Pulmonary

Pulmonary Embolism

Anil Gopinath

Thomas R. Gildea

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Definition and etiology

Pulmonary embolism (PE) refers to the presence of endogenous or exogenous substances within the pulmonary vascular bed that result in partial or complete hindrance to blood flow. Among all causes for PE, deep venous thrombosis is the most common (Box 1).

Box 1: Causes of Pulmonary Embolism
Most Common
  • Lower limb deep venous thrombosis (majority of cases)
Less Common
  • Air embolism
  • Amniotic fluid embolism
  • Cement (polymethylmethacrylate) embolism
  • Fat embolism
  • Hydatid embolism
  • Iodinated oil
  • Metallic mercury embolism
  • Septic pulmonary embolism (infective endocarditis, catheter, infected pacemaker leads)
  • Talc embolism
  • Tumor embolism
  • Miscellaneous (catheter fragments, cotton fibers)

Adapted from Han D, Lee KS, Franquet T, et al: Thrombotic and nonthrombotic pulmonary arterial embolism: Spectrum of imaging findings. Radiographics 2003;23:1521-1539.


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Prevalence and risk factors

Pulmonary embolism is, in the overwhelming majority, a consequence of deep venous thrombosis (DVT); the two together constitute venous thromboembolism (VTE). The incidence of PE thus reflects the presence of risk factors for VTE in a given population (Box 2).

Box 2: Risk Factors for Venous Thromboembolism
Strong Risk Factors (Odds Ratio >10)
  • Fracture (hip or leg)
  • Hip or knee replacement
  • Major general surgery
  • Major trauma
  • Spinal cord injury
Other Risk Factors
  • Immobility
  • Cancer therapy
  • Previous venous thromboembolism
  • Malignancy
  • Increasing age
  • Pregnancy and the postpartum period
  • Estrogen-containing oral contraception or hormone replacement therapy
  • Selective estrogen receptor modulators
  • Acute medical illness
  • Heart or respiratory failure
  • Inflammatory bowel disease
  • Nephrotic syndrome
  • Myeloproliferative disorders
  • Paroxysmal nocturnal hemoglobinuria
  • Obesity
  • Smoking
  • Varicose veins
  • Central venous catheterization
  • Inherited or acquired thrombophilia

Adapted from Geerts WH, Pineo GF, Heit JA, et al: Prevention of venous thromboembolism: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:338S-400S; and Anderson FA Jr, Spencer FA: Risk factors for venous thromboembolism. Circulation 2003;107:I9-I16.


A brief recap of venous anatomy may be helpful. The deep venous system of the lower extremities includes the anterior tibial, posterior tibial, and peroneal veins. The anterior and posterior tibial veins join to form a common trunk: the popliteal vein. The peroneal vein either joins the anterior and posterior tibial veins to form the popliteal vein or joins a variable length after its formation. The soleal and gastrocnemius veins, which lie within the eponymous muscles, drain into the popliteal vein.

There are many known risk factors for VTE and PE (see Box 2). These seemingly disparate risk factors may be easier to comprehend if Virchow's triad (venous stasis, hypercoagulability, and endothelial injury) is remembered. The pathogenic mechanisms underlying the risk factors for VTE are either the de novo development or an accentuation of pre-existing elements of Virchow's triad. Thus, trauma can result in immobility (venous stasis), tissue injury (leading to hypercoagulability), and endothelial injury. Patients who have pre-existing risk factors for VTE (e.g., hypercoagulability) may be more at risk for developing VTE after a predisposing event (e.g., surgery or trauma) than another person who experiences similar events but is free from risk factors. The presence of several risk factors in a patient results in a synergistic increase in the risk for VTE.

A subset of patients with DVT will develop pulmonary embolism. The location of the thrombus within the deep venous system is a key factor in this progression. Proximal (knee and above) deep vein involvement portends an increased risk of pulmonary embolism. A high probability ventilation/perfusion () scan (suggestive of PE) was seen in 40% to 50% of patients with symptomatic proximal DVT but with no symptoms of PE.1 The real incidence of PE is probably higher, even when false-positive high-probability scans are accounted for, because the sensitivity of a high-probability scan is only about 50%. Quantifying symptomatic PE in untreated proximal DVT is understandably difficult; one review suggested an incidence of 50% over a 3-month period in this group.1

In contrast, progression with distal (calf) DVT is less common. Asymptomatic distal (calf) DVT progresses in only about one sixth of patients to involve more-proximal veins.1 Symptomatic distal DVT extends proximally in up to one third of such episodes.

