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internal medicine Board Review Manual Statement of Editorial Purpose The Hospital Physician Internal Medicine Board Review Manual is a peer-reviewed study guide for residents and practicing physicians preparing for board examinations in internal medicine. Each manual reviews a topic essential to the current practice of internal medicine.

PUBLISHING STAFF PRESIDENT, Group PUBLISHER

Bruce M. White editorial director

Debra Dreger SENIOR EDITOR

Bobbie Lewis associate EDITOR

Rita E. Gould assistant EDITOR

Farrawh Charles executive vice president

Barbara T. White executive director of operations

Jean M. Gaul

Venous Thromboembolism Series Editor: Darilyn V. Moyer, MD Professor of Medicine, Vice Chair of Education, Program Director, Internal Medicine Residency Program, Temple University, Philadelphia, PA

Issue Editor and Contributor: Bizath S. Taqui, MD Assistant Professor of Medicine, Temple University, Philadelphia, PA

Contributors: Kathleen Coppola, MD Assistant Professor of Medicine, Temple University, Philadelphia, PA

Giuliana DeFrancesch, MD Assistant Professor of Medicine, Temple University, Philadelphia, PA

Mary S. Kraemer, MD Assistant Professor of Medicine, Temple University, Philadelphia, PA

Keith McNellis, MD Assistant Professor of Medicine, Temple University, Philadelphia, PA

Himani S. Shishodia, MD Attending Physician, St. Lukes-Roosevelt Hospital, New York, NY

PRODUCTION Director

Suzanne S. Banish PRODUCTION associate

Table of Contents

Kathryn K. Johnson ADVERTISING/PROJECT director

Patricia Payne Castle sales & marketing manager

Deborah D. Chavis NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the Amer­ ican Board of Internal Medicine.

Endorsed by the Association for Hospital Medical Education

Epidemiology and Pathogenesis. . . . . . . . . . . . . . 2 Diagnostic Testing. . . . . . . . . . . . . . . . . . . . . . . . . 4 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Prevention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Review Questions. . . . . . . . . . . . . . . . . . . . . . . . 16 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Cover Illustration by Kathryn K. Johnson

Copyright 2007, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and production of all published materials, including selection of topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment.

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Internal Medicine Board Review Manual

Venous Thromboembolism EPIDEMIOLOGY AND PATHOGENESIS Mary S. Kraemer, MD, and Giuliana DeFrancesch, MD EPIDEMIOLOGY Venous thromboembolism (VTE) is defined by the presence of either deep venous thrombosis (DVT) and/ or pulmonary embolism (PE). The exact incidence of VTE in the United States is unknown. The incidence of symptomatic first-time VTE adjusted for age and sex for the U.S. population is estimated to be between 70 and 113 cases per 100,000 person-years. These data are derived from studies of Caucasian populations.1 The incidence of PE relative to DVT depends on the inclusion of autopsy data. When autopsy data are not included, one third of patients with symptomatic VTE have PE and two thirds have DVT alone. When autopsy data are included, the proportion is reversed—55% of patients have PE and 45% have only DVT.1 The incidence of VTE increases with age. After age 40 years, the risk of VTE doubles with each decade. The incidence appears to be similar in males and females.2 Asian-Pacific Islanders and Hispanics have a 2.5 to 4-fold lower risk of symptomatic VTE compared with Caucasians and African Americans.2 There may also be seasonal variation, with VTE being more common in the winter months.2 Depending on the series, up to 50% of first-time VTE patients have no identifiable risk factor and VTE is classified as idiopathic.1 Of these idiopathic cases, up to 10% of patients have an occult cancer at the time of diagnosis.3 RISK FACTORS In the mid-19th century, Rudolf Virchow identified factors contributing to thrombosis. He postulated that injury to the blood vessel wall (endothelial damage), changes in blood flow (stasis), and alterations in blood constituents (hypercoagulability) are the main causes of thrombus formation. Many predisposing factors for VTE (Table 1) affect 1 or more components of Virchow’s triad.2 Surgery Surgery is a risk factor for VTE because of direct

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injury to the vascular endothelium and postoperative periods of immobilization or stasis. Major general surgery, requiring more than 30 minutes of anesthesia time and involving the thorax or abdominal cavities, is associated with a 15% to 30% incidence of VTE.4 Major orthopedic surgery, especially involving the hip and knee, is associated with an even higher (40%–60%) incidence of VTE. Finally, trauma surgery patients and neurosurgery patients with spinal cord injury have a very high (60%–80%) risk of VTE. It should be emphasized that these rates refer mainly to asymptomatic DVT detected by screening. However, there is good evidence that such thrombi correlated with symptomatic outcomes and death from PE.4 Malignancy Cancer is a hypercoagulable state but may also cause endothelial damage as a result of tumor invasion of blood vessels. Patients with cancer have a 7-fold higher risk of VTE. The risk may be even higher in patients with advanced disease or metastasis.5 Chemotherapy conveys an additional risk.6 Patients with VTE have a 3-fold higher risk of being diagnosed with cancer within 3 months, especially if they are older or present with idiopathic thrombosis.7 Thus, patients with idiopathic VTE need a thorough history and physical examination as well as screening for age- and sex-appropriate malignancies. Prior VTE Prior VTE is a strong independent risk factor for subsequent VTE. The risk is even higher in those patients for whom there was no cause identified for the first event.8 Pregnancy and Postpartum The antenatal and postpartum period is associated with a 5-fold increase in VTE,9 with an estimated incidence of 1 in 1000 pregnant women.10 It is thought that the hypercoagulable state of pregnancy exists to protect against maternal hemorrhage, which remains the leading cause of maternal death in the developing world. In the United States, the leading cause of maternal death is pulmonary embolism.11 The risk extends through the postpartum (6 weeks after delivery) period, and venous clots are most often found in the left lower extremity.10

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Ve n o u s T h ro m b o e m b o l i s m Oral Contraception The link between hormone therapy and VTE was first identified in the 1960s after the advent of oral contraceptive pills (OCPs). At that time, a higher incidence of VTE was noted in a new demographic of young, otherwise healthy woman. The risk of VTE in first-generation OCPs was associated with high levels of estrogen. Secondgeneration OCPs, with less estrogen, were associated with lower risk of VTE. However, risk of VTE increased again in third-generation OCPs because they contained high levels of progestogens, such as desogestrel.12 Hormone replacement therapy (HRT) also conveys an increased risk of VTE. Age, obesity, smoking and inherited thrombophilias further increase the risk of VTE associated with OCPs and HRT. The risk of VTE appears to be highest during the first 6 to 12 months of therapy.13 A personal history of VTE is an absolute contraindication to using OCPs. Routine screening for thrombophilia is not currently required prior to initiating OCPs or HRT because of expense and relatively low risk of fatal PE.13

Table 1. Risk Factors for Venous Thromboembolism

Thrombophilia Patients without obvious risk factors for VTE should be considered for evaluation for inherited or acquired thrombophilias. These include antithrombin deficiency, protein C and S deficiency, prothrombin mutation, and factor V Leiden mutation. Factor V Leiden mutation is the most common of the inherited prothrombotic disorders, affecting 5% of the population of northern European descent.14 This point mutation, found in 20% of patients with first time VTE,14 causes factor V to be resistant to inhibition by activated protein C, an endo­genous anticoagulant. Recurrent, idiopathic, or severe VTE in unusual locations suggests the presence of a thrombophilia. Inherited thrombophilia is also suggested by thrombosis in patients younger than age 50 years or in patients with family history of VTE. Acquired thrombophilias such as antiphospholipid antibody syndrome and hyperhomocysteinemia may present with arterial as well as venous thrombosis.14 Testing for the factor V Leiden and prothrombin mutations can be performed at the time of presentation with acute thrombosis.14 Because protein C and S levels and antithrombin levels are measured with functional assays, and the levels may be decreased by either the acute clot or by anticoagulants, testing for these disorders should be deferred until after treatment of the acute thrombosis.14 Levels should return to baseline 2 to 4 weeks after warfarin discontinuation.14

Weak risk factors (odds ratio < 2)

Medical Diseases The incidence of VTE has been reported to be

Strong risk factors (odds ratio > 10)

Fracture (hip or leg)



Hip or knee replacement



Major general surgery



Major trauma



Spinal cord injury

Moderate risk factors (odds ratio 2–9)

Arthroscopic knee surgery



Central venous lines



Chemotherapy



Congestive heart or respiratory failure



Hormone replacement therapy



Malignancy



Oral contraceptive therapy



Paralytic stroke



Pregnancy, postpartum



Previous venous thromboembolism



Thrombophilia



Bed rest > 3 days



Immobility due to sitting (eg, prolonged car or air travel)



Increasing age



Laparoscopic surgery (eg, cholecystectomy)



Obesity



Pregnancy, antepartum



Varicose veins

Adapted with permission from Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003;107(23 Suppl 1): 9–16.

at least as high in hospitalized medical patients as in patients undergoing general surgery, ranging from 10% to 26% in absence of prophylaxis.15 Acute medical conditions associated with venous stasis include cardiopulmonary disease, infections, ischemic stroke, and myocardial infarction. As stated, cancer is notorious for inducing a hypercoagulable state. Obesity has also been identified as an important independent risk factor for VTE. Immobility There is a strong correlation between long periods of immobility and the likelihood of VTE. However, there is a lack of consensus regarding the exact definition of immobility. The majority of clinical trials have inclusion criteria where the patients spend more than two thirds of their waking hours in bed.16

