Pulmonary Embolism

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Chapter 57 Pulmonary Embolism

Pulmonary embolism (PE) and deep vein thrombosis (DVT) are different manifestations of the same pathologic process best grouped under the designation venous thromboembolism (VTE). As a disease entity, VTE is responsible for significant morbidity and mortality while imparting great socioeconomic impact. Appropriately, much attention has been devoted to its diagnosis and treatment. Although the medical literature has at times presented conflicting opinions, increased numbers of better-designed trials are helping to build consensus toward the optimal approach for the management of PE. This is not to say that significant controversies do not still exist. As in all areas of medicine, as one question is answered, others arise. This chapter presents an overview of the most important literature regarding the clinical approach to PE.

Epidemiology, Risk Factors, and Pathogenesis


PE is a common clinical problem. In the United States, hospital-based studies estimate the incidence of PE at 1 case per 1000 persons per year, equating to 200,000 to 300,000 hospital admissions per year. Estimates suggest that as many as 30,000 to 50,000 people die from PE annually in the United States, with an estimated 3-month disease-specific mortality rate of 10%. In nearly 20% of cases, the presenting clinical manifestation is sudden death. Data reported from Europe and other parts of the world are broadly similar.

Significant differences in mortality associated with PE for age, gender, and race have been observed. Age-adjusted PE mortality rates are as much as 50% higher among African Americans than whites. Within and between racial strata, PE mortality rates are 20% to 30% higher in men than in women. African American men have the highest reported mortality from PE, at 6.0 deaths per 100,000 persons, followed by African American women at 4.8 deaths per 100,000 persons. The mortality for PE in white males is 2.4 deaths per 100,000 persons and is the lowest in white females at 2.3 deaths per 100,000 persons. The incidence of PE also is age-dependent, with increasing incidence of death with advancing age. From 1979 to 1998, accounting for both gender and race, age-specific mortality rates doubled for each 10-year age group after 15 to 24 years.

In recent decades, the overall mortality rate from PE has decreased dramatically. From 1998 to 2009, the annual in-hospital mortality decreased by approximately 30%. The decline has been observed across gender and ethnic groups and has been attributed to improved risk factor modification, including improved prophylaxis of DVT, better detection and treatment of DVT, and/or enhanced PE diagnostic techniques, which has led to a decrease in disease misclassification.

Risk Factors

The etiopathogenesis of VTE, which includes PE and DVT, is a dynamic process resulting from synergistic interaction between acquired and genetic risk factors. Historically, Rudolph Virchow is credited with describing the classic triad of vascular endothelial injury, hypercoagulability, and venous stasis as the combination of host factors that predispose to VTE. VTE risk factors traditionally are categorized as either genetic (inherited thrombophilia) or acquired.

Inherited Thrombophilia

Inherited thrombophilias may result from qualitative or quantitative defects in coagulation factor inhibitors (antithrombin, protein C, protein S), increased levels or function of coagulation factors (activated protein C resistance, factor V Leiden mutation, prothrombin gene mutation, elevated factor VIII levels), hyperhomocysteinemia, defects in fibrolysis, or altered platelet function. Epidemiologic features of the common inherited thrombophilias are shown in Table 57-1.

Antithrombin Deficiency

Formerly termed antithrombin III, antithrombin (AT) is a single-chain vitamin K–independent glycoprotein belonging to the serine protease inhibitor superfamily. AT functions as a natural anticoagulant by binding and inactivating thrombin and the activated coagulation factors IXa, Xa, XIa, and XIIa. The AT molecule also has an active heparin-binding site, which, when heparin-bound, has marked affinity and function for binding and inactivating coagulation factors such as thrombin. The augmentation of the inhibitory activity of AT by heparin is the basis for the clinical use of heparin therapy. Mutations in AT lead to decreased ability of the molecule to inhibit the coagulation cascade, thereby leading to increased risk for thrombosis. AT deficiency is inherited as an autosomal dominant trait affecting males and females equally. Most affected persons are heterozygotic for AT deficiency, because homozygotic inheritance typically is fetal-lethal. Heterozygote AT-deficient people have AT levels that are 40% to 70% of normal. Two different types of AT deficiency caused by more than 250 mutations have been described: Type I AT deficiency is characterized by a quantitative reduction in normally functioning AT. Type II AT deficiency is characterized by both quantitative and qualitative defects, with three different subtypes classified on the basis of the type of receptor defect: (1) abnormality of active thrombin binding site, (2) abnormality of heparin-binding site, and (3) abnormalities of both thrombin- and heparin-binding sites. These classification categories are clinically relevant in that defects in the active thrombin-binding site confer a higher risk for VTE than defects that involve only the heparin-binding site or that are strictly quantitative.

