin and warfarin treatment. The AMPLIFY study showed that, in comparison with the standard anticoagulant regimen apixaban therapy resulted in a 16% reduction in the risk of a composite endpoint that included recurrent symptomatic venous thromboembolism (VTE) or VTE-associated death. [94, 95]

This advance thus offers the prospect of a safe and effective regimen of anticoagulation for patients with the advantages of simplicity and cost-effectiveness in comparison to current management strategies.

Dabigatran

Dabigatran (Pradaxa) was approved by the FDA in 2014 for the treatment of DVT and PE and reducing venous thromboembolic recurrence. In the RE-COVER and RE-COVER 2 studies, patients with DVT and PE who had received initial parenteral anticoagulation (eg, IV heparin, SC LMWH) for 5-10 days were randomized to warfarin or dabigatran. These two trials showed dabigatran was noninferior to warfarin in reducing DVT and PE and was associated with lower bleeding rates. [96, 97]

Edoxaban

Edoxaban (Savaysa) was approved by the FDA in January 2015 for the treatment of DVT and PE in patients who have been initially treated with a parenteral anticoagulant for 5-10 days. Approval was based on the Hokusai-VTE study, which included 3,319 patients with PE. Of these patients, 938 had right ventricular dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide levels. The rate of recurrent VTE in this subgroup was 3.3% in the edoxaban group and 6.2% in the warfarin group. Edoxaban was noninferior to high-quality standard warfarin therapy and caused significantly less bleeding in a broad spectrum of patients with VTE, including those with severe pulmonary embolism. [98]

Betrixaban

Betrixaban, a factor Xa inhibitor, was approved by the FDA in June 2017. It is indicated for prophylaxis of VTE in adults hospitalized for acute medical illness who are at risk for thromboembolic complications owing to moderate or severe restricted mobility and other risk factors that may cause VTE.

Approval of betrixaban was based on data from the phase 3 APEX studies. These randomized, double-blind, multinational clinical trials compared extended-duration betrixaban (35-42 days) to short-duration enoxaparin (6-14 days) for VTE in 7513 acutely medically ill hospitalized patients with VTE risk factors.

Patients in the betrixaban group took an initial dose of 160 mg orally on day 1, followed by 80 mg once daily for 35-42 days, and received a placebo injection once daily for 6-14 days. Patients in the enoxaparin group received 40 mg subcutaneously once daily for 6-4 days and took an oral placebo once daily for 35-42 days.

Efficacy was measured in 7441 patients using a composite outcome score composed of the occurrence of asymptomatic or symptomatic proximal deep vein thrombosis, nonfatal pulmonary embolism, stroke, or VTE-related death. Betrixaban showed significant decreases in VTE events compared with enoxaparin. [99, 100]

Fondaparinux

In patients with acute PE, fondaparinux as initial treatment is favored over IV UFH and over SC UFH. [5] The choice between fondaparinux and LMWH should be based on local considerations to include cost, availability, and familiarity of use. Fondaparinux is a synthetic polysaccharide derived from the antithrombin binding region of heparin. Fondaparinux catalyzes factor Xa inactivation by antithrombin without inhibiting thrombin.

Once-daily fondaparinux was found to have similar rates of recurrent PE, bleeding, and death as IV UFH, according to one randomized open-label study of 2213 patients with symptomatic pulmonary embolism. [101]

In general, the use of LMWH or fondaparinux is recommended over IV UFH and SC UFH. This is because of a more predictable bioavailability, more rapid onset of full anticoagulant effect, and the benefit of not typically needing to monitor anticoagulant effect. However, if uncertainty arises regarding the accuracy of dosing, factor Xa levels can be monitored to determine efficacy.

Warfarin therapy

A vitamin K antagonist such as warfarin should be started on the same day as anticoagulant therapy in patients with acute PE. [5] Parenteral anticoagulation and warfarin should be continued together for a minimum of at least five days and until the INR is 2.0.

The anticoagulant effect of warfarin is mediated by the inhibition of vitamin K–dependent factors, which are II, VII, IX, and X. The peak effect does not occur until 36-72 hours after drug administration, and the dosage is difficult to titrate.

A prothrombin time ratio is expressed as an INR and is monitored to assess the adequacy of warfarin therapy. The recommended therapeutic range for venous thromboembolism is an INR of 2-3. This level of anticoagulation markedly reduces the risk of bleeding without the loss of effectiveness. Initially, INR measurements are performed on a daily basis; once the patient is stabilized on a specific dose of warfarin, the INR determinations may be performed every 1-2 weeks or at longer intervals.

Duration of anticoagulation therapy

A patient with a first thromboembolic event occurring in the setting of reversible risk factors, such as immobilization, surgery, or trauma, should receive warfarin therapy for at least 3 months. No difference in the rate of recurrence was observed in either of 2 studies comparing 3 versus 6 months of anticoagulant therapy in patients with idiopathic (or unprovoked) first events. [102, 103] The current recommendation is anticoagulation for at least 3 months in these patients; the need for extending the duration of anticoagulation should be reevaluated at that time.

The current ACCP guidelines recommend that all patients with unprovoked PE receive three months of treatment with anticoagulation over a shorter duration of treatment and have an assessment of the risk-benefit ratio of extended therapy at the end of three months (grade 1B). [5] Patients with a first episode of venous thromboembolism and with a low or moderate risk of bleeding should have extended anticoagulant therapy (grade 2B). Patients with a first episode of venous thromboembolism who have a high bleeding risk should have therapy limited to three months (grade 1B).

In patients with a second unprovoked episode of venous thromboembolism and low or moderate risk of bleeding, extended anticoagulant therapy is recommended (grades 1B and 2B, respectively). In patients with a second episode of venous thromboembolism and a high risk of bleeding, three months of anticoagulation is preferred over extended anticoagulation (grade 2B).

Patients who have PE and preexisting irreversible risk factors, such as deficiency of antithrombin III, protein S and C, factor V Leiden mutation, or the presence of antiphospholipid antibodies, should be placed on long-term anticoagulation.

Cancer patients

Patients who have PE in association with an active neoplasm provide challenges for long-term management because of their increased continuing risk for recurrent VTE and PE. The ninth edition of the ACCP guidelines recommends that such patients receive extended anticoagulation as opposed to three month therapy if they are at low or moderate risk of bleeding complications (grade 1B).[5] If patients with active neoplasm are at high risk of bleeding, it is still suggested that they receive extended therapy, though the supporting evidence is less conclusive (grade 2B). For the treatment of PE in cancer patients, LMWH is recommended in preference to a vitamin K antagonist such as warfarin (grade 2B). However, some cancer patients choose not to have long-term treatment with LMWH because of the need for daily injections and treatment costs. If cancer patients with PE choose not to have treatment with LMWH, a vitamin K antagonist such as warfarin is preferred over dabigatran or rivaroxaban (grade 2C).

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a transient prothrombotic disorder initiated by heparin. The main features of HIT are (1) thrombocytopenia resulting from immunoglobulin G–mediated platelet activation and (2) in vivo thrombin generation and increased risk of venous and arterial thrombosis.

The highest frequency of HIT, 5%, has been reported in post–orthopedic surgery patients receiving up to 2 weeks of unfractionated heparin. HIT occurred in approximately 0.5% of post–orthopedic surgery patients receiving LMWH for up to 2 weeks.

HIT may manifest clinically as extension of the thrombus or formation of new arterial thrombosis. HIT should be suspected whenever the patient's platelet count falls to less than 100,000/µL or less than 50% of the baseline value, generally after 5-15 days of heparin therapy. For patients receiving heparin where the risk of HIT is thought to be greater than 1%, guidelines suggest that platelet counts be obtained every two or three days from day 4 to day 14 of therapy, or until the heparin is stopped (grade 2C). [5] The definitive diagnosis is made by performing a platelet activation factor assay.

The treatment of patients who develop HIT is to stop all heparin products, including catheter flushes and heparin-coated catheters, and to initiate an alternative, nonheparin anticoagulant, even when thrombosis is not clinically apparent. In patients with HIT with or without thrombosis, the use of lepirudin, argatroban, or danaparoid is preferred over continued use of heparin, LMWH, or either initiation or continuation of a vitamin K antagonist (grade 1C). [5]

If a vitamin K antagonist has already been started when HIT is diagnosed, guidelines recommend that it be discontinued and that vitamin K should be administered (grade 2C). [5] When HIT has been confirmed, vitamin K antagonists should not be started until the platelet count has recovered to at least 150 x 109/L (grade 1C), it should be started at low doses (ie, 5 mg of warfarin), and it should be given concomitantly with a nonheparin anticoagulant for a minimum of five days and until the INR is within the target range (grade 1C).[5] In patients with renal failure who have HIT and thrombosis, argatroban is preferred over other nonheparin anticoagulants (grade 2C). [5]

Resistance to heparin

Few patients with venous thromboembolism require large doses of heparin for achieving an optimal activated partial thromboplastin time (aPTT). Those patients who do require them have increased plasma concentrations of factor VIII and heparin-binding proteins. Increased factor VIII concentration causes dissociation between aPTT and plasma heparin values. The aPTT is suboptimal, but patients have adequate heparin levels upon protamine titration. This commonly occurs in patients with a concomitant inflammatory disease.

Monitoring the antifactor Xa assay results in this situation is safe and effective and results in less escalation of the heparin dose when compared with monitoring with aPTT. Whenever a therapeutic level of aPTT cannot be achieved with large doses of UFH, either determination of plasma heparin concentration or therapy with LMWH should be instituted.

Embolectomy

Either catheter embolectomy and fragmentation or surgical embolectomy is reasonable for patients with massive pulmonary embolism who have contraindications to fibrinolysis or who remain unstable after receiving fibrinolysis. [104] If these procedures are not available locally, it is reasonable to consider transferring the patient to an institution with experience in one of these procedures, providing the transfer can be accomplished safely.