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Ve n o u s T h ro m b o e m b o l i s m NATURAL HISTORY Most (90%) of pulmonary emboli originate from thrombi that dislodge from proximal leg veins.17 Most of these thrombi develop from clots that form in the calf veins and extend to the proximal venous system. Without treatment, 25% to 30% of symptomatic calf DVT will progress, usually within the first week of presentation.17 Of patients with symptomatic proximal vein DVT, 40% to 50% will have high probability ventilationperfusion (V/Q) scans but no symptoms of PE.17 Furthermore, 70% of patients with acute PE have DVT on venography and 50% have DVT on compression ultrasound.17 Less common sources of PE include iliac veins, renal veins, and right heart and upper extremity veins. Without treatment, 50% of patients with symptomatic proximal DVT or PE have recurrent thrombosis within 3 months. The risk of recurrence after stopping anticoagulation is 10% per year in patients with continuing risk factors or “idiopathic” VTE as compared with 3% per year in patients with transient risk factors.17 Approximately 10% of patients with PE die within the first hour.18 Of the patients who survive at least 1 hour, the diagnosis is established and treatment is initiated in only 30% of patients.18 A large international multicenter registry of PE patients revealed 17.4% mortality rate at 3 months.19 Death is more likely due to missed diagnosis as opposed to inadequate treatment.18 Anticoagulant treatment has been shown to be effective in decreasing recurrence and mortality rates.20 The mortality rate directly attributed to PE is difficult to determine and, as stated, varies with the inclusion of autopsy data. It is also confounded by the presence of coexisting conditions such as malignancy or chronic cardiopulmonary disease, which may also contribute to death rates. PATHOPHYSIOLOGY Deep Venous Thrombosis The first component of Virchow’s triad is hypercoagulability, or a tendency toward thrombosis. Hypercoagulable disorders can be inherited or acquired. The second component, venous stasis, affects thrombosis by inhibiting the dilution of clotting factors as well as limiting the arrival of natural anticoagulants. Finally, endothelial damage exposes collagen and triggers platelet activation, adhesion, and aggregation in a manner similar to physiologic hemostasis.21 Pulmonary Embolism Gas exchange abnormalities associated with PE include hypoxemia from vascular occlusion–induced V/Q mismatch, increased alveolar dead space, and

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right-to-left shunting.22 Hypocapnia and respiratory alkalosis occur due to alveolar hyperventilation caused by reflex stimulation of irritant receptors.22 In contrast, patients with massive PE may be hypercapneic due to increased dead space and impaired minute ventilation.22 The hemodynamic response to PE depends on the size of the embolus as well as the patients underlying cardiopulmonary status. Healthy young patients with good cardiopulmonary reserve may be able to compensate for small emboli. However, in patients with large emboli or poor reserve, obstruction and neurohormonal activation lead to increased pulmonary vascular resistance, right heart strain, and right ventricular dilatation and hypokinesis.22 In addition, there is a displacement of the interventricular septum toward the left ventricle, leading to decreased left ventricular diastolic filling and decreased left ventricular preload.22 As a result, cardiac output is compromised and systolic pressures drop.

DIAGNOSTIC TESTING Himani S. Shishodia, MD, and Bizath S. Taqui, MD DEEP VENOUS THROMBOSIS The first step in evaluating a patient for DVT is clinical assessment. Classic symptoms and signs for DVT include leg pain, swelling, tenderness, erythema, and edema. However, none of these symptoms or signs has been found to be either sensitive or specific for the diagnosis of DVT.23 This problem with imprecision has led to the development of clinical prediction rules, or tools that quantify the relative contribution of various historical, physical examination, and laboratory findings toward a diagnosis. These rules help a clinician establish a pretest clinical probability for the presence of a disease. In the case of suspected DVT, the Wells score24 is the most widely used and validated clinical prediction rule (Table 2). Validation studies have shown a prevalence of DVT between 17% and 85% among patients with high probability Wells scores, between 0% and 38% among those with moderate probability scores, and between 0% and 13% among those with low probability scores.25 The median positive likelihood ratio for the highest risk level is 6.2 and the median negative likelihood ratio for lowest risk level is quite low, suggesting that the clinical prediction rule has a substantial impact in these 2 groups.25 Of note, the negative predictive value for

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Ve n o u s T h ro m b o e m b o l i s m the Wells score is 96%, but the positive predictive value is only 75%.25 The Wells score does not perform as well in the moderate-risk category.25 It is also not as helpful for older patients, patients with comorbidities, and patients with prior history of VTE.25 Finally, the score has been derived from and tested mainly in the outpatient or emergency department population and should be used with caution in inpatients.26 In a recent overview, the Wells score demonstrated good validity in outpatients and inpatients as well as for clinicians at various degrees of training.27

Table 2. Simplified Clinical Model for Assessment of Deep Vein Thrombosis (DVT)

d-Dimer d-dimer

is a plasma protein produced after lysis of cross-linked fibrin by plasmin. It is a breakdown product of blood clots and is elevated in patients with VTE because of the activation of coagulation and fibrinolysis.28 However, it is not specific for VTE and is elevated in many other conditions, including infection, malignancy, surgery, trauma, inflammatory disease, and pregnancy.28 Also of significance is its elevation in older adults, especially those older than 80 years.28 There are 2 major categories of d-dimer tests and many different assays in each category. The qualitative tests require visual inspection to determine a positive or negative result. These tests include latex agglutination assays and the newer whole blood agglutination assays. An example of the latter is the SimpliRED assay (Agen Biomedical, Brisbane, Australia), the qualitative test with the most clinical data. The qualitative assays are simple to perform, have a rapid turnaround time, and are inexpensive. They have a sensitivity of 85% to 90% and specificity of 70%.29 The main problem with qualitative assays is poor interobserver reliability. Thus, they require interpretation by trained observers. The quantitative tests (standard or rapid enzyme-linked immunosorbent assay [ELISA]) have a higher sensitivity 98% (95% to 100%) but lower specificity (as low as 40%) in comparison with qualitative tests.30 The d-dimer cutoff used in the literature and in clinical practice is 500 ng/mL.30 Physicians should be aware of the type of assay used in their hospital. d-dimer use should be dictated by the pretest clinical probability for VTE. The test is most useful in patients with low pretest clinical probability. In this group, either high- or moderate-sensitivity assays are appropriate for ruling out VTE and are associated with a 3-month incidence of VTE between 0.4% and 0.5%.30 In patients with moderate pretest probability, a high-sensitivity assay is preferred and has a 3-month incidence of VTE 0.5%.30 d-dimer is not useful in patients with high pretest probability for VTE.

Clinical Variable

Score*

Active cancer (treatment ongoing or within previous 6 months or palliative)

1

Paralysis, paresis, or recent plaster immobilization of the lower extremities

1

Recently bedridden for 3 days or more or major surgery within the previous 12 weeks requiring general or regional anesthesia

1

Localized tenderness along the distribution of the deep venous system

1

Entire leg swelling

1

Calf swelling at least 3 cm larger than asymptomatic leg (measured 10 cm below the tibial tuberosity)†

1

Pitting edema confined to the symptomatic leg

1

Collateral superficial veins (nonvaricose)

1

Previously documented DVT Alternative diagnosis at least as likely as DVT

1 –2

Reprinted with permission from Wells PS, Owen C, Doucette S, et al. Does this patient have deep vein thrombosis? JAMA 2006;295:199– 207. *A score of 3 or higher indicates a high probability of DVT; 1 or 2, a moderate probability; and 0 or lower, a low probability. †In patients with symptoms in both legs, the more symptomatic leg was used.

Venous Imaging Contrast venography is considered the gold standard for the diagnosis of DVT. Contrast dye is injected into the venous circulation and radiograms are diagnostic if there is an intraluminal filling defect. Venography has several limitations, including invasiveness, expense, and complication risk, including contrast-induced allergies, renal failure, and thrombosis. Therefore, it is no longer widely utilized and has been replaced by noninvasive methods for DVT diagnosis. Venous compression ultrasound is the most accurate noninvasive test for the diagnosis of proximal DVT. It utilizes B-mode techniques to image the venous system. The major diagnostic criterion for compression ultrasound is the failure of compressibility of a venous segment, presumably due to an occlusive thrombus. In many centers, Doppler waveform analysis and color imaging are combined with the B-mode compression ultrasound. Duplex ultrasound (compression ultrasound with Doppler analysis) has a sensitivity of 97% and specificity of 98% for diagnosing symptomatic thromboses in the proximal veins of the lower extremity.31 For diagnosis of distal or calf vein thrombosis, compression ultrasound has a decline in sensitivity to 73%.32

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Ve n o u s T h ro m b o e m b o l i s m Since most pulmonary emboli originate in the proximal veins and extension of calf DVT is rare after 1 week, many centers had limited testing to proximal veins and scheduled repeat ultrasound at 1 week.31 However, in symptomatic patients, only 10% to 20% of thrombi detected are isolated to the calf, and only 20% to 30% of these thrombi will extend to the proximal venous system.17 Thus, in cases of serial testing, only 1% to 2% of patients with initial negative ultrasound have demonstrated proximal extension at 1 week.31 This low rate of extension, in combination with the inconvenience and cost of serial ultrasound, has prompted most centers to adopt complete compression ultrasound, in which the entire deep venous system (proximal and distal) is imaged.31 Studies have shown that exclusion of DVT with a single negative result on complete compression ultrasound is associated with a 0.8% incidence of DVT at 3 months,33 making this a safe and effective strategy to rule out DVT. Ultrasound maintains high specificity but has lower sensitivity in asymptomatic patients.33 This may not be a major limitation, since two thirds of asymp­ tomatic thrombi are confined to the calf veins and do not cause clinically significant PE.33 MRI is the diagnostic test of choice for suspected iliac vein or inferior vena cava thrombosis. In the second and third trimester of pregnancy, MRI is more accurate than duplex ultrasound because the gravid uterus alters Doppler venous flow characteristics.33 In suspected calf vein thrombosis, MRI is more sensitive than any other noninvasive study.33 Expense and lack of availability limit its use. Venous ultrasound of the proximal veins is abnormal in about 50% of patients 1 year after initial episode of VTE.33 In comparison with chronic DVT, acute DVT is usually occlusive, nonechogenic, and continuous.33 Serial ultrasound may also help to differentiate acute and chronic thrombosis. However, there is no ideal modality to diagnose recurrent DVT. PULMONARY EMBOLISM Epidemiologic studies have shown that most people who die from PE die from diagnostic errors rather than a lack of response to therapy.18 PE manifests as a spectrum of presentations depending on the size and number of emboli as well as the patient’s age and clinical condition. There is no single symptom, sign, laboratory abnormality, or noninvasive test that is sensitive or specific for PE. On the other hand, PE is also “over-diagnosed,” and patients are often subjected to inappropriate testing and potentially harmful treatment. Consistent and precise diagnosis of PE is one of the most difficult challenges in medicine.