Despite a low prevalence, AT deficiency is considered the most severe inherited thrombophilia, with increased risk of thrombosis as much as 20-fold over that in the absence of such deficiency. In patients with AT deficiency, VTE typically develops during the latter part of the second or third decade of life. The most common sites of thrombosis include the lower extremity and iliofemoral veins. However, other sites including the upper extremities, mesenteric veins, vena cava, renal veins, and retinal veins have been reported. Thrombotic events in AT-deficient persons often are precipitated by acquired thrombophilic risk factors such as surgery, trauma, pregnancy, drugs, or infection. Approximately 60% of affected persons experience recurrent thrombotic events, and clinical signs of PE are evident in up to 40% of these patients.

The diagnosis of AT deficiency should be determined by a functional assay of heparin cofactor activity, which is able to detect all cases of AT deficiency of clinical relevance. AT levels usually are not influenced by warfarin therapy but can be decreased during the acute phase of a thrombotic event, in disseminated intravascular coagulation, or with the concomitant use of heparin. Heparin therapy can lower AT levels by as much as 30%. Screening for AT deficiency is recommended within at least 2 weeks of an acute thrombotic event or at least 5 days after discontinuation of heparin therapy.

Protein C Deficiency

Protein C is a vitamin K–dependent glycoprotein synthesized in the liver. Protein C is activated by the thrombin-thrombomodulin complex. Protein C circulates as an inactive precursor and exerts its anticoagulant function after activation to the serine protease, activated protein C. Once activated, protein C proteolytically degrades activated coagulation factors Va and VIIIa. More than 160 qualitative or quantitative mutations in protein C have been described. Protein C is inherited as an autosomal dominant trait affecting both males and females equally. Homozygous persons typically have more severe and earlier-onset thrombophilia.

Two different subtypes of inherited protein C deficiency have been identified. Type I deficiency is a quantitative disorder characterized by parallel reductions in functional and antigenic levels of protein C to 50% of normal levels. Type II deficiency is a qualitative defect with reductions in functional levels of protein C but preserved antigenic function.

The prevalence of protein C deficiency is estimated at 0.2% to 0.4% in the general population and 3% to 5% in people with VTE. Three clinical syndromes are associated with protein C deficiency: (1) VTE in teenagers and adults, (2) neonatal purpura fulminans in homozygous or doubly heterozygous newborns, or (3) warfarin-induced skin necrosis. Acquired protein C deficiency occurs in a variety of clinical settings, including liver disease, infection, septic shock, disseminated intravascular coagulation, acute respiratory distress syndrome, and postoperative states, and in association with chemotherapeutic drugs.

The diagnosis of protein C deficiency should be made by means of functional testing based on activation with thrombin-thrombomodulin or snake venom. Pregnancy and oral contraceptive use can increase plasma protein C levels. Protein C levels are decreased in acute thrombotic events and during therapy with warfarin. In the absence of warfarin therapy and known medical conditions that result in acquired protein C deficiency, patients with a protein C level less than 55% of normal are very likely to have a genetic abnormality, whereas levels from 55% to 65% normal are consistent with either a deficient state or low normal values. Thus, repeat testing and/or genetic testing is recommended in most populations.

Protein S Deficiency

Protein S is a vitamin K–dependent glycoprotein synthesized by hepatocytes, megakaryocytes, and endothelial cells. Protein S functions as a cofactor of activated protein C for the degradation of activated factors Va and VIIIa. Protein S circulates in plasma in equilibrium as a free functionally active form and an inactive form bound to a carrier protein (C4BP). The bioavailability of protein S is closely linked to the concentration of C4BP. C4BP functions as an important regulator in the protein C–protein S inhibitor pathway.