In patients with submassive acute PE, either catheter embolectomy or surgical embolectomy may be considered if they have clinical evidence of an adverse prognosis (ie, new hemodynamic instability, worsening respiratory failure, severe right ventricular dysfunction, or major myocardial necrosis). These interventions are not recommended for patients with low-risk or submassive acute pulmonary embolism who have minor right ventricular dysfunction, minor myocardial necrosis, and no clinical worsening. [104]

Vena Cava Filters

Patients with acute PE should not routinely receive vena cava filters in addition to anticoagulants. [5] An ideal IVC filter should be easily and safely placed using a percutaneous technique, biocompatible and mechanically stable, and able to trap emboli without causing occlusion of the vena cava. [105]

IVC interruption by the insertion of an IVC filter (Greenfield filter) is only indicated in the following settings:

• Patients with acute venous thromboembolism who have an absolute contraindication to anticoagulant therapy (eg, recent surgery, hemorrhagic stroke, significant active or recent bleeding)

• Patients with massive PE who survived but in whom recurrent embolism invariably will be fatal

• Patients who have objectively documented recurrent venous thromboembolism, adequate anticoagulant therapy notwithstanding

In patients with a time-limited indication for IVC filter placement (eg, a short-term contraindication to anticoagulation), it is reasonable to select a retrievable IVC filter and evaluate the patient periodically for filter retrieval. After placement of an IVC filter, anticoagulation should be resumed once contraindications to anticoagulation or active bleeding complications have resolved. [104]

Supportive Care

Compression stockings

For patients who have had a proximal DVT, the use of elastic compression stockings provides a safe and effective adjunctive treatment that can limit postphlebitic syndrome. Stockings with a pressure of 30-40 mm Hg at the ankle, worn for 2 years following diagnosis, are recommended (grade 2B) to reduce the risk of postphlebitic syndrome.

True gradient compression stockings are highly elastic, providing a gradient of compression that is highest at the toes and gradually decreases to the level of the thigh. This reduces capacitive venous volume by approximately 70% and increases the measured velocity of blood flow in the deep veins by a factor of 5 or more. Compression stockings of this type have been proven effective in the prophylaxis of thromboembolism and are also effective in preventing progression of thrombus in patients who already have DVT and pulmonary embolism.

A 1994 meta-analysis calculated a DVT risk odds ratio of 0.28 for gradient compression stockings (as compared to no prophylaxis) in patients undergoing abdominal surgery, gynecologic surgery, or neurosurgery.

Other studies found that gradient compression stockings and LMWH were the most effective modalities in reducing the incidence of DVT after hip surgery; they were more effective than subcutaneous UFH, oral warfarin, dextran, or aspirin.

The ubiquitous white stockings known as anti-embolic stockings or "Ted hose" produce a maximum compression of 18 mm Hg. Ted hose rarely are fitted in such a way as to provide even that inadequate gradient compression. Because they provide such limited compression, they have no efficacy in the treatment of DVT and pulmonary embolism, nor have they been proven effective as prophylaxis against a recurrence.

True 30-40 mm Hg gradient compression pantyhose are available in sizes for pregnant women. They are recommended by many specialists for all pregnant women because they not only prevent DVT, but they also reduce or prevent the development of varicose veins during pregnancy.

Additional support therapies

Activity is recommended as tolerated. Early ambulation is recommended over bed rest when feasible (grade 2C recommendation).

Pharmacologic support of the cardiovascular system may be necessary. Dopamine and dobutamine are the usual inotropic agents. Mechanical ventilation may be necessary to provide respiratory support and as adjunctive therapy for a failing circulatory system.

Children with sickle cell disease who present with pulmonary symptoms require treatment with a macrolide and cephalosporin antibiotic. Their clinical status should be closely monitored in order to anticipate those children who may develop acute chest syndrome. [45] Transfusion with packed red blood cells (either simple or exchange) improves oxygenation immediately, helping to break the vicious cycle outlined above.

IV fluids may help or may hurt the patient who is hypotensive from pulmonary embolism, depending on which point on the Starling curve describes the patient's condition. A cautious trial of a small fluid bolus may be attempted, with careful surveillance of the systolic and diastolic blood pressures and immediate cessation if the situation worsens after the fluid bolus. Improvement or normalization of blood pressure after fluid loading does not mean the patient has become hemodynamically stable.

Individuals with acute, submassive pulmonary embolisms have low levels of endogenous activated protein C. A study by Dempfle et al determined that administering drotrecogin alfa (activated) along with therapeutic doses of enoxaparin enhanced the inhibition of fibrin formation in these patients. [106]

Drotrecogin alfa was withdrawn from the worldwide market October 25, 2011 after analysis of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS)-SHOCK clinical trial. Drotrecogin alfa failed to demonstrate a statistically significant reduction in 28-day all-cause mortality in patients with severe sepsis and septic shock. Trial results observed a 28-day all-cause mortality rate of 26.4% in patients treated with activated drotrecogin alfa compared with 24.2% in the placebo group of the study.

Long-Term Monitoring

PT should be measured on a regular basis; the goal is an INR of 2-3.

The length of treatment depends on the presence of risk factors. If no underlying risk factors are present, therapy can be stopped within 1-2 months. If risk factors are present, especially anticardiolipin antibodies, therapy should continue for at least 4-6 months.

Long-term anticoagulation is essential for patients who survive an initial DVT or pulmonary embolism. The optimum total duration of anticoagulation is controversial, but general consensus holds that at least 6 months of anticoagulation is associated with significant reduction in recurrences and a net positive benefit. [107]

Patients may have treatment initiated using concomitant warfarin and unfractionated heparin for 5 days in the hospital, with discharge on warfarin alone when the international normalized ratio (INR) is 2. Alternatively, patients may be discharged on concomitant therapy with a LMWH and warfarin for at least 5 days. The LMWH is then discontinued in the outpatient setting when the INR reaches 2

Pulmonary Embolism in Pregnancy

The risk of venous thromboembolism is increased during pregnancy and the postpartum period. Pulmonary embolism is the leading cause of death in pregnancy. DVT and pulmonary embolism are common during all trimesters of pregnancy and for 6-12 weeks after delivery.

Diagnosis

The diagnostic approach to patients with pulmonary embolism should be exactly the same in a pregnant patient as in a nonpregnant one. A nuclear perfusion lung scan is safe in pregnancy, as is a chest CT scan.

Guidelines by the professional societies on the diagnosis of pulmonary embolism make this difficult assessment easier and reduce the risks of radiation to the fetus. If the patient has a low pretest probability for pulmonary embolism and a normal D-dimer test result, clinical exclusion from further investigations is recommended. When the suspicion is high, the patients should have bilateral leg Doppler assessment. If the results are positive, the patient should be treated for pulmonary embolism. If the results are negative, CT pulmonary angiography is the next step. To rule out contrast-induced hypothyroidism, all neonates exposed to the iodinated contrast in utero should have their serum thyrotropin level checked in the first week of life.

Treatment

Heparin and fibrinolysis are safe in pregnancy. Failure to treat the mother properly is the most common cause of fetal demise.

Pregnant patients diagnosed with DVT or pulmonary embolism may be treated with LMWH throughout their pregnancy. Warfarin is contraindicated, because it crosses the placental barrier and can cause fetal malformations. Unfractionated heparin is category C. Therefore, LMWH at full anticoagulation doses should be continued until delivery. Women experiencing a thromboembolic event during pregnancy should receive therapeutic treatment with unfractionated heparin or LMWH during pregnancy, with anticoagulation continuing for 4-6 weeks postpartum and for a total of at least 6 months.

In addition to the thrombotic risks in pregnancy, women of childbearing age who are prescribed warfarin should be advised of the teratogenic effects of this drug. Alteplase is a category C drug, and should only be given following a judicious assessment of the risk-to-benefit ratio.

Pregnant women who are in a hypercoagulable state or who have had previous venous thromboembolism should receive prophylactic anticoagulation during pregnancy.

Consultations

Fibrinolytic therapy should not be delayed while consultation is sought. The decision to treat pulmonary embolism by fibrinolysis is properly made by the responsible emergency physician alone, and fibrinolytic therapy is properly administered in the ED.

A pulmonologist is often consulted before the true diagnosis is made because of the nonspecific nature of the symptoms, and consultation with a cardiologist is warranted to rule out a cardiac etiology for the presenting symptoms and signs and to perform ECHO and pulmonary angiography.

If embolectomy is considered, consultation with a cardiac surgeon is mandatory. Few data are available regarding the use of surgical embolectomy in children. Consider embolectomy in the setting of massive cardiac failure when time is insufficient for natural or pharmacologic thrombolysis or if thrombolysis is contraindicated. Thrombotic endarterectomy is another surgical treatment option for patients with hemodynamic compromise from large pulmonary emboli. Thrombotic endarterectomy is only performed at certain centers and has a high mortality rate, but it can be successful in certain populations.

A hematologist can suggest an appropriate workup for a procoagulant defect and can recommend an anticoagulation regimen. Consultation with a hematologist is essential in children with sickle cell disease. A free clinical consultation service for complex cases of thromboembolism in children is available for clinicians by calling 1-800-NO-CLOTS (1-800-662-5687).

An interventional radiology consultation may be helpful for catheter-directed fibrinolysis in selected patients. In rare cases, arranging for placement of a venous filter may be appropriate if the patient is not a candidate for thrombolytic therapy.

Prevention

Preventing idiopathic outpatient pulmonary embolism is difficult, if not impossible. That said, the majority of pulmonary embolisms occur in hospitalized patients. The incidence in these cases can be reduced through appropriate prophylaxis, achieved mechanically or via the administration of heparin, LMWH, or warfarin. [5]

The incidence of venous thrombosis, pulmonary embolism, and death can be significantly reduced by embracing a prophylactic strategy in high-risk patients. Prevention of DVT in the lower extremities inevitably reduces the frequency of pulmonary embolism; therefore, populations at risk must be identified, and safe and efficacious prophylactic modalities should be used.

