TVP - Clin North Am 2017

D e e p Ven o u s T h ro m b o s i s
a, b
Mark Olaf, DO *, Robert Cooney, MD, MSMedEd, RDMS
KEYWORDS
Deep venous thrombosis Venous thromboembolism Anticoagulation
Novel oral anticoagulant Vitamin K antagonist
KEY POINTS
Deep venous thrombosis (DVT) is part of the venous thromboembolic spectrum and is a
relatively common condition.
Evaluation and diagnosis are performed by risk stratification utilizing the Wells score,
d-dimer testing, and duplex ultrasound.
Treatment depends on individual conditions, but usually consists of anticoagulation for a
finite or infinite period of time, depending on the suspected etiology of the thrombosis.
Adjunctive therapies such as caval filters, thrombolysis, and clot extraction play specific
and limited roles.
Risks and benefits of anticoagulation or other modalities should be discussed with and
individualized for patients.
An adjunctive search for causes of venous thromboembolism (VTE) should be investi-
gated, beginning by looking for causes of provoked DVT, considering malignancy in the
appropriate population, and finally assessing personal and family history in consideration
of risks for thrombophilia.
Upper Extremity DVT is a rare condition that is usually associated with catheters, implant-
able devices, malignancy, or thrombophilia and is primarily treated with anticoagulation.
INTRODUCTION
Deep venous thrombosis (DVT) is part of a spectrum of venous thromboembolic dis-

orders that includes superficial thrombophlebitis and pulmonary embolism.1 DVT may
be defined as “the formation of a blood clot within a deep vein.2” Although DVT most
commonly occurs in the deep veins of the lower leg and thigh, it may also occur within
the upper limb deep veins, visceral veins, and even the vena cava.2
Disclosures: The authors attest that they have no commercial or financial conflicts of interest
relevant to the material presented.
a
Department of Emergency Medicine, Geisinger Medical Center, 100 North Academy Avenue,
Danville, PA 17822-2005, USA; b Emergency Medicine Residency Program, Geisinger Medical
Center, 100 North Academy Avenue, Danville, PA 17822-2005, USA
* Corresponding author.
E-mail address: mfolaf@geisinger.edu
Emerg Med Clin N Am 35 (2017) 743–770

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744 Olaf & Cooney
EPIDEMIOLOGY
The true incidence of DVT is unknown. The estimated risk for first time venous throm-
boembolism (VTE) is 100 cases per 100,000 persons per year, yielding an annual inci-
dence of 0.1%3 and generating an annual US incidence of over 1 million patients per
year. The incidence of DVT appears to be equal between the sexes,4 although women
present 1.6 times more often for evaluation of suspected DVT.5 DVT occurs more
commonly as people age, with the rate in persons aged 60 years and older rising to
nearly 1%.6 VTE remains a disease with high morbidity and mortality. The case fatality
rate for VTE has been reported to be 10.6% at 30 days and 23% at 1 year.7 With
prompt diagnosis and treatment, mortality declines dramatically. The 10-year recur-
rence rate after diagnosis of first-time DVT is approximately 25%. This peaks at
6 months and gradually declines to 2% per patient per year after 3 years, but is depen-
dent on the etiology of the thrombosis.8 The estimated overall mortality from VTE in the
United States ranges from 60,000 to 100,000 deaths per year.9 A subset of DVT is up-
per extremity DVT (UEDVT), which is far less common than lower extremity DVT
(LEDVT). The prevalence of UEDVT is 0.15%, which constitutes about 1% to 4% of
all DVTs.10 Survival rates of patients with UEDVT are also lower than those with
LEDVT.10
PATHOPHYSIOLOGY
Virchow’s triad of alterations in blood flow, endothelial vascular injury, and derange-
ments in the constitution of blood remain relevant over 150 years after they were first
described.11 Stasis, whether caused by obstruction or immobilization, is thought to
prevent the clearance and dilution of activated clotting factors.12 Injury to the vascular
endothelium prevents the inhibition of coagulation and activates the clotting cascade.
A propensity toward clotting secondary to hypercoagulability may be inherited or
acquired.12
DVT commonly begins in the calf, and, less commonly, the proximal veins of the
lower extremity. Obstruction of venous outflow leads to swelling and pain with the
subsequent activation of the inflammatory cascade.12 Many DVTs isolated within
the calf veins will spontaneously resolve and are unlikely to embolize and cause pul-
monary embolism (PE).13 Twenty-five percent of isolated calf vein DVTs will subse-
quently extend into more proximal deep veins.14 It is estimated that 50% of these
may embolize, resulting in PE.15 DVT occasionally compromises vascular flow within
the extremity, resulting in phlegmasia cerulea dolens, a painful and limb-threatening
vascular disorder.12
There are many risk factors for the development of DVT (Table 1). Pregnancy in-
creases the risk secondary to mechanical obstruction of the inferior vena cava, relative
immobility, and hormonal influence. The increase in risk is approximately 0.13% and
begins in the first trimester.2 Oral contraceptive (OCP) use roughly doubles the risk of
VTE in patients, but the overall risk remains low because of the use of OCPs in gener-
ally healthy and young patients.2 Malignancies may double the risk of developing a
DVT, although this risk is highly dependent upon the type of cancer, the use of chemo-
therapy or surgical treatment options, and immobility.2 Table 1 shows estimated rela-
tive risks for multiple conditions.12
In hospitalized surgical patients of all types, older data2 suggest that up to 25% of
postoperative patients suffer VTE when not given prophylaxis, with higher rates (40%–
60%) noted in postoperative orthopedic patients. Newer data suggest that with appro-
priate prophylaxis, this rate worldwide has dropped to 1%, and is perhaps 2% to 3%
in the United States.2 Medical patients admitted to the hospital also have about a 25%
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Deep Venous Thrombosis 745
Table 1
Selected conditions and associated relative risks for venous thromboembolism
Condition Approximate Relative Risk

Antithrombin deficiency 25
Protein C or S deficiency 10
Factor V Leiden mutation Heterozygous: 5; homozygous: 50
Prothrombin gene mutation 2.5
Major surgery or trauma 5–200
History of VTE 50
Antiphospholipid antibodies 2–10
Cancer 5
Medical illness with hospitalization 5
Age >50 5
Age >70 10
Pregnancy 7
Estrogen OCPs: 5; hormone replacement: 2
Estrogen chemotherapy Tamoxifen: 5; raloxifene: 3
Obesity 1–3
Hyperhomocysteinemia 3
Elevated factors VIII, IX or X (>90th percentile) 2.2–3
Data from Bates SM, Ginsberg JS. Clinical practice. Treatment of deep-vein thrombosis. N Engl J
Med 2004;351(3):268–77.
risk of VTE without DVT prophylaxis.2 Among these patients, stroke patients carry the
highest risk, up to 50%. Acute coronary syndrome patients have VTE rates of about
20% without prophylactic measures.2 Obesity is associated with increased risk of
VTE. A body mass index (BMI) over 30 is estimated to roughly double the risk of
VTE through a mechanism of venous stasis related to decreased lower extremity mus-
cle contraction and venous pump.2 Individuals with a personal history of VTE are at
increased risk for subsequent VTE 5 times above the normal population.2 Although
often suspected by patients and some clinicians, there is no evidence to suggest un-
complicated varicose veins increase risk of VTE.2
Long-haul flights are often assumed to be an independent risk for VTE, although the
medical literature fails to adequately describe the associated risk. The proposed path-
ogenesis of VTE during air travel is related to relative hypoxia in airplane cabins, venous
stasis from prolonged sitting, and dehydration.16 The rate of VTE (PE or DVT) on long-
haul flights has been estimated to lie between 1.1 case per million person-days (roughly
the rate of VTE in the healthy population) to 2000 times that (3%–12% of travelers).16
One analysis postulates flights of 8 hours or more may pose an increased risk of VTE
if additional risk factors are present.17 In a separate outcome study in which 545 pa-
tients (6.9%) had VTE, risks of VTE were substantially increased by the presence of
limb, whole-body, or neurologic immobility, but not by travel greater than 8 hours.18
There is general consensus in the literature that many underlying prothrombotic condi-
tions (age >40, obesity, OCP use, genetic thrombophilia) enhance the risk of developing
VTE during long travel, whether by airplane, train, or car.16
Superficial thrombophlebitis (ST) is a distinct disease entity from DVT but has similar
causal mechanisms, with an associated risk of DVT of 6.8% to 40%.19 The high range
of associated DVT is thought to be caused by variation in study design; therefore ST is
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746 Olaf & Cooney
not thought to be an independent risk for DVT. However, it is considered prudent to

