Diagnosis And Management Of March 2015

Volume 17, Number 3

Deep Venous Thrombosis In Authors

Kar-mun C. Woo, MD, RDMS

The Emergency Department

Assistant Professor, Department of Emergency Medicine, Mount Sinai
Beth Israel, New York, NY
Jacob K. Goertz, MD, RDMS
Assistant Professor, Department of Emergency Medicine, Mount Sinai
Abstract Beth Israel, New York, NY

Peer Reviewers
Although the clinical presentations of deep venous thrombosis Steven A. Godwin, MD, FACEP
are notoriously subtle and nonspecific, risk stratification tools Professor and Chair, Department of Emergency Medicine; Assistant
Dean for Simulation Education; University of Florida College of
such as the Wells clinical model have improved the efficiency Medicine-Jacksonville, Jacksonville, FL
of the diagnostic evaluation. The emergency clinician may be Christopher R. Tainter, MD, RDMS
guided down several pathways, including D-dimer assays and/ Department of Emergency Medicine, Department of Anesthesiology,
Division of Critical Care, University of California-San Diego, La Jolla,
or ultrasonography. New oral anticoagulants offer alternatives CA
to the traditional heparins and vitamin K antagonists in the
CME Objectives
treatment of deep venous thrombosis. This review examines the
Upon completion of this article, you should be able to:
current literature, evidence, and guidelines in the diagnosis and
1. Risk stratify a patient with suspected first-time DVT for pretest
management of deep venous thrombosis. It also explores some probability of disease.
of the controversies and developments regarding risk strati- 2. Choose appropriate diagnostic testing for patients with
fication, including special populations, age-adjusted D-dimer suspected DVT.
thresholds, isolated distal deep venous thrombosis, upper ex- 3. Describe the anticoagulant regimens used to treat patients with a
confirmed diagnosis of DVT.
tremity deep venous thrombosis, outpatient treatment, and the
Prior to beginning this activity, see Physician CME Information on the
new oral anticoagulants. back page.

Editor-In-Chief
Andy Jagoda, MD, FACEP
Professor and Chair, Department of
Emergency Medicine, Icahn School
of Medicine at Mount Sinai, Medical
Director, Mount Sinai Hospital, New
York, NY
Associate Editor-In-Chief
Kaushal Shah, MD, FACEP
Associate Professor, Department of
Emergency Medicine, Icahn School
of Medicine at Mount Sinai, New
York, NY
Editorial Board
William J. Brady, MD
Professor of Emergency Medicine
and Medicine, Chair, Medical
Emergency Response Committee,
Medical Director, Emergency
Management, University of Virginia
Medical Center, Charlottesville, VA
Calvin A. Brown III, MD
Director of Physician Compliance,
Credentialing and Urgent Care
Services, Department of Emergency
Medicine, Brigham and Women's
Hospital, Boston, MA
Mark Clark, MD
Assistant Professor of Emergency
Medicine, Program Director,
Emergency Medicine Residency,
Mount Sinai Saint Luke's, Mount
Sinai Roosevelt, New York, NY
Peter DeBlieux, MD James Damilini, PharmD, BCPS
Professor of Clinical Medicine,
Interim Public Hospital Director
of Emergency Medicine Services,
Louisiana State University Health
Science Center, New Orleans, LA
Nicholas Genes, MD, PhD
Assistant Professor, Department of
Emergency Medicine, Icahn School
of Medicine at Mount Sinai, New
York, NY
Michael A. Gibbs, MD, FACEP
Professor and Chair, Department
of Emergency Medicine, Carolinas
Medical Center, University of North
Carolina School of Medicine, Chapel Michael S. Radeos, MD, MPH
Hill, NC
Steven A. Godwin, MD, FACEP
Professor and Chair, Department
of Emergency Medicine, Assistant
Dean, Simulation Education,
University of Florida COM-
Jacksonville, Jacksonville, FL
Gregory L. Henry, MD, FACEP
Clinical Professor, Department of
Emergency Medicine, University
of Michigan Medical School; CEO,
Medical Practice Risk Assessment,
Inc., Ann Arbor, MI
John M. Howell, MD, FACEP
Clinical Professor of Emergency
Medicine, George Washington
University, Washington, DC; Director Alfred Sacchetti, MD, FACEP
of Academic Affairs, Best Practices,
Inc, Inova Fairfax Hospital, Falls
Church, VA
Shkelzen Hoxhaj, MD, MPH, MBA
Chief of Emergency Medicine, Baylor Robert Schiller, MD
College of Medicine, Houston, TX
Eric Legome, MD
Chief of Emergency Medicine,
Kings County Hospital; Professor of
Clinical Emergency Medicine, SUNY
Downstate College of Medicine,
Brooklyn, NY
Keith A. Marill, MD
Research Faculty, Department of
Emergency Medicine, University
of Pittsburgh Medical Center,
Pittsburgh, PA
Charles V. Pollack Jr., MA, MD,
FACEP
Professor and Chair, Department of
Emergency Medicine, Pennsylvania
Hospital, Perelman School of
Medicine, University of Pennsylvania,
Philadelphia, PA
Assistant Professor of Emergency
Medicine, Weill Medical College
of Cornell University, New York;
Research Director, Department of
Emergency Medicine, New York
Hospital Queens, Flushing, NY
Ali S. Raja, MD, MBA, MPH
Vice-Chair, Emergency Medicine,
Massachusetts General Hospital,
Boston, MA
Robert L. Rogers, MD, FACEP,
FAAEM, FACP
Assistant Professor of Emergency
Medicine, The University of
Maryland School of Medicine,
Baltimore, MD
Assistant Clinical Professor,
Department of Emergency Medicine, Associate Professor of Emergency
Thomas Jefferson University,
Philadelphia, PA
Chair, Department of Family Medicine,
Beth Israel Medical Center; Senior
Faculty, Family Medicine and
Community Health, Icahn School of
Medicine at Mount Sinai, New York, NY
Scott Silvers, MD, FACEP
Chair, Department of Emergency
Medicine, Mayo Clinic, Jacksonville, FL
Corey M. Slovis, MD, FACP, FACEP
Professor and Chair, Department
of Emergency Medicine, Vanderbilt
University Medical Center, Nashville, TN Michael Guthrie, MD
Stephen H. Thomas, MD, MPH
George Kaiser Family Foundation
Professor & Chair, Department of
Emergency Medicine, University of
Oklahoma School of Community
Medicine, Tulsa, OK
David M. Walker, MD, FACEP, FAAP
Director, Pediatric Emergency
Services, Division Chief, Pediatric
Emergency Medicine, Elmhurst
Hospital Center, New York, NY
Ron M. Walls, MD
Professor and Chair, Department of
Emergency Medicine, Brigham and
Women's Hospital, Harvard Medical Giorgio Carbone, MD
School, Boston, MA
Critical Care Editors
William A. Knight IV, MD, FACEP
Associate Professor of Emergency
Medicine and Neurosurgery, Medical
Director, EM Midlevel Provider
Program, Associate Medical Director,
Neuroscience ICU, University of
Cincinnati, Cincinnati, OH
Scott D. Weingart, MD, FCCM
Medicine, Director, Division of ED
Critical Care, Icahn School of Medicine Dhanadol
at Mount Sinai, New York, NY
Senior Research Editors
Clinical Pharmacist, Emergency
Room, St. Josephs Hospital and
Medical Center, Phoenix, AZ
Joseph D. Toscano, MD
Chairman, Department of Emergency
Medicine, San Ramon Regional
Medical Center, San Ramon, CA
Research Editors
Emergency Medicine Residency,
Icahn School of Medicine at Mount
Sinai, New York, NY
Federica Stella, MD
Emergency Medicine Residency,
Giovani e Paolo Hospital in Venice,
University of Padua, Italy
International Editors
Peter Cameron, MD
Academic Director, The Alfred
Emergency and Trauma Centre,
Monash University, Melbourne,
Australia
Chief, Department of Emergency
Medicine Ospedale Gradenigo,
Torino, Italy
Amin Antoine Kazzi, MD, FAAEM
Associate Professor and Vice Chair,
Department of Emergency Medicine,
University of California, Irvine;
American University, Beirut, Lebanon
Hugo Peralta, MD
Chair of Emergency Services,
Hospital Italiano, Buenos Aires,
Argentina
Rojanasarntikul, MD
Attending Physician, Emergency
Medicine, King Chulalongkorn
Memorial Hospital, Thai Red Cross,
Thailand; Faculty of Medicine,
Chulalongkorn University, Thailand
Suzanne Y.G. Peeters, MD
Emergency Medicine Residency
Director, Haga Teaching Hospital,
The Hague, The Netherlands
Case Presentations
Your first patient of the shift is a 42-year-old woman
who details a family history of protein S deficiency and
presents with new-onset atraumatic left calf swelling and
pain. The proximal compression ultrasound is normal, but
your patient is understandably still nervous, and your
own suspicion for DVT remains high as well. You wonder
about the next best steps to ensure a safe discharge.
As your shift gets progressively busier, your ultra-
sound technician informs you that he is backed up with
studies and will take a while before he is caught up
again. Unfortunately, your next patient is a 22-year-old
otherwise healthy man sent from a clinic to rule out
DVT, with a handwritten script requesting an ultra-
sound. The patient reports unilateral left calf pain after
starting a new exercise regimen and has no other risk
factors or predispositions for DVT. You wonder if you
can safely rule out a DVT in this patient with a D-dimer
instead of the ultrasound.
In the meantime, a patient whom your colleague had
previously signed out to you as admitted for a straight-
forward, proximal DVT of the left lower extremity now
approaches the nurses station expressing his frustration
about the extended wait for his inpatient bed upstairs. The
patient no longer wants to stay and asks why he cannot
just follow up with his primary care doctor tomorrow.
You wonder if it would be safe to discharge him with an
outpatient treatment plan.
Introduction
Deep venous thrombosis (DVT) is commonly
diagnosed and managed in the emergency depart-
ment (ED), accounting for about 1 in 1000 patients
per year.1 In just the past 2 decades, the evaluation
and recognition of DVT have significantly advanced
from the days of uncertainty about how to address
notoriously vague physical signs and symptoms and
performing unwieldy venograms. Clinical judgment
is supplemented by the use of standardized risk
stratification tools, primarily the Wells clinical score,
which has undergone several modifications over
time. Uncomfortable venograms have been replaced
with noninvasive proximal or whole-leg ultrasound.
In addition, the use of D-dimer assays to exclude
DVT in appropriately risk-stratified patients has
increased rapidly, reducing the need for ultrasound
in certain patients.
Evidence-based recommendations, including several
clinical practice guidelines, help clinicians navigate the
expanding array of available diagnostic tools and thera-
peutic options. On the diagnostic side, ultrasonography
is migrating to the bedside and into the hands of emer-
gency clinicians, while newer evidence challenges the
upper-limit thresholds of D-dimer interpretation in select
populations. On the therapeutic side, updated guide-
lines now challenge the emergency clinician to consider
Copyright 2015 EB Medicine. All rights reserved. 2
outpatient management of proximal DVT as well as initial
nontreatment of certain types of DVT. Furthermore,
the newest oral formulations of anticoagulants offer
an enticing glimpse of a possible future without daily
injections, dietary restrictions, and frequent international
normalized ratio (INR) checks. In short, there is much new
ground to cover.
Critical Appraisal Of The Literature
A literature search of PubMed and the Cochrane
Database of Systematic Reviews was carried out us-
ing combinations of the following key search terms:
DVT, D-dimer, Wells score, Wells criteria, venous throm-
boembolism, proximal ultrasound, whole-leg ultrasound,
distal DVT, calf vein DVT, and anticoagulation. Targeted
literature searches were also performed for recurrent
DVT, pregnancy and DVT, upper extremity DVT, inferior
vena cava filter, thrombolysis and DVT, thrombectomy and
DVT, and novel oral anticoagulants.
There are several comprehensive evidence-
based guidelines on the diagnosis and therapy of
acute DVT, most notably the 2012 American College
of Chest Physicians (ACCP) ninth edition recom-
mendations for antithrombotic therapy and preven-
tion of thrombosis.1-4 Throughout this review, level
of evidence and strength of recommendations are
ranked as per the Grading of Recommendations As-
sessment, Development and Evaluation (GRADE)
Working Group.5,6 Definitions for strength of recom-
mendation and levels of evidence are available at:
http://journal.publications.chestnet.org/article.
aspx?articleid=1084215. Other available guidelines to
consider include the American College of Emergency
Physicians (ACEP) clinical policy recommendations
for suspected DVT (which have not been revisited
since 2003),7 the 2013 guidelines provided by the
Institute for Clinical Systems Improvement regarding
venous thromboembolism (VTE) diagnosis and treat-
ment,8 and the 2013 fifth edition of the International
Consensus Statement on Prevention and Treatment of
Venous Thromboembolism.2
The heterogeneity of various available D-dimer
assays and discordant versions of the Wells clini-
cal prediction rule make interpretation of available
data challenging. Many diagnostic and therapeutic
studies have combined or extrapolated analyses of
DVT from pulmonary embolism (PE) cohorts. Spe-
cial subsets of patients, such as those with recurrent
or upper extremity DVT and pregnant patients,
are often excluded from larger analyses, so docu-
mentation of their experience is much less robust.
Finally, randomized controlled trials concerning the
emerging novel oral anticoagulants have primarily
targeted noninferiority. Post marketing experience
and direct comparisons are limited, and recommen-
dations for their use are not formally graded by
most existing guidelines.
www.ebmedicine.net March 2015
 Pathophysiology And Anatomy
Pathophysiology
Formation of a deep venous thrombus is influenced
by the elements of the Virchow triad: venous stasis,
vascular endothelial injury, and hypercoagulabil-
ity.9 The identified risk factors for DVT affect one or
more of the elements of this triad and are classified
as either intrinsic or extrinsic, and either provoked or
unprovoked. (See Table 1.) Intrinsic causes include
inherited thrombophilias, the most common of
which (in order of decreasing relative risk [RR]) are
antithrombin deficiency, protein C or S deficiency,
and factor V Leiden and prothrombin gene muta-
tions. Acquired intrinsic causes include malignancy,
advanced age (especially > 75 years), antiphospho-
lipid syndrome, nephrotic syndrome, and obesity.10
Provoked DVT is precipitated by extrinsic factors,
most commonly immobilization of > 48 hours dura-
tion, recent hospitalization, recent surgery, localized
or generalized trauma, pregnancy, oral contracep-
tives or hormone replacement therapy, air travel (> 8
hours in duration11), transient infectious disease, and
deterioration of general condition or frailty.10
One of the strongest risk factors for development
of DVT is a history of prior DVT or PE, although previous
undiagnosed or silent VTE may account for unidenti-
fied risk factors. Many patients will have 1 intrinsic
risk factors with a subsequent acquired or extrinsic risk
factor.10,12,13 Recognition of the predisposing conditions
helps in the risk stratification of patients with suspected
DVT and elucidates the potential etiology in patients
with confirmed DVT.
If not appropriately diagnosed and treated, DVT
Table 1. Risk Factors For Development Of
Deep Venous Thrombosis
Hypercoagulability
Antithrombin deficiency
l
Protein C deficiency
l
Protein S deficiency
l
Factor V Leiden
l
Prothrombin gene mutations
l
Antiphospholipid syndrome
l
Homocysteinuria
l
Nephrotic syndrome
l
Immobilization > 48 hours
Recent hospitalization or surgery
Malignancy
Trauma
Pregnancy
Exogenous hormone use
Deterioration in general condition
Prior DVT or VTE
Abbreviations: DVT, deep venous thrombosis; VTE, venous thrombo-
embolism.
March 2015 www.ebmedicine.net
has the potential for significant morbidity and mortality,
including development of PE, recurrent DVT, or post-
thrombotic syndrome. PE is the most common compli-
cation; it is usually caused by lower extremity DVT and it
accounts for a 1-month mortality rate of 9.4% from first-
time DVT. It is estimated that 40% to 50% of patients
with DVT may harbor a silent PE.14-17 When it is treated,
the mortality from DVT drops to < 6%, although the
2-year mortality from DVT may be as high as 20%.16,17
Accurate diagnosis is imperative, as the risk of acute dis-
ease must be balanced with the risks of treatment with
anticoagulation.18
Anatomy
The majority (84%) of patients diagnosed with
DVT present with lower extremity thrombosis, with
smaller percentages presenting with isolated calf
(13%) or upper extremity DVT (16%).13 Although
venous drainage flows only in a proximal direction
and anatomic variation is common, it is easier to
conceptualize the anatomy of the deep veins in the
opposite direction, ie proximally to distally. (See
Figure 1, page 4.) The inferior vena cava (IVC) bifur-
cates into the iliac veins, dividing into internal and
external branches. When the external iliac passes
underneath the inguinal ligament, it is renamed the
common femoral vein. At about 5 to 7 cm inferior
to the inguinal ligament, the common femoral vein
bifurcates into the femoral vein and the deep femo-
ral vein, which courses to the lateral thigh muscles.
The femoral vein (also referred to as the "superficial"
femoral vein, which is a misnomer in that it is part
of the deep venous system) continues posterior to
the femoral artery, coursing inferiorly and medially
along the upper thigh before passing through the
popliteal fossa to become the popliteal vein. At the
popliteal fossa, the popliteal vein lies lateral to the
popliteal artery, before coursing more posteriorly as
it travels distally. At the level of the popliteal tri-
furcation, the popliteal vein branches into the deep
veins of the calf, with the anterior tibial vein cours-
ing anteromedially, the posterior tibial vein posteri-
orly, and the peroneal vein laterally. The muscular
veins including the gastrocnemius and soleus
veins branch off the deep veins of the calf, with
some debate as to whether or not they should still
be considered part of the deep venous system.19 In
contrast to the deep venous system, the superficial
venous system includes the greater saphenous vein,
which branches off the femoral vein inferior to the
inguinal ligament, and the lesser saphenous vein,
which commonly branches off the popliteal vein.
3 Reprints: www.ebmedicine.net/empissues
Differential Diagnosis
The signs and symptoms of DVT overlap with
many other conditions. (See Table 2.) Overall, the
prevalence of confirmed thrombosis in patients
suspected of having DVT is about 19%, with rates
ranging from 5% in patients with low probability to
53% in patients with high probability for DVT.20 As
such, the majority of patients presenting with signs
or symptoms suggestive of DVT will ultimately be
diagnosed with alternate conditions. For instance,
lower extremity swelling may be caused by pre-ex-
isting orthopedic abnormalities or paralysis.21 Table
2 summarizes the findings from a recent outpatient
study of 1028 patients suspected of having DVT,
Figure 1. Schematic Representation Of The
Lower Extremity Veins
Ilac veins
2
3 Emergency Department Evaluation
4
Femoral veins
5 consists of unilateral pain, swelling, edema, ery-
6 of course, the classic Homans sign (demonstrated by
Popliteal vein/
Trifurcation area
7 8 9 obscuring which variables are most helpful in the
Distal veins 10 11 12
only 13.4% of whom were ultimately diagnosed with
DVT.22 As many as half of all patients with a history
of prior DVT may have persistent pain and swelling
in the affected extremity from postthrombotic syn-
drome, further complicating the clinical evaluation.23
Prehospital Care
There are no published guidelines on prehospital
management of DVT. Since the primary acute con-
cern in patients with suspected DVT is progression
to PE, emergency medical services personnel should
be cognizant of the patient with a swollen painful
lower extremity who is or becomes hemodynami-
cally unstable or who develops chest pain, shortness
of breath, or other signs of acute cardiopulmonary
distress. Management should consist of supportive
care and transport to an appropriate facility. The
stable patient with suspected DVT may be transport-
ed by a basic life support ambulance. If the patient
is or becomes unstable and resources are available,
1
transport via an advanced life support provider
should be considered.
Inguinal ligament
History And Physical Examination
The textbook presentation of lower extremity DVT
thema, warmth, tenderness to palpation along the
Adductor canal
deep venous system, secondary dilation of superfi-
Knee joint cavity cial collateral veins or a palpable venous cord, and,
eliciting of calf pain with passive, abrupt dorsiflex-
13 ion of the foot). As every practicing emergency clini-
cian knows, however, actual clinical presentations
of DVT can be insidiously subtle and nonspecific,
clinical diagnosis of DVT.
To address this uncertainty, Goodacre et al per-
formed a meta-analysis of over 50 diagnostic cohorts
with suspected DVT to evaluate test characteristics
of these variables.24 Based on the strongest positive