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Diagnosis

There is no clinical feature and no single diagnostic test that reliably distinguishes patients with and without PE. In any patient, the presence of multiple signs, symptoms, and historical features that are known to occur with a higher frequency in patients with PE increases the likelihood of PE. This rationale underlies the development of clinical prediction models for PE (Tables 1 and 2) and, in turn, implies that excessive reliance on any one element for diagnosing PE can be misleading. This approach has been formally evaluated for clinical prediction models for DVT where individual elements of the Wells clinical prediction rule for DVT were less helpful for diagnosing DVT than when combined in a prediction model.2 It is likely that a similar situation exists for clinical prediction rules for PE as well.

Table 1: Clinical Prediction Rules (Wells Score)
Variable Points
Clinical signs and symptoms of DVT (minimum of leg swelling and pain with palpation of the deep veins) 3
Alternative diagnosis is less likely than PE 3
Heart rate >100 bpm 1.5
Immobilization or surgery in the previous 4 wk 1.5
Previous DVT or PE 1.5
Hemoptysis 1
Malignancy (on treatment, treated in the last 6 mo or palliative) 1

DVT, deep venous thrombosis; PE, pulmonary embolism.

Table 2: Risk Categories Based on Wells Score
Cumulative Score Risk Category
Version Used in PIOPED II
<2 Low
2-6 Intermediate
>6 High
Version Used in CHRISTOPHER Study
≤4 PE unlikely
>4 PE likely

PE, pulmonary embolism; PIOPED, Prospective Investigation of Pulmonary Embolism Diagnosis.
Adapted from Wells PS, Anderson DR, Rodger M, et al: Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: Increasing the model's utility with the SimpliRED D-dimer. Thromb Haemost 2000;83:416-420.

Efforts to identify modalities (e.g., helical computed tomography [CT]) that have a high negative predictive value independent of clinical assessment have not been entirely successful. In particular, there are concerns about selection bias in studies on helical CT, the modality on which most attention has been focused in the search for a context-independent test.3 At present, diagnostic algorithms that include clinical prediction rules, laboratory tests, and imaging are the most reliable ways to diagnose PE.

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Clinical features

Symptoms commonly associated with pulmonary embolism include dyspnea, chest pain, cough, hemoptysis, apprehension, palpitations, syncope, and sweating. Pleuritic chest pain and sudden dyspnea are significantly more common in patients with pulmonary embolism but are not pathognomonic.4 Signs commonly associated with PE include tachypnea, tachycardia, neck vein distention, a fourth heart sound, a loud pulmonary component of the second heart sound, inspiratory crackles, pleural rub, and low-grade fever (<38.0° C). Tachypnea and tachycardia are more common in patients with PE, but the other signs are not helpful in distinguishing between patients with and without PE.4

Clinical Prediction Rules

The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study results suggested that the clinical impression of an experienced physician, arrived at by the synthesis of clinical symptoms, signs, laboratory data, and imaging, had reasonable correlation with the actual incidence of pulmonary embolism in each of the incidence categories (low, intermediate, and high).5 Clinical prediction rules thus evolved in a milieu of accumulating data that underscored the unreliability of individual signs or symptoms or a syndromic approach to the diagnosis of PE and the possibility of improved diagnostic performance from a systematic evaluation of a group of key factors (risk factors, signs, symptoms, imaging) that were helpful in discriminating between patients with and without PE.

Many different clinical prediction rules have been proposed.6 The simplified (or modified) Wells prediction rule7 has been used in most prospective validation studies (see Table 1). It evaluates seven factors and categorizes patients into three risk categories: low, intermediate, and high. In a prospective study that used the simplified Wells prediction rule, the incidence of PE was 1.3%, 16.2%, and 40.6% in the low-, intermediate-, and high-risk categories, respectively.8

Wells and colleagues,7 in the same study, included alternative cutoff values for the clinical prediction rule that yielded a dichotomous outcome (“PE likely” and “PE unlikely”) instead of the three risk categories (see Table 1). This was done to help dichotomize the patient population into those who did not need further investigations (those who were in the “PE unlikely” group and had negative D-dimer tests) and all others who would need further workup. With this dichotomous model and additional D-dimer testing, 46% of the patients in their validation cohort were categorized as “PE unlikely” and had negative D dimers.7 In this subgroup (PE unlikely and negative D dimer), the rate of PE was only 1.7%. In comparison, only 27% of patients had a combination of low risk and negative D dimer as assessed by the three-category model in the same study.7 The dichotomous model was thus able to limit further investigations in 46% of patients, with no increase in the incidence of PE on follow-up. A prospective study has confirmed the safety of the two-category approach along with CT angiography and D-dimer testing.9