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Symptoms and Signs As stated, the clinical presentation of PE depends in part on the size and number of emboli. A small embolus, causing less than 50% obstruction of the pulmonary circulation, may be asymptomatic or cause only dyspnea on exertion.26 Pleuritic chest pain and hemoptysis may also occur, especially with pulmonary infarction. Fever, tachypnea, and sinus tachycardia are common. In contrast, a sudden obstruction of more than 50% of the pulmonary circulation manifests as right heart strain with or without hemodynamic compromise.26 Both “acute minor” and “acute massive” forms of PE are characterized by a sudden onset. Somewhere in between are patients with “subacute massive” PE. In this scenario, more than 50% obstruction of pulmonary circulation is caused by multiple small or moderately sized emboli that accumulate over several weeks, thus allowing the right ventricle to adapt.26 These patients have right heart strain but preserved systolic pressures. In addition to size and number of emboli, age and coexisting conditions also have an impact. Younger patients with good cardiopulmonary reserve may present more subtly. On the other hand, PE may be difficult to distinguish from chronic obstructive pulmonary disease, congestive heart failure, acute coronary syndromes, or pneumonia in older patients with coexisting cardiopulmonary disease. Thus, the threshold for considering the diagnosis should be low, especially in patients who present with acute or worsening dyspnea or chest pain. As in the case of DVT, symptoms and signs for PE are neither sensitive nor specific. The landmark PIOPED study demonstrated that “classic” symptoms and signs in patients suspected of having PE occurred with equal frequency in patients with and without PE.34 In addition, basic tests such as arterial blood gases, electrocardiogram, and chest radiograph are also unreliable when viewed in isolation. The absence of hypoxemia on arterial blood gases does not exclude PE.35 The A-a gradient is normal in 20% of patients with confirmed PE on pulmonary angiogram.36 The most common findings on electrocardiogram are sinus tachycardia, incomplete or complete right bundle branch block and atrial tachyarrhythmias. The classic S1Q3T3 pattern is neither sensitive nor specific for PE.37 The most common finding on chest radiograph is normal lungs.37 Findings such as abrupt cutoff of pulmonary vasculature (Westermark’s sign) and wedge shaped opacity (Hampton’s hump) are rare.37 Electrocardiogram and chest radiograph are most useful for ruling out other diagnoses on the differential.

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Ve n o u s T h ro m b o e m b o l i s m Table 3. PIOPED Data on Pulmonary Embolism (PE) Status Clinical Science Probability, % Scan Category

80%–100% n with PE/N

%

High probability

28/29

Intermediate probability

27/41

Low probability Near normal/normal Total

20%–79% n with PE/N

%

0%–19% n with PE/N

%

All Probabilities n with PE/N

%

96

70/80

66

66/236

88

5/9

56

103/118

87

23

11/68

16

104/345

6/15

40

30

30/191

16

4/90

4

40/296

0/5

14

0

4/62

6

1/61

2

51/128

61/90

4

68

170/569

30

21/228

9

252/887

28

Adapted with permission from The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 1990;263:2753–9.

Prediction Rules Ever since the PIOPED study34 demonstrated the fallibility of individual symptoms and signs for predicting PE, there has been an emphasis on combining symptoms, signs, and risk factors to estimate an overall pretest probability. The PIOPED group demonstrated that empiric judgment of clinicians was accurate in predicting PE. The prevalence of PE was 9%, 30%, and 68% in the low, intermediate, and high pretest clinical probability groups, respectively (Table 3).34 Since PIOPED, an effort has been made to create standardized clinical prediction rules. The 2 most widely used and validated rules are the simplified Wells score for PE38 and the Geneva rule39 (Table 4 and Table 5). The Geneva rule has recently been revised and no longer requires arterial blood gas sampling and chest radiograph interpretation. The Wells score is still criticized for including the need to assess whether an alternative diagnosis is more probable than PE. This is a subjective component and has only moderate interobserver agreement. Both rules have been validated in elderly patients over age 75 years.40 Both rules have been derived and more extensively tested in emergency department or outpatient populations.41 In contrast, the PISA-PED rule was derived from mainly hospitalized patients.42 In most studies, clinical prediction rules have demonstrated similar accuracy in the low- and high-risk categories to the empiric clinical judgment of experienced physicians.41 (Table 6) Thus, the choice of clinical prediction rule may not be as important as the actual practice of using either empiric or standardized method to assess pretest clinical probability. This is particularly important since there is no current standalone test that is acceptable to rule in or rule out the diagnosis of PE. d-Dimer d-Dimer

tests have similar characteristics and

Table 4. The Simplified Wells Scoring System Findings

Score*

Clinical signs/symptoms of deep venous thrombosis (minimum of leg swelling and pain with palpation of the deep veins of the leg)

3.0

No alternate diagnosis likely or more likely than pulmonary emboli

3.0

Heart rate > 100 bpm

1.5

Immobilization or surgery in last 4 weeks

1.5

Previous history of deep venous thrombosis or pulmonary emboli

1.5

Hemoptysis

1.0

Cancer actively treated within last 6 months

1.0

Adapted with permission from Chunilal SD, Eikelboom JW, Attia J, et al. Does this patient have pulmonary embolism? JAMA 2003;290:2849– 58. *Category scores are as follows: low probability, < 2; moderate, 2–6; and high, > 6. Patient’s clinical score is calculated by the summing of the scores (weight) of the predictor variables that are present.

accuracy for PE as they do for DVT. The high sensitivity assays can be used to rule out PE in patients with low or moderate pretest probability.43 However, the moderate sensitivity assays are useful for ruling out PE in patients with low pretest probability only.43 As in the case of DVT, d-dimer is not useful in patients with high pretest probability.43 Venous Imaging As stated, in patients with acute PE, DVT is detectable by bilateral ascending venography in 75% and by compression ultrasound of proximal veins in 50%.17 In addition, an abnormal proximal compression ultrasound is found in 5% to 10% of patients with nondiagnostic lung scans.43 However, because positive predictive value is only 75% in this setting, venography should be considered prior to initiating anticoagulant

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Ve n o u s T h ro m b o e m b o l i s m Table 5. The Revised Geneva Score Regression Coefficients

Points

Age > 65 yr

0.39

1

Previous DVT or PE

1.05

3

Surgery (under general anesthesia) or fracture (of the lower limbs) within 1 mo

0.78

2

Active malignant condition (solid or hematologic malignant condition, currently active or considered cured < 1 yr)

0.45

2

Variable Risk factors

Symptoms Unilateral lower-limb pain

0.97

3

Hemoptysis

0.74

2

75–94 bpm

1.20

3

≥ 95 bpm

0.67

5

1.34

4

Clinical signs Heart rate

Pain on lower-limb deep venous palpation and unilateral edema Clinical probability Low

0–3 total

Intermediate

4–10 total

High

≥ 11 total

DVT = deep venous thrombosis; PE = pulmonary embolism. (Adapted with permission from Le Gal G, Righini M, Roy PM, et al. Pre­diction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med 2006;144:165–71.)

therapy.43 In patients with nondiagnostic lung scans and negative venous ultrasound, low pretest probability or negative d-dimer is associated with low risk of VTE recurrence.43 Finally, incorporation of venous ultrasound is also an important strategy in patients who have negative computed tomography pulmonary angiogram (CTPA), since this is not yet a stand-alone test. CT venography (CTV) and magnetic resonance venography (MRV) are emerging technologies that may replace compression ultrasound in the future.31 CTV has the added benefit of being performed simultaneously with CTPA, as was the case in the PIOPED II study.44 Conventional Pulmonary Angiography Pulmonary angiography has traditionally been the reference standard for diagnosis of PE. However, it is invasive, costly, and cannot be performed in patients with renal insufficiency. It is associated with a small but definite mortality rate of 0.5% and morbidity rate of

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0.8%.34 In addition, it is no longer available in many centers and is rarely performed, decreasing the expertise in interpretation of results. Finally, a negative pulmonary angiogram does not preclude the development of VTE, as demonstrated by a 1.6% long-term recurrence rate in the PIOPED study.34 This is still the reference standard against which the safety of withholding anticoagulant therapy after negative tests for PE is assessed. However, the definitive diagnosis for VTE is probably pathologic confirmation, which for obvious reasons is unacceptable as a diagnostic test. Noninvasive Pulmonary Imaging Due to the invasiveness of conventional pulmonary angiography, V/Q scanning ini­tially became the procedure of choice for suspected PE. The original PIOPED study was a large prospective trial comparing V/Q scan (in combination with pretest probability) with pulmonary angiogram.34 The pretest probability was established prior to the V/Q scan by experienced clinicians. Radiologists then interpreted and classified the V/Q scan findings into categories of high, nondiagnostic (intermediate or low), and normal. Each level of pretest probability was combined with each category of V/Q scan result, and the combination was compared with findings on pulmonary angiogram and/or longterm recurrence of VTE.34 The PIOPED study showed that a normal V/Q scan had an almost 100% negative predictive value for PE and essentially excluded the diagnosis.34 Also, a high probability V/Q scan (in conjunction with an intermediate to high pretest probability) had an 85% to 95% positive predictive value for PE and was considered an adequate rule-in criterion.34 The problem arises from the fact that most scans were nondiagnostic and required further investigation.34 Prior to the advent of CTPA, this further investigation included serial ultrasound, venography, and pulmonary angiogram. Although advances in V/Q scan technology and revisions in interpretation criteria have decreased the number of nondiagnostic scans, it still has the limitation of providing indirect evidence for PE through V/Q mismatches. CTPA is an evolving technology that has replaced the V/Q scan as the procedure of choice for PE in most centers.45 It is faster and easier to perform, taking less than 30 seconds with a single breath hold to minimize motion artifact. It allows direct visualization of the thrombus and provides information about alternative diagnoses and/or coexisting cardiopulmonary diseases. There is better interobserver agreement than for V/Q scans. The main disadvantages of CTPA are its contraindication in renal insufficiency and its inability

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Ve n o u s T h ro m b o e m b o l i s m Table 6. Positive and Negative Predictive Values of CTA as Compared with Previous Clinical Assessment High Clinical Probability Variable

Intermediate Clinical Probility

Low Clinical Probability

n/Total N

Value (95% CI)

n/Total N

Value (95% CI)

n/Total N

Value (95% CI)

Positive predictive value of CTA

22/23

96 (78–99)

093/101

92 (84–96)

22/38

58 (40–73)

Positive predictive value of CTA or CTV

27/28

96 (81–99)

100/111

90 (82–94)

24/42

57 (40–72)

Negative predictive value of CTA

09/15

60 (32–83)

121/136

89 (82–93)

158/164*

96 (92–98)

Negative predictive value of both CTA and CTV

09/11

82 (48–97)

114/124

92 (85–96)

146/151*

97 (92–98)

Note: the clinical probability of pulmonary embolism is based on the Wells score: less than 2.0, low probability; 2.0 to 6.0, moderate probability; and more than 6.0, high probability. CI = confidence interval; CTA = computed tomography angiography; CTV = computed tomography venography. (Adapted with permission from Stein PD, Fowler SE, Goodman LR, et al; PIOPED II Investigators. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 2006;354:2317–27.).