14

Table 2. Differential Diagnosis For

Suspected Deep Venous Thrombosis22
Diagnosis Percentage
Legend: 1, external iliac vein; 2, common femoral vein; 3, greater
saphenous vein; 4, deep femoral vein; 5, femoral vein; 6, popliteal Muscle strain / tear / hematoma 16.0%
vein; 7, anterior tibial confluent segment; 8, posterior tibial confluent Deep venous thrombosis 13.4%
segment; 9, peroneal confluent segment; 10, anterior tibial veins; 11,
Chronic venous insufficiency 12.6%
posterior tibial veins; 12, peroneal veins; 13, gastrocnemius muscle
veins; 14, soleus muscle veins. Cellulitis 10.9%
Superficial thrombophlebitis 9.4%
Reprinted with permission from G. Palareti and S. Schellong. Isolated Lymphedema 4.8%
distal deep vein thrombosis: what we know and what we are doing.
Baker (popliteal) cyst 3.9%
Journal of Thrombosis and Haemostasis. 2001 International Soci-
ety on Thrombosis and Haemostasis. Other 29%

Copyright 2015 EB Medicine. All rights reserved. 4 www.ebmedicine.net March 2015

likelihood ratios (LR+) with 95% confidence inter-
vals (CI), the features that proved independently
predictive of DVT included malignancy, history of
previous DVT, recent immobilization, difference
in calf diameter, and recent surgery. In contrast,
Homans sign, calf pain, calf swelling, and obesity
did not carry high enough LR+ to serve as reliable
indicators of DVT. (See Table 3.) No single feature
had a low enough negative likelihood ratio (LR-) to
reliably exclude DVT, but absence of calf swelling
(LR- 0.67; 95% CI, 0.58-0.78) and lack of difference
in calf diameter (LR- 0.57; 95% CI, 0.44-0.72) may
indicate a slight reduction in the likelihood of DVT.
Not surprisingly, it is more effective to look at a
combination of the clinical features, risk factors, and
alternate diagnoses than to focus on isolated vari-
ables.24 For instance, a high Wells score incorporat-
ing a scripted combination of the above factors (see
Table 4) yielded a much more predictive LR+ of 5.2
(95% CI, 4.0-6.0) while a low Wells score rendered
the disease less likely, with an LR- of 0.25 (95% CI,
0.21-0.29). When physicians dichotomized their clini-
cal judgment to high versus low, high-probability
estimations resulted in an LR+ of 6.2 (95% CI, 1.0-
40.0) while low-probability estimations were more
fine-tuned at an LR- of 0.18 (95% CI, 0.13-0.26).
When the clinical suspicion for DVT is high, the
emergency clinician should simultaneously assess
for the complications of DVT. In addition to PE, DVT
with massive clot burden can cause a severe form of
venous obstruction known as phlegmasia cerulean
dolens, which is characterized by sudden-onset
swelling, bluish discoloration, and even loss of arte-
rial pulses that can lead to gangrene and loss of the
limb. Prompt consultation for thrombolysis or surgi-
cal thrombectomy is indicated in this situation. More
common is concurrent or long-term postthrombotic
syndrome, which affects up to one-half of patients
Table 3. Diagnostic Value Of Clinical
Features Of Deep Venous Thrombosis24
Clinical Feature LR+ 95% CI
Highly Predictive
Malignancy 2.71 2.16-3.39
Previous DVT 2.25 1.57-3.23
Recent immobilization 1.98 1.70-2.30
Difference in calf diameter 1.80 1.48-2.19
Recent surgery 1.76 1.40-2.20
Less Predictive
Homans sign 1.40 1.18-1.66
Calf pain 1.08 0.96-1.20
Calf swelling 1.45 1.25-1.69
Obesity 0.85 0.59-1.23
Abbreviations: DVT, deep venous thrombosis; LR+, positive likelihood
ratio; CI, confidence interval.
March 2015 www.ebmedicine.net
(especially those with recurrent ipsilateral DVT) and
causes symptoms of venous insufficiency, persistent
pain and swelling, skin discoloration, varicose veins,
and, in severe cases, nonhealing lower extremity
ulcerations.23
Risk Stratification
Since its inception in 1995, the Wells clinical
model has been the most often-cited prediction
rule for stratifying pretest probability of sus-
pected first-time lower extremity DVT. Wells et
al used signs and symptoms, risk factors, and the
potential for alternative diagnoses to prospec-
tively score outpatients referred for suspected
DVT as having either low (< 0 points), moderate
(1-2 points), or high ( 3 points) pretest prob-
ability. These risk groups corresponded to a DVT
prevalence of 5%, 33%, and 85% on venography,
respectively (P < .001), while demonstrating high
interobserver reliability (kappa = 0.85) using
their original 12-point clinical model.25
Table 4. Wells Clinical Model For Predicting
The Pretest Probability Of Deep Venous
Thrombosis
Clinical Characteristic Score
Active cancer (patient receiving treatment for cancer 1
within the previous 6 mo or currently receiving palliative
treatment)
Paralysis, paresis, or recent plaster immobilization of the 1
lower extremities
Recently bedridden for 3 days or more, or major surgery 1
within previous 12 wk requiring general or regional
anesthesia
Localized tenderness along the distribution of the deep 1
venous system
Entire leg swollen 1
Calf swelling at least 3 cm larger than that on the 1
asymptomatic side (measured 10 cm below the tibial
tuberosity)
Pitting edema confined to the symptomatic leg 1
Collateral superficial veins (nonvaricose) 1
*Previously documented deep venous thrombosis 1
Alternative diagnosis at least as likely as deep venous -2
thrombosis
Three-tiered scoring method20: High 3; moderate = 1 to 2; low < 0.
Two-tiered scoring method27: Likely > 2; unlikely < 1.
* Later added to modified versions of Wells scoring;27,20 absent from
original scoring.25,26
From The New England Journal of Medicine. Philip S. Wells, David R.
Anderson, Marc Rodger, et al. Evaluation of D-dimer in the diagnosis
of suspected deep-vein thrombosis. Volume 349, pages 1227-1235.
Copyright 2003 Massachusetts Medical Society. Reprinted with
permission from Massachusetts Medical Society.
5 Reprints: www.ebmedicine.net/empissues
 In 1997, using a simplified 9-point version of
this model, Wells et al prospectively demonstrated
the safety of a more focused application of serial
ultrasounds tailored to pretest probability by elimi-
nating the traditional repeat ultrasound at 1-week
follow-up in patients with low pretest probability of
DVT.26 Differences in the prevalence of DVT in the
low, moderate, and high pretest probability groups
were maintained at 3%, 17%, and 75%, respectively
(P < .00001), while interobserver reliability between
study nurses and physicians remained high
(kappa = 0.75).
Yet another modification of the Wells clinical model
accounts for inclusion of patients with previously docu-
mented DVT by adding a point to the clinical score for
this history, while also differentiating pretest probability
into "likely" versus "unlikely" categories.27 In this 2003
iteration of the Wells criteria, Wells et al randomized
1096 outpatients with suspected DVT to either initial
ultrasound or D-dimer testing, and the results dem-
onstrated a safe reduction in ultrasounds in unlikely
patients via the alternative use of D-dimer. Patients who
were prospectively scored as clinically likely to have DVT
demonstrated a 28% rate of DVT on 3-month follow-
up, compared with a 5.5% rate in the clinically unlikely
category.
In 2006, Wells et al revisited their earlier 3-tiered
clinical model and similarly modified it with the
additional point for prior history of DVT.20 (See
Table 4, page 5.) A systematic review of 14 prospec-
tive cohorts that included 8239 outpatients with
suspected DVT revealed pooled prevalences of 5%,
17%, and 53% for DVT in the low, moderate, and
high pretest probability categories, respectively. The
3-tiered stratification of pretest probability forms the
suggested basis for tailoring the diagnostic work-up
toward a patient with suspected DVT in multiple
current guidelines.1,2,7,8 While available guidelines
agree that a negative D-dimer is sufficient initial
testing in low pretest probability groups, the ACCP
additionally advocates for the use of initial D-dimer
testing in moderate pretest probability patients
under specific conditions. (See Clinical Pathway
for the Diagnostic Evaluation of a Suspected First
Lower Extremity DVT, page 14).
Despite how widely the Wells clinical score is
cited in the literature, its comparative performance
against clinician gestalt remains unclear. Although
dedicated studies are limited, Goodacre et al sug-
gested similar performance between unstructured
clinician assessments and standardized Wells scor-
ing.24 A more recent single-center prospective cohort
with a high prevalence of DVT (47%) reported an LR+
of 6.82 for empirical estimation of high probability by
vascular specialists versus an LR+ of 2.23 for a likely
score via Wells criteria applied by emergency physi-
cians.28 This suggests that, with the appropriate expe-
rience, empirical estimation may be as predictive as, if
not more predictive than, Wells scoring. Nonetheless,
Copyright 2015 EB Medicine. All rights reserved. 6
its explicit standardization and ease of application
continue to make the Wells scoring tool ideal for both
ongoing research and clinical practice.
Additional research evaluates the interobserver
variability of the Wells clinical model, as well as its ap-
plicability both to broader and more specific populations.
External calculations of interobserver variability using
the score have ranged from a kappa of 0.58 between
resident and senior vascular medicine specialists29 to 0.74
between emergency physicians and nurse practitioners
using 3-tiered Wells scoring,30 to 0.836 between emer-
gency physicians and vascular specialists using 2-tiered
Wells scoring.28
In 2005, Oudega et al suggested that the Wells
criteria may not perform as reliably in the primary care
setting,31 although the earlier version of Wells scoring
used in this analysis did not account for prior document-
ed DVT. Subgroup analysis of a combined meta-analysis
of 10,002 patients has uncovered additional insights with
regard to patients with prior history of DVT and active
malignancy.32 In 941 patients with suspected recurrent
DVT, correction from the original Wells criteria to the
modified version (by adding a point for prior history of
DVT) improved the false-negative rate of DVT from 2.5%
(95% CI, 1.2-5.4) to 1.0% (95% CI, 0.6-1.6). However, sub-
group analysis of 834 patients with active cancer revealed
that the combination of an unlikely score and a nega-
tive D-dimer resulted in a higher miss rate of 2.2% (95%
CI, 0.5-8.6), suggesting that imaging may have stronger
benefit in this subset of patients than risk stratification
and laboratory testing alone.
Diagnostic Studies
D-dimer
The D-dimer is considered a nonspecific but sensi-
tive biomarker for VTE. Because it may be elevated
in a number of nonthrombotic conditions (eg, recent
surgery, infection, trauma, malignancy, pregnancy,
stroke, and advanced age), D-dimers are more help-
ful in excluding the diagnosis of VTE with a nega-
tive result in the appropriately risk-stratified patient
than in confirming VTE when positive.
The various methods of D-dimer testing result
in different sensitivities and specificities for VTE that
should be viewed as institution-specific, based on the
particular type of assay used. Microplate enzyme-
linked immunosorbent assays (ELISAs) and newer-
generation quantitative latex agglutination (or immu-
noturbidimetric) assays are considered highly sensitive
for DVT (93%-94% sensitive), whereas whole blood D-
dimer assays such as SimpliRED are only moderately
sensitive (at 83%), although they offer a more rapid
turnaround time and demonstrate a higher specificity
(approximately 71%).1,33-35
Given the current state of numerous coexisting
D-dimer assays and techniques across laboratories,
the astute clinician should be familiar with local
www.ebmedicine.net March 2015
laboratory practices and maintain awareness of tech-
nique-specific units of measurement (eg, fibrinogen
equivalent units [FEU] vs D-dimer units [DDU]) and
laboratory-specific variable magnitudes of measure-
ment that are not always easily converted from one
to another.36
Laboratory variability notwithstanding, for the
purposes of excluding lower extremity DVT, a nega-
tive D-dimer result should be interpreted within
the context of the test method's degree of sensitivity
(moderate vs high) and the patient's clinical pretest
probability of DVT.1 (See Table 3, page 5; and Clini-
cal Pathway For The Diagnostic Evaluation Of A
Suspected First Lower Extremity DVT, page 14.) A
negative result using a moderate-sensitivity assay
may be sufficient to safely rule out DVT without
further testing in a patient with low pretest clinical
probability; however, a moderate-risk patient would
need at least a negative high-sensitivity D-dimer in
order to complete the workup without imaging. In
patients with moderate to high pretest probability of
DVT, a negative D-dimer result, in combination with
an initial negative proximal compression ultrasound,
may safely eliminate the need for follow-up serial
or initial whole-leg ultrasound. There is insufficient
evidence to support the safety of using only D-dimer
to rule out DVT in high-risk patients. The practice is
inefficient (fewer than 15% of high-risk outpatients
will yield a negative result37), and relying on D-
dimer results without imaging in high-risk patients
is not recommended.1
Adjusted D-dimer Thresholds
Although D-dimer testing is generally interpreted
in a binary manner, using the traditional cut-off (ie,
> 500 mcg/L FEU or < 500 mcg/L FEU) to yield
a positive or negative result, more recent studies
advocate adjusting the D-dimer threshold in se-
lect patient groups to improve specificity without
sacrificing sensitivity. Newer literature suggests that
future strategies may allow for routine use of higher
D-dimer cut-offs in patients with predefined low
pretest probability and for elderly patients. Consid-
erations for D-dimer in recurrent DVT, DVT during
pregnancy, and upper extremity DVT are discussed
in the Special Populations section (page 12).
In 2004, a retrospective study demonstrated that
D-dimer test specificity could be improved, while
maintaining equally high negative predictive values,
by using a higher D-dimer cut-off in patients with low
pretest probability of DVT.38 A 2013 follow-up prospec-
tive randomized multicenter controlled trial stratified
and studied the safety of using a higher threshold of <
1 mcg/mL FEU for outpatients with low pretest prob-
ability of suspected first-time DVT, compared with the
standard threshold of < 0.5 mcg/mL.37 Both testing
strategies resulted in similar rates of VTE at 3-month
follow-up in patients with low pretest probability (0.0%
vs 0.3%), while also reducing the number of ultrasounds
March 2015 www.ebmedicine.net
in this group at an absolute rate of 21%. The safety
of this approach and its ability to decrease the initial
number of ultrasounds was also externally validated in
a post hoc analysis of a population with a much higher
DVT prevalence (22% vs 7%).39
Because D-dimer levels increase with age, tradi-
tional cut-off values have less utility in elderly patients
for excluding VTE (eg, 500 mcg/L FEU).40,41 In response,
there has been growing interest in applying age-ad-
justed cut-offs for patients aged > 50 years, determined
by multiplying the patients age in years times 10. For
example, a patient who is 80 years old would be allowed
an age-adjusted cut-off of up to 800 mcg/L FEU.
A 2013 meta-analysis of 12,497 patients using age-
adjusted D-dimer cut-offs for suspected VTE (either PE
or DVT) demonstrated higher specificities using age-ad-
justed cut-offs while still maintaining a sensitivity > 97%
in all age groups.42 The use of age-adjusted D-dimer
cut-offs for DVT was adapted from the use of a retro-
spectively validated strategy with PEs.43 A DVT-specific
meta-analysis combining cohorts with various D-dimer
assays and versions of the Wells criteria found a higher
exclusion rate of DVT in 1672 patients with nonhigh
probability when using an age-adjusted cut-off (51%)
versus the exclusion yield with the standard 500 mcg/L
FEU cut-off (42%), while still maintaining similar false-
negative rates in the age-adjusted (0.8%) and standard
(0.7%) groups.44 This has also been retrospectively vali-
dated in the primary care and outpatient DVT referral
settings in patients with low clinical probability.45,46
More recently, a prospective validation study of
3346 patients using age-adjusted D-dimer thresholds
to exclude suspected PE demonstrated a false-negative
rate of 0.3%,47 lending further credibility to the move-
ment toward age-adjusted thresholds. If the DVT
evidence continues to mirror the PE trend, a similar
prospective validation for DVT can be expected in the
near future.
Imaging Studies
Although rarely utilized in recent years due to the ad-
vances in ultrasonography, contrast venography has,
historically, been the gold standard for the diagnosis
of lower extremity DVT. After cannulating and inject-
ing radiopaque dye into the distal venous system, the
diagnosis is made by visualization of filling defects,
abrupt termination of the dye column, nonfilling of
the venous system, or diversion of flow.48 Patients
with an adequate, negative study demonstrate a 1.3%
(95% CI, 0.2-4.4) risk of developing DVT within 3
months.1,21 However, this method has many limita-
tions, including the need for invasive testing, failure
to cannulate an appropriate vein in the dorsal foot,
inadequate visualization of veins, high interobserver
variability of the results, and even postprocedure
thrombosis.21 Despite these shortcomings, contrast
venography established the < 2% risk threshold
standard against which modern forms of diagnostic
7 Reprints: www.ebmedicine.net/empissues
testing are compared, and it remains a follow-up test 67.0) and specificity of 93.8% (95% CI, 93.1-94.4).50
of choice when initial imaging is nondiagnostic.49 Other disadvantages of whole-leg ultrasound include
Current modalities for imaging (duplex ultrasonog- the increased complexity of the examination, increased
raphy, computed tomography [CT] venography, and time to perform the examination, an increase in the
magnetic resonance imaging [MRI]) offer less inva- proportion of technically inadequate examinations, and
sive and more readily available alternatives. the potential for overtreatment of distal calf thrombi
that may not pose significant risk for propagation.58
Ultrasound Many studies that compared serial proximal
Venous duplex ultrasonography of the proximal compression ultrasound with whole-leg ultrasound
deep veins is the most common means of evaluating (while withholding anticoagulation after initial
for the presence of DVT.49,50 Duplex ultrasonogra- negative studies) have demonstrated that both strat-
phy combines 2-dimensional grayscale (B-mode) im- egies have a similar incidence of VTE on 3-month
aging with Doppler color flow or spectral imaging. follow-up (0.9%-2.0% for proximal compression
Imaging of the deep venous system is performed ultrasound vs 1.2% for whole-leg ultrasound).57,59
from the proximal common femoral vein through However, whole-leg ultrasound may diagnose more
the popliteal trifurcation.51 DVT is confirmed by DVT than needs to be treated, with isolated distal
a combination of the following: abnormal venous DVT accounting for 52.1% of diagnosed DVT in a
compression on B-mode ultrasound (normally, the meta-analysis of whole-leg ultrasonography.23,60
vein should fully collapse with compression); the When determining the role of ultrasound in
presence of an echogenic thrombus within the lu- the diagnostic workup, pretest probability for
men of the vein; abnormal Doppler color flow or DVT should be risk stratified so that diagnostic
visualization of filling defects with color Doppler; or testing can be tailored accordingly.1,2,8 (See Clini-
abnormal spectral Doppler flow.50,52 (See Figure 2.)
Meta-analysis of duplex ultrasonography compared
with venography demonstrates a sensitivity of 96.5% Figure 2. Duplex Ultrasound Image Of Deep
(95% CI, 95.1-97.6) and specificity of 94.0% (95% CI, Venous Thrombosis
92.8-95.1) for diagnosis of proximal DVT by duplex
ultrasound.50 Limitations of duplex ultrasonography
include limited evaluation of DVT proximal to the
common femoral vein (ie, iliac veins), inability to
visualize the femoral vein within the adductor canal,
and, with traditional proximal duplex ultrasonogra-
phy, nonimaging of the calf veins.49 Because the risk
of propagation of an undiagnosed distal calf vein
thrombus could be as high as 25%, serial ultrasonog-
raphy at 1 week was traditionally recommended for
all patients.53,54 However, later literature found only
a 1.3% yield of propagation on repeat ultrasound
(95% CI, 0.97-1.9).50 Utilization of a risk stratification
scheme may eliminate the need for the follow-up
ultrasound. In a low-risk population (DVT unlikely),
Wells et al found that only 1.4% (95% CI, 0.4-3.8)
had DVT on follow-up after a single proximal
ultrasound, calling into question the need to obtain
repeat ultrasounds in patients who are risk stratified
with unlikely probability of DVT.27,50
Whole-leg duplex compression ultrasonography
can also be performed as an extension of the standard
proximal duplex compression ultrasound. Because both
the proximal and calf veins are studied with whole-leg
ultrasonography, alternative diagnoses (such as super-
ficial thrombophlebitis or musculoskeletal pathology)
are more readily recognized and isolated distal calf
thrombosis may be revealed. Especially important in an To view a full-color version of this image, go to:
ED population, a negative whole-leg ultrasound may www.ebmedicine.net/USDuplexDVT
obviate the need for a repeat study in appropriately A noncompressible echogenic thrombus with color Doppler filling de-
stratified patients.55-57 However, evaluation of the distal fect within the lumen is demonstrated in the femoral vein at the level
veins is significantly less accurate than the proximal of the saphenofemoral junction.
veins, with a pooled sensitivity of 63.5% (95% CI, 59.8- Image courtesy of Jacob Goertz, MD, RDMS.