perform a duplex ultrasound of the affected limb to evaluate for ST and concomitant
DVT.19 Complete assessment and treatment of ST are beyond the scope of this article,
but when DVT is diagnosed in the setting of nonsuppurative ST, the treatment of DVT
is unchanged.
Underlying thrombophilia is an independent risk for VTE, above and beyond the
aforementioned risks. Approximately 50% of individuals with VTE are found to have
inherited thrombophilia disorders.2 Thrombophilic testing identifies an etiology in
about one-third of patients but has not been shown to alter outcome or duration of
therapy in the past.12 Table 2 demonstrates the quantified risks of recurrent VTE
from specific thrombophilic disorders.
Thrombophilia is broadly classified into loss-of-function (protein C, protein S, anti-
thrombin III) or gain-of-function (factor V Leiden and prothrombin 20210A gene muta-
tion) protein disorders that fail to provide homeostasis between clot formation and
dissolution. Factor V Leiden is present in about 5% of the population, with heterozy-
gotes at 3 times increased risk of VTE compared with the normal population, and ho-
mozygotes 50 to 80 times the normal population.2 Prothrombin 20210A is a noncoding
gene mutation that leads to elevated plasma prothrombin levels. Hyperhomocysteine-
mia and elevated levels of coagulation factors VIII, IX, and XI are suggested to have an
additive, but not independent, effect in generating VTE.2
In cases of UEDVT, the subclavian (74%) and axillary (38%) veins are most
commonly affected.10 Risk factors for UEDVT are cancer, central venous catheters,
and thrombophilia. Central venous catheters (CVCs) are the largest independent
risk for the development of UEDVT, but only 3% of those with these devices develop
a clot. Cancer appears to be an important risk factor in UEDVT in those DVTs that are
not related to CVCs.10 Implantable pacemakers have a rate of UEDVT of about 5%.
UEDVT is thought to be less common than LEDVT because of higher rates of flow,
increased mobility, and use of the upper extremity compared with the lower extrem-
ities and less stasis from gravity.10
PRESENTATION
The presentation of DVT can range from completely asymptomatic to pain, heaviness,
or a cramping sensation in the affected extremity. Local swelling or discoloration of the
Table 2
Selected inherited conditions and estimated risks of recurrent venous thromboembolism after
cessation of anticoagulant therapy
Estimated Relative Risk of Recurrent

Risk Factor Venous Thromboembolism
Antithrombin deficiency 1.5–3
Protein C or S deficiency 1.5–3
Factor V Leiden mutation 1–4
Prothrombin gene mutation 1–5
Antiphospholipid antibodies 2–4
Elevated factor VIII or IX levels 1–7
Hyperhomocysteinemia 1–3
Data from Bates SM, Ginsberg JS. Clinical practice. Treatment of deep-vein thrombosis. N Engl J
Med 2004;351(3):268–77.
reservados.
affected limb may accompany these complaints.5 Multiple eponymous signs and tests
(Michaelli sign, Mahler sign, Homan test, Loewenberg test) attempt to quantify or
qualify the history and examination findings.5 Despite the focus on calf tenderness,
the signs and tests have failed to consistently or adequately diagnose DVT and
have diagnostic accuracies around 50%.20,21 Thus, these subjective and objective
findings lack the sensitivity and specificity to diagnose DVT.22
The differential diagnosis for LEDVT is broad. In one study, DVT was found in 21%
of patients, while alternative diagnoses were found 8% of the time or less and
included Baker cyst (3%), general edema (8%), calf hematoma (4%), superficial
vein thrombosis (5%), muscle vein thrombosis (4%), cellulitis and erysipelas (4%),
and varicose veins (3%).5 Also included in the differential are Achilles tendonitis,
trauma, abscess, torn gastrocnemius muscle, acute arterial ischemia, venous or
lymphatic obstruction, femur fracture, hemarthrosis of the knee, torn meniscus,
congestive heart failure, nephrotic syndrome, liver failure, soft tissue tumor, and
others.5
UEDVT is most commonly found after a patient develops swelling of the upper ex-
tremity. Few are associated with erythema (6% in one study), although pain (40%)
was the most common associated complaint.10 CVC-related UEDVT is less
commonly associated with pain or symptoms because of slower clot growth. These
CVC-associated clots are often more subtle and suggested by transient hand
edema after dialysis, high dialysis pressures, or difficulty drawing blood from the
catheter.10
DIAGNOSING DEEP VENOUS THROMBOSIS
As already indicated, physical examination and elements of a patient’s history are

poor independent predictors of VTE and are therefore not sufficient for the diagnosis
of DVT. Comprehensive evaluation for VTE should always begin with risk stratification,
followed by adjunctive testing based upon an identified level of risk. Adjunctive testing
for DVT usually includes d-dimer or duplex ultrasound testing, and in very limited
cases may include venography.
Risk Stratification
To improve upon the poor sensitivity and specificity of clinical examination findings,
several scoring systems have been developed. Despite these objective analysis tools,
1 meta-analysis demonstrated that nonformal physician judgment was comparable to
the validated scoring systems.23
The Wells Scoring System

Developed in 1995, the Wells score (Table 3) is the most widely used clinical decision
instrument (CDI) for the diagnosis of DVT.5 The CDI risk stratifies patients into low, in-
termediate, or high risk for DVT based upon a point system that identifies risk factors
and has been further developed to dichotomize patients into high and low probability
categories.24 The interobserver reliability of the Wells score is excellent (kappa 0.85),
with the most variability seen in the element of the score that considers the likelihood
of an alternative diagnosis.24 Currently, the Wells score is recommended for use in
practice in order to dichotomize or trichotomize patients into risk categories, and
both methods have been independently validated.25,26
In the original, 3-part risk stratification assessment, a Wells score (see Table 3)
indicates levels of risk and includes low (Wells score 0 or less), moderate (Wells score
1–2), and high pretest probability (Wells score 3 or more) categories.26
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748 Olaf & Cooney
Table 3
The Wells scoring system for deep venous thrombosis
Findings on History and Examination Point Value