At present, sufficient data support the use of the Wells prediction rule (either the two- or three-category modification) in conjunction with a sensitive D-dimer test in patient populations known to have a relatively low incidence of PE.7,9

Any score not validated prospectively or developed in a patient population that is distinctly different (ethnicity, encounter setting, high vs. low incidence of PE, pre-screened patient population with a low incidence of alternative diagnosis) from the one the score is being applied to might not categorize patients as well as in the original study. In a retrospective study of PIOPED patients, the Wells score performed poorly in specific subgroups (surgical, ICU and CCU groups), but its diagnostic accuracy was acceptable for outpatients.10

It is unlikely that a particular schema will suffice for all clinical situations, and therefore it is difficult to recommend a particular prediction rule for universal use. The rigid application of clinical scores is not advocated; in the modified Wells score, this is explicitly avoided by the inclusion of a high scoring criterion that reminds the clinician to judge whether an alternative diagnosis is less likely than PE (see Table 1).4 Thus, with due diligence, clinical assessment models (modified Wells score, Geneva score) can be used by physicians of varying levels of experience to classify patients into low-, intermediate-, and high-risk categories as accurately as experienced physicians can by their clinical gestalt.3

D Dimer

D dimer is produced by the breakdown of cross-linked fibrin by the fibrinolytic system. D-dimer levels are elevated in acute thromboembolism and result from the lysis of cross-linked fibrin within the thrombus. D-dimer levels are, however, elevated in other conditions (e.g., postoperative state, cancer, pregnancy) and thus are not pathognomonic for thromboembolic disease. Because elevated D-dimer levels are nonspecific and are not diagnostic for PE, the value of D-dimer testing rests on the ability of a negative test (a low value) to predict the absence of PE.

A highly sensitive D-dimer test would ensure levels above the chosen threshold for nearly all patients with PE. However, such high sensitivity often comes at the cost of low specificity (high false-positive rates). Even if elevated levels are not taken as evidence of PE, positive D-dimer tests usually result in further investigations, each with its adverse effects and inherent false-positive and false-negative rates. If more patients are directed toward further investigations after a highly sensitive D-dimer test, the advantage of detecting a higher number of true positives will be offset to a greater or lesser degree by the cost and adverse effects associated with investigating a greater absolute number of patients. As is evident, a balance between high sensitivities (ensuring that no patients with PE are missed) and high specificity (ensuring that no normal patient receives anticoagulation for an erroneous diagnosis of PE) is essential. A false-negative rate of 1% to 2% is considered acceptable for a diagnostic protocol (not each individual test) in view of similar numbers encountered with pulmonary angiography, which is considered the gold standard.4

An appropriate protocol categorizes a patient into differing risk categories with a clinical prediction rule (e.g., low, intermediate, and high risk for the Wells score), thus estimating the pretest probability based on incidence rates for similar patients in historical validation studies (e.g., 1%-3% for the low-risk category in the Wells score). An appropriate protocol also selects a test with an appropriate likelihood ratio (e.g., negative likelihood ratio of 0.13 for the ELISA assay) and yields a post-test probability (<1% for this example). Thus, an adequate match between the patient population and the selected clinical prediction rule is necessary to ensure a reasonably accurate estimation of the pretest probability. Similarly, a test with an appropriate likelihood ratio is necessary to ensure that it significantly changes the pretest probability.4

These considerations have a direct bearing on D-dimer tests used in diagnosing PE. Many different assays are used for D-dimer assessment. A meta-analysis by Stein11 demonstrated better sensitivity and likelihood ratios for enzyme-linked immunosorbent assay (ELISA)-based methods than for other assays. The sensitivity of the quantitative rapid ELISA assay was 95%, with a negative likelihood ratio of 0.13 (cutoff value <500 ng/mL). A negative test thus effectively excludes patients who have a low pretest probability. These variations underscore the importance of knowing the particular assay used locally.

The results of a D-dimer test, irrespective of the sensitivity of the assay, cannot be interpreted in isolation. The diagnostic accuracy of D-dimer test is less in hospitalized patients than in outpatients.12 The incidence of a false-negative D-dimer result in patients categorized as “PE likely” or high probability for PE was considerable (10.3% and 20%, respectively) in one study, although a less-sensitive whole-blood assay was used.7 Even when sensitive assays are used, the false-negative rate rises as the pretest probability rises. These considerations reiterate the necessity for interpreting results from diagnostic studies as well from clinical prediction rules in the context of the various factors that can influence the manifestations and sequelae of PE.