Copyright 2015 EB Medicine. All rights reserved. 8 www.ebmedicine.net March 2015

cal Pathway For The Diagnostic Evaluation Of A
Suspected First Lower Extremity DVT, page 14.)
This may be accomplished using validated scoring
systems (eg, Wells score) or, alternatively, clinical
gestalt. (See the Risk Stratification section, page 5.)
For a patient with low or moderate pretest probabil-
ity, proximal ultrasound may be utilized as either
the initial diagnostic test or after prompting by a
positive D-dimer result (Grade 1B). (See the D-
dimer section, page 6.) If the proximal ultrasound
is negative in a patient with low pretest probability,
DVT is excluded without need for serial proximal
ultrasound Grade 1B. If the proximal ultrasound is
negative in a patient with moderate pretest prob-
ability, either a concurrent D-dimer test on the index
visit (Grade 1C) if not already performed, or a serial
proximal ultrasound should be arranged (Grade
1B-C). Alternatively, in the patient with moderate
pretest probability, whole-leg instead of proximal
ultrasound can be elected (Grade 1B), particularly
if the patient has more-severe symptoms or may be
unable to return for serial testing. For patients with
high pretest probability, the initial test of choice is
proximal or whole-leg ultrasound (Grade 1B), as the
use of initial D-dimer testing in this population is
not recommended.1
Point-Of-Care Emergency Ultrasound
Focused point-of-care ultrasound has become
commonplace in the practice of emergency medi-
cine, and examination of the lower extremities for
DVT is among the core ultrasound applications for
emergency physicians.61 Unlike a comprehensive
duplex compression ultrasound, focused emergency
ultrasound consists of a 2-point compression-only
examination focusing on the common femoral vein
and the popliteal vein. Using a linear 5 to 10 MHz
probe, the common femoral vein is compressed seri-
ally from proximal to the saphenofemoral junction
distally past the confluence of the deep femoral vein
and femoral vein. The popliteal vein is then com-
pressed from the popliteal trifurcation proximally.62
Studies have demonstrated that point-of-care
lower extremity ultrasound is fast and accurate, and
decreases time to disposition in the ED.62-64 A recent
meta-analysis of ultrasound performed by emer-
gency physicians demonstrated a pooled sensitivity
of 96.1% (95% CI, 90.6-98.5) and specificity of 96.8%
(95% CI, 94.6-98.1) in the evaluation of DVT.63 Poten-
tial areas of concern for point-of-care lower extremity
ultrasound arise due to the inability to visualize of
certain parts of the anatomy, including the femoral
vein along the course of the leg, the calf veins, and,
more proximally, the iliac veins (where the addition of
Doppler findings can help identify thrombi). Also, the
compliance rate for recommended 5- to 7-day serial
studies can be low in the ED population.65 The rate at
which an isolated DVT in the femoral vein is not vi-
sualized in either the common femoral vein or in the
March 2015 www.ebmedicine.net
popliteal vein in a 2-point compression ultrasound
has not been established.66
Alternative Imaging Modalities
Computed Tomography Venography
In a meta-analysis, CT venography (which involves
helical CT imaging of the lower extremities following
venous injection of contrast) demonstrated a pooled
sensitivity of 95.9% (95% CI, 93.0-97.8) and specific-
ity of 95.2% (95% CI, 93.6-96.5) for lower extremity
DVT.67 Most of the included studies compared CT
venography to compression duplex ultrasonography,
reported only proximal DVT, and evaluated for DVT
as a part of a PE workup. CT venography has several
advantages: it is noninvasive, capable of diagnosing
pelvic or iliac vein thrombosis, and it can be per-
formed in conjunction with CT pulmonary angiog-
raphy to increase the sensitivity of evaluation for
VTE.68 CT venography can also be used to evaluate
for DVT in patients with indeterminate or technically
inadequate compression duplex ultrasound stud-
ies or in cases where performance of a compression
duplex ultrasound would be impossible, such as for a
patient with an overlying cast.67 Disadvantages of CT
venography include the risks involved with ionizing
radiation and intravenous contrast administration, as
well as lower sensitivity.68
Magnetic Resonance Imaging
MRI also has occasions for use in the diagnosis
of DVT. Several different techniques have been
documented, including visualization of blood flow
without administration of contrast (time-of-flight or
phase-contrast venography MRI), MRI with intrave-
nous gadolinium contrast, and magnetic resonance
direct thrombus imaging.1 Meta-analysis of MRI
demonstrated a pooled sensitivity of 91.5% (95%
CI, 87.5-94.5), with a higher sensitivity for proximal
DVT than distal DVT (93.9% vs 62.1%), and a pooled
specificity of 94.8% (95% CI, 92.6-96.5).69 Although
it avoids the ionizing radiation of CT venography,
MRI is more costly, more time-consuming, and less
frequently available. However, it remains an alterna-
tive for patients in whom compression duplex ultra-
sound is nondiagnostic and for whom CT or contrast
venography is contraindicated.
Current guidelines recommend against the routine
use of CT venography or MRI in patients with suspected
first (Grade 1C) or recurrent (Grade 1B) lower extremity
DVT.1 If subtle ultrasound findings or extensive unex-
plained swelling with high clinical suspicion suggest the
presence of an iliac vein DVT, use of CT venography or
MRI should be considered (Grade 1C).8,70
Treatment
Treatment for acute DVT is divided into 3 phases:
(1) initial (0 to ~7 days), (2) long-term (~7 days to
9 Reprints: www.ebmedicine.net/empissues
~3 months), and (3) extended (> ~3 months). Most
cases of proximal DVT and some cases of severe
or high-risk distal DVT will be treated with antico-
agulation in the initial and long-term phases, with
adjunct recommendations for early ambulation and
compression therapy to prevent or decrease sequelae
of postthrombotic syndrome. New oral direct inhibi-
tors, which act on factor Xa (eg, rivaroxaban and
apixaban) or thrombin (eg, dabigatran), are adding
to the array of anticoagulant options, and some of-
fer the advantages of monotherapy and once-daily
dosing in the initial phase of anticoagulation. Select
patients may require longer durations of therapy in
the extended phase of anticoagulation; additionally
or alternatively, they may benefit from specialized
interventions ranging from IVC filters to thrombo-
lytics or operative thrombectomies. (See Clinical
Pathway For Treatment Of Lower Extremity DVT,
page 15.)
Initial Anticoagulation
Parenteral anticoagulation has long been the main-
stay of first-line DVT treatment to prevent extension
or recurrence of clots (Grade 1B). Provided there is
no renal insufficiency or other contraindications,
fixed-dose subcutaneous low-molecular-weight
heparin (LMWH) or fondaparinux are preferred
(Grades 2B and 2C, respectively) over unfraction-
ated heparin (UFH),4 offering greater convenience,
adaptability to the outpatient setting, and lower
potential for heparin-induced thrombocytopenia.
Meta-analysis of 23 randomized controlled trials that
compared LMWH to UFH for VTE demonstrated
a favorable decrease in recurrent VTE (odds ratio
[OR], 0.70; 95% CI, 0.57-0.85), major hemorrhage
(OR, 0.58; 95% CI, 0.40-0.83), and death (OR, 0.77;
95% CI, 0.63-0.93) with LMWH.71 Once-per-day dos-
ing of LMWH at the same total daily dose (eg, 2 mg/
kg once daily vs 1 mg/kg twice daily) has shown
no significant increases in bleeding, extension, or
recurrence compared with twice-daily dosing and
is the preferred regimen (Grade 2C).4 Fondaparinux
proved noninferior to LMWH in a randomized dou-
ble-blind trial comparing the 2 regimens.72 However,
there are some caveats: LMWH and fondaparinux
will accumulate in patients with renal insufficiency
(creatinine clearance < 30 mL/min), and neither has
reliable monitoring capabilities or effective reversal
agents (although protamine and recombinant factor
VIIa may show partial response).73 Like LMWH and
fondaparinux, rivaroxaban and apixaban are, in part,
renally excreted.
Novel Oral Anticoagulants
The novel oral anticoagulants offer an attrac-
tive and potentially game-changing alternative to
the more traditional parenteral heparins and oral
vitamin K antagonists (VKAs). (For more informa-
Copyright 2015 EB Medicine. All rights reserved. 10
tion on new oral anticoagulants, see the October
2013 issue of Emergency Medicine Practice, available
at: www.ebmedicine.net/NOACs) Their use is
largely expanded from prior experiences with these
medications for postoperative DVT prevention and
stroke prevention in atrial fibrillation. Open-label
randomized trials of the direct factor Xa inhibitor,
rivaroxaban, in 3449 patients with DVT74 and 4832
patients with PE75 demonstrated noninferior rates of
recurrent VTE and decreased rates of major bleed-
ing (hazard ratio, 0.54; 95% CI, 037-0.79; P = .002) in
pooled analysis compared with standard LMWH/
VKA therapy,76 and it was the first of the novel oral
anticoagulants to obtain Food and Drug Adminis-
tration (FDA) approval for acute VTE treatment in
November 2012. More recently, in August 2014, the
FDA approved another factor Xa inhibitor, apixaban
(Eliquis), for initial therapy of acute VTE, following
on the heels of its randomized double-blinded trial
(N = 5395 patients with combined acute VTE) that
demonstrated noninferiority to LMWH/warfarin as
well as significantly decreased rates of major bleed-
ing (RR, 0.31; 95% CI, 0.17-0.55; P < .001).77
Although the risk of bleeding appears lower,
the reversal agents are still in development and the
partial reversal efficacy of prothrombin complex
concentrate (PCC), activated prothrombin complex
concentrate (aPCC), and recombinant human factor
VIIa are being investigated.78
Cost-effectiveness calculations appear to favor
oral anticoagulants over combination LMWH/
VKA therapy after accounting for medication pric-
ing, shorter hospital stays, and costs of medication
administration and INR monitoring.77 Regardless
of the type of medication selected, initial therapy
should be started immediately and continued for a
minimum of 5 days, until maintenance or long-term
anticoagulation reaches therapeutic levels (Grade
1B).4 The ACCP guidelines even suggest consider-
ing empiric initial anticoagulation while awaiting
confirmatory diagnosis in patients with high clinical
suspicion (Grade 2C) or in patients with intermedi-
ate clinical suspicion when delays to diagnosis > 4
hours are anticipated (Grade 2C).4
Long-Term Anticoagulation
Although the long-term (ie, maintenance) phase of
anticoagulation therapy through the first 3 months
may have previously fallen beyond the scope of ED
care, growing prioritization for outpatient treatment
of acute DVT as well as return visits for suspected
bleeds necessitate that the up-to-date emergency
clinician be familiar with these regimens as well.
Therapeutic options for maintenance therapy range
from continuation of LMWH to transitioning to oral
VKAs or a new oral direct inhibitor anticoagulant.
In noncancer patients, VKAs have traditionally been
the oral maintenance anticoagulation agents of choice.
www.ebmedicine.net March 2015
Nonetheless, they require the ability to establish close
INR monitoring and dietary counseling, are notori-
ous for drug-drug interactions, and necessitate initial
parenteral therapy to bridge the transition to therapeu-
tic INR levels between 2 and 3. To avoid unnecessary
and prolonged hospital stays, guidelines recommend
commencing VKA therapy on the first day of diagnosis4
and continuing parental therapy for a minimum of 5
days until the INR is therapeutic for 24 hours (Grade 1B).
There is some debate as to the quantity of the initial
loading dose (5 mg or 10 mg orally).79,80 Oral VKAs have
long-standing proven methods of anticoagulation
reversal with vitamin K, fresh frozen plasma, and, for life-
threatening bleeds, PCC.
Of the new oral anticoagulants, rivaroxaban and
apixaban offer the added benefit of monotherapy
from the time of initial anticoagulation; they are also
associated with a lower risk of bleeding than the
standard LMWH/VKA combination.15,74,75,77 As an
alternative, dabigatran, a direct thrombin inhibitor,
reflects similar rates of recurrent VTE, major bleed-
ing, and death compared with VKAs, although it
requires initial bridging with parenteral anticoagula-
tion.81,82 A fourth new oral anticoagulant, the factor
Xa inhibitor edoxaban (Savaysa), is currently under
FDA review for long-term therapy following initial
parenteral therapy. It also demonstrated noninferior-
ity to VKAs in randomized, double-blind testing (N
= 8292) and, additionally, it reflected decreased rates
of clinically relevant bleeding (hazard ratio, 0.81;
95% CI, 0.71-0.94; P = .004).83 However, as previ-
ously discussed, unlike VKAs, the new oral antico-
agulants currently lack a dedicated reversal agent in
the setting of acute bleeding, and their varying rates
of renal excretion limit their use in patients with
decreased creatinine clearance.84
Patients with active cancer carry a higher risk
of recurrent VTE, bleeding, and variable responses
to traditional VKA therapy. Systematic review of
randomized trials has shown LMWH to be superior
to VKA therapy in this population, with a 6.7% rate
of recurrent VTE in the LMWH arm, compared with
12.9% in the VKA group (RR, 0.53; 95% CI, 0.36-0.76; P
= .0007).85 Subgroup analysis combining the DVT and
PE trials for rivaroxaban (n = 597 patients) suggests
a net clinical benefit with rivaroxaban (hazard ratio,
0.60; 95% CI, 0.36-0.99) after accounting for trends
toward decreased recurrent VTE (hazard ratio, 0.69;
95% CI, 0.36-1.33) and major bleeds (hazard ratio,
0.53; 95% CI, 0.23-1.23),76 but the overall experience
with this new class of medications in this subset of
patients is still limited. In the meantime, daily LMWH
injections for at least 6 months remain the general
first-line recommendation for long-term and extend-
ed-term treatment in patients with active cancer.4,79
Extended Anticoagulation
For most uncomplicated acute DVT in noncancer
March 2015 www.ebmedicine.net
patients, 3 months of treatment are recommended
(Grade 1B).4 Extension of therapy beyond this dura-
tion, generally using the same anticoagulant agent
used for long-term therapy, may depend on presence
or absence of provoking factors (eg, recent surgery),
known hypercoagulability, prior history of DVT,