Active cancer 1
Treatment or palliation within 6 mo
Bedridden recently 3 d or major surgery within 12 wk 1
Calf swelling >3 cm compared with the other leg 1
Measured 10 cm below tibial tuberosity
Collateral (nonvaricose) superficial veins present 1
Entire leg swollen 1
Localized tenderness along the deep venous system 1
Pitting edema, confined to symptomatic leg 1
Paralysis, paresis, or recent plaster immobilization of the lower extremity 1
Previously documented DVT 1
Alternative diagnosis to DVT at least as likely 2
A 2-level risk assessment is also valid and combines the moderate- and higher-risk
patients into one category. Low-risk (<2 points) and combined intermediate/high-risk
(2 or more points) categories are thus created.26
Both the 2-level and 3-level risk stratification techniques are used in clinical practice
with adjunctive d-dimer and duplex ultrasound scanning to evaluate for DVT. A 2003
clinical policy recommendation from the American College of Emergency Physicians
supports the use of DVT risk stratification using the Wells criteria along with d-dimer
testing to safely exclude DVT (Level B recommendation).27
D-dimer
D-dimer is a molecular marker that results from the dissolution of cross-linked
fibrin. It is often elevated in thrombotic conditions; however, it may also be
elevated in nonthrombotic conditions including pregnancy, malignancy, trauma,
infection, and inflammatory conditions and is therefore not a specific marker for
DVT.2,28 Multiple assays are available, with the enzyme linked immunosorbent
assay (ELISA) possessing the highest sensitivity (94%).2,28 The current recommen-
ded testing strategy for first-time DVT includes assessment of pretest probability
combined with high sensitivity d-dimer testing and compression ultrasound
assessment.25
In the dichotomized risk stratification approach, patients in the low category can
safely undergo d-dimer testing, and if negative, the diagnosis of DVT can be reason-
ably excluded. If the d-dimer level is elevated, or if the pretest probability of DVT is in-
termediate or high based on the CDI, a duplex of the lower extremity should be
performed.26,27
In the trichotomized version, low-probability patients (Wells score 0 or less), should
be offered the use of d-dimer, or proximal vein ultrasound. In moderate-probability pa-
tients (Wells score 1–2), highly sensitive d-dimer, proximal-vein ultrasound, or whole-
leg ultrasound is favored over other modalities. In low- and moderate-risk patients, if
d-dimer is negative, no further testing is warranted, while a positive d-dimer testing
prompts compression ultrasound, but does not necessitate treatment.25 In high pre-
test probability patients, d-dimer testing should not be utilized, and one should pro-
ceed with duplex ultrasound of the extremity to evaluate for DVT.25 In addition, in a
patient with a moderate or high pretest probability, if compression ultrasound is
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utilized and is initially negative, repeat testing with compression ultrasound or a mod-
erate or high sensitivity d-dimer is recommended at 1 week follow-up.25 In cases
where a patient has high pretest probability and there is no immediate access to utra-
sound, a single dose of low molecular weight heparin and a return visit within 12 hours
for planned ultrasound are reasonable.
Testing for recurrent DVT is controversial, but recommendations favor the same mo-
dalities as for primary DVT assessment. Repeat duplex testing is warranted if d-dimer
is positive but initial duplex is negative.26
Age-Adjusted D-dimer
Increased age has the propensity to increase d-dimer values and may therefore
decrease the diagnostic accuracy and specificity of the d-dimer. A 2014 systematic
review found that age-adjusted (age 10 mg per liter as the upper limit of normal)
d-dimer values in older, nonhigh-risk patients increased the specificity and did not
significantly decrease the sensitivity of the study.29 It is important to note that this
was a derivation study, not a validation study, and to date the results have not under-
gone validation. Although not specifically evaluating the age-adjusted D-dimer on
DVT, the ADJUST-PE trial did validate age-adjusted D-dimer for use in the evaluation
of acute PE.30
Pregnancy Adjusted D-dimer
Data have shown a consistent elevation in d-dimer levels as pregnancy pro-
gresses.31,32 This would serve to reduce the specificity of the d-dimer test, prompting
unnecessary further evaluation. In 1 small study of asymptomatic women, none of the
women had a d-dimer value less than the traditional cutoff value of 0.50 mg/L in the
third trimester. The authors advocate for a prospective validation of cutoff values at
0.750, 1.0, and 1.5 mg/L for the first, second, and third trimesters, respectively. A small
trial prospectively validated 3 d-dimer cutoff values at 286, 457, and 644 ng/mL in the
first, second, and third trimesters, respectively and found 100% sensitivity for the
adjusted values. The authors note their trial should be viewed as a pilot study and
advocate for additional, larger studies.32
Ultrasound
Duplex ultrasound imaging, which includes B-mode imaging of veins as well as pulsed
Doppler flow assessment, can evaluate for DVT in the proximal veins with specificity of
94% and sensitivity of 90%.28 A meta-analysis pooled 7 studies and demonstrated a
0.57% 3-month rate of VTE after single negative LE compression ultrasound.33 Duplex
imaging modalities may include proximal-vein-only methods or whole leg scanning.
Positive compression ultrasound of the lower extremity is sufficient to warrant treat-
ment, and venography is not recommended for confirmation.25 Although venography
remains an option, it may be associated with decreased availability, increased discom-
fort, and more complications, but it has a lower false-positive rate.25 A 2003 clinical pol-
icy recommendation from ACEP supports (level B evidence) the use of venous
ultrasonography to safely exclude all proximal and symptomatic distal DVT.27 Serial ul-
trasounds are recommended for high-probability cases with negative initial imaging.27
Ultrasound Sites
A 2014 study identified 362 individuals with DVT on compression ultrasound, of whom
6.3% had findings of isolated thrombi in proximal veins. The study authors used the
data to support the recommendation of the addition of femoral and deep femoral
vein evaluation to standard compression ultrasound of the common femoral and
reservados.
750 Olaf & Cooney
popliteal veins.34 In agreement with this are the 2015 guidelines from the American
Institute of Ultrasound in Medicine (AIUM), which recommend35:
“The fullest visualized extent of the common femoral, femoral, and popliteal veins
must be imaged using an optimal gray scale compression technique. The popliteal
vein is examined distally to the tibioperoneal trunk. The proximal deep femoral and
proximal great saphenous veins should also be examined. Venous compression is
applied every 2 cm or less in the transverse (short axis) plane with adequate pressure
on the skin to completely obliterate the normal vein lumen.”
In addition, focal symptoms require individualized assessment.35
For a normal examination, the minimum assessment and imaging documentation
should include gray scale images with and without compression of the35
Common femoral vein
Junction of the common femoral vein with the great saphenous vein
Proximal deep femoral vein separately or along with the proximal femoral vein
Proximal femoral vein
Distal femoral vein
Popliteal vein
In addition, color spectral Doppler waveforms from the long axis should be recorded
at these levels35:
Right common femoral or external iliac vein
Left common femoral or external iliac vein
Popliteal vein on symptomatic side or on both sides if the examination is bilateral
Abnormal examination findings require documentation and imaging of the abnormal
finding.35
For upper extremity assessment, the 2015 AIUM guidelines recommend that gray
scale images or cine loops should be recorded without and with compression at
each of the following levels35:
Internal jugular vein
Peripheral subclavian vein
Axillary vein
Brachial vein in the upper arm
Cephalic vein in the upper arm
Basilic vein in the upper arm
Focal symptomatic areas, if present
Color and spectral Doppler images are recorded at each of the following levels using
the appropriate color technique to show filling of the normal venous lumen:
Internal jugular vein
Subclavian vein
Axillary vein
If seen, the innominate vein should be recorded with color Doppler imaging.
At a minimum, both the right and left subclavian venous spectral Doppler wave-
forms should be recorded to evaluate for asymmetry or loss of cardiovascular pulsa-
tility and respiratory phasicity.35
Emergency Department Physician-Performed Imaging