to sufficiently visualize subsegmental arteries. CTPA is also relatively contraindicated in pregnant patients and those with anaphylactic reactions to contrast dye. Since its introduction in the beginning of the 1990s, there have been many studies and systematic reviews attempting to establish the sensitivity and specificity of CTPA for diagnosing PE. Individual trials have varied in quality, been subject to referral bias, used different types and techniques of CT scanning (single detector vs. more modern multidetector), and identified various reference standards to which CTPA test characteristics have been compared. One systematic review demonstrated a wide range of sensitivity (45%–100%) and specificity (78%–100%) of CTPA for diagnosing PE.46 However, other systematic reviews have used different inclusion criteria and have yielded varying results. Two more recent reviews have garnered attention due to their promising results. The reviews concluded that patients with a negative CTPA had a 1.4% rate of VTE at 3 months,47 or the test had a 99.4% negative predictive value.48 As stated by the authors of these reviews, this was comparable to data from conventional pulmonary angiography and better than V/Q data. These reviews have several limitations including heterogeneity of individual studies, publication bias, language bias, and reference standard bias. Their results should not be used to conclude that a negative CTPA test result alone is adequate justification for withholding anticoagulation. In most of the included studies, additional tests were performed whose results influenced the decision of whether or not to anticoagulate. Instead, these and other studies demonstrated that the combination of non-high pretest probability, negative CTPA, and negative venous imaging of lower extremities was associated with a low (1.5%–1.8%) rate of VTE at 3 months.49

The literature has lagged behind technology advances, with many studies evaluating single-detector CTPA as opposed to the newer and higher resolution multidetector CTPA. This technology is 8 times faster than single-detector CTPA, has fewer motion artifacts, and has higher resolution images. There have been several recent studies evaluating the accuracy of multidetector CTPA. The most notable of these studies was the PIOPED II study, which compared multidetector CTPA with or without CT venography (in conjunction with pretest clinical probability) to a composite reference standard of venography, compression ultrasound, and V/Q scan and/or conventional pulmonary angiography.44 In PIOPED II, a positive CTPA in a high- or intermediate-risk patient had an acceptable positive predictive value (92%–96%) for confirming PE, and a negative CTPA in a low-risk patient had an acceptable negative predictive value (96%) for ruling out PE.44 Likelihood ratios for CTPA-CTV were 16.5 for a positive study and 0.11 for a negative study.44 Multidetector CTPA-CTV had a higher sensitivity than CTPA alone (90% vs. 83%), with similar specificity (95%– 96%).44 Recently, the PIOPED II investigators suggested systematic approaches to evaluation of PE based on pretest probability and the results of their study (Figure 1, Figure 2, and Figure 3).50 Risk Stratification The International Cooperative Pulmonary Embolism Registry (ICOPER) identified age older than 70 years, cancer, congestive heart failure, chronic obstructive pulmonary disease, and systolic blood pressure less than 90 mm Hg as significant predictors of increased mortality.19 Elevated cardiac biomarkers such as troponins and B-type natriuretic peptide are also independent

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Ve n o u s T h ro m b o e m b o l i s m Positive D-dimer rapid ELISA

CT angiography or CT angiography/CT venography

CT angiography negative, NPV 96% CT angiography/CT venography negative, NPV 97%

No treatment

CT angiography positive, PPV 58% CT angiography/CT venography positive, PPV 57%

Segmental, PPV 68% Subsegmental, PPV 25%

Main or lobar pulmonary embolism, PPV 97%

Options: • Repeat CT angiography or CT angiography/CT venography if poor quality • If CT angiography only, ultrasonography or MRI venography • Pulmonary scintigraphy • Digital subtraction angiography • Serial ultrasonography

Treat

Figure 1. Low probability clinical assessment of pulmonary embolism. CT = computed tomography; ELISA = enzyme-linked immuno­ assorbent assay; MRI = magnetic resonance imaging; NPV = negative predictive value; PPV = positive predictive value. (Adapted with permission from Stein PD, Woodard PK, Weg JG, et al; PIOPED II Investigators. Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II Investigators. Radiology 2007;242:15–21.)

Positive D-dimer rapid ELISA

CT angiography or CT angiography/CT venography

CT angiography negative, NPV 89% CT angiography/CT venography negative, NPV 92%

No treatment

CT angiography positive, PPV 92% CT angiography/CT venography positive, PPV 90%

Treat

Option if CT angiography only, ultrasonography or MRI venography

Figure 2. Moderate probability clinical assessment of pulmonary embolism. CT = computed tomography; ELISA = enzyme-linked immunoassorbent assay; MRI = magnetic resonance imaging; NPV = negative predictive value; PPV = positive predictive value. (Adapted with permission from Stein PD, Woodard PK, Weg JG, et al; PIOPED II Investigators. Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II Investigators. Radiology 2007;242:15–21.)

predictors of early mortality and justify performance of echocardiography.51 Patients with right ventricular dysfunction on echocardiography have an increased

risk of hypotension, cardiogenic shock, and early death.51 Finally, right ventricle size on CTPA also helps predict morbidity and mortality.51

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Ve n o u s T h ro m b o e m b o l i s m CT angiography or CT angiography/CT venography

CT angiography negative, NPV 60% CT angiography/CT venography negative, NPV 82%

Options: • Repeat CT angiography or CT antiography/CT venography if poor quality • If CT angiography only, ultrasonography, or MRI venography • Pulmonary scintigraphy • Digital subtraction angiography • Serial ultrasonography

CT angiography positive, PPV 96% CT angiography/CT venography positive, PPV 96%

Treat

Figure 3. High probability clinical assessment of pulmonary embolism. CT = computed tomography; MRI = magnetic resonance imaging; NPV = negative predictive value; PPV = positive predictive value. (Adapted with permission from Stein PD, Woodard PK, Weg JG, et al; PIOPED II Investigators. Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II Investigators. Radiology 2007;242:15–21.)

TREATMENT Keith McNellis, MD, and Kathleen Coppola, MD INITIAL TREATMENT The main aim of VTE therapy is to prevent extension of thrombosis and embolization to the lungs. Other long-term goals include reduction in the incidence of recurrent VTE, prevention of post-thrombotic syndrome (PTS), and avoidance of pulmonary hypertension.52 Anticoagulants have been the mainstay of VTE therapy since Barritt and Jordan53 demonstrated the efficacy of heparin and warfarin in reducing morbidity and mortality in patients with acute PE. Since then, a vast array of drugs have emerged, including a low-molecular-weight heparin (LMWH), direct thrombin inhibitors, and factor Xa inhibitors. Heparin First discovered in 1916, unfractionated heparin (UFH) exerts its anticoagulant effect by binding to antithrombin.54 The resulting heparin–antithrombin complex inhibits the activity of factor Xa and thrombin.55 Only one third of the molecules of UFH have the required sequence for binding to antithrombin. UFH also contains molecules that bind to other plasma proteins that are present in variable amounts in each

individual. Thus, UFH has an unpredictable effect in different people.52 UFH is metabolized by the liver and has side effects of bleeding, heparin-induced thrombocytopenia (HIT), and osteoporosis.52 The dosing of UFH is based on 1 of 2 schedules and requires intra­ venous administration and frequent monitoring of the activated partial thromboplastin time to insure a therapeutic level of anticoagulation is achieved. Fractionated heparin, also known as LMWH, is formed by enzymatic and chemical cleavage of UFH. LMWH retains the ability to inhibit factor Xa and thrombin, but its smaller size decreases nonspecific binding to other plasma proteins. Compared with UFH, LMWH has increased bioavailability, a longer half-life, and a more predictable dose response.52 In addition, LMWH is associated with a lower incidence of HIT, potentially lower risk of bleeding, and lower risk of osteoporosis.52 It has a dose-dependent renal clearance, which needs to be taken into consideration in patients with renal insufficiency. Other considerations include dosing difficulties in obese patients and problems with reversibility in cases of bleeding. There are currently 8 LMWHs, each with its own molecular weight and dosing regimen. There is insufficient evidence to differentiate amongst these LMWHs based on efficacy and safety.52 LMWHs do not require monitoring to insure therapeutic anticoagulation. The utility of anti–factor Xa assay is controversial. Its correlation with anticoagulant effect and bleeding risk is unclear.56 Early studies demonstrated that LMWH had better

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Ve n o u s T h ro m b o e m b o l i s m efficacy and safety when compared with UFH, particularly for reducing mortality at 3 to 6 months’ followup.57 The more recent evidence has shown a lower magnitude of benefit of LMWH over UFH.58 The majority of the evidence is with respect to therapy for DVT rather than PE.59 However, a recent metaanalysis provided convincing evidence that LMWH is safe and efficacious in patients with noncritical PE. Cost-effectiveness analyses have shown a benefit or at least equivalency for LMWH in comparison with UFH regardless of treatment setting.60

result of a massive PE and who have been meticulously screened for risk of bleeding.66 Surgical embolectomy may be considered in patients with massive or submassive PE in whom fibrinolysis is contraindicated or has failed. Other indications for embolectomy include paradoxical embolism, persistent right heart thrombi, and hemodynamic or respiratory compromise requiring cardiopulmonary resuscitation.67 Finally, catheter-based pulmonary embolectomy is an emerging strategy that may be an option in patients with contraindications to open surgical embolectomy.68

Indirect Factor Xa Inhibitors Fondaparinux is an indirect factor Xa inhibitor. It has a linear pharmacokinetic profile,61 allowing for weight-based daily dosing and negating the need for continuous monitoring.61 It does not bind to platelet factor 4 and theoretically should not cause thrombocytopenia.61 It has renal clearance.61 In 2 large, multicenter clinical trials, fondaparinux was as effective and safe as UFH for the treatment of PE62 and as effective and safe as enoxaparin for the treatment of DVT.63

Thrombolytics and Embolectomy Thrombolytics have been evaluated in patients with either massive or submassive PE. Given the paucity of randomized clinical trial data, the indications for thrombolytic therapy are controversial. Most of the evidence was based on short-term outcomes, such as de-escalation of therapy and resolution of hemodynamic abnormalities.64 There are no definitive data for mortality benefit from thrombolytics.64 There are also no definitive evidence for initiating thrombolytic therapy in patients who are hemodynamically stable but have echocardiographic evidence of right ventricular dysfunction/failure.65 The major limitation of thrombolytic therapy is the 1% to 3% risk of intracranial hemorrhage.64 Based on risk-benefit analysis, many experts recommend that thrombolytics should be reserved for patients who have cardiogenic shock as a