active malignancy, bleeding risk, and, more recently,
the use of D-dimer assays to predict future VTE
recurrence.86 To be fully aware of the risks of bleed-
ing, potential reversal agents (or lack thereof), and
treatment alternatives, emergency clinicians should
familiarize themselves with both the old and the
new anticoagulants.
Inferior Vena Cava Filters
An IVC filter is a permanent or retrievable (optional)
vascular filter designed to mechanically trap large
emboli and prevent massive PE in the approximately
4% of patients with DVT who have contraindications
to anticoagulation or who have recurrent PE while
they are therapeutically anticoagulated. Placement
of an IVC filter might also be appropriate for DVT
patients who are pregnant or have cancer. An IVC
filter may also be considered prophylactically in
high-risk patients with significant trauma or spinal
surgery.87 Current guidelines recommend use of an
IVC filter in patients with acute proximal DVT, as
well as patients for whom there are contraindica-
tions for anticoagulation (Grade 1B).2,4,8 The Society
of Interventional Radiology makes further recom-
mendations regarding the choice of retrievable ver-
sus permanent filters based on the patients expected
duration of elevated risk for PE or contraindication
for anticoagulation.88
No randomized controlled studies compare IVC fil-
ter placement to anticoagulation, and no trials compare
the various filter designs.87,89 The Prevention du Risque
d'Embolie Pulmonaire par Interruption Cave (PREPIC)
study found that, in comparison with anticoagulation
alone, placement of an IVC filter in combination with
anticoagulation decreased the rate of PE (15% vs 9%;
RR, 0.37; 95% CI, 0.17-0.79), increased the rate of recur-
rent DVT (RR, 1.52; 95% CI, 1.02-2.27), and had no effect
on development of postthrombotic syndrome (RR,
0.87; 95% CI, 0.66-1.13) or death (RR, 0.97; 95% CI, 0.74-
1.28).90 A subsequent Cochrane review (a major com-
ponent of which was the PREPIC study) reached similar
conclusions.87 Complications of IVC filter placement
include DVT, filter migration or embolization, and IVC
stenosis or perforation, with complication rates increas-
ing in relation to prolonged duration of the placement
procedure.89 Of course, there is an elevated risk of
thrombogenicity with the presence of any intravascular
foreign body. Given the risk of DVT, the ACCP guide-
lines recommend the use of a conventional course of
anticoagulant medication for patients in whom an IVC
filter has been placed if the risk of bleeding has resolved
(Grade 2B).4
11 Reprints: www.ebmedicine.net/empissues
Thrombolysis And Thrombectomy
Treatment modalities that remove the thrombus have
the potential to immediately increase the patency of
the vein and decrease the short-term and long-term
effects of DVT, including vascular compromise, PE,
and postthrombotic syndrome. The available modali-
ties include systemic thrombolysis, catheter-directed
thrombolysis, interventional mechanical clot removal,
or surgical thrombectomy. Early thrombus removal
strategies are preferred in patients with limb-threat-
ening venous ischemia due to iliofemoral DVT (eg,
phlegmasia cerulean dolens) (Grade 1A).4,70
Treating lower extremity venous thrombosis
with thrombolysis (as opposed to anticoagulation)
results in active lysis of the clot, with disadvan-
tages primarily related to the increased risk of
bleeding.91 Thrombolysis can be performed using
either systemic thrombolytic therapy or localized
catheter-directed therapy, with or without mechani-
cal thrombus fragmentation or aspiration (phar-
macomechanical thrombolysis). Catheter-directed
thrombolysis achieves clot lysis more rapidly and
with lower doses of thrombolytic agents than
systemic thrombolysis, and pharmacomechanical
thrombolysis can, potentially, further shorten the
procedure and reduce the necessary dose of throm-
bolytic medication.4,70
A Cochrane review demonstrated significantly
more complete clot lysis with thrombolysis (systemic
or localized) than with anticoagulation at follow-up
within 1 month (RR, 4.91; 95% CI, 1.66-14.53) and
> 6 months (RR, 2.37; 95% CI, 1.48-3.80), as well as
decreased rates of postthrombotic syndrome (RR,
0.64; 95% CI, 0.52-0.79). Patients treated with throm-
bolysis had an increased risk of bleeding (RR, 2.23;
95% CI, 1.41-3.52) but no change in occurrence of PE
(RR, 1.00; 95% CI. 0.33-3.05) or recurrent DVT (RR,
1.41; 95% CI, 0.37-5.40). There were also no changes
in early mortality within 1 month (RR, 0.76; 95% CI,
0.32-1.89) or intermediate mortality within 6 years
(RR, 1.12; 95% CI, 0.319-1.89).91 There is a paucity
of studies directly comparing systemic to catheter-
directed thrombolysis. In one study, patients treated
with catheter-directed thrombolysis had better pre-
served valvular competence (44% vs 15%;
P = .049), less deep venous reflux (44% vs 81%;
P = .03), and a trend toward improved venous
patency in comparison with patients treated with
systemic thrombolysis.92 When comparing catheter-
directed thrombolysis to anticoagulation alone and
systemic thrombolysis to anticoagulation alone,
benefits and risks are similar.91
Current guidelines recommend the use of anticoag-
ulant therapy over both systemic and catheter-directed
thrombolysis (Grade 2C) and advise that thrombolysis
should be considered only in patients meeting all of the
following criteria: iliofemoral DVT, < 14 days since onset
of symptoms, good functional status, life expectancy of
Copyright 2015 EB Medicine. All rights reserved. 12
1 year, low risk of bleeding, and no other contraindica-
tions to thrombolytic therapy.4
Surgical Management
Historically, prior to development of anticoagulant
medications, surgical thrombectomy was the treat-
ment for iliofemoral DVT; now it is reserved for pa-
tients who have contraindications to thrombolysis or
for whom other treatment modalities have failed.93
Current recommendations (Grade 2C) state that
operative thrombectomy should be considered only
if all of the following criteria are present: iliofemo-
ral DVT, < 7 days since onset of symptoms, good
functional status, life expectancy of 1 year, and
readily available resources and expertise.4,70 Surgical
thrombectomy involves a venotomy and removal of
the clot. Embolization is prevented by placement of
a proximal occluding balloon catheter and the use of
positive pressure ventilation to reverse blood flow
in the IVC.94 Benefits of surgical thrombectomy for
iliofemoral DVT include increased venous patency
(75%-80%, compared with 35% for anticoagulation
alone), preservation of venous valve competency,
and fewer postthrombotic complications.93,94 Risks
include blood loss, embolization of thrombus, and
development of postprocedure DVT due to endothe-
lial disruption.93 Due to additional postthrombec-
tomy risk of DVT, it is recommended that patients
receive anticoagulation postoperatively if there are
no contraindications.4
Special Populations
Recurrent Deep Venous Thrombosis
The diagnosis of recurrent DVT is complicated by a
number of factors. Although the Wells clinical model
was modified to allow for inclusion of patients with
prior DVT, many earlier cohort studies excluded
patients with a documented history of DVT. Patients
with prior DVT are prone to postthrombotic syn-
drome of the affected leg, which can be difficult to
distinguish from a new thrombotic episode. Ultraso-
nography may pose technical difficulties in inter-
pretation of chronic versus acute thrombus in an
ipsilateral extremity that still bears residual abnor-
malities, requiring direct comparison with the exact
location and venous diameters of prior thrombi
during compression.
A handful of studies have evaluated the utility of
D-dimer in this more complicated subset of patients.
Rathburn et al prospectively evaluated 300 consecu-
tive patients with suspected recurrent DVT, conduct-
ing sensitive D-dimer tests on all the patients.95 They
found a 0.75% rate of confirmed thromboembolism on
3-month follow-up (95% CI, 0.02-4.09), which increased
to 1.5% (95% CI, 0.18-53%) when including an initially
indeterminate result in a patient whose repeat acute
thrombosis was confirmed just outside the 3-month
www.ebmedicine.net March 2015
window. Bates et al reported a 98% negative predictive
value (95% CI, 96-99) for a negative D-dimer result from
their prospective multicenter cohort study.96
Noting these diagnostic limitations, coupled
with early but promising results from unstratified
D-dimer testing, the ACCP guidelines suggest 1 of
3 diagnostic workup options for this population, as
appropriate1: (1) a single highly sensitive D-dimer
(especially if the prior ultrasound is not available
for comparison), followed by a proximal compres-
sion ultrasound if the D-dimer is positive; (2) serial
proximal compression ultrasounds on day 1 and day
7 (1); or (3) negative initial proximal compression
ultrasound with a concurrent initial D-dimer (of ei-
ther moderate or high sensitivity), with no need for
follow-up testing if the D-dimer is negative. Patients
whose ultrasounds are abnormal but equivocal for
acute thrombus (particularly if there is no prior
ultrasound for direct comparison) are advised to
undergo either a more rapid follow-up ultrasound
prior to the 1-week ultrasound or a formal venog-
raphy for confirmation. During serial testing, it is
considered safe to withhold anticoagulation.1,96
The next progression in the diagnosis of acute
recurrent DVT is to incorporate risk stratification into
this diagnostic algorithm. Previously, a small prospec-
tive study of 105 patients used the combination of
dichotomized, modified Wells scoring and D-dimer
testing to evaluate the safety of this management
approach. Although the subset of patients unlikely to
have DVT with a negative D-dimer accounted for only
15% of evaluated patients in this population with a high
(45%) prevalence of DVT, none of these 6 patients had a
DVT on 3-month follow-up.97 More recently, subgroup
analysis of a combined meta-analysis of 10,002 patients
with suspected DVT yielded 941 patients with a prior
confirmed history of DVT.32 Using the original Wells cri-
teria in this subset risked a 2.5% rate of DVT in patients
with low pretest probability and a negative D-dimer
(95% CI, 1.2-5.4). However, using the modified version of
scoring, whereby an additional point is added for previ-
ous DVT, the combination of a low-risk score (< 1) with
a negative D-dimer resulted in a more acceptable miss
rate of 1.0% (95% CI, 0.6-1.6). This suggests that using
the modified Wells scoring and a negative D-dimer is
likely safer in ruling out recurrent acute DVT than using
an unstratified approach. The data are still not as robust
as for diagnosis of first-time DVT, and larger prospective
validations specific to this population and the use of risk
stratification are needed.
Isolated Deep Distal Vein Thrombosis
The clinical significance and treatment of isolated
deep distal vein thrombosis (IDDVT) remains con-
troversial. IDDVT can occur anywhere in the distal
veins of the calf, including the deep calf veins (pero-
neal, posterior tibial, and anterior tibial veins) and
the muscular veins (soleus and gastrocnemius veins).
Together, isolated deep calf vein thrombosis and iso-
March 2015 www.ebmedicine.net
lated calf muscle vein thrombosis comprise IDDVT,
although there is some debate as to whether or not
the calf muscle veins should be considered part of the
deep venous system.19
Most DVT starts in the calf; the historic rate of
extension to the proximal veins generally occurring
within the first 2 weeks is up to 25%. Recent studies
have documented lower rates of propagation to the
proximal veins (8%-16%), with a 1.6% to 3.4% risk of
PE.19,53,98 In thrombosis isolated to the muscular veins,
only 3% propagate to the proximal veins.99 Further-
more, up to 90% resolve spontaneously without treat-
ment.19,53,98 In a review of studies diagnosing calf vein
DVT by either venography or whole-leg ultrasound,
the overall prevalence of DVT ranged between 14%
and 37%, 23% to 59% of whom were diagnosed with
isolated calf DVT.19 Patients with isolated calf DVT are
more likely to be younger, have transient provoking
risk factors (eg, hospitalization, recent surgery, trauma,
or travel), and, therefore, have a decreased rate of DVT
recurrence, compared with patients who have proximal
DVT (2.6% vs 8.4%).19,98
Treatment of isolated distal DVT must balance
these lower risks of propagation, embolization,
and recurrence with the reduced benefits of treat-
ment and the risks of anticoagulation.100 The goal of
diagnosis in this population is to identify the subset
that would actually benefit from therapy,4 in contrast
with patients who should be observed via serial ul-
trasounds for propagation of thrombus to the proxi-
mal system. There is a paucity of studies regarding
this treatment paradigm. A 2012 meta-analysis
identified 8 studies, with a total of 454 patients, and
found a decrease in PE (OR, 0.12; 95% CI, 0.02-0.77;
P = .03) and thrombus propagation (OR, 0.29; 95%
CI, 0.14-0.62; P = .04) with anticoagulation.101 A 2012
review also acknowledged the heterogeneity of the
literature but noted that unprovoked calf DVT (in-
cluding a history of malignancy or thrombophilia)
has been demonstrated to be more likely to propa-
gate than provoked calf DVT (such as that occurring
after trauma or surgery); that there was no benefit to
extending anticoagulation from 6 weeks to 12 weeks
in low-risk patients with transient risk factors, and
that the risk of major bleeding after treatment with
anticoagulants ranged from 0% to 6%.98
Current guidelines have mixed recommendations
regarding treatment of distal DVT. The International
Consensus Statement recommends 3 months of anti-
coagulation for distal DVT,2 while the ACCP guidelines
caution that routine treatment of distal calf veins is not
warranted, as the risk of bleeding from anticoagulation
can outweigh the relatively low risk of propagation
or extension into a clinically significant VTE. As such,
only serial imaging of the lower extremities for the
first 2 weeks is recommended in patients with isolated
provoked distal DVT without severe symptoms or risk
factors for extension (Grade 2B). Anticoagulation should
be reserved only for patients with severe symptoms or
13 Reprints: www.ebmedicine.net/empissues
 Clinical
Clinical Pathway
Pathway ForFor The Diagnostic
Emergency Evaluation
Department Of A Suspected
Management Of Multiple
First Lower ExtremityShocks
Deep Venous Thrombosis1