Helical Computed Tomography

There has been a profusion of studies evaluating the role of spiral CT in suspected PE. One issue that has been examined is whether the pulmonary angiogram can still be considered the gold standard in the current era of multidetector CT (MDCT) given the substantial interobserver variation with angiography.13,14 However, although interobserver agreement improves with thinner-collimation MDCT scanners,15 there is no conclusive proof that agreement rates are significantly greater than with pulmonary angiogram in studies that directly compare these modalities.16,17 In addition, there is no conclusive proof that MDCT has greater sensitivity than pulmonary angiography in detecting subsegmental emboli; two studies produced discordant results.16,17 Thus, there is no reason, at present, to believe that prior studies with pulmonary angiograms need to be re-examined in light of the improvements in CT technology.

More importantly, it may well be that subsegmental emboli do not have the same implications as larger proximal emboli. In the original PIOPED study, 20 patients were inadvertently left untreated as a result of missed diagnosis on initial pulmonary angiograms that were later reclassified as positive angiograms by the central panel of angiogram readers.18 The overwhelming majority of the patients (84%) had segmental or more distal clots. There were no differences in mortality or recurrent PE (fatal or nonfatal) between the treated and untreated groups. The absence of a detrimental effect with small subsegmental PE might explain why clinical outcomes do not differ significantly in untreated patients with negative CT angiograms (single detector or multiple detector) even though the sensitivity for subsegmental PE is less for single-detector CT when compared with multidetector CT.19,20 In addition, the mortality and recurrence rates are not significantly different from those for patients with negative pulmonary angiogram.20 As an editorial pointed out, outcome studies and accuracy studies might not yield similar results.21 As it pertains to subsegmental PE, it may be that beyond some threshold, increasing accuracy in diagnosis does not translate into better outcomes; that is, all clots might not have equal significance. However, these conclusions do not apply to all patient populations; subsegmental emboli can be significant in patients with prior cardiopulmonary disease and may be important as a marker of a prothrombotic state and increased risk of recurrence in those who have persistent risk factors.

These observations tie in neatly with two studies that evaluated the use of multidetector CT within a diagnostic algorithm.9,22 The Christopher study9 used a modified Wells score and a sensitive D-dimer assay. Patients who were in the “PE unlikely” group and had a negative D-dimer result had no further investigations. All other patients had a CT, either multidetector or single detector. Patients in the “PE likely” group who had negative CT scans had rates of fatal or nonfatal PE that were no different from rates in the “PE unlikely” group who had negative D-dimer rates and were not different from rates in historical controls with negative pulmonary angiograms.9 The majority were outpatients, and the incidence of PE and the prevalence of persistent risk factors (e.g., malignancy, paralysis) were low.9

The PIOPED II study classified patients into low-, intermediate-, and high-risk categories using modified Wells criteria.7 There was an interaction among CT angiogram results (with or without CT venography), the risk category, and PE location such that a positive CT angiogram (CTA) and CT venogram (CTV) was more likely to reflect the presence of an actual thrombus (positive predictive value) when the pretest probability was high and when the thrombus was proximally located. CTA plus CTV had higher sensitivity than CTA alone, but it had equivalent sensitivity to CTA assessment in conjunction with risk category. When the clinical assessment was discordant with the CTA results, the negative predictive value was lower and further investigations (USG, pulmonary angiogram, scan) were necessary to exclude PE.22

At present, single-detector or multidetector CT scan results need to be assessed in light of the pretest probability. Proximal thrombi are detected well across all risk categories, whereas false-positive and false-negative rates for subsegmental clots are high when the risk category and CT scan results are discordant. Because there is no consensus on the management of subsegmental clots, further workup is recommended when such discordant results are seen. A recent article by the PIOPED II investigators outlines one such algorithm.23

Ventilation-Perfusion Scanning

scanning was the first-line imaging test study until the advent of helical CT. The performance characteristics of scanning have been documented meticulously in the landmark PIOPED study.5 The combination of high or low pretest clinical probability and concordant scan results predicts the presence or absence of PE with a high degree of accuracy. The traditional problem with scanning has been the high incidence of nondiagnostic tests and indeterminate results and consequently the inability to definitively categorize a majority of the tested patients.