LONG-TERM TREATMENT Vitamin K Antagonists The long-term treatment of VTE usually involves vitamin K antagonists most commonly warfarin. Warfarin and heparin can usually be started si­multaneously except in patients with known protein C deficiency. These patients require therapeutic level of anticoagulation with heparin prior to warfarin initiation in order to prevent skin necrosis. The recommended initiation dose for warfarin has been 5 mg, which was shown to achieve therapeutic INR as fast as the 10-mg loading dose.69 However, a recent outpatient study demonstrated faster achievement of target INR with the 10-mg loading dose.70 However, the study also demonstrated increased rates of bleeding associated with the higher loading dose. The optimal dosing of warfarin achieves a goal INR of 2 to 3.64. This INR range has been shown to be more effective than low-intensity dosing (1.5–2.0) and does not have increased rate of bleeding.71 Patients should be educated about warfarin interactions with food, alcohol, and other medications. There are also genetic variations of warfarin metabolism that are present in some individuals.72 The optimal duration of longterm anticoagulant therapy with vitamin K antagonists is not well substantiated. Duration is influenced by the patient’s prior history of VTE, underlying risk factor for thrombosis, and potential for bleeding. Patients with a permanent or idiopathic risk factor, malignancy, or recurrent VTE may require longer anticoagulation.71 However, patients with calf vein DVT may do as well with shorter duration VTE.71 In general, studies have demonstrated a “step-wise decline” in the incidence of VTE as the duration of anticoagulation increases from 3 months or less to 12 months or more.71 However, benefit of extended therapy needs to be weighed against the increased risk of major bleeding that has also been demonstrated. Of note, total adverse events (recurrent VTE or major bleeding or death) declined as duration of therapy increased.71 It should also be noted that the benefit of longer therapy disappears after the

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Direct Thrombin Inhibitors Direct thrombin inhibitors also have the advantages of predictable dose response and reduced incidence of thrombocytopenia.61 However, they do not have an antidote for cases of severe bleeding.61 Argatroban and lepirudin are 2 intravenous direct thrombin inhibitors that are U.S. Food and Drug Administration–approved for the prevention and/or treatment of VTE in patients with HIT.61 Ximelagatran is an oral direct thrombin inhibitor that has been withdrawn from the market because of an increased risk of hepatic toxicity.61

Ve n o u s T h ro m b o e m b o l i s m anticoagulants are discontinued.71 The American College of Cardiology has made suggestions based on the available data:73 Patient

Duration of Therapy

First VTE, transient risk factor

3 to 6 months

First VTE, idiopathic

At least 6 months

First VTE, spontaneous AND either lifethreatening OR associated with more than 1 genetic abnormality

Consider indefinite

First VTE and active cancer

Lifelong or until cancer inactive

Second VTE, transient risk factor

At least 12 months

Second spontaneous VTE OR third VTE

Lifelong

Low-Molecular-Weight Heparin LMWH has been evaluated as an alternative to vitamin K antagonists. Most of the studies were open-label and had extensive exclusion criteria that limit generalizability of their results.71 In addition, the studies may have lacked power.71 In general, the rates of recurrent VTE were not significantly different for LMWH as compared with vitamin K antagonists, and bleeding rates were equivalent or lower for LWMH.71 It should be noted that the data for long-term LMWH therapy for PE, as opposed to DVT, is limited.71 Also, current cost-effectiveness analysis favors warfarin over LMWH for treatment of DVT.71 At the moment, LMWH is reserved for patients with difficult to control INR or cancer patients. In patients with malignancy, there is evidence to support the superiority of LMWH over warfarin.74 IVC Filters Inferior vena cava (IVC) filters are indicated in patients for whom anticoagulation is contraindicated, in those who experience recurrent PE despite adequate anticoagulation, and possibly in patients with PE who have poor cardiopulmonary reserve.72 Vena cava interruption has been used in treatment of DVT to prevent pulmonary embolism since the early 1970s. However, there has been only 1 randomized clinical trial evaluating the efficacy of IVC filters to prevent recurrent VTE.75 Patients in the IVC filter group had significantly fewer total PE after 12 days and fewer symptomatic PE at 8 years. However, the IVC filter group also had significantly higher rates of DVT. There was no difference in mortality between the groups. Both groups received early anticoagulation, so the study did not provide information about effectiveness of filters in patients in whom anticoagulation is contraindicated. Retrievable IVC filters have recently been approved as an alternative for patients with temporary contraindication to anticoagulation, but data for these are limited.76

treatment issues Post-Thrombotic Syndrome PTS or postphlebitic syndrome refers to a constellation of symptoms and signs that occurs in 20% to 50% of patients with symptomatic DVT as a result of impaired venous flow of blood caused by DVT. The clinical manifestations of PTS include persistent edema, pain, hyperpigmentation, eczematoid dermatitis, pruritus, ulceration, and cellulitis. Although there is some evidence to suggest the benefit of catheter-directed thrombolysis in preventing PTS, additional trials are needed to determine the precise indications of such therapy in patients with DVT.71 There is evidence to support the use of compression stockings in preventing PTS, with the most benefit derived from use early after diagnosis of DVT.77 Pregnancy Warfarin is contraindicated in pregnancy due to increased risk of fetal bleeding and teratogenesis, especially if administered between 6 and 12 weeks of gestation. In contrast, UFH and LMWH do not cross the placenta and may be used during pregnancy. While LMWH as a prophylactic therapy for pregnant women has been extensively studied, fewer than 200 pregnant women have been treated with LMWH in observational studies of treatment of DVT or pulmonary embolism.71 The data for management of VTE in pregnant patients are based on observational studies of LMWH or IVC filter, most of which were underpowered.71 The evidence for IVC filter in pregnant women is weak.71 Although, the evidence is not optimal, the American College of Chest Physicians (ACCP) has made recommendations for both prophylaxis and treatment of VTE during pregnancy.78 Malignancy Recent evidence has emerged supporting the use of LMWH over warfarin in patients with cancer who have VTE. According to 1 trial, LMWH in full doses for the first month followed by 50% to 75% of the initial regimen has the potential to provide a more effective anticoagulant regimen in cancer patients with VTE and does not carry an increased risk of bleeding.74

PREVENTION Keith McNellis, MD, and Kathleen Coppola, MD The first trials demonstrating the benefit of VTE prevention concerned surgical patients and were published in the 1970s. Since then, there have been abundant

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Ve n o u s T h ro m b o e m b o l i s m Table 7. Levels of Thromboembolism Risk in Surgical Patients Without Prophylaxis DVT, % Level of Risk

Pulmonary Embolism, %

Calf

Proximal

Clinical

Fatal

Successful Prevention Strategies

2

0.4

0.2

< 0.01

No specific prophylaxis; early and “aggressive” mobilization

Moderate risk Minor surgery in patients with additional risk factors Surgery in patients aged 40–60 yr with no additional risk factors

10–20

2–4

1–2

0.1–0.4

LDUH q 12 hr; LMWH ≤ 3400 U daily; GCS or IPC

High risk Surgery in patients > 60 yr, or age 40–60 yr with additional risk factors (prior VTE, cancer, molecular hypercoagulability)

20–40

4–8

2–4

0.4–1.0

LDUH q 8 hr; LMWH ≥ 3400 U daily; or IPC

Highest risk Surgery in patients with multiple risk factors (age > 40 yr, cancer, prior VTE) Hip or knee arthroplasty, hip fracture surgery Major trauma, spinal cord injury

40–80

10–20

4–10

0.2–5

Low risk Minor surgery in patients < 40 yr with no additional risk factors

LMWH > 3400 U daily; fondaparinux; oral VKA INR, 2–3; or IPC/GCS + LDUH/LMWH

GCS = graduated compression stockings; INR = international normalized ratio; IPC = intermittent pneumatic compression; LDUH = low-dose unfractionated heparin; LMWH = low-molecular-weight heparin;VKA = vitamin K antagonist. (Adapted with permission from Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001;119(1 Suppl):134S.)

data demonstrating the efficacy of DVT prophylaxis in almost all subsets of hospitalized patients, most recently in acutely ill medical patients. The goals of prophylactic therapy are to reduce the risk of DVT and its associated morbidities (eg, PTS) and to prevent morbidity and mortality from PE. Risk of thrombosis is based on patient characteristics, type of surgery and anesthesia, type of acute medical illness, and degree of immobility. Many hospitalized patients have multiple risk factors and risk assessment models for VTE potential have been developed but not validated.79 Assessment should be individualized for each patient, taking into account risk of bleeding as well as thrombosis.

General, Gynecologic, and Urologic Surgery Patients undergoing thoracic, gynecologic, or urologic surgery appear to have similar rates of VTE,

varying between 15% to 30% in patients not receiving thromboprophylaxis.80 Most clinical trials and several meta-analyses comparing LMWHs with low-dose UFH showed equivalent efficacy and safety, although a significant reduction of asymptomatic DVT in LMWH group was found in some studies.81 Bleeding rates were difficult to compare because drug doses varied in different studies. The first dose of low-dose UFH or LMWH is given 2 to 3 hours before an operation, with the following exceptions: For patients receiving high-dose LMWH, it should be administered the evening before surgery. For patients at high risk for bleeding, the preoperative dose is usually omitted. In patients who have high risk of bleeding and only moderate risk of thrombosis, graduated compression stockings or intermittent pneumatic compression should be considered as alternatives to pharmacologic prophylaxis.80 In patients who have high risk of bleeding as well as high risk of thrombosis, a combined form of mechanical and pharmacologic prophylaxis may be preferred, and the anticoagulant administration should begin 1 or 2 days after surgery.80 Anticoagulation is discontinued after 5 to 7 days unless the patient has cancer or remains immobilized.4 Several studies have shown that most operations performed as same-day surgery are associated with a very low throm-

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PREVENTION IN SURGICAL PATIENTS The ACCP categorized surgical patients based on age (younger or older than age 40 years), anesthesia duration (less than or greater than 30 minutes), coexisting medical disease, and type and location of surgery. Patients were subsequently classified as being at low, moderate, or high risk for VTE (Table 7).4