Suspected first lower extremity DVT

Determine clinical pretest probability

(Grade 2B)

Moderate
Low probability High probability
probability

D-dimera POSITIVEc Proximal US Whole-leg USb

Low probability: moderate- or (Grade 1B) (Grade 1B)
high-sensitivity test
Moderate probability: high-
sensitivity test
(Grade 1B)

NEGATIVE NEGATIVE POSITIVE NEGATIVE POSITIVE

No DVT YES Was patient previously Treat for DVT No DVTd

(Grade 1B) stratified as low (Grade 1B) (Grade 1B)
probability?

NO

Isolated distal
Proximal DVT
DVT
Serial proximal D-dimer
USe Moderate probabil-
Moderate prob- POSITIVE ity: moderate- or
ability (Grade high-sensitivity test High risk of propa-
Test for DVT gation or severe
1B-C) (Grade 1C)
(Grade 1B) symptoms?
High probability High probability:
(Grade 1B) high-sensitivity test (See "Ultrasound"
NO section, page 8)
(Grade 1B)
POSITIVE NEGATIVE
NEGATIVE YES

Treat for DVT No DVTc

Serial US Treat for DVT
(Grade 1B) (Grade 1B)
(Grade 2C) (Grade 2B)

a
Preferred initial strategy for patients with low probability (Grade 2B) and for select patients with moderate probability (see "D-dimer" section, page 6).
(Grade 2C)
b
Whole-leg US may be preferred in patients unable to return for serial testing and for those with severe symptoms or at high risk for propagation of distal
DVT.
c
Alternative acceptable strategy if moderate risk would be to proceed to whole-leg US. (Grade 1B)
d
Extensive unexplained swelling in patient with high probability should prompt consideration of isolated iliac DVT.
e
Alternative acceptable strategy if high risk would be to proceed to whole-leg US. (Grade 1B)
Abbreviations: DVT, deep venous thrombosis; US, ultrasound.
Definitions for strength of recommendation and levels of evidence are available at: http://journal.publications.chestnet.org/article.aspx?articleid=1084215.

Copyright 2015 EB Medicine. All rights reserved. 14 www.ebmedicine.net March 2015

 Clinical Pathway
Clinical Pathway For Treatment
For Emergency Of Lower
Department ExtremityOf Multiple
Management
Deep Venous Thrombosis
Shocks 4,8

Treatment indicated for

lower extremity DVT

Complicated DVT or contraindications

YES
to anticoagulation?

NO

Start initial anticoagulation

Parenteral: LMWHa SC or UFH IV or
fondaparinuxa SC (Grade 1B)
or
NOAC: rivaroxaban PO or apixaban
PO (Ungradedb)

Outpatient treatment appropriate?

Adequate outpatient follow-up
NO Adequate home circumstances
No significant comorbidities
Normal renal function

YES

Transition to long-term outpatient anticoagulation (Grade 1B)

Parenteral bridge (5 days): LMWH or fondaparinux (Grade 1B) and initiation of oral VKAc
until INR 2-3 (Grade 1B) or dabigatran (Ungradedb)
or
Continuation of NOAC: rivaroxaban or apixaban (Ungradedb) Other treatments (see text)
or IVC filter (Grade 1B)
Continuation of parenteral therapy in select populations (eg, active cancer) (Grade 2B) Catheter directed thrombolysis
(Grade 2C)
Systemic thrombolysis (Grade 2C)
Surgical thrombectomy (Grade 2C)
YES
Inpatient treatment Treatment complications or failure?

NO

Outpatient treatment
Long-term anticoagulation for a minimum of 3 months
(Grade 1B)
Consideration of extended anticoagulation (> 3 months) in
select patients (eg, active cancer or second unprovoked
DVT) (Grade 1B)
Adjuvant measures (eg, compression stockings (Grade
2B), early ambulation (Grade 2C))

Abbreviations: ACCP, American College of Chest Physicians; DVT, deep venous thrombosis; INR, international normalized ratio; IV, intravenous; IVC,
inferior vena cava; LMWH, low-molecular-weight heparin; NOAC, novel oral anticoagulant; PO, by mouth; SC, subcutaneous; UFH, unfractionated heparin;
VKA, vitamin K antagonist.
a
Preferred initial strategy. (Grade 2C)
b
No ACCP grade of recommendation available at time of publication of guidelines. Studies have demonstrated noninferiority compared with standard treat-
ment. LMWH (Grade 2C) or VKA antagonist (Grade 2B) suggested over NOAC.
c
Preferred regimen (Grade 2C).
Definitions for strength of recommendation and levels of evidence are available at: http://journal.publications.chestnet.org/article.aspx?articleid=1084215.