A randomized. controlled trial sought to determine whether CTPA was noninferior to scanning in ruling out PE in acutely symptomatic patients.24 The primary endpoint was met, demonstrating that CTPA was not inferior to scanning in ruling out PE. The study also demonstrated that if the group of patients with nonhigh probability scan results and PE unlikely by Wells score also had negative D-dimer tests and negative leg ultrasonography, the outcomes at 3 months were similar to those of patients who had negative CTPA and negative leg USG. This suggests that indeterminate results on scans are not dead ends but can be clinically useful if incorporated into an appropriate algorithm.

Echocardiography

Echocardiography is usually not considered a diagnostic modality for pulmonary embolism, although a sensitivity of 60% to 80% and a specificity of 95% to 100% have been reported with transesophageal echocardiogram.25 Transthoracic echocardiography is more commonly used during workup of pulmonary embolism and is mainly used to detect the presence of right ventricular dysfunction. In hemodynamically unstable patients who are believed to have a PE, this finding defines the PE as massive and is an indication for thrombolysis.

Diagnostic Algorithms

The diagnostic algorithms used in two prospective studies, the Christopher study9 and the PIOPED II study,22 have been validated by the favorable outcomes observed in these studies. However, these algorithms might not be universally applicable. Both strategies were validated in studies that were primarily composed of outpatients, had a low-to-moderate incidence of PE, and had a low incidence of persistent thrombogenic risk factors. This might not be appropriate in the hospitalized, the critically ill, and other groups not represented in the study. The PIOPED II investigators synthesized available evidence and expert opinion to recommend an algorithm organized by the pretest clinical risk category (Figs. 1 to 3).23

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Treatment

Lifestyle Modification

Patients with PE and those with lower-limb DVT are often advised bed rest for the initial few days of therapy. For patients with DVT, there is no evidence of a beneficial effect of absolute bed rest or increased risk of adverse events with mobilization.26 Early mobilization with compression stockings may be helpful in decreasing the incidence of post-thrombotic syndrome.26 Absolute bed rest might not be mandatory for every patient with PE as well, given data from historical cohort studies in patients with PE and the large fraction of patients with symptomatic DVT who have occult PE. However, the effect of PE on the patient's cardiopulmonary status needs to be assessed while making the decision for mobilization given the increased incidence of VTE in older patients who often have pre-existing cardiopulmonary disease.

Medical Options

Current treatment regimens in PE are derived from trials evaluating different anticoagulation drugs and regimens in patients with DVT. This approach is appropriate because both DVT and PE are parts of the spectrum of VTE. However, regardless of the similarity in the pathogenic mechanisms, the occurrence of PE is still a signal event. Patients who present with PE are more likely to die of recurrent VTE than patients who present with DVT. Whether this is because of an intrinsic difference in disease mechanisms or a difference in the comorbidities inherent in patient populations with PE is unknown.27

Treatment should be started promptly in VTE disease. Failure to achieve rapid and full anticoagulation in the first 24 hours is associated with an increase in long-term (months) recurrence rates for VTE.28 Thus, treatment regimens for PE, except in special circumstances (e.g., renal failure, pregnancy), should include prompt administration of an adequate dose of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) and concurrent administration of oral warfarin. Monitoring activated partial thromboplastin time (aPTT) for UFH and prothrombin time (usually expressed as the international normalized ratio [INR]) for the anticoagulant activity of warfarin is essential for achieving and maintaining safe and effective anticoagulation. Because of the predictable pharmacokinetics of LMWH, and consequently the ability to give weight-based doses without having to monitor coagulation parameters, LMWH is advocated as first-line therapy for DVT and nonmassive PE in current guidelines.

Heparin

Heparin acts mainly through enhancing the activity of antithrombin III (ATIII). Heparin binding to ATIII induces conformational changes that accelerate the intrinsic slow thrombin inhibitory activity of ATIII. The transformed ATIII then binds and inhibits factors within the coagulation cascade, including thrombin, as well as other activated factors including Xa, IXa, XIa, and XIIa. Inhibition of thrombin activity also results in inhibition of thrombin-induced platelet activation and factors V and VIII.

Heparin is a heterogeneous mixture of different chain lengths, and only about one third of the chains possess the binding site, a specific pentasaccharide sequence, for ATIII. The remainder of the chain length, irrespective of the presence of the pentasaccharide sequence, binds nonspecifically to various proteins in the coagulation cascade. The inhibition of factor Xa differs in that the only requirement for factor Xa inhibition is the presence of the pentasaccharide sequence that binds to ATIII. These binding characteristics have led to the development of drugs that are effective in Xa inhibition but that do not inhibit other factors (fondaparinaux) or inhibit them weakly (LMWH). Inhibition of other clotting factors requires, in addition to the pentasaccharide sequence, the bridging action resulting from nonspecific interaction of the remainder of the heparin chain with domains on the clotting factors. The nonspecific charge-dependent interactions of heparin are responsible for most of the limitations and adverse effects of heparin.