Ve n o u s T h ro m b o e m b o l i s m botic risk and do not require a specific form of thromboprophylaxis.82 However, these patients should still be assessed for individual thrombotic risk.80 Orthopedic Surgery The risk of VTE in patients undergoing major orthopedic surgery is very high, ranging from 40% to 60% for overall DVT and 10% to 30% proximal DVT in the absence of prophylaxis.4 LMWH was more efficacious than low-dose UFH in this population and is the most commonly used method worldwide.4 Warfarin was less effective than LMWH in preventing both asymptomatic and symptomatic VTE during hospital stay, but it seemed to be equally effective when evaluated over a longer period of follow-up.83 It is still used in the United States due to its cost as well as evidence of lower bleeding rates in comparison with LMWH. Fondaparinux has been evaluated extensively in patients undergoing major orthopedic surgery and showed greater efficacy than enoxaparin in preventing venographic DVT after hip and knee replacement as well as after hip fracture surgery.4 Disadvantages of fondaparinux include cost and increased risk of minor bleeding. Prolonged (4– 5 weeks) anticoagulation was associated with a significant reduction of DVT in patients with elective and traumatic hip surgery but not in patients undergoing knee implantation, whose risk of VTE is very high in the first 2 weeks after surgery but low afterward.4 For minor orthopedic surgeries, thromboprophylaxis with LMWH is recommended in patients with additional thrombotic risk factors or following a prolonged or complicated procedure, whereas uncertainty remains regarding the need for specific thromboprophylaxis in other cases.4 Trauma, Vascular Surgery, and Neurosurgery Patients who have sustained major trauma, especially those with spinal cord injury and pelvic fractures, are at particularly high risk of DVT, with an incidence of 60% to 80%.4 Studies have shown that in patients who have sustained major trauma, including spinal cord injury, LMWH is superior to low-dose UFH.84 The optimal duration of thromboprophylaxis for these patients is not known, but individuals with spinal cord injury and paralysis should receive prophylaxis for a minimum of 3 months.4 The incidence of DVT in elective vascular surgical procedures varies from ~15% to 30%.4 Procedures in the proximal vascular tree such as aortoiliac bypass surgery appeared to carry a greater VTE risk than more distal procedures such as femoropopliteal bypass.4 Because these patients are often on concomitant aspirin and antiplatelet therapy, they are at increased risk of bleeding. Thromboprophylaxis in

these patients should be reserved for individuals with additional risk factors for VTE.4 Neurosurgical patients have at least a moderately elevated risk of VTE but also have a high bleeding risk because of the location of their surgery. For patients at increased risk of bleeding, traditional intermittent pneumatic compression was superior to venous foot pump.4 It is therefore recommended that these patients receive thromboprophylaxis with intermittent pneumatic compression devices and/or graduated compression stockings.4 Neuraxial Anesthesia Pharmacologic prophylaxis should be used with caution in patients undergoing neuraxial anesthesia because cases of perispinal hematomas have been reported.85 PREVENTION IN MEDICAL PATIENTS The incidence of VTE has been reported to be at least as high in hospitalized medical patients as in patients undergoing general surgery, ranging from 10% to 26% in the absence of prophylaxis.15 PE is responsible for 10% of the deaths that occur in the hospital, and 75% of fatal PE occur in medical patients.15 Patients at particularly high risk for developing VTE include those with additional risk factors, such as a previous history of VTE, advanced age, restricted mobility, obesity, chronic cardiopulmonary disease, ischemic stroke, myocardial infarction, or cancer. However, it is difficult to predict which of these patients will develop clinically significant disease. Thus, routine prophylaxis should be considered for all hospitalized medical patients at potential risk for VTE (Figure 4). Three recent, large randomized controlled trials have investigated thromboprophylaxis in hospitalized medical patients. The MEDENOX trial demonstrated a 63% risk reduction in DVT for enoxaparin compared with placebo.86 In the PREVENT trial, dalteparin was associated with a 45% risk reduction in VTE.87 Finally, the ARTEMIS trial demonstrated a 49.5% risk reduction in DVT with fondaparinux.88 In addition, cost-benefit analyses have favored LMWH over low-dose UFH for prophylaxis of medical patients.89 The ACCP recommends that patients admitted to the hospital with congestive heart failure, severe respiratory disease, or who are confined to bed and have 1 or more additional risk factors, including active cancer, previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease, receive low-dose UFH (3 times daily) or LMWH.4 The optimal duration of therapy is unknown, and mechanical prophylaxis with graduated compression stockings or intermittent pneumatic compression should be used if anticoagulant therapy

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Ve n o u s T h ro m b o e m b o l i s m Acute medical illness Evidence-based

Acute cardiac disease, active cancer requiring therapy, sepsis, acute respiratory diseases, stroke, paraplegia

Consensus-based

No evidence for benefit of VTE prophylaxis Acute inflammatory infections with immobility, inflammatory bowel disease

No acute medical illness

None

Other factors*

History of VTE or malignancy; complicating acute infectious disease; age > 75 yr

Predisposing risk factors

Figure 4. Venous thromboembolism (VTE) risk assessment model for hospitalized, medically ill patients. Hospitalized medical patients can be stratified by acute medical illness and the presence of predisposing risk factors to determine which patients, using evidence-based or consensus-based recommendations, should be given VTE prophylaxis. * “Other factors” include prolonged immobility, age > 70 years, varicose veins, obesity, hormone therapy, pregnancy, nephrotic syndrome, dehydration, thrombophilia, or thrombocytosis. (Adapted with permission from Spyropoulos AC. Emerging strategies in the prevention of venous thromboembolism in hospitalized medical patients. Chest 2005;128:958–69.)

is contraindicated in any of these patients.4 A systematic review published by the Agency for Healthcare Research and Quality listed the “appropriate use of prophylaxis to prevent VTE in patients at risk” as the highest-ranked safety practice based on overwhelming evidence demonstrating improved patient outcomes and reduction in health care costs.4 Multiple recent patient registries, have demonstrated an underutilization of thromboprophylaxis, especially in general medical patients.90 As a result, computer alert programs have been implemented. In a recent trial, such a program increased physician utilization of VTE prophylaxis and resulted in a 41% risk reduction in the frequency of symptomatic DVT or PE.91

reasons scarce. The ACCP78 has made suggestions for VTE prophylaxis in pregnancy based on the available data (Table 8).

review QUESTIONS

PREVENTION DURING PREGNANCY As stated, warfarin is contraindicated during pregnancy, but heparin formulations and aspirin at various doses are tolerated. Although the data for prevention in this population are better than the data for treatment, the evidence from randomized trials is, for obvious

1. A 30-year-old healthy man presents to your office with complaints of unilateral calf pain for 12 hours. He has no past medical or surgical history. There is no swelling, erythema, or other abnormalities on examination. Which of the following would be the most appropriate next step in the management of this patient? A. Check d-dimer assay B. Check lower extremity Doppler compression ultrasound C. Empiric therapy with LMWH until he can obtain an ultrasound test of his leg

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Ve n o u s T h ro m b o e m b o l i s m D. CTPA to evaluate for asymptomatic PE E. None of the above Answer: A. The scenario presents a healthy patient with no history of previous DVT, and no physical examination signs to suggest VTE. Using the Wells scoring system for DVT, he would be considered low clinical probability. Prospective management trials have shown that when d-dimer is combined with low pretest clinical probability, particularly in young healthy patients, VTE can be safely ruled out along with saving health care dollars by avoiding further testing. 2. A 50-year-old woman presents to the emergency department (ED) complaining of her heart racing accompanied by sudden shortness of breath. Her heart rate is 105 bpm, and the rhythm is sinus. Her oxygen saturation on room air is within normal limits. She has just returned home from inpatient rehabilitation following knee replacement surgery. She has a history of diabetes mellitus, hypertension, and currently complains of some midsternal chest pain. She has been taking prophylactic doses of LMWH to date following surgery. She has had multiple prior admissions for panic and anxiety. How do you proceed with this patient’s management? A. Provide reassurance since she is on LMWH and have her follow up with her psychiatrist B. Admit the patient and proceed with your diagnostic workup of PE with CTPA and lower extremity Doppler compression ultrasound C. Admit the patient and proceed with diagnostic workup of PE using SimpliRED d-dimer and compression Doppler ultrasound D. Provide reassurance that she is not having a PE, but rule her out for acute coronary syndrome Answer: B. Per modified Wells score for PE, the patient has intermediate pretest probability for PE. She needs further diagnostic testing for PE. Although she is on prophylaxis with LMWH, there could have been some degree of noncompliance (although less likely since she was in a supervised environment) and the possibility of repeat event cannot be ruled out by this alone. The evaluation of PE in patients with intermediate pretest probability may begin with a high sensitivity ddimer test such as rapid ELISA but not with a moderate sensitivity test such as SimpliRED. If the high sensitivity test is not available or if it is elevated, further imaging with either a CTPA or V/Q scan is necessary in addition to venous imaging. ACS is always a possibility, but PE evaluation is also necessary. Finally, psychiatric

Table 8. ACCP Recommendations for VTE Prophylaxis in Pregnancy Antenatal and postpartum anticoagulation suggested if: Single prior episode of VTE and confirmed thrombophilia Strong family history Multiple prior episodes of VTE Antithrombin deficiency, prothrombin mutation, factor V Leiden mutation Antenatal anticoagulation or clinical surveillance (plus postpartum anticoagulation): Single prior episode of VTE with transient risk factor, no longer present Single idiopathic episode of VTE (not on long-term therapy) All other thrombophilia Congenital thrombophilia or APLA screening suggested for: Recurrent miscarriages Prior severe/recurrent preeclampsia, abruptions, or otherwise unexplained intrauterine death ASA plus anticoagulation suggested if: APLA and a history of multiple early pregnancy losses OR any late pregnancy loss OR severe/recurrent preeclampsia, IUGR, or abruption Congenital thrombophilic deficit and history of multiple early pregnancy losses OR any late pregnancy loss OR severe/recurrent preeclampsia, or abruption APLA and history of VTE APLA and no prior history of VTE, pregnancy loss or other complication: Clinical surveillance, anticoagulation, and/or ASA In addition: *All patients with prior VTE should receive antenatal and postpartum graduated stockings Note: Dosing regimens vary depending on category of risk (refer to ACCP); APLA = antiphospholipid antibody; ASA = acetylsalicyclic acid; IUGR = intrauterine growth retardation; VTE = venous thromboembolism. (Adapted from permission from Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest 2004;126(3 Suppl):627S–644S.)

disorders such as generalized anxiety and panic attacks are diagnoses of exclusion. 3. A 37-year-old woman with breast cancer and prior history of DVT presents to the ED with acute onset of pleuritic chest pain, dyspnea, and hemoptysis. On examination, her temperature is 99°F, pulse is 112 bpm, blood pressure is 100/70 mm Hg, and respiratory rate is 24 breaths/min. She has significant thigh and calf swelling of her right leg.