March 2015 www.ebmedicine.net 15 Reprints: www.ebmedicine.net/empissues

with risk factors for extension (Grade 2C). These risk fac-
tors include positive D-dimer, extensive thrombosis (eg,
> 5 cm in length, > 7 mm maximum diameter, or involv-
ing multiple veins), lack of reversible provoking factor,
active cancer, history of VTE, and inpatient status.4 If
anticoagulation therapy is chosen, the ACCP guidelines
currently recommend the full 3-month duration of ther-
apy for distal DVT; however, as discussed above, shorter
durations may be equally effective in select populations.
Deep Venous Thrombosis In Pregnancy
Pregnancy is a known risk factor for VTE and VTE is
a leading cause of maternal mortality,102 yet preg-
nant patients have routinely been excluded from
studies of suspected DVT (including the develop-
ment of Wells clinical score). Further complicating
the presentation, pregnant patients may exhibit very
different characteristics from the general population.
As pregnancy progresses, patients are more likely to
develop leg swelling and discomfort independent of
DVT. D-dimer levels also rise with advancing gesta-
tional age, prompting proposals to consider validat-
ing higher testing thresholds for this population.103
In addition, there are anatomic variations in preg-
nancy-related DVT. More than 80% of pregnancy-re-
lated DVT involves the left lower extremity, and 17%
may be isolated to the iliac veins and, therefore, eas-
ily missed by proximal compression ultrasounds.104
Further compounding the diagnostic difficulties, the
overall prevalence of confirmed DVT in pregnant
patients with suspected disease appears generally
lower (8%-9%) than in nonpregnant cohorts,105-107
even though the risk of VTE in pregnant patients is
4-fold higher than in the general population.108
Accounting for these limitations and consider-
ations, the American Congress of Obstetricians and
Gynecologists (ACOG) and the ACCP recommend
ultrasonography as the initial diagnostic test of choice
for pregnant patients with suspected lower extremity
DVT.1,109 If this test is negative, the ACOG recommends
serial ultrasound or additional imaging, and they do
not endorse the use of D-dimer testing in the pregnant
patient. In contrast, the ACCP guidelines allow for either
a follow-up serial proximal ultrasound performed on a
more frequent basis (tested on days 3 and 7) or a sensi-
tive D-dimer test conducted at the time of presentation.
A positive D-dimer on the initial visit should prompt
a stronger emphasis on the importance of follow-up
ultrasounds on days 3 and 7. Involvement of the entire
leg, buttocks, or back should trigger suspicion of iliac
vein thrombosis and prompt follow-up with the requi-
site imaging when standard proximal serial compression
ultrasounds are negative.1
In the meantime, a clinical prediction rule for
pregnant patients is in the process of development
and validation, though sample sizes remain lim-
ited.105-107 The first study to address this challenge
prospectively evaluated 194 pregnant patients with
Copyright 2015 EB Medicine. All rights reserved. 16
suspected DVT at multiple sites and determined the
following 3 clinical variables to be highly predic-
tive105: (1) symptoms in the left leg; (2) calf circum-
ference difference > 2 cm; and (3) first-trimester
pregnancy. Each of the 17 patients (8.8%) diagnosed
with DVT in this cohort had at least 1 of these 3
clinical variables. With increasing presence of these
variables, DVT prevalence rose from 0% (95% CI,
0-4.2) to 16.4% (95% CI, 10.5-24.7). Two subsequent
multicenter post hoc analyses of pregnant patients
appear to externally validate these findings,106,107
with pooled statistics from all 3 studies revealing a
DVT prevalence of 0.8% (95% CI, 0.2-2.7) in patients
who lacked all 3 clinical features.107 The authors
of the study caution that, with an upper CI limit >
2% for pooled DVT prevalence, this prediction rule
should not be used without adjunct D-dimer or
ultrasonographic testing.106 Prospective validation in
larger populations of pregnant patients remains the
next challenging step in order to evaluate whether
the current standard of initial imaging may similarly
evolve into a more selective strategy, as has progres-
sively become the case in nonpregnant patients.
Use Of Anticoagulant Agents In Pregnancy
Heparins, both unfractionated heparin and LMWH,
do not cross the placenta and are considered safe for
use in pregnancy, whereas VKAs cross the placenta,
are potentially teratogenic, and can cause bleeding in
the fetus. Also, during pregnancy, there is a decreased
anticoagulant response to unfractionated heparin, as
well as the potential for heparin-induced thrombocy-
topenia. Therefore, according to both the ACCP and
ACOG recommendations, the treatment of choice for
DVT in pregnancy is LMWH (Grade 1B), with adjust-
ment of dosing to account for the pharmacokinetics
of pregnancy. Anticoagulation should be continued
through the first 6 weeks of the postpartum period
and for a minimum of 3 months (Grade 2C), although
studies supporting this recommendation tend to be
retrospective and observational in nature.4,109 Use
of LMWH is supported over VKAs for treatment of
VTE in all trimesters of pregnancy (Grade 1A in first
trimester, Grade 1B in second and third trimesters)
and during imminent delivery (Grade 1A).4 There are
limited data regarding the use of fondaparinux and
no data regarding the use of the novel oral anticoagu-
lants in pregnancy. Based on this current evidence,
the ACOG and ACCP guidelines recommend limit-
ing the use of fondaparinux to patients with severe
reactions to heparin (Grade 2C) and avoiding the use
of the novel oral anticoagulants during pregnancy
(Grade 1C).102,109
Upper Extremity Deep Venous Thrombosis
Upper extremity DVT tends to have a different etiol-
ogy, and it is much less common than lower extremity
DVT, occurring in 10% to 15% of documented cases
www.ebmedicine.net March 2015
of VTE, with an incidence of approximately 0.4 to 1
per 10,000 persons per year.13,110 Complications from
upper extremity DVT are also less frequent, with a
lower risk of pulmonary embolism (4%-6% for upper
extremity DVT vs 15%-32% for lower extremity DVT),
fewer recurrences (2%-5% vs 19%), and lower rates of
postthrombotic syndrome (5% vs 29%).110,111
Anatomically, the deep venous system of the
upper extremity, from proximal to distal, consists of
the subclavian vein, which passes underneath the
clavicle and exits the thoracic outlet under the first
rib, becoming the axillary vein. The axillary vein then
passes underneath the teres major muscle, becom-
ing the brachial vein, which then courses inferiorly
alongside the brachial artery and the median nerve
medial to the humerus. Numerous anastomoses with
the superficial venous system (the basilic and cephalic
veins) occur before the veins enter the cubital fossa,
becoming the superficial veins of the forearm.
Twenty percent of upper extremity DVT is of
primary etiology, such as from venous thoracic outlet
obstruction as a result of anatomic abnormalities or
effort-induced repetitive microstress of the vessels
(Paget-Schroetter syndrome). The remaining 80% has
a secondary etiology, such as indwelling catheters or
pacemaker wires, surgery, or trauma.110 Older age
(average age of 38 years for upper extremity DVT vs
49 for lower extremity DVT), obesity, oral contracep-
tive use, thrombophilias (18% for upper extremity vs
39% for lower extremity), and malignancy are less
common etiologies of upper extremity DVT than
lower extremity DVT.110,111
Like lower extremity DVT, the presentation of
upper extremity DVT can be subtle; pain, swelling,
edema, paresthesias, discoloration, and weakness are
common signs and symptoms.110 However, unlike the
well-established diagnostic paradigm for the evalua-
tion of lower extremity DVT, there is a paucity of data
regarding the evaluation of upper extremity DVT.1
With ultrasonography emerging as the preferred
imaging test,110 meta-analysis has demonstrated an
overall sensitivity of 97% (95% CI, 90-100) and speci-
ficity of 96% (95% CI, 87-100), with no improvement
in accuracy upon adding color Doppler.112 Compres-
sion ultrasonography is limited by the inability to
visualize or compress the proximal central deep veins
due to the overlying bony structures.110
Risk Stratification
A 2008 study developed and validated a clinical pre-
diction score for upper extremity DVT.113 The score
adds 1 point each for pain, edema, and the presence
of foreign venous material (eg, catheter or pacemak-
er), and subtracts 1 point if an alternative diagnosis is
more likely. A score of 0 or -1 is considered low risk,
although upper extremity DVT may be diagnosed in
13% of patients. A score of 1 is considered intermedi-
ate risk, with a 38% prevalence of upper extremity
DVT, while a score of > 2 is considered high risk,
March 2015 www.ebmedicine.net
with a 69% prevalence of upper extremity DVT in the
validation study.113 The use of D-dimer testing has not
been well studied in the evaluation of upper extrem-
ity DVT, although one study of 52 patients reported a
sensitivity of 100% (95% CI, 78-100) and specificity of
14% (95% CI, 4-29).114 CT venography and MRI have
not been well studied in the evaluation of upper ex-
tremity DVT, but may have a role in the diagnosis of
the proximal upper extremity deep veins that are not
amenable to compression ultrasonography.1,115
Diagnosis
The current ACCP guidelines recommend initial
evaluation for upper extremity DVT with compres-
sion duplex ultrasonography (Grade 2C) followed
by testing with a moderate or highly sensitive
D-dimer; serial ultrasound; or imaging with venog-
raphy, CT, or MRI if there is a high clinical suspicion
and the initial ultrasound is negative (Grade 2C).
Upper extremity DVT can be excluded in patients
with a negative compression duplex ultrasound
and subsequent negative D-dimer, CT, MRI, or
venography (Grade 1C). Patients in whom the initial
compression duplex ultrasound was negative, with
a subsequent positive D-dimer, and those with a
suboptimal compression duplex ultrasound should
undergo venography (Grade 2B), unless there is a
compelling alternative diagnosis (Grade 2C).
A multicenter trial of 406 patients suspected of hav-
ing upper extremity DVT validated the use of a diagnos-
tic algorithm consisting of sequential application of clin-
ical risk stratification, D-dimer testing, and compression
ultrasonography. Using the clinical decision rule derived
and validated by Constans,113 patients were stratified
as either unlikely (score of 1) or likely (score of 2) to
have upper extremity DVT. Patients unlikely to have DVT
underwent initial testing with D-dimer, did not undergo
further testing if the test was negative, and proved a
0% rate of upper extremity DVT on 3-month follow-up
(95% CI, 0.0-4.2). Patients who were likely to have DVT
underwent compression ultrasonography, followed by
combination with D-dimer testing if the ultrasound was
negative. The combination of a negative ultrasound
and negative D-dimer resulted in a 1.2% rate of upper
extremity DVT at 3 months (95% CI, 0.0-6.5). The authors
concluded that this diagnostic paradigm was safe and
effective in excluding upper extremity DVT, with an
overall miss rate of 0.4% (95% CI, 0.0-2.2).116
Treatment
Since the goals of upper extremity DVT treatment
are the same as for lower extremity DVT namely,
prevention of DVT propagation, PE, and recurrence,
as well as prevention of postthrombotic syndrome
the treatment strategies have largely been extrapo-
lated from those for lower extremity disease. Strate-
gies include anticoagulation, thrombolysis, surgical
thrombectomy, superior vena cava filter placement,
and removal of any indwelling venous catheters.110
17 Reprints: www.ebmedicine.net/empissues
The current ACCP guidelines recommend initiation
of anticoagulation (Grade 1B) and continuation of
anticoagulation for at least 3 months (Grade 2B).
LMWH is preferred over UFH (Grade 2C).4 Data
from 4 observational studies with a total of 209
patients demonstrate a 1.9% rate of recurrence after
treatment, with no cases of PE.110 Indwelling venous
catheters should not be removed as long as the need
for them persists and the catheters remain functional
(Grade 2C); however, anticoagulation should be con-
tinued for as long as the catheter remains in place
(Grade 2C).4 In a study of 74 patients with catheter-
related upper extremity DVT treated with LMWH
(dalteparin), no patients had catheter failure or
extension of DVT resulting from leaving the catheter
in place.117 Catheter-directed or systemic throm-
bolysis may be performed for patients with severely
symptomatic massive upper extremity DVT and a
low risk of bleeding (Grade 2C), but anticoagulation
is preferred over thrombolysis (Grade 2C). Catheter-
directed or surgical interventions should be reserved
Risk Management Pitfalls For Deep Venous Thrombosis
(Continued on page 19)
1. The patient was high-risk, but had a negative
D-dimer.
Sole use of D-dimer tests in high-risk patients
is not recommended, as there is insufficient
evidence supporting their safety when they are
not used in combination with ultrasonography.
The majority of high-risk patients may have
a positive D-dimer for alternative reasons, so
starting with this test is also generally low-yield.
2. Radiology confirmed DVT of the calf, so I
anticoagulated as I normally do.
For routine, provoked, isolated distal DVT
without severe symptoms or risk factors, the risk
of bleeding posed by anticoagulation treatment
likely outweighs the risk of propagation of distal
thrombi into the proximal venous system. Thus,
current ACCP guidelines recommend serial
ultrasounds instead of routine anticoagulation
in uncomplicated distal DVT. However, this
decision may be discussed with patients to
determine their degree of comfort with this plan.
3. Although cancer is a risk factor for DVT, his
Wells clinical score identified him as unlikely
to have DVT and he had a negative D-dimer.
Based on subgroup analysis of patients with
active cancer, an unlikely Wells clinical score and
negative D-dimer resulted in a > 2% risk of acute
DVT. Thus, the combination does not appear
to be safe for use in this particular subset of
patients who harbor a higher risk for DVT.
Copyright 2015 EB Medicine. All rights reserved. 18
for patients with persistent symptoms and failure of
anticoagulation or thrombolysis.4,110 Patients found
to have venous thoracic outlet obstruction may need
to undergo surgical decompression, which, gener-
ally, has good outcomes.110
Controversies And Cutting Edge
As discussed throughout this review, new strategies in
the management of DVT are numerous, with still more
anticipated in the near future.
The Wells clinical score has undergone several
rounds of modifications over the years, improving its
ease of use and expanding its applicability to patients
with prior DVT, although perhaps it still requires further
modification in the setting of active malignancy. Despite
its standardized scoring rubric, its interobserver variability
is less consistent in external studies and it may not neces-