A 2013 meta-analysis of 16 studies that assessed the diagnostic accuracy of emer-
gency department physician lower extremity ultrasound for DVT demonstrated a
reservados.
kappa value of 0.83 between investigators, with a mean sensitivity of 96.5%.36 In the
studies analyzed, there was high variability in training among emergency department
physicians and variable study type (whole leg, 2 point, 3 point). Additional studies
regarding emergency department physician DVT diagnoses have been conducted
and have demonstrated highly variable results (sensitivity from 66% to 100%) but
were subject to poor study methods.37 Overall, the studies seem to demonstrate
that bedside performance of ultrasound for the evaluation of LEDVT by emergency
department physicians is reasonable, but perhaps dependent upon experience and
level of training.
Upper Extremity Deep Venous Thrombosis
Only about 50% of clinical investigations identify DVT in patients with suspected
UEDVT. Contrast venography is the gold standard but invasive and requires contrast
use. Ultrasound is 82% to 97% sensitive and 82% to 96% specific, and benefits from
portability and lack of radiation use.10 Recommendations for the evaluation of UEDVT
begin with risk stratification of patients into high or low probability. Both groups should
begin their evaluation with color flow duplex ultrasonography. If UEDVT is found on ul-
trasound, treatment should be initiated. In low-risk patients in whom ultrasound is
negative, serial ultrasound can be considered, or the evaluation can be stopped. In
high-risk patients, contrast venography is recommended for further evaluation.10
The approach to evaluation for LEDVT is summarized in Fig. 1.
MANAGEMENT
The management of DVT depends upon individual patient factors including the under-
lying etiology of the DVT, risks for bleeding, symptom severity, and patient preference.
Fig. 1. The two-tiered algorithmic approach to diagnosing DVT.
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752 Olaf & Cooney
Given the multitude of combinations and possibilities, The American College of Chest
Physicians has published guidelines for evaluation and management of VTE. These
consensus guidelines are evidence based and updated every few years, referred to
as the CHEST guidelines.38,39
Isolated Distal Calf Deep Venous Thrombosis
Isolated distal calf VTE is special, as these cases may not progress to proximal DVT or
PE. Authors suggest that all proximal LEDVT be treated and that calf vein DVT should
either be treated empirically or followed with serial ultrasound to devaluate for prox-
imal progression.26 Some authors recommend acute isolated DVT without severe
symptoms or risks for progression be followed with serial ultrasound rather than anti-
coagulation, while those patients with severe symptoms or high risk for progression be
treated with anticoagulation.39 Shared decision-making plays a large role in the deci-
sion to treat or perform serial imaging in isolated distal DVT, as patient preference may
affect adherence to the treatment plan.26
The remaining discussion of therapies reflects the treatment of proximal LEDVT.
Compression Stockings
Graded compression elastic stockings utilized for 2 years have demonstrated no
decreased risk of recurrence of DVT, but did reduce the risk of post-thrombotic syn-
drome (PTS) at 5 years.40 In patients with acute DVT of the leg, the CHEST guidelines
suggest not using compression stockings routinely to prevent PTS.38 This recommen-
dation focuses on prevention of the chronic complication of PTS and not on the treat-
ment of symptoms. For patients with acute or chronic symptoms, a trial of graduated
compression stockings is often justified.38 No specific compression value is mentioned
by the authors, and reference is only made to graded compression stockings.38
Inferior Vena Cava Filters
In patients with acute DVT or PE who are treated with anticoagulants, the routine use
of inferior vena cava (IVC) filters is not recommended.25 Although early embolism was
reduced by filter placement in one study, the effect was transient, and data at 2 years
indicated no significant reduction in mortality or recurrent symptomatic PE.41 In fact,
another study showed increased risk of subsequent DVT at 2-year follow-up after IVC
filter placement.41 IVC filters might be considered in patients who have acute DVT and
suffer complications necessitating cessation of anticoagulation, and in those who
have failed multiple forms of anticoagulation, including vitamin K antagonists (VKAs)
at both the traditional international normalized ratio (INR) of 2.0 to 3.0, as well as an
elevated INR of 3.0 to 4.0, and other therapies including low molecular weight heparin
(LMWH) or novel oral anticoagulants (NOACs).2
Aspirin
Aspirin therapy is not considered an adequate alternative to anticoagulation for treat-
ment of DVT or PE.39 However, after completion of traditional therapy, aspirin may be
an effective measure to prevent recurrence. The WARFASA and ASPIRE studies both
evaluated ASA versus placebo in patients with unprovoked (noncancer- and
nonimmobility-related VTE) after completion of traditional treatment for VTE. Both
studies demonstrated reduced rates of VTE in the aspirin groups.42,43 Multiple studies
of varying design, including 2 meta-analyses, have demonstrated reductions in VTE
among patients on ASA or placebo for cardiovascular risk control (primary preven-
tion).44–46 Pitfalls of studies related to the primary prevention of VTE with aspirin
are largely related to VTE prevention being a secondary outcome or the result of
reservados.
post-hoc analysis. In none of these studies was prevention of PE by ASA a primary end
point. Other large, population-based observational studies have failed to demonstrate
an effect on VTE prevention by ASA.47,48
Given the previously mentioned data, the risks and benefits of aspirin for prevention
of recurrent DVT should be considered upon cessation of traditional anticoagulation.
Although the data are not conclusive, aspirin therapy for secondary prevention of DVT
seems a reasonable and probably effective measure, and should be considered and
weighed against the risk of bleeding in the appropriate patient. In those patients
with unprovoked DVT and low risk of bleeding, and in whom cessation of therapy is
planned, the CHEST guidelines recommend aspirin therapy, as long as there is no
contraindication to such therapy.39 Additionally, the use of aspirin for other primary
or secondary prevention purposes (eg, stroke) should be assessed.49
Aspirin has also been studied for primary prevention of VTE after orthopedic sur-
gery, with conflicting results. The American Academy of Orthopedic Surgeons, in a
2009 statement, recommended primary prevention of VTE with ASA, based on the
Pulmonary Embolism Prevention Study.44,50 CHEST recommendations now recom-
mend ASA therapy as an alternative therapy to heparin or LMWH. A study published
in 2013 was halted prematurely because of poor patient recruitment, but has been
cited as evidence of aspirin noninferiority compared with dalteparin treatment.44,51
Anticoagulation
A seminal work by Barritt and Jordan was a small and technically poor study that
seemingly demonstrated the efficacy of anticoagulation for the prevention of progres-
sion of VTE following initial diagnosis.52 Although their methods were flawed, several
more rigorous subsequent studies have proven the benefit of anticoagulation on
morbidity and mortality.40
Current options for anticoagulation in VTE include
1. Anticoagulation with heparin or a LMWH, with transition to a VKA until the INR
is greater than 2 on 2 consecutive days
2. Oral dabigatran or edoxaban after 5 days of heparin or LMWH
3. Oral apixaban or rivaroxaban only, with loading doses
4. LMWH treatment only for those patients with active cancer53
Treatment options regarding anticoagulation are categorized by the mechanism or
class of drug when studied or described in the literature.
Unfractionated heparin
Unfractionated heparin (UFH) is an anticoagulant that complexes with antithrombin III
(ATIII), producing a conformational change and converting the ATIII molecule into a
potent inhibitor of thrombin. ATIII exerts its anticoagulant effect through inhibition of
thrombin and factor Xa.54
UFH is delivered intravenously and requires partial thromboplastin time (PTT) moni-
toring.12 The range of PTT depends on reagent and desired coagulation parameters. A
fixed ratio of 1.5 to 2.5 times the control value is suggested but often results in variable
and subtherapeutic degrees of anticoagulation.12 More ideal is the correlation of PTT
values with ex vivo values of antifactor Xa between 0.3 and 0.7 u/mL.12 Weight-based
nomograms are often used to estimate the amount of heparin required for anticoagu-
lation.12 Adverse effects include hemorrhage in up to 7% of patients and osteoporosis
in patients with prolonged (longer than one month) use.12 The risk of hemorrhage is
affected by age and concomitant use of thrombolytic or antiplatelet agents.12
Heparin-induced thrombocytopenia (HIT) is an immune-mediated phenomenon
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754 Olaf & Cooney
defined by the presence of heparin-dependent immunoglobulin G (IgG) antibodies,

which appear to activate platelets in a complex of heparin, platelet, and platelet factor
4, occurring in up to 2.7% of patients receiving heparin.55 The thrombocytopenia can
be complicated by thrombotic events, likely through platelet activation, and usually
occurs on or after day 5 of heparin therapy. Patients with a history of HIT should
receive heparin alternatives to anticoagulation.12
Low Molecular Weight Heparins