The QThrombosis algorithm is intended to identify currently asymptomatic adults at greatest future risk of venous thrombosis based on established risk factors. According to the study in which it was developed and validated, QThrombosis estimates the absolute risk of venous thrombosis at 1 year and 5 years into the future, information that can be used to guide prophylaxis and medication decisions. [108]

Medicolegal Concerns

Pulmonary embolism is an extremely common disorder. It presents with nonspecific clinical features and requires specialized investigations for confirmation of diagnosis. Therefore, many patients die from unrecognized pulmonary embolism. The other common pitfalls are as follows:

• Disregarding patient's complaints of unexplained dyspnea as anxiety or hyperventilation

• Blaming complaints of unexplained chest pain on musculoskeletal pain

• Failing to recognize, diagnose, and treat DVT

• Failing to initiate an appropriate diagnostic workup in patients with symptoms consistent with pulmonary embolism

• Failing to initiate therapeutic anticoagulant therapy with heparin in patients suspected to have pulmonary embolism, before the V/Q scan or other investigations

• Failure to advise of risk factors, such as smoking, pregnancy, and use of the oral contraceptive pill

• Failure to diagnose predisposing or associated conditions

Future Research

Advances over the past several decades have significantly improved physicians’ ability to diagnosis pulmonary embolism and have refined the treatment of this disorder. However, several areas need further research and properly conducted therapeutic trials. The role of LMWH and the optimal duration of anticoagulant therapy in different subgroups of patients with venous thromboembolism require further study.

Because warfarin therapy results in bleeding, future studies should determine whether less intense warfarin therapy is effective in preventing recurrences of pulmonary embolism.

Whether drugs that inhibit the action of thrombin (eg, hirudin) are useful in treating patients with venous thromboembolic disease also needs to be determined by future trials.

Guidelines Summary

Guidelines for the diagnosis and management of pulmonary embolism (PE) have been issued by the following organizations:

• American Academy of Family Physicians (AAFP)/American College of Physicians (ACP) [4]

• American College of Physicians (ACP) [109]

• American College of Emergency Physicians (ACEP) [110]

• American College of Radiology (ACR) [69]

• American College of Chest Physicians [5, 111]

• American Heart Association (AHA) [104]

• American College of Obstetricians and Gynecologists (ACOG) [112]

• American Society of Hematology [113]

Clinical Scoring Guidelines

A 2007 clinical practice guideline from the American Academy of Family Physicians (AAFP) and the American College of Physicians (ACP) recommends that validated clinical prediction rules be used to estimate pretest probability of pulmonary embolism (PE) and to interpret test results. [4] The guideline, Current Diagnosis of Venous Thromboembolism in Primary Care, advocates use of the Wells prediction rule for this purpose but notes that the Wells rule performs better in younger patients without comorbidities or a history of venous thromboembolism (VTE) than in other patients.

In 2015, the ACP released guidelines for the evaluation of patients with suspected acute PE, which included the following recommendations [109] :

• Plasma D-dimer tests are more appropriate for those at intermediate risk for a PE, and no testing may be necessary for some patients at low risk.

• Use either the Wells or Geneva rules to choose tests based on a patient's risk for PE.

• If the patient is at low risk, clinicians should use the eight Pulmonary Embolism Rule-Out Criteria (PERC); if a patient meets all eight criteria, the risks of testing are greater than the risk for embolism, and no testing is needed.

• For patients at intermediate risk, or for those at low risk who do not meet all of the rule-out criteria, use a high-sensitivity plasma D-dimer test as the initial test.

• In patients older than 50 years, use an age-adjusted threshold (age × 10 ng/mL, rather than a blanket 500 ng/mL), because normal D-dimer levels increase with age.

• Patients with a D-dimer level below the age-adjusted cutoff should not receive any imaging studies.

• Patients with elevated D-dimer levels should then receive imaging.

• Patients at high risk should skip the D-dimer test and proceed to CT pulmonary angiography, because a negative D-dimer test does not eliminate the need for imaging in these patients.

• Clinicians should only obtain ventilation-perfusion scans in patients with a contraindication to CT pulmonary angiography or if CT pulmonary angiography is unavailable.

• Clinicians should use validated clinical prediction rules to estimate pretest probability in patients in whom acute PE is being considered.

In contrast, the 2011 guidelines of the American College of Emergency Physicians (ACEP) find that either objective criteria or gestalt clinical assessment can be used to risk-stratify patients with suspected PE. There is insufficient evidence to support the preferential use of one method over another (level B). For patients with a low pretest probability for suspected PE, PERC may be used to exclude the diagnosis based on historical and physical examination data alone (level B). Other key recommendations include the following [110] :

• Negative quantitative D-dimer assay results can be used to exclude PE in patients with a low pretest probability for PE (level A).

• Negative quantitative D-dimer assay results may be used to exclude PE in patients with an intermediate pretest probability for PE (level C).

• For patients with a low or PE unlikely (Wells score 4) pretest probability for PE who require additional diagnostic testing (eg, positive D-dimer result, or highly sensitive D-dimer test not available), a negative, multidetector CT pulmonary angiogram alone can be used to exclude PE (level B).

• For patients with an intermediate or high pretest probability for PE and a negative CT pulmonary angiogram result in whom a clinical concern for PE still exists and CT venogram has not already been performed, consider additional diagnostic testing (eg, D-dimer, lower extremity imaging, VQ scanning, traditional pulmonary arteriography) prior to exclusion of VTE disease (level C).

• Venous ultrasound may be considered as initial imaging in patients with obvious signs of deep venous thrombosis (DVT) for whom venous ultrasound is readily available, patients with relative contraindications for CT scan (eg, borderline renal insufficiency, CT contrast agent allergy), and pregnant patients. A positive finding in a patient with symptoms consistent with PE can be considered evidence for diagnosis of VTE disease and may preclude the need for additional diagnostic imaging in the emergency department (level B).

Imaging Guidelines

In its 2011 guidelines, the American College of Radiology (ACR) considers

multislice CT pulmonary angiography to be the standard of care for the detection of pulmonary embolism (PE). Additional recommendation include the following [69] :

• A chest radiograph cannot exclude or confirm PE, but it is important (as a complementary study) as it can guide further investigations and suggest alternative diagnoses.

• Any test that can confirm either deep venous thrombosis (DVT) (ie, lower-extremity venous duplex) or PE is sufficient. Only certain studies, however, have sufficient accuracy to exclude PE.

• Ventilation/perfusion (V/Q) scanning appears to have high overall accuracy.

• In pregnancy, with radiation a particular concern, the choice between perfusion scanning and CT pulmonary angiography depends on local equipment and expertise, as well as patient factors (normal chest radiograph, ability to breathhold).

Antithrombotic and Thrombolytic Therapy Guidelines

In 2016, the American College of Chest Physicians (ACCP) updated recommendations on 12 topics that were in the 9th edition of their Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis guidelines, and address three new topics. [111]

Key new or revised recommendations include the following:

• Dabigatran, rivaroxaban, apixaban, or edoxaban are preferred over vitamin K antagonist (VKA) therapy as long-term (first 3 months) anticoagulant therapy for noncancer patients (all grade 2B).

• Low-molecular-weight heparin (LMWH) is recommended over VKA therapy, dabigatran, rivaroxaban, apixaban, or edoxaban as long-term (first 3 months) anticoagulant therapy for patients with cancer-associated thrombosis (all grade 2C).

• Aspirin is recommended over no aspirin to prevent recurrent venous thromboembolism (VTE) in patients who are stopping anticoagulant therapy and do not have a contraindication to aspirin (grade 2B).

• In most patients with acute pulmonary embolism (PE) not associated with hypotension, systemically administered thrombolytic therapy is recommended against (grade 1B).

• In selected patients with acute PE who deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk, systemically administered thrombolytic therapy is preferred over no such therapy (grade 2C).

According to ACCP 9th edition guidelines, immediate therapeutic anticoagulation should be initiated for patients in whom deep venous thrombosis (DVT) or PE (grade 1B) is suspected. [5] Anticoagulation therapy reduces mortality rates from 30% to less than 10%. Diagnostic investigations should not delay empirical anticoagulant therapy in patients with high or intermediate risk of PE (grade 2C).

For acute PE, the ACCP guidelines recommend starting LMWH or fondaparinux, preferred over unfractionated heparin (UFH) (grade 2C for LMWH; grade 2B for fondaparinux) or subcutaneous heparin (grade 2B for LMWH; grade 2C for fondaparinux). [5] If patients are to be treated with LMWH, once-daily treatment is preferred to twice-daily treatment (grade 2C).

Patients who are considered to be low risk should be discharged early from hospital (grade 2B).

Patients should have an oral anticoagulant (warfarin) initiated at the time of diagnosis, and they should have UFH, LMWH, or fondaparinux discontinued only after the international normalized ratio (INR) is 2.0 for at least 24 hours but no sooner than 5 days after warfarin therapy has been started (grade 1B). The recommended duration of UFH, LMWH, and fondaparinux is based on evidence suggesting that the relatively long half-life of factor II, along with the short half-lives of protein C and protein S, may provoke a paradoxical hypercoagulable state if these agents are discontinued prematurely.

The ACCP guidelines for antithrombotic and thrombolytic therapy are summarized as follows [5] :

• Thrombolytic therapy should be used in patients with acute PE associated with hypotension (systolic BP < 90 mm Hg), who do not have a high bleeding risk (grade 2C).

• Thrombolytic therapy is suggested in select patients with acute PE not associated with hypotension and with a low bleeding risk whose initial clinical presentation or clinical course after starting anticoagulation suggests a high risk of developing hypotension (grade 2C).

• Assessment of PE severity, prognosis, and risk of bleeding dictates whether thrombolytic therapy should be started. Thrombolytic therapy is not recommended for most patients with acute PE not associated with hypotension (grade 1C).