Unfractionated heparin (UFH) is typically used in venous thromboembolic disease in an inpatient setting to achieve rapid anticoagulation. The rapid achievement of adequate anticoagulation during the acute phase of VTE prevents recurrent DVT and also averts the potential prothrombotic effects of warfarin during the first few days of administration. LMWH is recommended over UFH for patients with VTE except for patients with submassive PE or renal failure, patients scheduled for invasive procedures, and patients who are critically ill and in whom rapid, reliable cessation of the anticoagulant effect is important.

Intravenous administration of a weight-based loading dose (80 U/kg) and maintenance dose (18 U/kg) of UFH is recommended for achieving adequate anticoagulation rapidly. UFH can also be administered subcutaneously for full therapeutic anticoagulation, although this route is much less commonly used. Adequate anticoagulation with heparin results when a plasma concentration of 0.3 to 0.7 IU/L (as measured by factor Xa inhibition) is achieved. Historically, an aPTT level 1.5 to 2.5 times the control value was believed to represent adequate anticoagulation with heparin. However, there is wide variability in the actual level of anticoagulation achieved for a given aPTT range depending on the reagent used for the aPTT test. This makes it imperative that aPTT values that correlate with adequate anticoagulation (as defined by factor Xa inhibition) be established for the particular reagent used in the local laboratory, and the heparin protocol used in any institution must be tailored to reflect variations in aPTT. aPTT reflects the level of factor IIa inhibition more closely than the level of factor Xa inhibition.

aPTT values are obtained 6 hours after initiation of therapy and 6 hours after dose changes. These values are best used in conjunction with a protocol to adjust heparin dosage until aPTT values are in the desired range (as described earlier). Values are obtained daily thereafter unless warranted otherwise by the clinical status.

Adverse effects of heparin include bleeding and heparin-induced thrombocytopenia, Osteoporosis can occur with long-term use. Skin lesions, hypoaldosteronism, and hypersensitivity reactions are rare complications. Bleeding while on UFH is usually managed by discontinuing heparin administration; protamine reverses the anticoagulant effect of heparin, but it is infrequently used except in special settings.

Low-Molecular-Weight Heparins

LMWHs are derived from heparin by enzymatic or chemical depolymerization; different methods yield different mixtures of heparin chains. The different LMWHs are therefore not interchangeable. Depolymerization yields shorter chain lengths with reduced binding to specific proteins (coagulation factors, plasma proteins), macrophages, endothelial cells, platelets, and osteoblasts and is responsible for the superior pharmacokinetic and adverse-effect profile of LMWH as compared with UFH. As for UFH, a third of the LMWH chains contain the specific pentasaccharide sequence that binds to ATIII. As a consequence of the shorter chain length, only 25% to 50% of LMWH chains can bind to thrombin, in comparison with UFH, whose chain length is almost always long enough to bind to thrombin. This results in a greater anti-Xa to anti-IIa activity for LMWH, as compared with UFH, where the ratio is 1 : 1. Anti–factor Xa assay is used instead of aPTT (which reflects anti–factor IIa activity) if monitoring is deemed necessary in patients treated with LMWH.

Monitoring is not recommended during LMWH therapy except in special circumstances such as renal failure and in obese patients. Anti–factor Xa activity usually peaks 4 hours after administration. The optimum level of anti–factor Xa activity is not established; a range of 0.6 to 1.0 IU/L has been advocated for twice-daily administration with enoxaparin and nadroparin (cf. therapeutic range for UFH: 0.3-0.7 IU/L) for treatment of venous thromboembolism.

Warfarin

Warfarin is the drug most commonly used for long term-anticoagulation. Vitamin K is reduced in a two-step process from an epoxide form to a reduced form (vitamin KH2), which then takes part in a reaction that carboxylates (γ-carboxylation) clotting factors and yields the epoxide form again. Carboxylation is necessary for optimal activity of clotting factors II, VII, IX, and X and of protein C and protein S. Warfarin inhibits both of the enzymes that convert vitamin K epoxide to reduced vitamin K; inhibition of the enzyme catalyzing the first step is far more effective than inhibition of the second step. This underlies the rationale for administering vitamin K1 (the product of the first step) exogenously to counter excessive anticoagulation produced by warfarin.