Three subtypes of protein S deficiency have been defined on the basis of total protein S concentrations, free protein S concentrations, and activated protein C cofactor activity. Type I protein S deficiency is associated with approximately 50% of normal protein S levels, more marked decrease in free protein S concentrations, and decreased functional activity. Type II deficiency is characterized by normal total and free protein S levels but decreased functional activity. Type III deficiency, also known as type IIa, is characterized by normal total protein levels but decreased free protein concentrations and decreased functional activity. Conditions that result in reductions in protein C levels, as mentioned in the preceding section, can similarly influence protein S levels. The prevalence of protein S deficiency is estimated to be 0.03% to 0.1% in the general population and 1% to 5% in patients with VTE. The clinical presentation of VTE in patients with protein S deficiency is similar to that in those with protein C deficiency. Warfarin-induced skin necrosis has been reported with protein S deficiency.

Measurement of the free protein S concentration is the preferred screening test for protein S deficiency. As with protein C, acute thrombosis, pregnancy, oral contraceptive use, comorbid disease, or use of warfarin can alter assay results. Heparin does not alter plasma protein S or protein C concentrations and thus is an acceptable antithrombotic agent for use during diagnostic workup. In patients on warfarin therapy, recommendations support waiting at least 2 weeks after discontinuation to investigate for suspected protein S deficiency.

Factor V Leiden and Activated Protein C Resistance

Factor V Leiden is the most common recognized cause of inherited thrombophilia, accounting for 20% to 50% of new VTE cases. Factor V circulates in the plasma as an inactive cofactor. After activation by thrombin, factor Va serves as a cofactor in the conversion of prothrombin to thrombin. In 1993, investigators in Leiden, The Netherlands, identified a single point mutation in the factor V gene in a cohort of patients with unexplained VTE. The molecular defect is a single amino acid change (arginine506 to glutamine) at one of the activated protein C (APC) cleavage sites, making the factor V molecule resistant to activated protein C at this site. The result of this genetic defect, termed factor V Leiden, is the most common cause of inherited APC resistance, although other mutations have been identified. Factor V Leiden is a common mutation. The prevalence of factor V Leiden in the general population is estimated at 5%. People who are heterozygous for the factor C Leiden mutation have approximately a five-fold increase in VTE risk over that in the general population. People who are homozygous for the mutation are estimated to have an 80-fold increase in VTE risk over that in the general population.

The major clinical manifestation of thrombosis in people with factor V Leiden is venous. Thrombosis in the deep veins of the lower extremities is common, whereas involvement of superficial, portal, and cerebral veins is less common. As might be expected with the high frequency of this mutation in the general population, a synergistic effect with other inherited or acquired VTE risk factors has been observed. In addition to inherited APC resistance, acquired APC resistance has been reported. Users of third-generation oral contraceptives, patients with malignancy, and persons with connective tissue disease—in particular, systemic lupus erythematosus and the antiphospholipid antibody syndrome—have APC resistance.

Activated partial thromboplastin time (aPTT)–based assays serve as the screening test for APC resistance. The aPTT is performed in the presence and then absence of a standardized amount of APC, and the two clotting times are expressed as an APC ratio (aPTT in the presence to aPTT in the absence of APC). APC resistance is associated with a reduced APC ratio. Results of the standard aPTT screening test may be influenced by a variety of factors, including inflammatory states, pregnancy, oral contraceptives, antiphospholipid antibodies, and anticoagulation. Genetic testing for the factor V Leiden mutation also is available.


Homocysteine is an intermediary amino acid formed by the conversion of methionine to cysteine. Hyperhomocysteinemia may result from either acquired or heritable factors. Homocysteine is metabolized by means of two pathways. The first involves the cystathionine B-synthase (CBS) enzyme and requires vitamin B6 as a cofactor. The second involves the enzyme methionine synthase and requires both vitamin B12 and methyltetrahydrofolate reductase (MTHFR). Acquired forms of hyperhomocysteinemia may result from dietary deficiencies in vitamin B12 or B6 or folate. Inherited forms may result from genetic defects in the CBS or MTHFR enzymes.

Evidence suggests that hyperhomocysteinemia is a risk factor for VTE. In people with homocysteine levels higher than two standard deviations above normal, the odds ratio for VTE is two to three times greater than in the control groups. Elevated homocysteine levels also have been associated with premature coronary artery disease and cerebrovascular disease, although debate regarding the strength of these associations continues.

Screening for hyperhomocysteinemia is suggested in patients with unexplained VTE. Sensitive laboratory assays are available for the quantification of total plasma homocysteine concentrations. If elevated plasma homocysteine levels are identified, additional laboratory evaluation may be warranted. Treatment varies with the underlying cause but typically involves supplementation with folate and vitamins B12 and B6.