• All patients with unprovoked PE receive 3 months of treatment with anticoagulation rather than a shorter duration of treatment, and they have an assessment of the risk-to-benefit ratio of extended therapy at the end of 3 months (grade 1B).

• Patients with a first episode of VTE and with a low or moderate risk of bleeding should have extended anticoagulant therapy (grade 2B). Patients with a first episode of VTE who have a high bleeding risk should have therapy limited to 3 months (grade 1B). In patients with a second unprovoked episode of VTE and low or moderate risk of bleeding, extended anticoagulant therapy is recommended (grades 1B and 2B, respectively). In patients with a second episode of VTE and a high risk of bleeding, 3 months of anticoagulation is preferred rather than extended anticoagulation (grade 2B).

• Patients who have PE and preexisting irreversible risk factors, such as deficiency of antithrombin III, proteins S and C, factor V Leiden mutation, or the presence of antiphospholipid antibodies, should be placed on long-term anticoagulation.

Guidelines on Advanced Therapies for Acute VTE

In 2011, guidelines to help emergency department and other physicians determine which patients with venous thromboembolism (VTE) should receive advanced therapies rather than simple anticoagulation were issued by the American Heart Association (AHA). [104] Recommendations for management of acute pulmonary embolism (PE) are as follows:

• Therapeutic anticoagulation with subcutaneous low-molecular-weight heparin (LMWH), intravenous or subcutaneous unfractionated heparin (UFH) with monitoring, unmonitored weight-based subcutaneous UFH, or subcutaneous fondaparinux should be given to patients with objectively confirmed PE and no contraindications to anticoagulation (class I).

• Therapeutic anticoagulation during the diagnostic workup should be given to patients with intermediate or high clinical probability of PE and no contraindications to anticoagulation (class I).

• Fibrinolysis is reasonable for patients with massive acute PE and acceptable risk of bleeding complications (class IIa).

• Fibrinolysis may be considered for patients with submassive acute PE judged to have clinical evidence of adverse prognosis (new hemodynamic instability, worsening respiratory insufficiency, severe right ventricular dysfunction, or major myocardial necrosis) and low risk of bleeding complications (class IIb).

• Fibrinolysis is not recommended for the following patients(class III): (1) Low-risk PE; (2) Submassive acute PE with minor right ventricular dysfunction, minor myocardial necrosis, and no clinical worsening; and (3) With undifferentiated cardiac arrest.

Recommendations for catheter-based interventions include the following:

• For patients with massive PE and contraindications to fibrinolysis, catheter embolectomy and fragmentation or surgical embolectomy is reasonable, depending on the expertise available (class IIa).

• For patients with massive PE who remain unstable after receiving fibrinolysis, catheter embolectomy and fragmentation or surgical embolectomy is reasonable (class IIa).

• For patients with massive PE who cannot receive fibrinolysis or who remain unstable after fibrinolysis, consider transfer to an institution experienced in either catheter embolectomy or surgical embolectomy if these procedures are not available and safe transfer can be achieved (class IIa).

• Either catheter embolectomy or surgical embolectomy may be considered for patients with submassive acute PE judged to have clinical evidence of adverse prognosis (new hemodynamic instability, worsening respiratory failure, severe right ventricular dysfunction, or major myocardial necrosis) (class IIb).

• Catheter embolectomy and surgical thrombectomy are not recommended for patients with low-risk PE or submassive acute PE with minor right ventricular dysfunction, minor myocardial necrosis, and no clinical worsening (class III).

Recommendations for use of vena cava filters include the following:

• Patients with confirmed acute PE (or proximal deep venous thrombosis [DVT]) with contraindications to anticoagulation or with active bleeding complications should receive an inferior vena cava (IVC) filter (class I).

• Anticoagulation should be resumed in patients with an IVC filter once contraindications to anticoagulation or active bleeding complications have resolved (class I).

• Patients who receive retrievable IVC filters should be evaluated periodically for filter retrieval within the specific filter’s retrieval window (class I).

• Placement of an IVC filter is reasonable for patients with recurrent acute PE despite therapeutic anticoagulation (class IIa).

• A permanent IVC filter device is reasonable for patients with a long-term contraindication to anticoagulation (class IIa).

• A retrievable IVC filter device is reasonable for patients with a short-term contraindication to anticoagulation therapy (class IIa).

• Placement of an IVC filter may be considered for patients with acute PE and very poor cardiopulmonary reserve, including those with massive PE (class IIb).

• An IVC filter should not be used routinely as an adjuvant to anticoagulation and systemic fibrinolysis in the treatment of acute PE (class III).

Pregnancy and Gynecological Surgery Guidelines

In 2011, the American College of Obstetricians and Gynecologists (ACOG) published a practice bulletin on the diagnosis, management, and prevention of thromboembolism during pregnancy. The key recommendations included the following [112] :

• Compression ultrasonography of the proximal veins is the recommended initial diagnostic test when signs or symptoms suggest new-onset deep veinous thrombosis (DVT) (level A).

• Women with a history of thrombosis who have not been thoroughly evaluated for possible underlying causes should receive testing for antiphospholipid antibodies, as well as for inherited thrombophilias (level C).

• Heparin compounds are preferred for anticoagulation (level B).

• Anticoagulation is recommended for women with acute thromboembolism during the current pregnancy or those at high risk of venous thromboembolism (VTE), such as women with mechanical heart valves (level C).

• In the last month of pregnancy, or sooner if delivery appears imminent, women receiving either therapeutic or prophylactic anticoagulation may be converted from low-molecular-weight heparin (LMWH) to unfractionated heparin (UFH), which has a shorter half-life (level C).

• Neuraxial blockade should be withheld for 10-12 hours after the last prophylactic dose of LMWH or 24 hours after the last therapeutic dose of LMWH (level C).

• For all women not already receiving thromboprophylaxis, placement of pneumatic compression devices before cesarean delivery is recommended. However, an emergency cesarean delivery should not be delayed for the placement of compression devices (level C).

• To minimize postpartum bleeding complications, a reasonable strategy is to resume anticoagulation therapy no sooner than 4-6 hours after vaginal delivery or 6-12 hours after cesarean delivery (level B).

• For women in whom restarting anticoagulation is planned after delivery, pneumatic compression devices should be left in place until the woman is ambulatory and anticoagulation therapy is resumed (level C).

• Warfarin, LMWH, and UFH are compatible with breastfeeding because they do not accumulate in breast milk and do not lead to anticoagulation in the infant (level B).

Anticoagulation Therapy Guidelines for VTE

The guidelines on optimal management of anticoagulation therapy for venous thromboembolism (VTE) were released on November 7, 2018, by the American Society of Hematology (ASH). [113]

Initial anticoagulant dose selection

In obese patients receiving low-molecular-weight heparin (LMWH) for treatment of acute VTE, it is suggested that initial LMWH dose selection be based on actual body weight rather than on a fixed maximum daily dose (ie, capped dose).

Drug-interaction management

For patients requiring administration of inhibitors or inducers of P-glycoprotein (P-gp) or strong inhibitors or inducers of cytochrome P450 (CYP) enzymes, it is suggested to use an alternative anticoagulant (eg, a vitamin K antagonist [VKA] or LMWH) rather than a direct oral anticoagulant (DOAC) to treat VTE.

Point-of-care INR testing

For patients receiving maintenance VKA therapy for VTE, home point-of-care international normalized ratio (INR) testing (patient self-testing [PST]) is suggested in preference to any other INR testing approach except patient self-management (PSM) in suitable patients (those who have demonstrated competency to perform PST and who can afford this option).

For patients receiving maintenance VKA therapy for VTE, point-of-care INR testing by the patient at home with self-adjustment of VKA dose (PSM) is suggested in preference to any other management approach, including PST in suitable patients (those who have demonstrated competency to perform PSM and who can afford this option).

Selecting the timing between INR measurements (INR recall interval)

For patients receiving VKA therapy for VTE, an INR recall interval of 4 weeks or less is suggested rather than an interval longer than 4 weeks after VKA dose adjustment due to an out-of-target-range INR.

For patients receiving maintenance VKA therapy for VTE, a longer (6-12 weeks) INR recall interval is suggested rather than a shorter (4 weeks) interval during periods of stable INR control.

Laboratory monitoring of anticoagulant response

For patients with renal dysfunction (creatinine clearance, < 30 mL/min) or obesity receiving LMWH therapy for VTE, it is suggested not to use anti–factor Xa concentration monitoring to guide LMWH dose adjustment.

For patients receiving DOAC therapy for VTE, it is suggested not to measure the DOAC anticoagulant effect during management of bleeding.

Transitions between anticoagulants

For patients transitioning from DOAC to VKA, overlapping DOAC and VKA therapy until the INR is within the therapeutic range is suggested in preference to LMWH or UFH “bridging therapy.”

Use of specialized AMS

For patients receiving anticoagulation therapy for VTE, specialized anticoagulation-management service (AMS) care is suggested in preference to care provided by the patient’s usual healthcare provider.

Structured patient education

For patients receiving oral anticoagulation therapy for VTE, supplementary patient education is suggested in addition to basic education.

Efforts to improve adherence to anticoagulant regimen

For patients receiving anticoagulation therapy for VTE, it is suggested not to use a daily lottery, electronic reminders, or a combination of the two to improve medication adherence. It is also suggested not to use visual medication schedules (provided to patients at each visit, along with brief counseling) to improve medication adherence.

Invasive procedure management

For patients at low-to-moderate risk for recurrent VTE who require interruption of VKA therapy for invasive procedures, VKA interruption alone is recommended in preference to periprocedural bridging with LMWH or UHF.

For patients interrupting DOAC therapy for scheduled invasive procedures, it is suggested not to perform laboratory testing for DOAC effect before procedures.

Excessive anticoagulation and bleeding management

For patients receiving VKA therapy for VTE with INR higher than 4.5 but lower than 10 and without clinically relevant bleeding, temporary cessation of VKA alone is suggested, without the addition of vitamin K.