LMWHs differ from unfractionated heparins in their pharmacokinetic and biologic
properties, namely decreased plasma protein binding and increased serum bioavail-
ability when delivered via a subcutaneous route. LMWH drugs can thus be adminis-
tered subcutaneously, do not require frequent laboratory monitoring, and exhibit
fewer biologic phenomena than unfractionated heparin.54
A 1999 meta-analysis found the use of LMWH decreased mortality in the treatment
of DVT when compared with UFH. In addition, the LMWH products demonstrated
similar safety profiles with respect to bleeding and were as effective as UFH in pre-
venting recurrent DVT.56 Most patients can be treated safely and effectively with
LMWH, with appropriate infrastructure in place.12 Outpatient treatment with LMWH
is reasonable in many patients, provided a high risk of bleeding (very advanced age,
recent surgery, history of renal of liver disease), serious coexisting illness, and massive
thrombosis are absent. Direct comparisons of LMWH and UFH have shown lower VTE
recurrence rates, less major bleeding, and lower mortality rates with treatment using
LMWH.57
In patients who have recurrent VTE on long-term LMWH (and are believed to be
compliant), increasing the dose of LMWH by one-quarter to one-third is recommen-
ded.39 Recurrent VTE while on therapeutic-dose anticoagulant therapy is unusual
and should prompt evaluation for underlying malignancy, antiphospholipid syndrome,
evaluation of compliance with anticoagulation, and whether the perceived recurrent
VTE is an acute finding or a chronic VTE.39
In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or
NOACs and are believed to be compliant, the CHEST guidelines recommend switch-
ing to treatment with LMWH, at least temporarily.39
Specific adverse events associated with LMWH include the HIT phenomena, as well
as bleeding. LMWH can cross-react with the antibodies that cause HIT and should
thus be avoided in patients with a history of HIT.12 Use of LMHW (dalteparin) in women
during pregnancy demonstrated less decline in bone mineral density compared with
UFH during and no significant difference in osteoporosis 3 years after delivery,
compared with healthy women who did not require anticoagulation.58
Warfarin and Vitamin K Antagonists

VKAs include warfarin, acenocoumarol, phenprocoumon, and others, which inhibit
gamma carboxylation of factors II, VII, IX, X, C, and S. Drug absorption is rapid and
complete, but therapeutic levels take 4 to 5 days to obtain, owing to the mechanism
of action of the drugs.53
VKA therapy is traditionally started on the same days as parenteral anticoagulation
with heparin or LMWH and titrated to an INR of 2 to 3.12 A small randomized
controlled trial demonstrated a significant reduction (20% vs 6.7%) in VTE recurrence
in those patients treated with intravenous unfractionated heparin and transitioned to
a vitamin K antagonist versus a vitamin K antagonist alone, respectively.53 Utilized at
an INR of 2.0 to 3.0, VKAs have been shown to reduce the risk of recurrent throm-
boembolism.12 INRs higher than 3 have demonstrated increased risks of bleeding
reservados.
without benefit of reduced recurrence of DVT. Although INRs higher than 3 were rec-
ommended for the management of DVT in patients with antiphospholipid syndrome,
2 trials failed to demonstrate superiority compared with standard (INR 2–3)
recommendations.59,60
In trials comparing VKA therapy to novel (or direct) oral anticoagulant therapy, VTE
recurrence rates for LMWH/VKA therapy were 2.2% to 3.5% in patients treated for 3 to
12 months, with a risk of major bleeding 8.5% to 10.3%.53 A large VTE registry found
VTE recurrence rates of 2.5%, similar to recent trials, but increased risk of major
bleeding, about 2.5% beyond that seen in the same trials.53
In addition to bleeding risks, adverse effects of warfarin therapy include vascular
purpura and consequent skin necrosis in the first few weeks of therapy, which has
been associated with protein C deficiency and malignancy. Coumarin derivatives
are known teratogens and should be avoided in pregnancy.61 The rate of recurrent
DVT while on well-coordinated VKA is about 2%.38 The risk of bleeding at 90 days
is about 2.2%.62 Long-term therapy with VKAs has demonstrated decreased risks
of recurrent VTE compared with short-term (3 months) therapy (relative risk 0.20),
but was associated with increased risks of bleeding (relative risk 3.44) and no signif-
icant difference in mortality.63
Novel (Direct) Oral Anticoagulant Therapy

The direct or novel oral anticoagulant therapies differ from VKAs in mechanism,
from UFH and LMWH at their sites of action, and from argatroban, in that these
novel medications are orally bioavailable. Dabigatran, like argatroban, is a univalent
direct thrombin inhibitor, inhibiting thrombin (factor IIa) at its active site. Rivaroxa-
ban, apixaban, and edoxaban are factor Xa inhibitors. Collectively, the NOAC drugs
exhibit relatively rapid onsets of action, with peak levels being achieved 1 to 4 hours
after oral dosing. The half-lives approximate 12 hours.64 Advantages of these ther-
apies include ease of dosing, lack of need for monitoring, and improved manage-
ment for anticoagulation for procedures that might cause bleeding.49 In support of
this is the fact that antifactor IIa and antifactor Xa activities are directly proportional
to drug levels.53 Renal function plays a large role in the elimination of these drugs,
and compromised renal function may lead to accumulation, supratherapeutic
drug levels, and consequential bleeding. Apixaban and Rivaroxaban have the ad-
vantages of not requiring heparin bridging to attain therapeutic levels. In addition,
the NOACs have far fewer drug-drug interactions when compared with warfarin,
allowing for more stable levels and drug effects.65 It is important to note that
potent inhibitors or inducers of CYP3A4 or p-glycoproteins can affect NOAC
drug levels.65
All of the trials for the NOACs were designed as noninferiority trials when
compared with LMWH or VKAs, although different criteria for noninferiority were uti-
lized across studies. The details of individual trials are discussed, but in general,
consistent findings of noninferiority of the NOACs were present throughout.65 Recur-
rence rates for VTE in these trials was about 2% for DOACs compared with 2.2% for
VKAs; however, study parameters for duration of treatment differed among the tri-
als.53 Recent meta-analyses showed similar rates of recurrent DVTs between the
NOACs and traditional therapies but reduced rates of major and fatal bleeding, as
well as all-cause mortality with the NOACs.66,67 A significant reduction in bleeding
among the NOACs was noted, with a number needed to treat (with NOAC as
opposed to VKAs) between 19 and 167.65 There are limited real-world data to deter-
mine the outcomes for patients outside of the selected study groups for the phase III
trials for these drugs.53
reservados.
756 Olaf & Cooney
Direct Thrombin Inhibitors

Dabigatran etexilate
RE-COVER and RE-COVER II were double-blinded trials that compared the treatment
of VTE with warfarin. Both demonstrated noninferiority for recurrent VTE or VTE-
related death and reduction in bleeding.68,69 The RE-MEDY study was a randomized
study that demonstrated the noninferiority of dabigatran to warfarin for extended ther-
apy for VTE, with a nonstatistically significant reduction in bleeding.69 RE-SONATE
was a placebo-controlled, double-blinded study with dabigatran versus placebo for
extended therapy after initial completion of VTE treatment for first VTE. Dabigatran
significantly reduced recurrent VTE in the study population.69
When dabigatran was compared with VKAs for long-term treatment of VTE, the data
showed an anticipated absolute risk difference of 5 fewer (per 1000) episodes (95%
confidence interval [CI]: 2–10) of major bleeding.38 Specifically, in the RE-LY trial, ma-
jor gastrointestinal (GI) bleeding compared with warfarin was significantly increased in
the twice-daily 150 mg dose, but comparable at the 110 mg twice-daily dose.
Bleeding in the 75 mg twice-daily dose was not assessed.70 Dabigatran at both the
150 mg and 110 mg dosing was associated with significantly less intracranial hemor-
rhage compared with warfarin.71 The RE-COVER trial showed lower rates of intracra-
nial hemorrhage in the dabigatran group as well.71
Factor Xa Inhibitors
Rivaroxaban
The EINSTEIN study assessed rivaroxaban against placebo for extended VTE preven-
tion after initial traditional anticoagulation for first VTE and demonstrated superior ef-
ficacy compared with placebo.72 EINSTEIN-DVT and EINSTEIN-PE were open-label
trials that demonstrated noninferiority of rivaroxaban compared with warfarin in the
treatment of DVT and PE, respectively. Similar bleeding rates were noted between
rivaroxaban and vitamin K antagonists.72,73
When rivaroxaban was compared with LMWH and VKAs in 2 studies that assessed
the acute and the long-term treatment of VTE, the anticipated absolute risk differ-
ence in major bleeding was 8 fewer (per 1000) episodes (95% CI: 3–11).38 In the
ROCKET-AF trial, rivaroxaban 20 mg daily demonstrated an increased risk of major
GI bleeding when compared with warfarin (hazard ratio 1.61).70 A post hoc analysis
of data showed similar rates of life-threatening bleeding (4 or more units of packed
red blood cells transfused) between the 2 groups and fewer (1 vs 5) fatal events
with rivaroxaban. The ROCKET-AF trial also demonstrated rivaroxaban to have
significantly less acute intracranial hemorrhage when compared with warfarin, with
lower rates of both intracerebral hemorrhage and subdural hemorrhage.71 In the
EINSTEIN-DVT trial, intracranial hemorrhage rates were not reported separately,
but bleeding in a critical location was similar between the rivaroxaban and warfarin
groups.71 In EINSTEIN-PE, lower rates of intracranial hemorrhage were observed
in the rivaroxaban group.71
Apixaban
The AMPLIFY study evaluated patients treated for first VTE and randomized patients
to 3 groups: 2.5 mg apixaban, 5 mg apixaban, or placebo for 12 months. Both doses of
apixaban demonstrated superior efficacy at preventing death compared with placebo
and equivalent rates of bleeding.74
In a comparison of apixaban to LMWH and VKAs for the acute and long-term treat-
ment of VTE, the absolute anticipated risk of major bleeding was 13 fewer episodes
(per 1000) (95% CI: 2 more to 10 fewer).39 The ARISTOTLE trial showed no significant
reservados.
differences in major GI bleeding between apixaban and warfarin and demonstrated