sarily improve upon clinical gestalt for more experienced
providers. In the laboratory, higher D-dimer thresholds
are being tested in select populations, including the
4. I told the patient to follow up for a repeat ul-
trasound, but he took a long flight the follow-
ing day anyway. What else could I have done?
After a negative proximal ultrasound, a patient
with moderate to high pretest probability of
disease still needs additional testing to safely
rule out DVT. While this has traditionally taken
the form of a serial ultrasound at 1 week, if the
patient is unable or unwilling to follow up, a
negative concurrent D-dimer test on the initial
ED visit or a negative whole-leg ultrasound
may obviate the need for follow-up testing.
Alternatively, a discussion with the patient
about the potential benefit versus harm of
empiric anticoagulation could be considered,
given his impending travel.
5. The patient did not want to be admitted and
was afraid of needles for self-injecting LMWH,
so I decided to try a new oral anticoagulant as
an outpatient regimen.
Not all of the new oral anticoagulants are
suitable for both initial and long-term
anticoagulation in the treatment of acute
DVT. Dabigatran, for instance, currently
requires a parenteral bridge during the initial
anticoagulation period. In addition to ensuring
normal creatinine clearance and close outpatient
follow-up, the emergency clinician should
advise the patient as to the uncertainties of
reversing anticoagulation in the setting of acute
bleeding.
www.ebmedicine.net March 2015
low-risk group and the elderly. The use of D-dimers in the
workup for suspected DVT that is recurrent, occurs during
pregnancy, or affects the upper extremities is actively
debated, with new clinical prediction rules being tested
and validated in these special populations.
The use of ultrasonography has become common-
place under the weakly supported recommendation that
all patients require serial proximal ultrasounds to exclude
propagation of potentially undiagnosed distal DVT.
However, patients at low risk for DVT likely do not require
serial imaging, nor do all patients ultimately require
imaging of the whole leg. Controversy still surrounds the
definition, significance, risk of extension, treatment, and
even the need to diagnose isolated distal DVT. Selective
serial observation may be superior to routine treatment
of isolated distal DVT, and shorter courses of anticoagula-
tion may be as effective as standard therapy.
Current recommendations now advocate for
outpatient management of acute proximal DVT, when
possible.4,8 Although there is uncertainty regarding
the reversal strategy for the new oral anticoagulants,
Risk Management Pitfalls For Deep Venous Thrombosis
(Continued from page 18)
6. The ultrasound was negative. How was I sup-
posed to know the patient still needed another
ultrasound a week later?
A single initial proximal ultrasound in a patient
with moderate to high pretest probability of
DVT does not rule out the possibility of distal
thrombosis in the calf veins. Particularly in
the first 2 weeks, distal DVT may carry up
to a 25% risk of propagation to the proximal
venous system where it becomes more clinically
significant and poses the threat of PE.
7. The patient had a prior DVT but was still
low-risk and had a negative D-dimer. I didnt
know there were multiple versions of the Wells
clinical score.
Be sure to add an additional point to the Wells
clinical score for history of previous DVT, as the
earlier versions excluded patients with suspected
recurrent DVT. Without this modification, an
unlikely score with a negative D-dimer can still
result in > 2% risk of acute DVT.
8. The patient had cancer and did not want to be
admitted, so I offered LMWH and an oral VKA
as an outpatient regimen.
Patients with cancer do not respond as well to
oral VKA therapy, which results in higher rates
of recurrent VTE compared with LMWH. First-
line recommended therapy for cancer patients
with acute DVT consists of daily LMWH
injections for a minimum of 6 months.
March 2015 www.ebmedicine.net
they appear to pose a lower risk of bleeding than the
standard LMWH/VKA combination therapy. As experi-
ence with these medications grows, a more comprehen-
sive incorporation of the new oral anticoagulants into
treatment guidelines for DVT can be anticipated in the
coming years.
Disposition
Admission for parenteral anticoagulation was previously
the expected disposition for most patients newly diag-
nosed with acute DVT, but newer guidelines open the
doors and, in fact, show preference for outpatient
treatment, when possible (Grade 1B).4,8 Assuming the
patient has normal renal function, the appropriateness
of an outpatient strategy is strongly dependent on the
patients reliability for follow-up and associated social
factors, including potential ability to either learn how to
self-inject LMWH or to arrange for services to administer
these medications and to conduct laboratory testing.
The evidence behind the safety of outpatient
9. The D-dimer was negative, though I dont
know what kind of test my hospital uses.
Knowing the sensitivity of the D-dimer test
used in ones institution allows for better
interpretation of the result within the context
of a patients pretest probability of DVT. Some
laboratories still use semiquantitative tests,
which are faster and more specific, but they
perform at a lower sensitivity. While a patient
with low pretest probability for DVT can be
ruled out with a D-dimer of either moderate
or high sensitivity, only a highly sensitive test
is sufficient to rule out DVT in a patient with
moderate pretest probability of DVT without the
use of imaging.
10. I had high suspicion, but the patient had 2
negative serial compression ultrasounds, so I
assumed the workup was complete.
A patient with high pretest probability of DVT
and negative serial ultrasounds may still need to
undergo imaging of the pelvic veins, especially
if the swelling is extensive and includes the
thigh and buttocks. Of note, pregnant patients
with DVT have a higher prevalence (17%) of
isolated iliac vein thrombosis.
19 Reprints: www.ebmedicine.net/empissues
treatment is derived from systematic reviews of stud-
ies that randomized patients to either home treatment
(with LMWH) or inpatient treatment (with either
LMWH or UFH).118 Patients treated at home had a
lower recurrence of VTE (RR, 0.61; 95% CI, 0.42-.90)
and trended toward lower mortality (RR, 0.72; 95%
CI, 0.45-1.15) and fewer major bleeds (RR, 0.67-1.36).
Significant limitations to these studies, however,
include high rates of exclusion as well as the fact that
the majority of inpatients were treated with UFH.
Only 1 small study (N = 201) used LMWH in its in-
patient arm, reporting no increase in combined rates
of VTE, PE, or major bleeding (3% vs 3.9%), while
effectively halving the overall costs from an economic
standpoint.119 Although the quality of evidence is
only moderate, the estimated savings of $500 to $2500
per patient are attractive enough, in the absence of ev-
idence of increased complications, to warrant a strong
recommendation from the ACCP for outpatient treat-
ment.4 Deliberation of disposition options should, of
course, incorporate individual patient preferences.120
If the patients home conditions and likelihood
of reliable follow-up are inadequate or the patients
renal function is limited, inpatient admission is indi-
cated for treatment of DVT. Patients with inadequate
creatinine clearance or a higher risk of bleeding, or
patients scheduled for procedures that could require
rapid reversal of anticoagulation, usually benefit
from parenteral UFH, rather than LMWH. Com-
plicated DVT may require alternatives to standard
anticoagulation, such as IVC filters, or intravenous
direct thrombin inhibitors in the case of heparin-
induced thrombocytopenia. Extensive clot burden
Cost-Effective Strategies
Not every patient needs an ultrasound on initial
diagnostic workup. Risk stratification and a D-dimer
can preclude the need for ultrasound in low-risk
patients, and, if the D-dimer is highly sensitive, in
moderate-risk patients without active cancer.
Point-of-care, focused emergency ultrasound is ac-
curate in diagnosing proximal lower extremity DVT
and decreases length of stay in the ED.
Not every patient needs a repeat proximal ul-
trasound. Risk stratification into the low pretest
probability group can obviate the need for further
testing. For patients identified as having moder-
ate to high pretest probability, a repeat ultrasound
may be avoided if a concurrent D-dimer on the
initial visit is negative or if a whole-leg (instead of a
proximal ultrasound) is performed and results are
negative.
Consider outpatient treatment of acute DVT if the
patient has good follow-up, an adequate home situ-
ation, and normal renal function.
Copyright 2015 EB Medicine. All rights reserved. 20
may, rarely, precipitate phlegmasia cerulean dolens,
which can require immediate operative thrombec-
tomy or thrombolysis.
Summary
DVT is a common disease with potential for mortal-
ity from PE and morbidity ranging from the com-
mon postthrombotic syndrome to rare loss of limb.
Although the clinical signs and symptoms of DVT
can be subtle, the diagnostic evaluation can benefit
from risk stratification of pretest probability, fol-
lowed by a systematic workup that includes ultra-
sonography and/or D-dimer testing. If there are
no contraindications, treatment of confirmed DVT
consists of a combination of initial and long-term
therapy for anticoagulation, the options for which
include UFH, LMWH, VKAs, and, more recently,
the novel oral anticoagulant agents. Future develop-
ments in the management of this disease include
fine-tuning risk stratification, particularly for certain
subsets of patients (ie, those with active cancer and
pregnant patients) and, pending postmarketing data
and availability of a reversal strategy, identification
of patients who can benefit from the new oral antico-
agulants as the treatment of DVT increasingly shifts
to the outpatient setting.
Case Conclusions
For the 42-year-old woman with a family history of protein
S deficiency, you initially recommended a repeat serial ul-
trasound at 1 week to rule out the possibility of distal clots
that could migrate proximally. Because her symptoms were
mild, there was likely no need for interim anticoagulation
between studies. However, the patient remained anxious,
so you offered the possibility of a same-day D-dimer test
instead. The test came back negative and she was reassured
to follow up with her primary care doctor.
You decided to order a D-dimer test on the 22-year-
old man sent from the clinic. Although you knew that
your lab used SimpliRED, you risk stratified the
patient into the low pretest probability group using
the Wells clinical score and were relieved to know that
a single negative test result even if only moderately
sensitive is sufficient to rule out DVT in an otherwise
healthy patient.
After carefully analyzing the risks and benefits of
the available treatment options and ensuring that your
third, previously admitted patient had a normal creatinine
clearance, you were able to arrange for the nurse to teach
him to self-inject LMWH at home. You gave him a pre-
scription for 5 days worth of LMWH and started him on
warfarin 10 mg for that night and the next day. You also
counseled him on dietary constraints while taking VKAs,
provided strict instructions to follow up with his primary
care doctor for further monitoring and INR checks, and
specified clear return precautions.
www.ebmedicine.net March 2015
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tematic review and meta-analysis. Eur Radiol. 2007;17(1):175-
181. (Systematic review and meta-analysis; 14 studies; 701
patients)
70. Meissner MH, Gloviczki P, Comerota AJ, et al. Early throm-
bus removal strategies for acute deep venous thrombosis:
clinical practice guidelines of the Society for Vascular
Surgery and the American Venous Forum. J Vasc Surg.
2012;55(5):1449-1462. (Clinical guidelines; systematic re-
view)
71. Erkens PM, Prins MH. Fixed dose subcutaneous low mo-
lecular weight heparins versus adjusted dose unfractionated
heparin for venous thromboembolism. Cochrane Database
Syst Rev. 2010(9):CD001100. (Meta-analysis; 9587 patients)
72. Buller HR, Davidson BL, Decousus H, et al. Fondaparinux
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2004;140(11):867-873. (Randomized double-blind trial; 2205
patients)
73. Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anti-
coagulants: antithrombotic therapy and prevention of
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evidence-based clinical practice guidelines. Chest. 2012;141(2
Suppl):e24S-e43S. (Review article)
74. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al.
Oral rivaroxaban for symptomatic venous thromboembo-
lism. N Engl J Med. 2010;363(26):2499-2510. (Randomized
controlled trials; 3449 patients [acute treatment], 1196
patients [continued treatment])
75. EINSTEIN-PE Investigators, Buller HR, Prins MH, et al. Oral
rivaroxaban for the treatment of symptomatic pulmonary
embolism. N Engl J Med. 2012;366(14):1287-1297. (Random-
ized controlled trial; 4832 patients)
76. Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxa-
ban versus standard therapy for the treatment of symp-
tomatic venous thromboembolism: a pooled analysis of
the EINSTEIN-DVT and PE randomized studies. Thromb J.
2013;11(1):21. (Pooled analysis of 2 randomized trials; 8282
patients)
77. Lefebvre P, Coleman CI, Bookhart BK, et al. Cost-effec-
tiveness of rivaroxaban compared with enoxaparin plus a
vitamin K antagonist for the treatment of venous thrombo-
embolism. J Med Econ. 2014;17(1):52-64. (Post hoc analysis)
78. Lee FM, Chan AK, Lau KK, et al. Reversal of new, factor-
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specific oral anticoagulants by rFVIIa, prothrombin complex
concentrate and activated prothrombin complex concen-
trate: a review of animal and human studies. Thromb Res.
2014;133(5):705-713. (Systematic review)
79. Garcia P, Ruiz W, Loza Munarriz C. Warfarin initiation
nomograms for venous thromboembolism. Cochrane Database
Syst Rev. 2013;7:CD007699. (Systematic review; 494 patients)
80. Wells PS, Forgie MA, Rodger MA. Treatment of venous
thromboembolism. JAMA. 2014;311(7):717-728. (Review
article)
81 Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus
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N Engl J Med. 2009;361(24):2342-2352. (Randomized double-
blind; 2539 patients)
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and pooled analysis. Circulation. 2014;129(7):764-772. (Ran-
domized, double-blind; 2589 patients)
83. Hokusai-VTE Investigators: Bller HR, Dcousus H, Grosso
MA, et al. Edoxaban versus warfarin for the treatment of
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2013;369(15):1406-1415. (Randomized controlled trial; 4921
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2015;131(1):82-90. (Double-blind randomized placebo-
controlled 2-way crossover study; 110 subjects)
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tients)

