Pulmonary Embolism

Key points

• Pulmonary embolism usually is caused by a thrombus in the proximal deep veins of the leg that breaks off and lodges in the lung
• Patients may be asymptomatic or may present with typical symptoms, including dyspnea and chest pain. Patients with massive pulmonary embolism may present with hypotension, shock, or sudden death
• An integrated diagnostic approach involving clinical prediction rules and noninvasive testing can be used to evaluate patients in whom pulmonary embolism is suspected. Clinical prediction rules stratify patients into low, moderate, or high pretest probability of pulmonary embolism categories, which, in turn, helps to determine the need for further diagnostic testing
• The aggressiveness of treatment is dependent on the severity of pulmonary embolism. Treatment of nonmassive pulmonary embolism involves rapid initiation of anticoagulant therapy. Thrombolysis is indicated in patients who are hemodynamically unstable (massive pulmonary embolism). Surgical or angiographic embolectomy only should be done in experienced institutions
• Prevention of deep vein thrombosis (DVT) in hospitalized patients is crucial to preventing pulmonary embolism

Background

Description

• Pulmonary embolism is an abrupt blockage of a pulmonary artery or one of its branches, most commonly by a thrombus that arises in the deep veins of the lower extremities
• Together, pulmonary embolism and DVT are known as venous thromboembolism (VTE)
• VTE frequently develops in patients with one or more components of Virchow triad:
  • Venous stasis, which can result from immobilization, congestive heart failure, and lesions impinging on a deep vein
  • Hypercoagulability of the blood, which can result from inherited defects in coagulation or fibrinolysis (thrombophilia) or acquired factors (eg, cancer, pregnancy, or use of oral contraceptives or hormone therapy)
  • Endothelial injury, which can arise from trauma, surgical procedures, or vascular disruption from catheter insertion or placement
• Pulmonary embolism may be provoked (ie, associated with thrombotic risk factors, such as surgery, significant immobility, cancer, or pregnancy) or unprovoked (idiopathic)
• Dyspnea is the most frequent symptom, and tachypnea is the most frequent sign
• Establishing the diagnosis can be difficult because the signs and symptoms of pulmonary embolism are nonspecific; more than 50% of pulmonary emboli are diagnosed postmortem

Epidemiology

Incidence and prevalence:

• Accurate epidemiologic data are difficult to obtain because most pulmonary emboli are detected on autopsy. However, it is estimated that pulmonary embolism occurs in 300,000 to 650,000 patients in the U.S. each year
• The annual incidence of VTE is approximately 1 in 1,000 persons

Demographics:

• Incidence of VTE increases with age
• Initial pulmonary embolism occurs equally in male and female patients, but recurrent pulmonary embolism appears to be more common in male patients
• Patients may have inherited causes of hypercoagulability that predispose them to the development of VTE

Causes and risk factors

Causes

VTE is the result of an imbalance between prothrombotic factors, which include the elements of Virchow triad (stasis, hypercoagulability, and endothelial damage), and antithrombotic factors, which include coagulation factor inhibitors, natural anticoagulants, and activation of the fibrinolytic pathway.

Risk factors

Hereditary factors:

• Inherited deficiencies of natural anticoagulants, including antithrombin III deficiency, protein C deficiency, and protein S deficiency
• Inherited resistance to inhibitors of coagulation, including factor V Leiden mutation (activated protein C resistance)
• Inherited defects resulting in increased levels of coagulation factors, including prothrombin gene mutation and increased levels of factors VIII, IX, and XII
• Inherited defects in the fibrinolytic pathway, including plasminogen defect or abnormality, plasminogen activator defect or abnormality, fibrinogen abnormality/dysfibrinogenemia, and factor XIII 34Val polymorphism

Acquired factors:

• Immobilization or paralysis, such as that due to non–weight-bearing lower extremity fractures, medical illnesses resulting in decreased mobility or confinement to bed, or prolonged travel
• Major surgery/trauma
• Central venous catheters
• Obesity
• Malignant disease or cancer chemotherapy
• Use of oral contraceptives or hormone therapy
• Pregnancy
• Advanced age
• Medical illnesses, such as paroxysmal nocturnal hemoglobinuria, myeloproliferative disorders, systemic lupus erythematosus, antiphospholipid antibody syndrome, ulcerative colitis, and Behçet syndrome

Mixed or unknown factors:

• High levels of factor VIII, IX, XI, fibrinogen, or plasminogen activator
• Activated protein C resistance in the absence of factor V Leiden mutation
• Hyperhomocysteinemia
• Elevated levels of lipoprotein(a)
• Low levels of tissue factor pathway inhibitor

Screening

Not applicable.