lower rates of intracranial hemorrhage in favor of apixaban.70
Edoxaban
A randomized, double-blinded, 12-month noninferiority trial demonstrated that in VTE
treated first with LMWH or heparin, edoxaban showed no significant difference in
recurrent VTE (3.2% vs 3.5% respectively), compared with warfarin. Additionally, a
significantly lower rate of major or clinically relevant nonmajor bleeding (8.5% vs
10.3% respectively) was observed.75 Another randomized, double-blind trial
(ENGAGE AF-TIMI 48) evaluated over 21,000 patients with atrial fibrillation and
increased risk of stroke. Significant reductions in rates of major bleeding (2.75% vs
3.43%), intracranial bleeding (0.39% vs 0.85%), and cardiovascular death (2.74%vs
3.17%) were observed with edoxaban.76 Edoxaban compared with VKA for long-
term treatment of VTE showed an anticipated absolute risk difference of 2 fewer ep-
isodes (per 1000) (95% CI: 3 more to 6 fewer) for major bleeding.25
Direct comparisons of GI bleeding, intracranial bleeding, or other types of bleeding
among the NOACs are not yet available but should be performed in the future to more
thoroughly assess the associated risks with each agent.
The safety of NOACs in pregnancy and children has not yet been sufficiently eval-
uated, and therefore specific recommendations cannot be made for the NOACs in
the treatment of DVTs in these populations. Studies in pregnancy have not yet been
conducted, and studies in children are underway currently.
Thrombolysis for deep venous thrombosis

Because of the risk of bleeding, thrombolysis of DVT is usually reserved for patients
with a low risk of bleeding and limb-threatening thrombosis.12,27 A Cochrane database
review of 17 studies suggested that any type of thrombolysis improved clot resolution
and reduced the risk of post-thrombotic syndrome, with an expected increase in
bleeding complications.77 UK guidelines recommend considering thrombolysis in spe-
cific patients with low risk of bleeding, good functional status, and iliofemoral DVT.28
Catheter-directed thrombolysis
In patients with acute proximal DVT of the leg, anticoagulant therapy alone over
catheter-directed thrombolysis (CDT) is recommended.25 A retrospective observa-
tional study of over 90,000 patients with lower extremity proximal DVT demonstrated
no difference in mortality between CDT plus anticoagulation versus anticoagulation
only, but did find an increased incidence of adverse events in the thrombolysis
group.78 However, a subset of patients with acute (within 14 days) iliofemoral DVT,
good functional status, and a life expectancy of at least a year with a low risk of
bleeding might be the most optimal candidates for the therapy, in cases where it is
offered.28
Recommendations by type of anticoagulant therapy

Choosing the type anticoagulant can be daunting. One can begin to narrow the op-
tions by basing the decision on the patient’s presumed underlying DVT etiology, in-
dividual risks, and clinical condition. Heparin is a reasonable choice for those
individuals with extensive or massive DVT or PE or high risk of bleeding, so that
levels may be monitored and doses properly titrated. This requires hospitalization.
NOACs may not be appropriate for these patients, as they have not been evaluated
in these respects. In cases of DVT in pregnancy or in the setting of active malig-
nancy, LMWH appears to be the best option. NOACs play a specific role at this
time and require that a particular set of conditions be met. In cases in which NOACs
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758 Olaf & Cooney
are available; consistent oral dosing is obtainable; patient preference is for no need
for monitoring; and in patients with normal renal function (Cr clearance >30 mL/
min), the NOACs rivaroxaban, apixaban, and edoxaban seem to be the best option.
Anticoagulation parameters are not required on a regular basis. However, in cases
in which NOACs are prohibited by cost, or the previously mentioned conditions are
not met, LMWH with transition to warfarin is the best option. In more specific cases,
patients with dyspepsia or recent acute coronary syndrome should avoid dabiga-
tran. Patients with recent upper GI bleeding had less recurrent bleeds while on
apixaban (compared with other NOACs) and should be offered this therapy as a first
choice.65
Upper extremity deep venous thrombosis management

Treatment options for UEDVT are as varied as those for LEDVT. Treatment of UEDVT is
related to risks of developing PE (which is lower in UEDVT than LEDVT), symptom
management, the development of recurrent DVT or PE, and management of patient
symptoms. Anticoagulation is the preferred management of UEDVT, and recommen-
dations largely mimic those for the treatment of LEDVT.10,39 Initial treatment recom-
mendations are for 3 months. The decision concerning removing a CVC related to
UEDVT is an individualized decision that is influenced by the symptoms of the DVT
as well as the necessity of the device. Although anticoagulation is routinely preferred
over thrombolysis, individualized treatment plans for thrombolysis can be made in
specific situations to help manage severe or refractory symptoms.10
COMPLICATIONS OF DEEP VENOUS THROMBOSIS
After diagnosis and treatment of VTE, monitoring of complications, evaluation of

potential causes, and duration of treatment should be investigated. Among compli-
cations of VTE, post-thrombotic syndrome (PTS) occurs in about 20% to 50% of
patients after DVT.39 PTS is a constellation of chronic clinical findings that are
induced by DVT. Symptoms may include leg heaviness, pain, cramps, pruritis,
and paresthesias. Objective signs may include pretibial edema, skin induration, hy-
perpigmentation, ectatic veins, ulcers, and painful calf compression. The highest
risks for developing PTS are extensive proximal DVT, ipsilateral recurrent DVT,
and ineffective or absent anticoagulation therapy.79 Phlegmasia cerulea dolens
(PCD) and phlegmasia alba dolens (PAD) are uncommon but catastrophic compli-
cations of DVT. Both conditions describe fulminant DVT of the extremity, with
PCD including obstructed arterial flow caused by increased compartmental pres-
sures.80 Significant morbidity and mortality are seen with PCD, with 12% to 15%
of survivors requiring amputation and a mortality rate of 25%.81 Although the exact
incidence of the disease is poorly reported, in 1 study of PCD, the observed rate
was just 7 times over 4.5 years.82 As noted previously, about 25% of DVTs will
demonstrate proximal progression, and 50% of these with result in PE.14,15 Aside
from these inherent complications from DVT, the remainder of complications
stem from bleeding related to treatment of DVT.
Even with treatment, VTE carries a high risk of death, but rates vary widely in the
literature.83 Short-term survival estimates from DVT range from 95% to 97%, while
long-term survival estimates range between 61% to 75%.83 In 1 study, estimates of
30-day mortality after diagnosis of DVT and PE were 6% and 12%, respectively.65
In another study, rates of survival for DVT were 96.2% at 7 days, 94.5% at 30 days,
and 94.5% at 1 year. These values were significantly different from the rates of PE,
which were 59.1%, 55.6%, and 47.7%, respectively.83
reservados.
FURTHER EVALUATION
In those patients with unprovoked DVT, undiagnosed malignancy is an additional