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Ve n o u s T h ro m b o e m b o l i s m An ABG is reported as pH 7.45, Paco2 32, Po2 of 70. Chest radiograph reveals new lung mass. Electrocardiogram shows sinus tachycardia. What will be the next step on the evaluation of this patient? A. Obtain d-dimer and if negative, discharge and follow up in 1 week B. Obtain lower extremity Doppler compression ultrasound and if negative, discharge and follow up in 1 week C. Obtain CTPA and order anticoagulation while waiting for results D. Obtain V/Q scan and order anticoagulation while waiting for results E. Obtain bronchoscopy with biopsy and bronchoalveolar lavage Answer: C. This patient has a high pretest probability per Wells scoring system, so d-dimer is not helpful. She has an abnormal chest radiograph, so V/Q scan will probably be indeterminate. The CTPA will give information about PE as well as alternative diagnoses for the potential lung mass. In cases of high pretest probability, anticoagulation should be started prior to obtaining diagnostic test results. 4. A pregnant woman with family history of VTE comes to your office seeking advice. She has no significant family history. What do you recommend? A. Given the risk of VTE during this pregnancy, she should be started on warfarin therapy after the first trimester B. Her chances of miscarriage are high, and she should consider terminating her pregnancy C. Given the risk of VTE during this pregnancy, she should be started on LMWH at prophylactic doses after the first trimester D. Given the risk of VTE during this pregnancy, she should be started on LMWH at therapeutic doses after the first trimester Answer: C. VTE management during pregnancy is a controversial subject. There is limited evidence for prophylaxis and even less evidence for treatment. Guidelines vary among different societies. The ACCP recommends that pregnant patients with family history of VTE receive prophylactic doses of LMWH starting in the second trimester and continuing during the postpartum period.

no personal history of VTE, but she does report that her mother died of a PE when she was in her 60s. She has been relatively sedentary lately due to severe osteoarthritis of her left hip. She has no allergies to any medications. Her physical examination is unremarkable except for pain with range of motion of the left hip. The patient’s absolute risk of developing a DVT is: A. 10% to 20% B. 15% to 40% C. 40% to 60% D. 60% to 80% Answer: C. The patient is undergoing major orthopedic surgery, in particular, hip arthroplasty, which puts her absolute risk of developing a DVT at 40% to 60%. Patients with a 10% to 20% risk of DVT would include lower-risk medical patients, while those with a 15% to 40% risk of DVT would include those undergoing general, major gynecologic, or urologic surgery. Those with the highest absolute risk of DVT (60%–80%) would include spinal cord injury and major trauma patients. 6. As the medical consultant, your recommendation for the type and duration of VTE prophylaxis for the patient in question 5 would be: A. Low-dose UFH (every 8 hr) for the length of the hospitalization or until the patient is ambulatory B. LMWH (> 3400 U/day) for the length of the hospitalization or until the patient is ambulatory C. LMWH (> 3400 U/day) for 28 days postoperatively D. Fondaparinux (2.5 mg/g) for 14 days postoperatively Answer: C. Based on the 2004 ACCP guidelines, the patient should receive LMWH (> 3400 U/day) for 28 to 35 days postoperatively because of her continued elevated risk of developing VTE. Low-dose UFH has been shown to be less effective at reducing VTE risk as other agents in this population, and is therefore not recommended for primary prophylaxis in patients undergoing major orthopedic procedures. Fondaparinux (2.5 mg/day) is recommended for primary prophylaxis in this patient population, as is warfarin (target INR, 2–3), but these agents should also be continued for 28 to 35 days postoperatively.

5. A 65-year-old woman is admitted to the hospital to undergo elective total hip replacement. She is postmenopausal, not receiving HRT, and has

7. Which of the following statements is false? A. Computer alert programs to increase physician

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Ve n o u s T h ro m b o e m b o l i s m utilization of VTE prophylaxis have been shown to be effective at reducing the frequency of DVT in hospitalized patients. B. Patients undergoing major surgery who are younger than age 60 years and have no additional risk factors for VTE are considered to be at moderate risk and can be treated for prophylaxis with low-dose UFH (every 12 hr) or LMWH (< 3400 U/day). C. Because of the high risk of bleeding associated with neurosurgical patients, it is recommended that they receive prophylaxis with only graduated compression stockings and/or intermittent pneumatic compression devices. D. One option for primary prophylaxis in patients admitted to the hospital with congestive heart failure, severe respiratory disease, sepsis, or who are confined to bed and have 1 or more additional risk factors is intermittent pneumatic compression. Answer: D. The acutely ill medical patient admitted with congestive heart failure, severe respiratory disease, sepsis, or who is confined to bed and has other risk factors (eg, active cancer, previous VTE, acute neurologic disease, or inflammatory bowel disease) should receive primary prophylaxis with low-dose UFH (3 times daily) or LMWH. 8. All of the following statements about long-term anticoagulation are true, except A. The frequency of recurrent thrombosis/extension of existing thrombosis in untreated patients is 15% to 50% B. Patients anticoagulated to goal INR 2–3 have lower risk of VTE than patients anticoagulated to goal INR of 1.5–2.0 C. Patients treated with indefinite vitamin K antagonist therapy have a similar risk of bleeding compared with patients treated for 6 months D. There is a trend toward fewer recurrences of VTE in patients treated for 4 to 12 months than in patients treated for less than 3 months Answer: C. Although longer therapy with vitamin K antagonists has been associated with decreased thrombosis, it is also associated with increased bleeding. It should be noted, however, that total adverse event rates (bleeding or thrombosis) declined as duration of therapy increased. 9. All of the following statements about VTE and pregnancy are true, except A. UFH has been shown to be safe in pregnancy

B. The risk of VTE in pregnancy is increased by a factor of 5 C. Vena cava filters have not been studied in randomized trials in pregnant women D. LMWH crosses the placenta and is contraindicated in pregnancy E. Warfarin crosses the placenta and is contraindicated in pregnancy Answer: D. Unlike warfarin, LMWH and low-dose UFH do not cross the placenta and thus are not contraindicated during pregnancy. 10. Which of the following statements about VTE and malignancy is TRUE? A. The risk of recurrent VTE is similar to the risk in patients without malignancy B. LMWH should be the long-term anticoagulation in patients with a significant disease burden C. Vitamin K antagonists should be avoided in patients with malignancy D. Thrombosis is avoided when anticoagulation is in the therapeutic range E. Vena cava filters are more effective than LMWH for the prevention of VTE in patients with malignancy Answer: B. LMWH has been shown to be superior to warfarin even at therapeutic INR ranges. Acknowledgments The authors thank Parag Desai, MD, Saurabh Kandpal, MD, Anish Koka, MD, Nicholas Panetta, MD, and Thomas Rice, MD, for their contributions to this article.

References 1. White RH. The epidemiology of venous thrombo­embolism. Circulation 2003;107(23 Suppl 1):I4–I8. 2. Anderson FA Jr, Spencer FA. Risk factors for venous thrombo­embolism. Circulation 2003;107(23 Suppl 1): 9–16. 3. Otten HM, Prins MH. Venous thromboembolism and occult malignancy. Thomb Res 2001;102:V187–94. 4. Geerts W, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:338S–400S. 5. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Maligan-

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Ve n o u s T h ro m b o e m b o l i s m cies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005;293:715–22. 6. Otten HM, Mathijssen L, ten Cate H, et al. Symptomatic venous thromboembolism in cancer patients treated with chemotherapy: an underestimated phenomenon. Arch Intern Medicine 2004;164:190–4. 7. Sorensen HT, Mellemkjaer L, Steffensen FH, et al. The risk of diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998;338:1169– 73. 8. Ageno W, Squizzato A, Garcia D, Imberti D. Epidemiology and risk factors of venous thromboembolism. Semin in Thromb Hemost 2006;32:651–8.

23. Anand SS, Wells PS, Hunt D, et al. Does this patient have deep vein thrombosis [published errata appear in JAMA 1998;279:1614 and 1998;280:328]? JAMA 1998;279: 1094–9. 24. Wells PS, Hirsh J, Anderson DR, et al. Accuracy of clinical assessment of deep-vein thrombosis [published erratum appears in Lancet 1995;346:516]. Lancet 1995;345:1326– 30. 25. Tamariz LJ, Eng J, Segal JB, et al. Usefulness of clinical prediction rules for the diagnosis of venous thromboembolism: a systematic review. Am J Med 2004;117:676–84. 26. Riedel M. Diagnosing pulmonary embolism. Postgrad Med 2004;80:309–19.

9. NIH Consensus Development. Prevention of venous thrombo­sis and pulmonary embolism. JAMA 1986;256:744– 9.

27. Kelly J, Hunt BJ. The utility of pretest probability assessment in patients with clinically suspected venous thromboembolism. J Thromb Haemost 2003;1:1888–96.

10. Phillips OP. Venous thromboembolism in the pregnant woman. J Reprod Med 2003;48(11 Suppl):921–9.

28. Kearon C, Julian JA, Newman TE, Ginsberg JS; McMaster Diagnostic Imaging Practice Guidelines Initiative. Noninvasive diagnosis of deep venous thrombosis [published erratum appears in Ann Intern Med 1998;129:425]. Ann Intern Med 1998;128:663–77.

11 . Chang J, Elam-Evans LD, Berg CJ, et al. Pregnancy-related mortality surveillance—United States 1991–1999, MMWR Surveill Summ 2003; 52:1–8. 12. Vandenbroucke JP, Rosing J, Bloemenkamp KW, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001;344:1527–35. 13. Moores L, Bilello, KL, Murin S. Sex and gender issues and venous thromboembolism. Clin Chest Med 2004;25: 281–97. 14. Hauer KE. Evolving approaches to the management of venous thromboembolic disease. Johns Hopkins Advanced Studies in Medicine 2005;5:140–148. 15. Turpie AG. Leizorovicz A. Prevention of venous thromboembolism in medically ill patients: a clinical update. Postgrad Med J 2006;82:806–9. 16. Gallus AS, Goghlan DC. Travel and venous thrombosis. Curr Opin Pulm Med 2002;8:372–8.

29. Wells PS, Owen C, Doucette S, et al. Does this patient have deep vein thrombosis? JAMA 2006;295:199–207. 30. 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. 31. McRae SJ, Ginsberg JS. Update in the diagnosis of deepvein thrombosis and pulmonary embolism. Curr Opin Anaesthesiol 2006;19:44–51. 32. Kyrle PA, Eichinger S. Deep vein thrombosis. Lancet 2005;365:1163–74. 33. Wells PS. Advances in the diagnosis of venous thrombo­ embolism. J Thromb Thrombolysis 2006;21:31–40.