Primary prevention

Summary approach

• Prevention is vital because pulmonary embolism can result in considerable morbidity and mortality
• Hospitalization with decreased mobility is one of the most common risk factors
• Medical and surgical inpatients should be assessed for the risk of DVT and pulmonary embolism and managed according to individual risk
• The 2012 American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis provide general recommendations regarding primary prevention of VTE as well as recommendations specific to patients undergoing general surgery, vascular surgery, gynecologic surgery, urologic surgery, laparoscopic surgery, orthopedic surgery, elective spine surgery, or neurosurgery; patients sustaining lower-extremity injuries, trauma, acute spinal cord injury, or burns; patients with cancer or other acutely or critically ill patients; and long-distance travelers
• The ACCP guidelines also recommend that the risk of DVT and pulmonary embolism be assessed in medical patients using a validated scoring system (ie, Padua Prediction Score). Patients at high risk should receive pharmacologic prophylaxis

Population at risk

Patients at increased risk for VTE, including those with inherited, acquired, or mixed/unknown risk factors.

Preventive measures

• Prolonged periods of immobilization resulting in venous stasis should be avoided
• Tobacco use contributes to vascular disease and is associated with an increased risk of DVT and pulmonary embolism in women taking oral contraceptives
• Alcohol use should be limited in patients receiving anticoagulant therapy and may need to be avoided in patients with erratic anticoagulant control
• Women taking oral contraceptives who are at risk for VTE should be advised to consider other nonhormonal forms of contraception; consultation with a specialist may be considered in the setting of pregnancy
• Obesity/excess weight should be avoided
• Thromboprophylaxis should be used in high-risk patients. The Padua Prediction Score, a prospectively validated risk assessment model for hospitalized medical patients provides a means of risk assessment
  • Weighted values are assigned to 11 known risk factors for VTE in hospitalized patients, and a score then is assigned using the weighted risk factors
  • Patients with a score of less than 4 are considered low risk, and those with a score of 4 or higher are considered high risk
• In high-risk patients, pharmacologic prophylaxis with a low-molecular-weight heparin (LMWH), low-dose unfractionated heparin, or fondaparinux should be considered
• The need for thromboprophylaxis in low-risk patients is less clear. In one meta-analysis, the risk reduction for DVT was 34 fewer cases of symptomatic DVT per 1,000 high-risk patients but only 1 fewer symptomatic DVT per 1,000 low-risk patients. The effect on major bleeding, all-cause mortality, and nonfatal pulmonary embolism was not statistically significant, although other studies found increased major bleeding in patients receiving pharmacologic prophylaxis

Evidence

• A systematic review of 40 trials evaluated the effectiveness and safety of the most commonly used pharmacologic prophylaxis (low-dose heparins) and mechanical prophylaxis in more than 52,000 nonsurgical patients who were presumed to be at increased risk for VTE and at low risk of bleeding. Trials included in the analysis did not necessarily use a validated risk assessment model for the identification of patients at high risk for VTE. Heparin prophylaxis provided no benefit in terms of total mortality or mortality caused by pulmonary embolism at 120 days and no significant reduction in the number of patients with symptomatic DVT compared to placebo. Heparin prophylaxis was associated with an absolute reduction of three pulmonary emboli per 1,000 patients but also with an absolute increase of nine bleeding events per 1,000 patients, four of which were major bleeding events. No important differences in outcome were observed in the 14 trials that compared unfractionated heparin to LMWH. Also, no benefits were observed in the three trials evaluating mechanical prophylaxis, although there was a fourfold increase in lower extremity skin damage.[1]Level of evidence: 1

Systematic reviews and meta-analyses have found that LMWHs are effective in preventing VTE in patients undergoing surgical procedures.