concern. Recommendations from the United Kingdom suggest that all patients with
unprovoked DVT undergo a full physical examination, chest radiograph, and labora-
tory testing including complete blood count, serum calcium, liver function testing,
and urinalysis. In patients over 40 years of age with unprovoked DVT and without
abnormal findings on the initial screening tests, abdominal-pelvic computed tomogra-
phy (CT) scanning is recommended to search for malignancy.28
Thrombophilia evaluation should be pursued in patients only after the cessation of
anticoagulation in the setting of unprovoked DVT.2 A review of available literature
found no North American guidelines for thrombophilia testing after unprovoked
DVT. UK guidelines (which were created with consideration of both economic and
disease-related factors) recommend no additional thrombotic workup for patients
who will continue anticoagulation.28 For those patients with unprovoked DVT who
will stop anticoagulation, antiphospholipid antibody screening is recommended. For
those patients with a first-degree relative with a history of VTE, additional thrombo-
philia testing is warranted.28
TREATMENT DURATION
Although it is often beyond the scope of care in the emergency department for the
acute VTE patient, the duration of treatment for VTE is a concern to many patients,
and it is reasonable for the emergency physician to be familiar with recommendations
for duration of treatment to provide general counseling at the time of diagnosis. Tran-
sient and nontransient risk factors can be identified, and risk of bleeding related to age
and history of bleeding can be evaluated. A great deal of the decision for duration fo-
cuses on risk of recurrence, comorbidities, and bleeding risk, and this review will focus
on these aspects.
Risk and Rates of Recurrence
Rates of recurrence are correlated to duration of treatment; as risk of recurrent DVT
increases, duration of therapy is theoretically prolonged. Therefore, to understand
duration of treatment, one must understand rates and risk of recurrence.
One manner of analyzing risk of recurrence is through the associated cause. The
rate of recurrence of VTE after trauma or surgery is about 3% per year.84–86
Cancer-associated recurrent VTE occurs at a rate of 10% per year.84–86 Unprovoked
VTE has a risk of recurrence of about 15% over the first 2 years. Rates of recurrence
also vary by time and are influenced by provocative factors.40,87 Table 4 categorizes
recurrence rates by risk factor and time period.
Table 4
Rates of recurrence of venous thromboembolism can also be categorized by time
Time Transient Risk Factor Rate Nontransient Risk Factor Rate

6 wk to 3 mo 2.5% per year 5% per year
3 mo to 6 mo 2.5% per year 5% per year
6 mo to 2 y 5% per year 10% per year
Beyond 2 y 2% per year 4% per year
From Prins MH, Hutten BA, Koopman MM, et al. Long-term treatment of venous thromboembolic
disease. Thromb Haemost 1999;82(2):892–8.
reservados.
760 Olaf & Cooney
Bleeding Risk
The associated risk of recurrence must be weighed against the risk of bleeding. Many
factors influence the risk of bleeding, and advancing age is well known to increase the
risk of bleeding (from VKAs) as follows40:
Less than 40 years: 0.6% per year
40 to 49 years: 1.0% per year
70 years and beyond: 3.2% per year
In addition to advancing age, the following risk factors have been identified as inde-
pendent and cumulative risks for bleeding:
Previous bleeding
Cancer
Metastatic Cancer
Renal failure
Liver failure
Thrombocytopenia
Previous stroke
Diabetes
Anemia
Antiplatelet therapy
Poor anticoagulant control
Comorbidity and reduced functional capacity
Recent surgery
Alcohol abuse
Nonsteroidal anti-inflammatory drugs
With none of the previously mentioned risk factors present, the baseline risk for
bleeding is estimated at 0.6%. Adding anticoagulant therapy increases the risk to
1.6%. If 1 risk factor is present, the baseline risk is 1.2%, and adding anticoagulation
increases the risk of bleeding to 3.2%. If 2 or more risk factors are present, the base-
line risk of bleeding is 4.8%, and adding anticoagulation increases this risk to 12.8%.39
These data are based on aggregate data and largely on VKA therapy. The authors note
that variability will exist from patient to patient, and that although the increased risk of
bleeding has not been validated in the manner described previously, the risk of
bleeding is cumulative from multiple risk factors.39
Multiple clinical tools and predictors have been created to assess risk of bleeding in
an objective and individualized manner for each specific patient. Unfortunately, a
calculator or prediction tool specific to VTE is unavailable.
The HAS-BLED score is used to estimate risk of bleeding for patients using anticoagu-
lation for the prevention of stroke due to atrial fibrillation.88 The tool identifies the following
risks: hypertension, abnormal renal/liver function, history of stroke, bleeding history or
predisposition, labile INR, elderly, and the use of drugs/alcohol concomitantly. The score
has been validated in comparison to other scores, and the data set utilized a direct
thrombin inhibitor (ximelagatran) in comparison to warfarin.88 It is important to note
that the validation study also identified concurrent aspirin use, diabetes, and heart failure
or left ventricular dysfunction as significant risks for bleeding while on anticoagulation.88
Another validated tool is the Outpatient Bleeding Risk Index, which was validated on
a data set of patients diagnosed with DVT or PE and undergoing standard LMWH/VKA
therapy.89 The data set suffered from not having many high-risk bleeding patients, but
reservados.
did have adequate numbers to discriminate between low and moderate risks of
bleeding, making it uniquely appropriate for risk assessment in lower-risk patients.
In the study, rates of major hemorrhage were zero per hundred person-years (0%–
2.8% 95% CI) and 4.3% (1.1%–11.1% 95% CI) for the low-risk and moderate-risk
groups, respectively.89
Treatment Duration
The efficacy of treatment and the associated reduction in morbidity and mortality
should be weighed against the probability of bleeding. It would be reasonable, for
example, to treat a younger individual for a more prolonged period (eg, 2 years), in
the setting of unprovoked DVT, and just as reasonable to treat an elderly individual
(eg, 70 years) for only 6 months, given the relative risks of recurrence, case fatality,
and bleeding.
The efficacy of prevention of recurrence can be expressed in terms of a reduction of
risk associated with a unit of time (eg, months of treatment needed to prevent an addi-
tional event).40 Multiple studies have demonstrated that short-term anticoagulation
(6 weeks to 6 months) demonstrates more robust efficacy in terms of prevented
DVT per month, as compared with extended anticoagulation. Authors have suggested
alterable risk factors (eg, immobilization, recent surgery) that might cause of VTE may
suggest a need for a shorter period of anticoagulation.40
Novel Oral Anticoagulant Efficacy and Risk for Extended (More than 3 Months)
Therapy
In cases in which extended therapy is pursued due to an estimated high risk of recur-
rence and low risk of bleeding, some NOACs offer advantages. The agents dabiga-
tran, apixaban, and rivaroxaban were all superior to placebo, with low major rates
of bleeding. In addition, a prophylactic dose (2.5 mg as opposed the therapeutic
dose of 5 mg) of apixaban significantly reduced VTE recurrence and had a trend to-
ward even lower rates of bleeding. Although no trial has been conducted, the data
would suggest that an investigation into extended therapy at lower doses would be
warranted. Similar trials with lower INR goals with warfarin did not prove beneficial
in preventing recurrent DVT.65 As mentioned previously, aspirin therapy as opposed
to no therapy after cessation of anticoagulant use remains a viable option and should
be based on risk of bleeding.
Specific Recommendations
Weighing individual risks and benefits for each patient is ideal. Identifying risk thresh-
olds for starting and stopping anticoagulation on an individual basis is best, but may
be difficult to calculate and translate. Therefore, the authors recommend the previ-
ously discussed CHEST guidelines to assist in the management cases, while still
contextualizing and individualizing therapy for the patient. A recommended treatment
algorithm, based on these guidelines, is provided in Fig. 2. Treatment guidelines and
algorithm serve to broadly contextualize treatment, but each patient requires individ-
ualized therapy for his or her specific situation.
Provoked Deep Venous Thrombosis