17. Kearon C. Natural history of venous thromboembolism. Circulation 2003;107(23 Suppl 1):I22–30.

34. The PIOPED Investigators. Value of the ventilation/ perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 1990;263:2753–9.

18. Dalen JE. Pulmonary embolism: what have we learned since Virchow? Natural history, pathophysiology, and diagnosis. Chest 2002;122:1440–56.

35. Stein PD, Goldhaber SZ, Henry JW, et al. Arterial blood gas analysis in the assessment of suspected acute pulmonary embolism. Chest 1996;109:78–81.

19. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386–9.

36. Stein PD, Goldhaber SZ, Henry JW. Alveolar-arterial oxygen gradient in the assessment of acute pulmonary embolism. Chest 1995;107:139–43.

20. Hyers TM. Venous thromboembolism. Am J Respir Crit Care Med 1999;159:1–14. 21 . Hoffman R, Benz E, Shattil S, et al. Hematology: basic principles and practice. 4th ed. New York: Churchill Livingstone; 2004. 22. Goldhaber SZ, Elliott CG. Acute pulmonary embolism: part I: epidemiology, pathophysiology, and diagnosis. Circulation 2003;108:2726–9.

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37. Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no preexisting cardiac or pulmonary disease. Chest 1991;100:598– 603. 38. Wells PS, Ginsberg JS, Anderson D, et al. Use of a clinical model for safe management of patients with suspected pulmonary embolism. Ann Intern Med 1998;129:997–1005. 39. Le Gal G, Righini M, Roy PM, et al. Prediction of pulmo-

www.turner-white.com

Ve n o u s T h ro m b o e m b o l i s m nary embolism in the emergency department: the revised Geneva score. Ann Intern Med 2006;144:165–71. 40. Righini M, Le Gal G, Perrier A, Bounameaux H. Effect of age on the assessment of clinical probability of pulmonary embolism by prediction rules [letter]. J Thromb Haemost 2004;2:1206–8. 41. Chunilal SD, Eikelboom JW, Attia J, et al. Does this patient have pulmonary embolism? JAMA 2003;290:2849–58. 42. Miniati M, Monti S, Bottai M. A structured clinical model for predicting the pre-test probability of pulmonary embolism. Am J Med 2003;114:173–9. 43. Kearon C. Diagnosis of pulmonary embolism. CMAJ 2003; 168:183–94.

heparin. Ann NY Acad Sci 1981;370:644–9. 56. Bounameaux H, de Moerloose P. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? No. J Thromb Haemost 2004;2:551–4. 57. The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997;337:657–62. 58. Mismetti P, Quenet S, Levine M, et al. Enoxaparin in the treatment of deep vein thrombosis with or without pulmonary embolism: an individual patient data meta-analysis. Chest 2005;128:2203–10.

44. Stein PD, Fowler SE, Goodman LR, et al; PIOPED II Investigators. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 2006;354:2317–27.

59. Quinlan DJ, McQuillan A, Eikelboom JW. Low-molecularweight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a metaanalysis of randomized, controlled trials. Ann Intern Med 2004;140:175–83.

45. Schoepf UJ, Goldhaber SZ, Costello P. Spiral computed tomography for acute pulmonary embolism. Circulation 2004;109:2160–7.

60. O’Brien JA, Caro JJ. Direct medical cost of managing deep vein thrombosis according to the occurrence of complications. Pharmacoeconomics 2002;20:603–15.

46. Eng J, Krishnan JA, Segal JB, et al. Accuracy of CT in the diagnosis of pulmonary embolism: a systematic literature review. AJR Am J Roentgenol 2004;183:1819–27.

61. Prandoni P, Lensing AW, Pesavento R. New strategies for the treatment of acute venous thromboembolism. Semin Thromb Hemost 2006;32:787–92.

47. Moores LK, Jackson WL Jr, Shorr AF, Jackson JL. Metaanalysis: outcomes in patients with suspected pulmonary embolism managed with computed tomographic pulmonary angiography. Ann Intern Med 2004;141:866–74.

62. Buller HR, Davidson BL, Decousus H, et al; Matisse Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism [published erratum appears in N Engl J Med 2004;350:423]. N Engl J Med 2003;349:1695–702.

48. Quiroz R, Kucher N, Zou KH, et al. Clinical validity of a negative computed tomography scan in patients with suspected pulmonary embolism: a systematic review. JAMA 2005;293:2012–7. 49. Musset D, Parent F, Meyer G, et al; Evaluation du Scanner Spirale dans l’Embolie Pulmonaire study group. Diagnostic strategy in patients with suspected pulmonary embolism: a prospective multicentre outcome study. Lancet 2002;360:1914–20. 50. Stein PD, Woodard PK, Weg JG, et al; PIOPED II Investigators. Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II Investigators. Radiology 2007;242:15–21. 51. Goldhaber SZ. Elliott CG. Acute pulmonary embolism: part II: risk stratification, treatment, and prevention. Circulation 2003;108:2834–8. 52. McRae SJ, Ginsberg JS. Initial treatment of venous thromboembolism [published errata appear in Circulation 2004;110(24 Suppl 1):IV33 and 2005;111:378]. Circulation 2004;110(9 Suppl 1):I3–9. 53. Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 1960;1:1309–12. 54. McLean J. The thromboplastic action of cephalin. Am J Physiol 1916;41:250–7. 55. Choay J, Lormeau JC, Petitou M, et al. Structural studies on a biologically active hexasaccharide obtained from

63. Buller HR, Davidson BL, Decousus H, et al; Matisse Investigators. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep vein thrombosis. Ann Intern Med 2004;140:867–73. 64. Buller HR, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy [published erratum appears in Chest 2005;127:416]. Chest 2004;126:401S–428S. 65. Thabut G, Thabut D, Myers RP, et al. Thrombolytic therapy of pulmonary embolism: a meta-analysis. J Am Coll Cardiol 2002;40:1660–7. 66. Dalen JE. Thrombolysis in submassive pulmonary embolism? No. J Thromb Haemost 2003;1:1130–2. 67. Aklog L, Williams CS, Byrne JG, Goldhaber SZ. Acute pulmonary embolectomy: a contemporary approach. Circulation 2002;105:1416–9. 68. Kucher N, Windecker S, Banz Y, et al. Percutaneous catheter thrombectomy device for acute pulmonary embolism: in vitro and in vivo testing. Radiology 2005;236:852–8. 69. Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5-mg and 10-mg warfarin loading doses. Arch Intern Med 1999;159:46–8. 70. Kovacs MJ, Rodger M, Anderson DR, et al. Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient

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Ve n o u s T h ro m b o e m b o l i s m treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial. Ann Intern Med 2003;138:714–9. 71. Segal JB, Streiff MB, Hoffman LV, et al. Management of venous thromboembolism: a systematic review for a practice guideline [published erratum appears in Ann Intern Med 2007;146:396]. Ann Intern Med. 2007;146:211–22. 72. Piazza G. Goldhaber SZ. Acute pulmonary embolism: part II: treatment and prophylaxis. Circulation 2006;114: e42–7. 73. Hirsh J, Fuster V, Ansell J; American Heart Association/ American College of Cardiology Foundation. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. J Am Coll Cardiol 2003;41:1633–52. 74. Lee AY, Levine MN, Baker RI, et al; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anti­coagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Invest­igators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146–53.

previous meta-analyses. Br J Surg 1997;84:750–9. 82. Baca I, Schneider B, Kohler T, et al. [Prevention of venous thromboembolism in patients undergoing minimally invasive interventions and brief inpatient treatment. Results of a multicenter, prospective, randomized, controlled study with a low molecular weight heparin.] [Article in German.] Chirurg 1997;68:1275–80. 83. Hull RD, Pineo GF, MacIsaac S. Low-molecular-weight heparin prophylaxis: preoperative versus postoperative initiation in patients undergoing elective hip surgery. Thromb Res 2001;101:V155–62. 84. Consortium for Spinal Cord Medicine. Prevention of thromboembolism in spinal cord injury. J Spinal Cord Med 1997;20:259–83. 85. Bergqvist D, Lindblad B, Matzsch T. Risk of combining low molecular weight heparin for thromboprophylaxis and epidural or spinal anesthesia. Semin Thromb Hemost 1993;19 Suppl 1:147–51. 86. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999;341:793–800.

75. Decousus H, Leizorovicz A, Parent F, et al; Prevention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med 1998;338:409–15.

87. Leizorovicz A, Cohen AT, Turpie AG, et al; PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004;110:874–9.

76. Millward SF, Oliva VL, Bell SD, et al. Gunther Tulip Retrievable Vena Cava Filter: results from the Registry of the Canadian Interventional Radiology Association. J Vasc Interv Radiol 2001;12:1053–8.

88. Cohen AT, Davidson BL, Gallus AS, et al; ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006;332:325–9.

77. Ginsberg JS, Hirsh J, Julian J, et al. Prevention and treatment of postphlebitic syndrome: results of a 3-part study. Arch Intern Med 2001;161:2105–9. 78. Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of anti­ thrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):627S–644S.

89. McGarry LJ, Thompson D, Weinstein MC, Goldhaber SZ. Cost effectiveness of thromboprophylaxis with a lowmolecular-weight heparin versus unfractionated heparin in acutely ill medical inpatients. Am J Manag Care 2004;10:632–42.

80. Pini M, Spyropoulos AC. Prevention of venous thromboembolism. Sem Thromb Hemost 2006;32:755–66.

90. Tapson VF, Decousus H, Piovella F, et al. A multinational observational cohort study in acutely ill medical patients of practices in prevention of venous thromboembolism: findings of the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE). Blood 2003;102:321a.

81. Koch A, Bouges S, Ziegler S, et al. Low molecular weight heparin and unfractionated heparin in thrombosis prophylaxis after major surgical intervention: update of

91. Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med 2005;352:969–77.

79. Ageno W. Applying risk assessment models in general surgery: overview of our clinical experience. Blood Coagul Fibrinolysis 1999;10 Suppl 2:S71–8.

test yourself with board-type questions Questions for self-assessment in selected specialties are available on Hospital Physician’s Web site. Go to www.turner-white.com, click on Hospital Physician, then click on “Board-Type Questions.” Copyright 2007 by Turner White Communications Inc., Wayne, PA. All rights reserved.

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