• A meta-analysis of randomized, controlled trials (RCTs) comparing LMWH versus placebo or no treatment for VTE prophylaxis in patients undergoing general surgery found that treatment with LMWHs resulted in significant reductions in both clinical VTE and clinical pulmonary embolism. Comparisons with data from trials involving unfractionated heparin showed that treatment with LMWHs was associated with a significant reduction in clinical VTE.[2]Level of evidence: 1
• A systematic review of 33 RCTs evaluating complications associated with VTE prophylaxis in a total of 33,813 patients undergoing surgery found that injection-site bruising (6.9%), wound hematoma (5.7%), drain-site bleeding (2.0%), and hematuria (1.6%) were the most common minor complications; major bleeding complications, such as gastrointestinal (0.2%) or retroperitoneal (<0.1%) bleeding, were infrequent.[3]Level of evidence: 1

LMWHs are superior to warfarin in preventing VTE in patients undergoing major orthopedic surgery.

• A meta-analysis of randomized trials in patients undergoing orthopedic surgery found that vitamin K antagonists are more effective than placebo or no treatment in reducing DVT and clinical pulmonary embolism, with a higher rate of wound hematoma. However, vitamin K antagonists are less effective than LMWH in preventing total DVT and proximal DVT.[4]Level of evidence: 1

LMWHs are superior to compression stockings in preventing VTE in patients undergoing knee arthroscopy.

• An RCT in 1,761 consecutive patients compared use of full-length graduated compression stockings for 7 days versus prophylactic LMWH (nadroparin, 3,800 anti-Xa IU) once daily for 7 or 14 days. The primary end point of asymptomatic proximal DVT (based on whole-leg ultrasonography), symptomatic VTE, and all-cause mortality was lower in patients receiving prophylactic LMWH for 7 days (14-day heparin treatment was discontinued prematurely).[5]Level of evidence: 1

In patients receiving thromboprophylaxis with LMWHs for hip surgery, postoperative initiation of treatment may be as effective as earlier treatment.

• A systematic review and meta-analysis found that there was no advantage to preoperative or perioperative initiation of LMWH thromboprophylaxis compared to postoperative treatment. The following incidences of DVT were reported: postoperative, 19.2%; perioperative, 12.4%; postoperative, 14.4%.[6]Level of evidence: 1

Fondaparinux is noninferior, if not superior, to LMWHs in the primary prevention of VTE in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty, and hip fracture surgery). Treatment with fondaparinux should be initiated at least 6 hours after surgical hemostasis to reduce the incidence of bleeding complications.

• A meta-analysis of four RCTs comparing fondaparinux versus enoxaparin in a total of 7,344 patients undergoing elective hip replacement, elective knee replacement, or surgery for hip fracture found that treatment with fondaparinux significantly reduced the incidence of VTE compared to enoxaparin (6.8% vs 13.7%). However, major bleeding occurred more frequently in patients receiving fondaparinux.[7]Level of evidence: 1
• Subsequent analysis of these data showed that the incidence of major bleeding complications was related to the timing of the initial dose of fondaparinux. Bleeding was significantly greater in patients receiving fondaparinux within 6 hours of surgery compared to initial dosing after 6 hours, although there was no difference in the incidence of thromboembolic complications between the two timing strategies.[8]Level of evidence: 1

Direct thrombin inhibitors are noninferior to LMWH or warfarin in preventing DVT after orthopedic surgery, but several direct thrombin inhibitors are associated with increased bleeding, and all are associated with increased all-cause mortality.

• A systematic review of 14 trials compared the efficacy and safety of prophylactic anticoagulation with direct thrombin inhibitors versus LMWH or vitamin K antagonists in the prevention of VTE in 21,642 patients undergoing major orthopedic surgery (total hip replacement or total knee replacement). No difference was observed in major VTE (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.69-1.19), although several direct thrombin inhibitors were associated with increased bleeding, and all were associated with increased all-cause mortality (OR, 2.06 [95% CI, 1.10-3.87]).[9]Level of evidence: 1

Compression stockings are effective in reducing the incidence of DVT in at-risk patients. The benefit is greater when used along with other prophylactic measures.

• A systematic review identified seven RCTs evaluating the use of graduated compression stockings as the sole preventive measure in a total of 1,027 patients at risk of developing DVT, the majority of whom were undergoing surgical procedures. The incidence of DVT was significantly reduced in patients wearing compression stockings compared to control subjects (15% vs 19%). The review also found that the addition of compression stockings to other prophylactic measures (heparin, dextran, aspirin, or sequential compression), as evaluated in nine RCTs (1,184 patients), significantly reduced the incidence of DVT compared to the prophylactic regimen alone (35% vs 14%), leading the authors to conclude that compression stockings were effective in preventing DVT in hospitalized patients.[10]Level of evidence: 1

References