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CME Questions 5. Which of the following anticoagulants is safe
to give to a patient with renal insufficiency?
a. UFH
Take This Test Online! b. Warfarin
c. LMWH
Current subscribers receive CME credit abso- d. Dabigatran
lutely free by completing the following test. Each e. A and B
issue includes 4 AMA PRA Category 1 CreditsTM,
4 ACEP Category I credits, 4 AAFP Prescribed 6. Which of the following anticoagulants has
Take This Test Online!
credits, and 4 AOA Category 2A or 2B credits. proven methods of reversal?
Monthly online testing is now available for cur- a. Warfarin
rent and archived issues. To receive your free b. LMWH
CME credits for this issue, scan the QR code c. Fondaparinux
below with your smartphone or visit d. Rivaroxaban
www.ebmedicine.net/E0315.
7. Which of the following anticoagulants is con-
sidered first-line long-term therapy for patients
with active cancer?
a. UFH
b. LMWH
c. Fondaparinux
d. Oral VKA
1. Which of the following veins is part of the
superficial venous system, rather than the deep 8. In a patient with low pretest probability of
venous system? DVT, which of the following is NOT an appro-
a. Superficial femoral vein priate initial diagnostic test?
b. Greater saphenous vein a. Moderate-sensitivity D-dimer
c. Anterior tibial vein b. High-sensitivity D-dimer
d. Peroneal vein c. Proximal compression ultrasound
d. Whole-leg ultrasound
2. Which of the following features most increases
the likelihood of having an acute DVT? 9. In a patient with moderate pretest probability
a. Homans sign of DVT, which of the following is NOT an ap-
b. Calf swelling propriate initial diagnostic test?
c. High Wells score a. Moderate-sensitivity D-dimer
d. History of malignancy b. High-sensitivity D-dimer
c. Proximal compression ultrasound
d. Whole-leg ultrasound
3. Which of the following risk factors was a later
addition to the original Wells clinical score? 10. In a patient with high pretest probability of
a. Active malignancy DVT, which of the following is appropriate as
b. Prior history of DVT an initial diagnostic test?
c. Age > 75 years a. High-sensitivity D-dimer
d. Alternate diagnosis at least as likely as DVT b. Proximal compression ultrasound
c. Whole-leg ultrasound
4. In addition to the popliteal vein, which of the d. B or C
following veins is evaluated during focused e. A, B, or C
point-of-care emergency ultrasound evaluation
for DVT?
a. Posterior tibial vein
b. External iliac vein
c. Common femoral vein
d. Saphenous vein

March 2015 www.ebmedicine.net 25 Reprints: www.ebmedicine.net/empissues

 Coming Soon In
Emergency Medicine Practice
Evaluation Of Potential
Upper Gastrointestinal
Bleeding In The Emergency
Department
AUTHORS:
MATTHEW DELANEY, MD
Assistant Professor, Assistant Medical Director,
Department of Emergency Medicine, University of
Alabama at Birmingham, Birmingham, AL
CHRISTOPHER J. GREENE, MD
Department of Emergency Medicine, University of
Alabama at Birmingham, Birmingham, AL
Upper gastrointestinal bleeding in the emergency
department can occur from a wide variety
of conditions with a similarly wide range of
disease severity. While the initial evaluation and
stabilization is standard for nearly all causes of
bleeding, beyond these initial steps, it is crucial to
distinguish between bleeding from a variceal or
nonvariceal source. Treatments such as antibiotics
and somatostatin analogues may benefit patients
with variceal bleeding, while therapies such as
proton pump inhibitors have limited utility in
this subset of patients but may benefit those
bleeding from nonvariceal sources. Patients with
ongoing bleeding and hemodynamic instability
may benefit from emergent endoscopy. There
are several risk stratification scoring systems for
patients with upper gastrointestinal bleeding;
however, to date, there is limited evidence to
identify low-risk patients who are suitable
candidates for outpatient treatment.
Copyright 2015 EB Medicine. All rights reserved. 26
Emergency Department
Management Of The Alcohol
Withdrawal Syndrome
AUTHORS:
GREG S. SWARTZENTRUBER, MD
Medical Toxicology Fellow, Division of Medical
Toxicology, Department of Emergency Medicine,
University of Pittsburgh Medical Center,
Pittsburgh, PA
JOSEPH H. YANTA, MD
Medical Toxicology Fellow, Division of Medical
Toxicology, Department of Emergency Medicine,
University of Pittsburgh Medical Center,
Pittsburgh, PA
Alcoholism is a prevalent medical and psychiatric
disease and, consequently, alcohol withdrawal
syndrome is encountered frequently in emergency
departments. Uncomplicated alcohol withdrawal,
or alcohol withdrawal tremor, is the most
common and least severe manifestation of
alcohol withdrawal syndrome; it can commonly
be managed on an outpatient basis with oral
benzodiazepines. Alcohol withdrawal seizure and
alcoholic hallucinosis are the first manifestations
of so-called complicated alcohol withdrawal.
They generally signify the need for inpatient
alcohol detoxification and, often, the use of
intravenous benzodiazepines. Delirium tremens
is the most severe and life-threatening form of
alcohol withdrawal. The key diagnostic criteria for
delirium tremens are an alteration in awareness or
attention (delirium) and tremor. Patients commonly
manifest hyperadrenergic signs and symptoms
that necessitate intensive care unit admission,
intravenous benzodiazepines, and, frequently,
adjunctive pharmacotherapy. An aggressive front-
loading approach with benzodiazepines is proposed
and the management of benzodiazepine-resistant
disease is addressed.
www.ebmedicine.net March 2015
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 Physician CME Information
Date of Original Release: March 1, 2015. Date of most recent review: February 10,
2015. Termination date: March 1, 2018.
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Copyright 2015 EB Medicine. All rights reserved. 28 www.ebmedicine.net March 2015