For patients with life-threatening bleeding during VKA therapy for VTE and an elevated INR, use of four-factor prothrombin complex concentrates (PCCs) is suggested in preference to fresh frozen plasma (FFP) as an addition to cessation of VKA and IV vitamin K.

For patients with life-threatening bleeding during oral direct Xa inhibitor therapy for VTE, it is suggested to use either four-factor PCC administration as an addition to cessation of oral direct Xa inhibitor or cessation of oral direct Xa inhibitor alone.

For patients with life-threatening bleeding during oral direct Xa inhibitor therapy for VTE, it is suggested to use coagulation factor Xa (recombinant), inactivated-zhzo in addition to cessation of oral direct Xa inhibitor rather than no coagulation factor Xa (recombinant), inactivated-zhzo.

For patients with life-threatening bleeding during dabigatran therapy for VTE, it is suggested to use idarucizumab in addition to cessation of dabigatran rather than no idarucizumab.

For patients with life-threatening bleeding during LMWH or unfractionated heparin (UFH) therapy for VTE, it is suggested to use protamine in addition to LMWH/UFH cessation rather than no protamine.

Anticoagulant resumption following bleeding

For patients receiving anticoagulation therapy for VTE who survive an episode of major bleeding, resumption of oral anticoagulation therapy within 90 days is suggested in preference to discontinuance of oral anticoagulation therapy.

Medication Summary

Immediate therapeutic anticoagulation is initiated for patients with suspected deep venous thrombosis (DVT) or pulmonary embolism (PE). Anticoagulation therapy with heparin reduces mortality rates from 30% to less than 10%. Anticoagulation is essential, but anticoagulation alone does not guarantee a successful outcome. DVT and PE may recur or extend despite full and effective heparin anticoagulation.

Chronic anticoagulation is critical to prevent relapse of DVT or PE following initial heparinization. Heparin works by activating antithrombin III to slow or prevent the progression of DVT and to reduce the size and frequency of PE. Heparin does not dissolve existing clot.

Anticoagulants

Class Summary

Heparin augments the activity of antithrombin III and prevents the conversion of fibrinogen to fibrin. Full-dose LMWH or full-dose unfractionated IV heparin should be initiated at the first suspicion of DVT or PE.

With proper dosing, several LMWH products have been found safer and more effective than unfractionated heparin both for prophylaxis and for treatment of DVT and PE. Monitoring the aPTT is neither necessary nor useful when giving LMWH, because the drug is most active in a tissue phase and does not exert most of its effects on coagulation factor IIa.

Many different LMWH products are available around the world. Because of pharmacokinetic differences, dosing is highly product specific. Several LMWH products are approved for use in the United States: enoxaparin (Lovenox), dalteparin (Fragmin), and tinzaparin (Innohep). Enoxaparin and tinzaparin are currently approved by the FDA for treatment of DVT. Dalteparin is FDA approved for prophylaxis and has approval for cancer patients. Each of the other agents has been approved by the FDA at a lower dose for prophylaxis, but all appear to be safe and effective at some therapeutic dose in patients with active DVT or PE.

Fractionated LMWH administered subcutaneously is now the preferred choice for initial anticoagulation therapy. Unfractionated IV heparin can be nearly as effective but is more difficult to titrate for therapeutic effect. Warfarin maintenance therapy may be initiated after 1-3 days of effective heparinization.

The weight-adjusted heparin dosing regimens that are appropriate for prophylaxis and treatment of coronary artery thrombosis are too low to be used unmodified in the treatment of active DVT and PE. Coronary artery thrombosis does not result from hypercoagulability but rather from platelet adhesion to ruptured plaque. In contrast, patients with DVT and PE are in the midst of a hypercoagulable crisis, and aggressive countermeasures are essential to reduce mortality and morbidity rates.

Enoxaparin (Lovenox)

Exonaparin was the first low-molecular-weight heparin (LMWH) released in the United States. It was approved by the FDA for both treatment and prophylaxis of DVT and PE. Enoxaparin enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, it preferentially increases the inhibition of factor Xa. LMWH has been used widely in pregnancy, although clinical trials are not yet available to demonstrate that it is as safe as unfractionated heparin. Except in overdoses, checking PT or aPTT has no utility, as aPTT does not correlate with anticoagulant effect of fractionated LMWH. Factor Xa levels can be monitored if concern arises about whether the dose is adequate.

Dalteparin (Fragmin)

Dalteparin is an LMWH with many similarities to enoxaparin but with a different dosing schedule. It is approved for DVT prophylaxis in patients undergoing abdominal surgery. Except in overdoses, checking PT or aPTT has no utility, as aPTT does not correlate with anticoagulant effect of fractionated LMWH. LMWH. Factor Xa levels can be monitored if concern arises about whether the dose is adequate.

Tinzaparin (Innohep)

Tinzaparin is approved for treatment of DVT in hospitalized patients. Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa.

Heparin (Hep-Lock U/P, Hep-Lock, Hep-Flush-10)

Heparin augments the activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. Heparin prevents the reaccumulation of a clot after spontaneous fibrinolysis. When UFH is used, the aPTT should not be checked until 6 hours after the initial heparin bolus, because an extremely high or low value during this time should not provoke any action

Warfarin (Coumadin, Jantoven)

Warfarin (Coumadin) interferes with the hepatic synthesis of vitamin K–dependent coagulation factors. It is used for the prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Never administer warfarin to patients with thrombosis until after they have been fully anticoagulated with heparin (the first few days of warfarin therapy produce a hypercoagulable state). Failing to anticoagulate with heparin before starting warfarin causes clot extension and recurrent thromboembolism in approximately 40% of patients, compared with 8% of those who receive full-dose heparin before starting warfarin. Heparin should be continued for the first 5-7 days of oral warfarin therapy, regardless of the PT time, to allow time for depletion of procoagulant vitamin K–dependent proteins.

Tailor the warfarin dose to maintain an INR in the range of 2.5-3.5. The risk of serious bleeding (including hemorrhagic stroke) is approximately constant when the INR is 2.5-4.5 but rises dramatically when the INR is over 5. In the United Kingdom, a higher INR target of 3-4 often is recommended.

Evidence suggests that 6 months of anticoagulation reduces the rate of recurrence to half of the recurrence rate observed when only 6 weeks of anticoagulation is given. Long-term anticoagulation is indicated for patients with an irreversible underlying risk factor and recurrent DVT or recurrent pulmonary embolism.

Procoagulant vitamin K–dependent proteins are responsible for a transient hypercoagulable state when warfarin is first started and stopped. This is the phenomenon that occasionally causes warfarin-induced necrosis of large areas of skin or of distal appendages. Heparin is always used to protect against this hypercoagulability when warfarin is started; when warfarin is stopped, however, the problem resurfaces, causing an abrupt, temporary rise in the rate of recurrent venous thromboembolism.

At least 186 different foods and drugs reportedly interact with warfarin. Clinically significant interactions have been verified for a total of 26 common drugs and foods, including 6 antibiotics and 5 cardiac drugs. Every effort should be made to keep the patient adequately anticoagulated at all times, because procoagulant factors recover first when warfarin therapy is inadequate.

Patients who have difficulty maintaining adequate anticoagulation while taking warfarin may be asked to limit their intake of foods that contain vitamin K.

Foods that have moderate to high amounts of vitamin K include Brussels sprouts, kale, green tea, asparagus, avocado, broccoli, cabbage, cauliflower, collard greens, liver, soybean oil, soybeans, certain beans, mustard greens, peas (black-eyed peas, split peas, chick peas), turnip greens, parsley, green onions, spinach, and lettuce.

Fondaparinux sodium (Arixtra)

Fondaparinux sodium is a synthetic anticoagulant that works by inhibiting factor Xa, a key component involved in blood clotting. It provides a highly predictable response and has a bioavailability of 100%. The drug has a rapid onset of action and a half-life of 14-16 hours, allowing for sustained antithrombotic activity over a 24-hour period. Fondaparinux sodium does not affect prothrombin time or activated partial thromboplastin time, nor does it affect platelet function or aggregation.

Thrombolytics

Class Summary

Thrombolysis is indicated for hemodynamically unstable patients with pulmonary embolism. Thrombolysis dramatically improves acute cor pulmonale. Thrombolytic therapy has replaced surgical embolectomy as the treatment for hemodynamically unstable patients with massive pulmonary embolism.

Fibrinolytic regimens currently in common use for pulmonary embolism include two forms of recombinant tPA, alteplase and reteplase. Alteplase usually is given as a front-loaded infusion over 90 or 120 minutes. Reteplase is a new-generation thrombolytic with a longer half-life; it is given as a single bolus or as 2 boluses administered 30 minutes apart.

The faster-acting agents reteplase and alteplase are preferred for patients with pulmonary embolism, because the condition of patients with pulmonary embolism can deteriorate extremely rapidly.

Many comparative clinical studies have shown that administration of a 2-hour infusion of alteplase is more effective (and more rapidly effective) than urokinase or streptokinase (both discontinued by the FDA) over a 12-hour period. One prospective, randomized study comparing reteplase and alteplase found that total pulmonary resistance (along with pulmonary artery pressure and cardiac index) improved significantly after just one half hour in the reteplase group as compared with 2 hours in the alteplase group. Fibrinolytic agents do not seem to differ significantly with respect to safety or overall efficacy.

Empiric thrombolysis may be indicated in selected hemodynamically unstable patients, particularly when the clinical likelihood of pulmonary embolism is overwhelming and the patient's condition is deteriorating. The overall risk of severe complications from thrombolysis is low and the potential benefit in a deteriorating patient with pulmonary embolism is high. Empiric therapy especially is indicated when a patient is compromised so severely that he or she will not survive long enough to obtain a confirmatory study. Empiric thrombolysis should be reserved, however, for cases that truly meet these definitions, as many other clinical entities (including aortic dissection) may masquerade as pulmonary embolism, yet may not benefit from thrombolysis in any way.