Warfarin dosage needs to be individualized because there is considerable variation in the effectiveness of any given dose of warfarin depending on genetic factors (race and inherited mutations), environmental factors (drugs and diet), and comorbid disease. An INR of 2.0 to 3.0 is recommended as the target for anticoagulation with warfarin for VTE. Higher INR ranges result in more bleeding complications, and lower INR targets result in greater recurrences of venous thromboembolic disease.

The initial oral dose is 5 to 10 mg once a day. Large loading doses (20 mg) are not recommended. The factors influencing the choice of the initial dose include the indication, patient profile and clinical status, and concurrent medications. The need to achieve a therapeutic level of anticoagulation rapidly is greater for acute VTE (DVT and PE) than for atrial fibrillation, because the risk for short-term and long-term recurrences increases with delay in appropriate therapy. Initiating anticoagulation with a warfarin dose of less than 5 mg may be optimal for inpatients, the elderly, and patients with organ failure.29 Irrespective of the initial dose, dosing algorithms, if applicable to the patient population in question, are useful in achieving early and stable anticoagulation.30

Length of Anticoagulation

The duration of anticoagulation depends mainly on the inciting risk factor. When the risk factor is transient, anticoagulation is recommended for 3 months after a first episode of PE. When the PE is believed to be secondary to idiopathic DVT, anticoagulation is recommended for 6 to 12 months, and indefinite anticoagulation may be considered depending on cardiopulmonary status and patient characteristics. For patients with PE in the context of malignancy, LMWH is recommended for 3 to 6 months and probably indefinitely or until resolution of the malignancy.

Thrombolytics

Thrombolytics are used to lyse existing thrombi and relieve the hemodynamic effects of PE. Massive PE is an accepted indication for thrombolytics. Thrombolytics are not indicated in patients with PE without evidence of RV dysfunction. Other indications (submassive PE) are controversial and under study.

Thrombolectomy

Nonmedical interventions for PE include catheter-based embolectomy and surgical embolectomy. These are limited to those who are hemodynamically compromised and are not able to receive standard treatment (thrombolysis). Experiences with these modalities are limited, and there is no consensus on indications or on patient groups who would benefit.

Guidelines

The American College of Chest Physicians issued a revised version of evidence-based guidelines for the management and diagnosis of venous thromboembolic disease in 2008. The guidelines provide summary recommendations, a comprehensive review of the evidence base for these recommendations, and the areas of uncertainty that remain. The material presented in this chapter draws on this excellent resource in many areas, especially in areas relating to drug pharmacology and pharmacokinetics. There are no substantial deviations from the management perspectives outlined in the guidelines.

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Summary

  • Pulmonary embolism is one manifestation of venous thromboembolic disease and usually develops from a venous thrombus involving the proximal lower-limb veins.
  • The systematic use of clinical prediction rules in conjunction with D-dimer testing and computed tomography helps in the diagnosis of PE.
  • Rapid and effective anticoagulation is the mainstay in the management of PE.
  • Low-molecular-weight heparin (for rapid short-term anticoagulation) and warfarin (for oral long-term anticoagulation) are currently recommended. A target INR of 2.0 to 3.0 is recommended. The duration of anticoagulation depends on the underlying risk factors.