Hypercoagulability Testing

Ongoing research continues to identify new and increasingly prevalent inherited thrombophilic defects in patients with VTE. Thus, which patients to screen, which tests to perform, and when to initiate hypercoagulability testing constitute important questions. Despite the high prevalence of inherited defects, only limited evidence or expert opinion indicates that the identification of an inherited thrombophilia influences either the duration of therapy or risk of recurrence. Arguments for screening acknowledge the increasing prevalence of identified inherited thrombophilias and, with the increase in the discovery of new mutations, the identification of persons with multiple prothrombotic defects. Multiple defects are now found in 1% to 2% of patients with initial-episode idiopathic VTE. Thus, the identification of patients with multiple defects may affect the risk of VTE recurrence, duration of anticoagulation therapy, and/or alteration of management when additional risk factors for the acquired form of VTE are present, such as surgery, pregnancy, or hormonal therapy. Arguments against screening cite the lack of available evidence supporting alteration in anticoagulation management in the presence of hereditary thrombophilia. The 2008 American College of Chest Physicians (ACCP) Antithrombotic and Thrombolytic Therapy Evidence-Based Clinical Practice Guidelines state that “the presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation in VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinates of risk of recurrence.” A 2009 Cochrane database study failed to identify a single randomized controlled trial evaluating the benefit of testing for inherited thrombophilia after VTE in relation to risk of recurrent VTE.

Given the lack of available evidence that testing and identifying inherited thrombophilia influences the duration of therapy, VTE outcomes from screening of asymptomatic relatives, or risk of recurrent VTE, current recommendations for screening are based primarily on clinical judgment and expert opinion. Key points to recognize regarding first-episode VTE are that (1) the strongest risk factor for recurrent VTE is a history of VTE—of particular importance if the first VTE event was idiopathic—and (2) all patients with VTE are at increased risk for recurrence for several years after the initial event. In view of current limitations in medical evidence regarding the impact of inherited thrombophilia with respect to duration of therapy and risk of recurrence, consultation with a hematologic expert is recommended regarding individual patient management decisions.

Screening for Inherited Thrombophilia

In general, the following patient groups may be considered for screening: (1) those with a first VTE before the age of 50 years without an identifiable risk factor such as recent surgery, (2) those with a history of recurrent VTE, and (3) those with a first-degree relative with recurrent VTE. All such patients should be considered “strongly thrombophilic” on the basis of thrombotic history and are appropriate candidates for hereditary thrombophilia testing. The standard testing approach to screening for inherited thrombophilias includes appropriate studies to detect activated protein C resistance/factor V Leiden mutation, prothrombin gene mutation, antiphospholipid antibodies, antithrombin deficiency, protein C deficiency, and protein S deficiency.

Several factors must be considered in decisions regarding screening for inherited thrombophilia in patients presenting with VTE. First, acute VTE can transiently reduce plasma levels of antithrombin, protein C, and protein S, resulting in erroneously low levels. Second, treatment with heparin can result in up to a 30% decrease in antithrombin levels over the first several days of therapy. Third, warfarin reduces the functional activity of protein C and protein S and can rarely elevate levels of antithrombin, potentially resulting in falsely normal levels of antithrombin in deficient patients. To sidestep the effects of therapy on measured levels, it is recommended to test for these defects at least 2 weeks after cessation of anticoagulation therapy. If levels are obtained at time of presentation and are within normal limits, then a deficiency generally is excluded. If levels are low at time of presentation, then repeat testing is recommended on cessation of initial therapy. Screening tests for factor V Leiden mutation, prothrombin gene mutation, anticardiolipin antibodies, or antiphospholipid antibodies are not affected by concurrent use of heparin or warfarin therapy. If an inherited thrombophilia is identified, it is recommended to screen all first-degree relatives of the patient.

Acquired Risk Factors

Acquired risk factors for VTE are far more prevalent than inherited thrombophilias. Box 57-1 lists common risk factors for acquired VTE.

Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a life-threatening disorder that follows exposure to unfractionated (UF) or, less commonly, low-molecular-weight heparin (LMWH). HIT classically manifests with a low platelet count (less than 150,000/μL) or a relative decrease in platelet count by 50% from baseline typically within 5 to 10 days of the initiation of heparin or LMWH therapy. The incidence of HIT among patients treated with UF heparin is 10 times higher than among those receiving LMWH. In patients with HIT, the risk of thrombosis is more than 30 times that in the control population. The risk of thrombosis remains high for days to weeks after discontinuation of heparin, even after the platelet counts return to normal.

HIT is caused by antibodies against complexes of platelet factor 4 (PF4) and heparin. The heparin-PF4–antibody complex binds to the platelet surface, where it is recognized by circulating IgA, IgG, and IgM antibodies. Immunoglobulin recognition leads to further platelet activation and release of PF4, thus creating a positive feedback loop. The activated platelets aggregate, resulting in thrombocytopenia and thrombosis. Early-onset HIT, defined as that with onset within hours after initiation of heparin therapy, may be seen in approximately 30% of patients with persistent antibodies to heparin if such therapy is given within the previous 3 months. Diagnosis of HIT is based on recognition of the clinical syndrome and specific serologic testing. Serologic assays can detect circulating IgG, IgA, and IgM heparin-dependent antibodies with high sensitivity (97%) but modest specificity (74% to 86%). Therefore, positive results on serologic assays must be confirmed by more specific tests, including serotonin release assays, heparin-induced platelet aggregation assays, or solid phase immunoassays.

The first intervention in a patient with suspected HIT is immediate cessation of all exposure to heparin, including heparin-bonded catheters and heparin flushes. LMWH should be avoided, because it may cross-react with heparin-induced antibodies. In addition to heparin cessation, patients with suspected HIT should be started on alternative anticoagulation because of high risk of thrombosis. In patients with suspected HIT and/or the need for alternative anticoagulation, direct thrombin inhibitors such as lepirudin or argatroban may be used. The duration of alternative anticoagulant therapy and the subsequent use of oral anticoagulants will depend on whether the patient has had a thrombotic event or requires continued anticoagulation. For patients with HIT without evidence of thrombus, therapeutic doses of alternative anticoagulation should be continued until the platelet counts return to normal. Consideration should be given to continuing anticoagulation therapy with alternative anticoagulation or warfarin for 2 to 4 weeks after the diagnosis of HIT, because of persistent high risks of thrombosis over this period. For a patient with HIT and thrombosis, therapeutic doses of alternative anticoagulation should be continued until the platelet count has normalized; then the patient should be transferred to warfarin therapy with at least a 5-day overlap until the international normalized ratio (INR) is in the therapeutic range for at least 48 hours. Skin necrosis and warfarin-induced venous gangrene of the limbs have been reported during shorter periods of overlap or shorter duration of therapeutic INR.


Between 60% and 90% of pulmonary emboli arise from the deep veins of the lower extremity and pelvis. Other sources of thrombi include the renal veins, upper extremities, or right side of the heart. Iliofemoral thrombi are the most frequently clinically recognized causes of PE. Thrombi dislodge and embolize to the pulmonary arteries, where they cause hemodynamic abnormalities and impair gas exchange. The hemodynamic response to PE is determined by the embolic burden in association with the host’s hemodynamic reserve and compensatory adaptive response. After traveling through the right heart, large thrombi may lodge and obstruct the main pulmonary arteries or travel distally within the pulmonary vascular tree, leading to hemodynamic alterations. In addition to the physical obstruction to flow, acute PE triggers the release of vasoactive substances, resulting in further increase in pulmonary vascular resistance and right ventricular afterload. Because right ventricular afterload increases, increased right ventricular wall tension may lead to right ventricular dilatation and hypokinesis with further right ventricular dysfunction, tricuspid regurgitation, and right ventricular failure. Right ventricular pressure overload can lead to flattening or bowing of the interventricular septum toward the left ventricle with resulting impairment of left ventricular filling, systemic arterial hypotension, and cardiac arrest. Increased right ventricular wall stress caused by right ventricular pressure overload may also lead to right-sided stress-induced ischemia.

Impaired gas exchange may result from impaired ventilation-perfusion matching, increased alveolar dead space, or right-to-left shunting through a patent foramen ovale. Stimulation of pulmonary irritant receptors results in hyperventilation, contributing to the observed hypocapnia and respiratory alkalosis. The presence of hypercapnia in acute PE suggests a large amount of physiologic dead space and impaired minute ventilation, which can result from massive PE.