Newborns may be relatively resistant to thrombolytics because of their lack of fibrinogen activity.

Reteplase (Retavase)

Reteplase is a second-generation recombinant tissue plasminogen activator (recombinant tPA) that forms plasmin after facilitating cleavage of endogenous plasminogen. In clinical trials, reteplase has been shown to be comparable to the recombinant tPA alteplase in achieving TIMI, 2 or 3 patency, at 90 minutes. Reteplase is given as a single bolus or as 2 boluses administered 30 minutes apart.

As a fibrinolytic agent, reteplase seems to work faster than its forerunner, alteplase, and may be more effective in patients with larger clot burdens. It has also been reported to be more effective than other agents in lysis of older clots. Two major differences help to explain these improvements. Because reteplase does not bind fibrin as tightly as does alteplase, this allows reteplase drug to diffuse more freely through the clot. Another advantage seems to be that reteplase does not compete with plasminogen for fibrin-binding sites, allowing plasminogen at the site of the clot to be transformed into clot-dissolving plasmin.

The FDA has not approved reteplase for administration to patients with pulmonary embolism. Studies of the drug's use for pulmonary embolism have employed the same dose approved by the FDA for coronary artery fibrinolysis.

Alteplase (Activase, Cathflo Activase)

Alteplase, a recombinant tPA, is used in the management of acute myocardial infarction (AMI), acute ischemic stroke, and pulmonary embolism. Alteplase is most often used to treat patients with pulmonary embolism in the ED. It is usually given as a front-loaded infusion over 90-120 minutes. It is FDA approved for this indication. Most ED personnel are familiar with alteplase's use, because it is widely employed in the treatment of patients with AMI. An accelerated 90-minute regimen is widely used, and most believe it is safer and more effective than the approved 2-hour infusion. An accelerated-regimen dose is based on patient weight.

Heparin therapy should be instituted or reinstituted near the end of or immediately following infusion, when the aPTT or thrombin time returns to twice normal or less.

Direct Thrombin Inhibitors and Factor Xa Inhibitors

Class Summary

Factor Xa inhibitors inhibit platelet activation by selectively blocking the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity. Direct thrombin inhibitors prevents thrombus development through direct, competitive inhibition of thrombin, thus blocking the conversion of fibrinogen to fibrin during the coagulation cascade.

Rivaroxaban (Xarelto)

Indicated for treatment of PE and for prevention of recurrence (following initial 6 months of treatment).

Apixaban (Eliquis)

Indicated for treatment of PE and for prevention of recurrence (following initial 6 months of treatment).

Dabigatran (Pradaxa)

Dabigatran is indicated for treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for 5-10 days. It is also indicated to reduce the risk of recurrence of DVT and PE in patients who have been previously treated.

Edoxaban (Savaysa)

Edoxaban is a factor Xa inhibitor indicated for treatment of DVT and PE in patients who have been initially treated with a parenteral anticoagulant for 5-10 days.

Betrixaban (Bevyxxa)

Betrixaban is indicated for prophylaxis of venous thromboembolism (VTE) in adults hospitalized for acute medical illness who are at risk for thromboembolic complications owing to moderate or severe restricted mobility and other risk factors that may cause VTE.

Prognosis

The prognosis of patients with pulmonary embolism depends on 2 factors: the underlying disease state and appropriate diagnosis and treatment. Approximately 10% of patients who develop pulmonary embolism die within the first hour, and 30% die subsequently from recurrent embolism. Mortality for acute pulmonary embolism can be broken down into 2 categories: massive pulmonary embolism and nonmassive pulmonary embolism.

Anticoagulant treatment decreases mortality to less than 5%. At 5 days of anticoagulant therapy, 36% of lung scan defects are resolved; at 2 weeks, 52% are resolved; and at 3 months, 73% are resolved. Most patients treated with anticoagulants do not develop long-term sequelae upon follow-up evaluation. The mortality in patients with undiagnosed pulmonary embolism is 30%.

In the PIOPED study, the 1-year mortality rate was 24%. [35] The deaths occurred due to cardiac disease, recurrent pulmonary embolism, infection, and cancer.

The risk of recurrent pulmonary embolism is due to the recurrence of proximal venous thrombosis; approximately 17% of patients with recurrent pulmonary embolism were found to have proximal DVT. In a small proportion of patients, pulmonary embolism does not resolve; hence, chronic thromboembolic pulmonary arterial hypertension results.

Elevated plasma levels of natriuretic peptides (brain natriuretic peptide and N -terminal pro-brain natriuretic peptide) have been associated with higher mortality in patients with pulmonary embolism. [36] In one study, levels of N -terminal pro-brain natriuretic peptide greater than 500 ng/L were independently associated with central pulmonary embolism and were a possible predictor of death from pulmonary embolism. [37]

In a study of 270 adult patients with symptomatic pulmonary embolism that was objectively confirmed, researchers found that elevated plasma lactate levels (≥2 mmol/L) were associated with an increased risk of mortality and other adverse outcomes, independent of shock, hypotension, right-sided ventricular dysfunction, or injury markers. [38]

Massive pulmonary embolism

As a cause of sudden death, massive pulmonary embolism is second only to sudden cardiac death. Massive pulmonary embolism is defined as presenting with a systolic arterial pressure less than 90 mm Hg. The mortality for patients with massive pulmonary embolism is between 30% and 60%, depending on the study cited. [25, 39, 40] Autopsy studies of patients who died unexpectedly in a hospital setting have shown approximately 80% of these patients died from massive pulmonary embolism.

The majority of deaths from massive pulmonary embolism occur in the first 1-2 hours of care, so it is important for the initial treating physician to have a systemized, aggressive evaluation and treatment plan for patients presenting with pulmonary embolism.

Nonmassive pulmonary embolism

Nonmassive pulmonary embolism is defined as having a systolic arterial pressure greater than or equal to 90 mm Hg. This is the more common presentation for pulmonary embolism and accounts for 95.5-96% of the patients. [39, 41]

Hemodynamically stabile pulmonary embolism has a much lower mortality rate because of treatment with anticoagulant therapy. In nonmassive pulmonary embolism, the death rate is less than 5% in the first 3-6 months of anticoagulant treatment. The rate of recurrent thromboembolism is less than 5% during this time. However, recurrent thromboembolism reaches 30% after 10 years. [30]

Patient Education

The importance of adherence to the treatment regimen should be repeatedly stressed. The patient should be instructed regarding what to do in the event of any bleeding complications. Because most patients are administered warfarin or low molecular weight heparin upon discharge from the hospital, they must be advised regarding potential interactions between these agents and other medications.

For patient education resources, see the patient education articles Pulmonary Embolism and Blood Clot in the Legs.

References

1. Amesquita M, Cocchi MN, Donnino MW. Pulmonary Embolism Presenting as Flank Pain: A Case Series. J Emerg Med. 2009 Mar 26. [Medline].

2. Carrascosa MF, Batán AM, Novo MF. Delirium and pulmonary embolism in the elderly. Mayo Clin Proc. 2009. 84(1):91-2. [Medline]. [Full Text].

3. Tapson VF. Acute pulmonary embolism. N Engl J Med. 2008 Mar 6. 358(10):1037-52. [Medline].

4. [Guideline] Qaseem A, Snow V, Barry P, Hornbake ER, Rodnick JE, Tobolic T, et al. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med. 2007 Jan-Feb. 5 (1):57-62. [Medline]. [Full Text].

5. [Guideline] Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ, American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb. 141 (2 Suppl):7S-47S. [Medline].

6. Ozsu S, Oztuna F, Bulbul Y, et al. The role of risk factors in delayed diagnosis of pulmonary embolism. Am J Emerg Med. 2011 Jan. 29(1):26-32. [Medline].

7. Kline JA, Runyon MS. Pulmonary embolism and deep venous thrombosis. In: Marx JA, Hockenberger RS, Walls RM, eds. Rosen's Emergency Medicine Concepts and Clinical Practice. 6th ed. 1368-1382. Vol 2.:

8. Boyden EA. Segmental Anatomy of the Lungs: Study of the Patterns of the Segmental Bronchi and Related Pulmonary Vessels. New York, NY: McGraw-Hill; 1955:. 23-32.

9. Mitchell RN, Kumar V. Hemodynamic disorders, thrombosis, and shock. In: Kumar V, Cotran RS, Robbins SL, eds. Basic Pathology. 6th ed. Philadelphia, Pa: WB Saunders; 1997:. 60-80.

10. Wharton LR, Pierson JW. JAMA. Minor forms of pulmonary embolism after abdominal operations.

11. Malek J, Rogers R, Kufera J, Hirshon JM. Venous thromboembolic disease in the HIV-infected patient. Am J Emerg Med. 2011 Mar. 29(3):278-82. [Medline].

12. Geerts WH, Code KI, Jay RM, Chen E, Szalai JP. A prospective study of venous thromboembolism after major trauma. N Engl J Med. 1994 Dec 15. 331(24):1601-6. [Medline].

13. van den Heuvel-Eibrink MM, Lankhorst B, Egeler RM, Corel LJ, Kollen WJ. Sudden death due to pulmonary embolism as presenting symptom of renal tumors. Pediatr Blood Cancer. 2008 May. 50(5):1062-4. [Medline].

14. Arzt M, Luigart R, Schum C, Lüthje L, Stein A, Koper I, et al. Sleep-disordered breathing in deep vein thrombosis and acute pulmonary embolism. Eur Respir J. 2012 Oct. 40(4):919-24. [Medline].

15. Stein PD, Beemath A, Matta F, Weg JG, Yusen RD, Hales CA, et al. Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. Am J Med. 2007 Oct. 120(10):871-9. [Medline]. [Full Text].

16. David M, Andrew M. Venous thromboembolic complications in children. J Pediatr. 1993 Sep. 123(3):337-46. [Medline].

17. Biss TT, Brandão LR, Kahr WH, Chan AK, Williams S. Clinical features and outcome of pulmonary embolism in children. Br J Haematol. 2008 Sep. 142(5):808-18. [Medline].