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References

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  8. Wells PS, Anderson DR, Rodger M, et al: Excluding pulmonary embolism at the bedside without diagnostic imaging: Management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and D-dimer. Ann Intern Med. 2001, 135: 98-107.
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  10. Ollenberger GP, Worsley DF. Effect of patient location on the performance of clinical models to predict pulmonary embolism. Thromb Res. 2006, 118: 685-690.
  11. Stein PD, Hull RD, Patel KC, et al: D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: A systematic review. Ann Intern Med. 2004, 140: 589-602.
  12. Schrecengost JE, LeGallo RD, Boyd JC, et al: Comparison of diagnostic accuracies in outpatients and hospitalized patients of D-dimer testing for the evaluation of suspected pulmonary embolism. Clin Chem. 2003, 49: 1483-1490.
  13. Diffin DC, Leyendecker JR, Johnson SP, et al: Effect of anatomic distribution of pulmonary emboli on interobserver agreement in the interpretation of pulmonary angiography. AJR Am J Roentgenol. 1998, 171: 1085-1089.
  14. Stein PD, Henry JW, Gottschalk A. Reassessment of pulmonary angiography for the diagnosis of pulmonary embolism: Relation of interpreter agreement to the order of the involved pulmonary arterial branch. Radiology. 1999, 210: 689-691.
  15. Schoepf UJ, Holzknecht N, Helmberger TK, et al: Subsegmental pulmonary emboli: Improved detection with thin-collimation multi-detector row spiral CT. Radiology. 2002, 222: 483-490.
  16. Qanadli SD, Hajjam ME, Mesurolle B, et al: Pulmonary embolism detection: Prospective evaluation of dual-section helical CT versus selective pulmonary arteriography in 157 patients. Radiology. 2000, 217: 447-455.
  17. Winer-Muram HT, Rydberg J, Johnson MS, et al: Suspected acute pulmonary embolism: Evaluation with multi-detector row CT versus digital subtraction pulmonary arteriography. Radiology. 2004, 233: 806-815.
  18. Stein PD, Henry JW, Relyea B. Untreated patients with pulmonary embolism. Outcome, clinical, and laboratory assessment. Chest. 1995, 107: 931-935.
  19. Engelke C, Rummeny EJ, Marten K. Pulmonary embolism at multi-detector row CT of chest: One-year survival of treated and untreated patients. Radiology. 2006, 239: 563-575.
  20. Le Gal G, Righini M, Parent F, et al: Diagnosis and management of subsegmental pulmonary embolism. J Thromb Haemost. 2006, 4: 724-731.
  21. Stein PD, Beemath A, Goodman LR, et al: Outcome studies of pulmonary embolism versus accuracy: They do not equate. Thromb Haemost. 2006, 96: 107-108.
  22. Stein PD, Fowler SE, Goodman LR, et al: Multidetector computed tomography for acute pulmonary embolism. N Engl J Med. 2006, 354: 2317-2327.
  23. Stein PD, Woodard PK, Weg JG, et al: Diagnostic pathways in acute pulmonary embolism: Recommendations of the PIOPED II Investigators. Radiology. 2007, 242: 15-21.
  24. Anderson DR, Kahn SR, Rodger MA, et al: Computed tomographic pulmonary angiography vs ventilation-perfusion lung scanning in patients with suspected pulmonary embolism: A randomized controlled trial. JAMA. 2007, 298: 2743-2753.
  25. Leibowitz D. Role of echocardiography in the diagnosis and treatment of acute pulmonary thromboembolism. J Am Soc Echocardiogr. 2001, 14: 921-926.
  26. Feldman LS, Brotman DJ. When can patients with acute deep vein thrombosis be allowed to get up and walk? Cleve Clin J Med. 2006, 73: 893-894, 896.
  27. Douketis JD, Kearon C, Bates S, et al: Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA. 1998, 279: 458-462.
  28. Hull RD, Pineo GF. Heparin and low-molecular-weight heparin therapy for venous thromboembolism: Will unfractionated heparin survive? Semin Thromb Hemost. 2004, 30: (Suppl 1): 11-23.
  29. Self TH, Reaves AB, Oliphant CS, Sands C. Does heart failure exacerbation increase response to warfarin? A critical review of the literature. Curr Med Res Opin. 2006, 22: 2089-2094.
  30. Ebell MH. Evidence-based initiation of warfarin (Coumadin). Am Fam Physician. 2005, 71: 763-765.

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Suggested Readings

  • American College of Chest Physicians Consensus Committee on Pulmonary Embolism. Opinions regarding the diagnosis and management of venous thromboembolic disease. Chest. 1998, 113: 499-504.
  • Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003, 107: I9-I16.
  • Antithrombotic Therapy for Venous Thromboembolic Disease. American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008, 133: 454S-545S. http://www.chestjournal.org/cgi/content/abstract/133/6_suppl/454S (accessed March 20, 2009)
  • Chunilal SD, Eikelboom JW, Attia J, et al: Does this patient have pulmonary embolism? JAMA. 2003, 290: 2849-2858.
  • Goldhaber SZ. Pulmonary embolism. N Engl J Med. 1998, 339: 93-104.
  • Goodacre S, Sutton AJ, Sampson FC. Meta-analysis: The value of clinical assessment in the diagnosis of deep venous thrombosis. Ann Intern Med. 2005, 143: 129-139.
  • Kearon C. Natural history of venous thromboembolism. Circulation. 2003, 107: I22-I30.
  • Stein PD, Fowler SE, Goodman LR, et al: Multidetector computed tomography for acute pulmonary embolism. N Engl J Med. 2006, 354: 2317-2327.
  • Stein PD, Woodard PK, Weg JG, et al: Diagnostic pathways in acute pulmonary embolism: Recommendations of the PIOPED II Investigators. Radiology. 2007, 242: 15-21.
  • Wells PS, Rodger M. Diagnosis of pulmonary embolism: When is imaging needed? Clin Chest Med. 2003, 24: 13-28.