18. Nuss R, Hays T, Chudgar U, Manco-Johnson M. Antiphospholipid antibodies and coagulation regulatory protein abnormalities in children with pulmonary emboli. J Pediatr Hematol Oncol. 1997 May-Jun. 19(3):202-7. [Medline].

19. Dollery CM. Pulmonary embolism in parenteral nutrition. Arch Dis Child. 1996 Feb. 74(2):95-8. [Medline]. [Full Text].

20. Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979-1998: an analysis using multiple-cause mortality data. Arch Intern Med. 2003 Jul 28. 163(14):1711-7. [Medline].

21. Burge AJ, Freeman KD, Klapper PJ, Haramati LB. Increased diagnosis of pulmonary embolism without a corresponding decline in mortality during the CT era. Clin Radiol. 2008 Apr. 63(4):381-6. [Medline].

22. DeMonaco NA, Dang Q, Kapoor WN, Ragni MV. Pulmonary embolism incidence is increasing with use of spiral computed tomography. Am J Med. 2008 Jul. 121(7):611-7. [Medline]. [Full Text].

23. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ 3rd. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998 Mar 23. 158(6):585-93. [Medline].

24. Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol. 2008 Mar. 28(3):370-2. [Medline]. [Full Text].

25. Sandler DA, Martin JF. Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis?. J R Soc Med. 1989 Apr. 82(4):203-5. [Medline]. [Full Text].

26. Kotsakis A, Cook D, Griffith L, Anton N, Massicotte P, MacFarland K, et al. Clinically important venous thromboembolism in pediatric critical care: a Canadian survey. J Crit Care. 2005 Dec. 20(4):373-80. [Medline].

27. Van Ommen CH, Peters M. Acute pulmonary embolism in childhood. Thromb Res. 2006. 118(1):13-25. [Medline].

28. Kabrhel C, Varraso R, Goldhaber SZ, Rimm E, Camargo CA Jr. Physical inactivity and idiopathic pulmonary embolism in women: prospective study. BMJ. 2011 Jul 4. 343:d3867. [Medline].

29. Schneider D, Lilienfeld DE, Im W. The epidemiology of pulmonary embolism: racial contrasts in incidence and in-hospital case fatality. J Natl Med Assoc. 2006 Dec. 98(12):1967-72. [Medline]. [Full Text].

30. Meyer G, Planquette B, Sanchez O. Long-term outcome of pulmonary embolism. Curr Opin Hematol. 2008 Sep. 15(5):499-503. [Medline].

31. Bernstein D, Coupey S, Schonberg SK. Pulmonary embolism in adolescents. Am J Dis Child. 1986 Jul. 140(7):667-71. [Medline].

32. Evans DA, Wilmott RW. Pulmonary embolism in children. Pediatr Clin North Am. 1994 Jun. 41(3):569-84. [Medline].

33. Rajpurkar M, Warrier I, Chitlur M, Sabo C, Frey MJ, Hollon W, et al. Pulmonary embolism-experience at a single children's hospital. Thromb Res. 2007. 119(6):699-703. [Medline].

34. Kuklina EV, Meikle SF, Jamieson DJ, Whiteman MK, Barfield WD, Hillis SD, et al. Severe obstetric morbidity in the United States: 1998-2005. Obstet Gynecol. 2009 Feb. 113(2 Pt 1):293-9. [Medline]. [Full Text].

35. Worsley DF, Alavi A. Comprehensive analysis of the results of the PIOPED Study. Prospective Investigation of Pulmonary Embolism Diagnosis Study. J Nucl Med. 1995 Dec. 36(12):2380-7. [Medline].

36. Cavallazzi R, Nair A, Vasu T, Marik PE. Natriuretic peptides in acute pulmonary embolism: a systematic review. Intensive Care Med. 2008 Dec. 34(12):2147-56. [Medline].

37. Alonso-Martínez JL, Urbieta-Echezarreta M, Anniccherico-Sánchez FJ, Abínzano-Guillén ML, Garcia-Sanchotena JL. N-terminal pro-B-type natriuretic peptide predicts the burden of pulmonary embolism. Am J Med Sci. 2009 Feb. 337(2):88-92. [Medline].

38. Vanni S, Viviani G, Baioni M, Pepe G, Nazerian P, Socci F, et al. Prognostic value of plasma lactate levels among patients with acute pulmonary embolism: the thrombo-embolism lactate outcome study. Ann Emerg Med. 2013 Mar. 61(3):330-8. [Medline].

39. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999 Apr 24. 353(9162):1386-9. [Medline].

40. Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest. 2002 Mar. 121(3):877-905. [Medline].

41. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation. 2006 Jan 31. 113(4):577-82. [Medline].

42. [Guideline] Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014 Nov 14. 35 (43):3033-69, 3069a-3069k. [Medline].

43. Vedovati MC, Becattini C, Agnelli G, Kamphuisen PW, Masotti L, Pruszczyk P, et al. MULTIDETECTOR COMPUTED TOMOGRAPHY FOR ACUTE PULMONARY EMBOLISM: EMBOLIC BURDEN AND CLINICAL OUTCOME. Chest. 2012 May 24. [Medline].

44. Restrepo CS, Artunduaga M, Carrillo JA, Rivera AL, Ojeda P, Martinez-Jimenez S, et al. Silicone pulmonary embolism: report of 10 cases and review of the literature. J Comput Assist Tomogr. 2009 Mar-Apr. 33(2):233-7. [Medline].

45. Vichinsky EP, Neumayr LD, Earles AN, Williams R, Lennette ET, Dean D, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000 Jun 22. 342(25):1855-65. [Medline].

46. Douma RA, Mos IC, Erkens PM, Nizet TA, Durian MF, Hovens MM, et al. Performance of 4 clinical decision rules in the diagnostic management of acute pulmonary embolism: a prospective cohort study. Ann Intern Med. 2011 Jun 7. 154(11):709-18. [Medline].

47. Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med. 2004 Apr 20. 140(8):589-602. [Medline].

48. Kearon C, Ginsberg JS, Douketis J, Turpie AG, Bates SM, Lee AY, et al. An evaluation of D-dimer in the diagnosis of pulmonary embolism: a randomized trial. Ann Intern Med. 2006 Jun 6. 144(11):812-21. [Medline].

49. Geersing GJ, Erkens PM, Lucassen WA, Büller HR, Cate HT, Hoes AW, et al. Safe exclusion of pulmonary embolism using the Wells rule and qualitative D-dimer testing in primary care: prospective cohort study. BMJ. 2012 Oct 4. 345:e6564. [Medline]. [Full Text].

50. Konstantinides S. Clinical practice. Acute pulmonary embolism. N Engl J Med. 2008 Dec 25. 359(26):2804-13. [Medline].

51. Kline JA, Hogg MM, Courtney DM, Miller CD, Jones AE, Smithline HA, et al. D-dimer and exhaled CO2/O2 to detect segmental pulmonary embolism in moderate-risk patients. Am J Respir Crit Care Med. 2010 Sep 1. 182(5):669-75. [Medline]. [Full Text].

52. Turedi S, Gunduz A, Mentese A, Topbas M, Karahan SC, Yeniocak S, et al. The value of ischemia-modified albumin compared with d-dimer in the diagnosis of pulmonary embolism. Respir Res. 2008 May 30. 9:49. [Medline]. [Full Text].

53. Tick LW, Nijkeuter M, Kramer MH, Hovens MM, Büller HR, Leebeek FW, et al. High D-dimer levels increase the likelihood of pulmonary embolism. J Intern Med. 2008 Aug. 264(2):195-200. [Medline].

54. Meyer T, Binder L, Hruska N, Luthe H, Buchwald AB. Cardiac troponin I elevation in acute pulmonary embolism is associated with right ventricular dysfunction. J Am Coll Cardiol. 2000 Nov 1. 36(5):1632-6. [Medline].

55. Jiménez D, Uresandi F, Otero R, Lobo JL, Monreal M, Martí D, et al. Troponin-based risk stratification of patients with acute nonmassive pulmonary embolism: systematic review and metaanalysis. Chest. 2009 Oct. 136(4):974-82. [Medline].

56. Becattini C, Vedovati MC, Agnelli G. Diagnosis and prognosis of acute pulmonary embolism: focus on serum troponins. Expert Rev Mol Diagn. 2008 May. 8(3):339-49. [Medline].

57. Kline JA, Zeitouni R, Marchick MR, Hernandez-Nino J, Rose GA. Comparison of 8 biomarkers for prediction of right ventricular hypokinesis 6 months after submassive pulmonary embolism. Am Heart J. 2008 Aug. 156(2):308-14. [Medline].

58. Aksay E, Yanturali S, Kiyan S. Can elevated troponin I levels predict complicated clinical course and inhospital mortality in patients with acute pulmonary embolism?. Am J Emerg Med. 2007 Feb. 25(2):138-43. [Medline].

59. Dellas C, Lankeit M, Reiner C, Schäfer K, Hasenfuß G, Konstantinides S. BMI-independent inverse relationship of plasma leptin levels with outcome in patients with acute pulmonary embolism. Int J Obes (Lond). 2012 Mar 20. [Medline].

60. Söhne M, Ten Wolde M, Boomsma F, Reitsma JB, Douketis JD, Büller HR. Brain natriuretic peptide in hemodynamically stable acute pulmonary embolism. J Thromb Haemost. 2006 Mar. 4(3):552-6. [Medline].

61. Kucher N, Printzen G, Goldhaber SZ. Prognostic role of brain natriuretic peptide in acute pulmonary embolism. Circulation. 2003 May 27. 107(20):2545-7. [Medline].

62. Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism: a systematic review and meta-analysis. Am J Respir Crit Care Med. 2008 Aug 15. 178(4):425-30. [Medline].

63. Scherz N, Labarère J, Méan M, Ibrahim SA, Fine MJ, Aujesky D. Prognostic importance of hyponatremia in patients with acute pulmonary embolism. Am J Respir Crit Care Med. 2010 Nov 1. 182(9):1178-83. [Medline]. [Full Text].

64. Ready T. Pulmonary Emboli Overdiagnosed by CT Angiography. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/807439. Accessed: July 15, 2013.

65. Wiener RS, Schwartz LM, Woloshin S. When a test is too good: how CT pulmonary angiograms find pulmonary emboli that do not need to be found. BMJ. 2013 Jul 2. 347:f3368. [Medline].

66. [Guideline] Remy-Jardin M, Pistolesi M, Goodman LR, Gefter WB, Gottschalk A, Mayo JR, et al. Management of suspected acute pulmonary embolism in the era of CT angiography: a statement from the Fleischner Society. Radiology. 2007 Nov. 245(2):315-29. [Medline].

67. Patel S, Kazerooni EA. Helical CT for the evaluation of acute pulmonary embolism. AJR Am J Roentgenol. 2005 Jul. 185(1):135-49. [Medline].

68. Stein PD, Woodard PK, Weg JG, Wakefield TW, Tapson VF, Sostman HD, et al. Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II Investigators. Radiology. 2007 Jan. 242(1):15-21. [Medline].

69. [Guideline] Bettmann MA, Baginski SG, White RD, Woodard PK, Abbara S, Atalay MK, et al. ACR Appropriateness Criteria® acute chest pain--suspected pulmonary embolism. J Thorac Imaging. 2012 Mar. 27 (2):W28-31. [Medline].

70. Ward MJ, Sodickson A, Diercks DB, Raja AS. Cost-effectiveness of lower extremity compression ultrasound in emergency department patients with a high risk of hemodynamically stable pulmonary embolism. Acad Emerg Med. 2011 Jan. 18(1):22-31. [Medline].

71. Drescher FS, Chandrika S, Weir ID, et al. Effectiveness and acceptability of a computerized decision support system using modified Wells criteria for evaluation of suspected pulmonary embolism. Ann Emerg Med. 2011 Jun. 57(6):613-21. [Medline].

72. Remy-Jardin M, Remy J, Deschildre F, Artaud D, Beregi JP, Hossein-Foucher C, et al. Diagnosis of pulmonary embolism with spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology. 1996 Sep. 200(3):699-706. [Medline].

73. Becattini C, Agnelli G, Vedovati MC, et al. Multidetector computed tomography for acute pulmonary embolism: diagnosis and risk stratification in a single test. Eur Heart J. 2011 Jul. 32(13):1657-63. [Medline].

74. Henzler T, Roeger S, Meyer M, Schoepf UJ, Nance JW Jr, Haghi D, et al. Pulmonary embolism: CT signs and cardiac biomarkers for predicting right ventricular dysfunction. Eur Respir J. 2012 Apr. 39(4):919-26. [Medline].

75. Gottschalk A, Stein PD, Sostman HD, Matta F, Beemath A. Very low probability interpretation of V/Q lung scans in combination with low probability objective clinical assessment reliably excludes pulmonary embolism: data from PIOPED II. J Nucl Med. 2007 Sep. 48(9):1411-5. [Medline].

76. Gupta A, Frazer CK, Ferguson JM, Kumar AB, Davis SJ, Fallon MJ, et al. Acute pulmonary embolism: diagnosis with MR angiography. Radiology. 1999 Feb. 210(2):353-9. [Medline].

77. Meaney JF, Weg JG, Chenevert TL, Stafford-Johnson D, Hamilton BH, Prince MR. Diagnosis of pulmonary embolism with magnetic resonance angiography. N Engl J Med. 1997 May 15. 336(20):1422-7. [Medline].

78. Vanni S, Polidori G, Vergara R, Pepe G, Nazerian P, Moroni F, et al. Prognostic value of ECG among patients with acute pulmonary embolism and normal blood pressure. Am J Med. 2009 Mar. 122(3):257-64. [Medline].

79. Boggs W. Bedside Echo Could Facilitate ER Diagnosis of Pulmonary Embolism. Medscape Medical News. Available at http://www.medscape.com/viewarticle/812942. Accessed: October 28, 2013.

80. Dresden S, Mitchell P, Rahimi L, Leo M, Rubin-Smith J, Bibi S, et al. Right Ventricular Dilatation on Bedside Echocardiography Performed by Emergency Physicians Aids in the Diagnosis of Pulmonary Embolism. Ann Emerg Med. 2013 Sep 23. [Medline].

81. Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. Am J Med. 2012 May. 125(5):465-70. [Medline].

82. Stein PD, Matta F, Keyes DC, Willyerd GL. Impact of Vena Cava Filters on In-hospital Case Fatality Rate from Pulmonary Embolism. Am J Med. 2012 May. 125(5):478-84. [Medline].

83. Chatterjee S, Chakraborty A, Weinberg I, Kadakia M, Wilensky RL, Sardar P, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014 Jun 18. 311(23):2414-21. [Medline].

84. Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10. 370(15):1402-11. [Medline].

85. Elliott CG. Fibrinolysis of pulmonary emboli--steer closer to Scylla. N Engl J Med. 2014 Apr 10. 370(15):1457-8. [Medline].

86. Barclay L. Fibrinolysis for Pulmonary Embolism Effective but Risky. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/823427. Accessed: April 19, 2014.

87. Aujesky D, Roy PM, Verschuren F, et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. Lancet. 2011 Jul 2. 378(9785):41-8. [Medline].

88. Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5. 366(14):1287-97. [Medline].

89. Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23. 363(26):2499-510. [Medline]. [Full Text].

90. Cohen AT, Dobromirski M. The use of rivaroxaban for short- and long-term treatment of venous thromboembolism. Thromb Haemost. 2012 Jun. 107(6):1035-43. [Medline].

91. Romualdi E, Donadini MP, Ageno W. Oral rivaroxaban after symptomatic venous thromboembolism: the continued treatment study (EINSTEIN-extension study). Expert Rev Cardiovasc Ther. 2011 Jul. 9(7):841-4. [Medline].

92. Hughes S. Rivaroxaban Stands up to standard anticoagulation for VTE treatment. Medscape Medical News. December 13, 2012. [Full Text].

93. Buller HR, on behalf of the EINSTEIN Investigators. Oral rivaroxaban for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies [abstract 20]. Presented at: 54th Annual Meeting and Exposition of the American Society of Hematology; December 8, 2012; Atlanta, Ga. [Full Text].

94. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29. 369(9):799-808. [Medline]. [Full Text].

95. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21. 368(8):699-708. [Medline]. [Full Text].

96. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10. 361(24):2342-52. [Medline]. [Full Text].

97. Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18. 129(7):764-72. [Medline].

98. Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10. 369(15):1406-15. [Medline]. [Full Text].

99. Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, et al. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med. 2016 Aug 11. 375 (6):534-44. [Medline]. [Full Text].

100. Gibson CM, Chi G, Halaby R, Korjian S, Daaboul Y, Jain P, et al. Extended-Duration Betrixaban Reduces the Risk of Stroke Versus Standard-Dose Enoxaparin Among Hospitalized Medically Ill Patients: An APEX Trial Substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban). Circulation. 2017 Feb 14. 135 (7):648-655. [Medline].

101. Garcia D, Ageno W, Libby E. Update on the diagnosis and management of pulmonary embolism. Br J Haematol. 2005 Nov. 131(3):301-12. [Medline].

102. Campbell IA, Bentley DP, Prescott RJ, Routledge PA, Shetty HG, Williamson IJ. Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. BMJ. 2007 Mar 31. 334(7595):674. [Medline]. [Full Text].

103. Pinede L, Ninet J, Duhaut P, Chabaud S, Demolombe-Rague S, Durieu I, et al. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation. 2001 May 22. 103(20):2453-60. [Medline].

104. Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ, et al. Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension: A Scientific Statement From the American Heart Association. Circulation. 2011 Apr 26. 123(16):1788-1830. [Medline]. [Full Text].

105. Ballew KA, Philbrick JT, Becker DM. Vena cava filter devices. Clin Chest Med. 1995 Jun. 16(2):295-305. [Medline].

106. Dempfle CE, Elmas E, Link A, et al. Endogenous plasma activated protein C levels and the effect of enoxaparin and drotrecogin alfa (activated) on markers of coagulation activation and fibrinolysis in pulmonary embolism. Crit Care. 2011 Jan 17. 15(1):R23. [Medline].

107. Boutitie F, Pinede L, Schulman S, Agnelli G, Raskob G, Julian J, et al. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials. BMJ. 2011 May 24. 342:d3036. [Medline]. [Full Text].

108. Hippisley-Cox J, Coupland C. Development and validation of risk prediction algorithm (QThrombosis) to estimate future risk of venous thromboembolism: prospective cohort study. BMJ. 2011 Aug 16. 343:d4656. [Medline]. [Full Text].

109. [Guideline] Raja AS, Greenberg JO, Qaseem A, Denberg TD, Fitterman N, Schuur JD, et al. Evaluation of Patients With Suspected Acute Pulmonary Embolism: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med. 2015 Nov 3. 163 (9):701-11. [Medline].

110. [Guideline] Fesmire FM, Brown MD, Espinosa JA, Shih RD, Silvers SM, Wolf SJ, et al. Critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected pulmonary embolism. Ann Emerg Med. 2011 Jun. 57 (6):628-652.e75. [Medline].

111. [Guideline] Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb. 149 (2):315-52. [Medline].

112. [Guideline] James A, Committee on Practice Bulletins—Obstetrics. Practice bulletin no. 123: thromboembolism in pregnancy. Obstet Gynecol. 2011 Sep. 118 (3):718-29. [Medline].

113. [Guideline] Witt DM, Nieuwlaat R, Clark NP, Ansell J, Holbrook A, Skov J, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018 Nov 27. 2 (22):3257-3291. [Medline].

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