Transient and alterable risks
For individuals with proximal lower extremity DVT whose risk for VTE can be altered (eg,
provoked DVT related to surgery, immobilization, or exogenous estrogen use), 3 months
of therapy are often adequate and recommended when compared with no therapy at all
or when compared with longer or shorter-term therapy.39 In these cases, dabigatran,
reservados.
762 Olaf & Cooney
Fig. 2. Recommended treatment algorithm based on the 2016 CHEST guidelines. (Data from
Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline
and expert panel report. Chest 2016;149(2):315–52.)
rivaroxaban, apixaban, and edoxaban are recommended over VKA therapy.39 In pa-
tients with a proximal DVT of the leg or PE provoked by a nonsurgical but transient
risk factor, treatment is recommended for 3 months regardless of bleeding risk.39
Malignancy-associated deep venous thrombosis

For individuals with cancer-associated VTE, LMWH is the preferred and recommen-
ded initial therapy over VKA therapy. Patients taking only LMWH versus those bridged
to VKAs have about half the rate of recurrent events.39,90
In patients with DVT of the leg or PE and active cancer (cancer-associated throm-
bosis), regardless of bleeding risk, extended anticoagulant therapy (no scheduled
stop date) is recommended over 3 months of therapy. It is recommended to reassess
the necessity of anticoagulation and anticipated duration on an annual basis.39 For
those patients who require continuation of therapy beyond 3 months, there is no
need to change the choice of anticoagulant after the first 3 months.39
Unprovoked Deep Venous Thrombosis

In patients with an unprovoked DVT of the leg, treatment with anticoagulation is rec-
ommended for at least 3 months over treatment of a shorter or longer duration.39
D-dimer and patient sex may be considered in the decision to extend anticoagulant
therapy 1 month after cessation.39
reservados.
In patients with a first DVT (ie, an unprovoked proximal DVT of the leg) and a low or
moderate bleeding risk, extended anticoagulant therapy (at least 3 months, no sched-
uled stop date) is preferred. However, in those patients with unprovoked DVT and high
bleeding risk, 3 months of anticoagulant therapy are suggested.
In the case in which a second unprovoked VTE occurs after cessation of therapy in a
patient who has a low or moderate bleeding risk, extended anticoagulant therapy (no
scheduled stop date) is recommended. In patients with high bleeding risk and recur-
rent unprovoked VTE, 3 months of anticoagulant therapy are recommended.39
Regardless of the etiology, the CHEST guidelines on duration of therapy serve as a
reminder to reassess the need for anticoagulation annually.
Isolated Distal Deep Venous Thrombosis

In patients with acute isolated distal DVT of the leg without severe symptoms or risk
factors for extension, serial imaging of the deep veins for 2 weeks is recommended
over initial anticoagulation.39 Consideration should be given to risk of bleeding, and
in those patients with a high bleeding risk, serial imaging is likely the preferred
strategy.
If the thrombus demonstrates no extension in those patients with acute isolated
distal DVT of the leg who are managed with serial imaging, no anticoagulation is rec-
ommended, unless severe symptoms are present. If the thrombus extends, anticoa-
gulation is recommended.39
In the case in which acute isolated distal DVT of the leg manifests with severe symptoms
or high risk of extension, empiric anticoagulation is recommended.39 In patients with
acute isolated distal DVT of the leg who are managed with anticoagulation, the same
recommendations for proximal lower extremity DVT treatment should be followed.39
CONTROVERSIES
The advent of the NOACs has been met with appropriate skepticism regarding the ef-
ficacy and adverse effects of these novel drugs. Recent literature has demonstrated
the noninferiority of dabigatran, rivaroxaban, apixaban, and edoxaban when
compared with traditional VKAs in the treatment of VTE.65,72,91–93
Despite the estimated lower risks of bleeding demonstrated in the phase 3 trials for
the NOACs (as well as data from a meta-analysis of 102,607 patients),94 1 concern
among many practitioners has been the lack of a reversal agent when unanticipated
or catastrophic bleeding occurs. Reversal of anticoagulation for anticipated proced-
ures (minor or major surgeries) is a justified but smaller concern, as the drugs all
have relatively short half-lives, and cessation of the drug alone is enough to
adequately reverse anticoagulation in 24 to 72 hours depending on the half-life of
the specific drug used and renal clearance of the patient. Risk of bleeding from surgery
is also a consideration, as is the reason for anticoagulation, when stopping anticoagu-
lation for anticipated procedures.
In cases of catastrophic bleeding in which emergent reversal of anticoagulation is
needed, in contrast to the traditionally used VKAs, heparin, or LMWH, the NOACs
initially did not have US Food and Drug Administration (FDA)-approved specific agents
for reversal. It is well known that warfarin and the VKAs can be reversed with vitamin K,
prothrombin complex concentrates (PCCs), and fresh-frozen plasma (FFP). Heparin
(and to some extent LMWH) can be reversed with protamine sulfate. To add to the
problem, standardized anticoagulation parameters such as the PT, activated partial
thromboplastin time (aPTT), and INR are not informative in assessing the degree of
anticoagulation with the NOACs.65
reservados.
764 Olaf & Cooney
Consideration for reversal of anticoagulation with NOACs begins with risk assess-
ment. Vital signs and rate of blood loss should be first assessed to determine any
emergent need for reversal. The location of bleeding and whether pressure can be
applied to a bleeding site should also be considered. In sources of occult bleeding
or that which cannot be visualized directly (eg, GI tract bleeding), serial blood counts
may prove beneficial. One should also consider alternative etiologies of bleeding,
including thrombocytopenia or qualitative platelet dysfunction. Few data exist
regarding effective drug therapies for reversal of NOAC-associated bleeding. Options
that have been described in the literature include95
Alteration of pharmacokinetics (decrease absorption from GI tract, remove from
circulation with hemodialysis)
Of the agents available, dabigatran is the only drug with which hemodialysis is
expected to be of benefit
Activated charcoal is expected to decrease absorption of dabigatran and apix-
aban, with unknown efficacy in the other NOACs
Antifibrinolytic therapies (eg, aminocaproic acid, tranexamic acid)
Plasma factor therapy: FFP, PCCs, cryoprecipitate
These therapies collectively have limited data for efficacy
Studies that have been performed have only investigated surrogate markers
for clinical outcome (eg, reversal of INR and bleeding time) and have demon-
strated no data on actual patient outcomes95
Specific antidotes95 bind the drug or inhibit a drug or class of drugs at the active
site, rendering the NOACs ineffective
Ciraparantag, which reverses the effects of direct thrombin inhibitors, factor Xa
inhibitors, and heparins
Andexanet alfa, which reverses the effect of factor Xa inhibitors
Idarucizumab, a humanized mouse monoclonal antibody fragment that re-
verses the effects of dabigatran and was FDA approved in October, 2015
Investigations into the efficacy and safety of these drugs are all being per-
formed. Considerations for procoagulant effects are among the highest
concern and have been demonstrated in 5 of 90 patients analyzed at a
phase III interim analysis. The true procoagulant effect cannot be analyzed
based on these data, as there was no placebo group for comparison95
One important consideration when evaluating the efficacy of anticoagulation reversal
with the NOACs is a comparison to the efficacy of reversal of more commonly used
agents, including VKAs. Although analysis of coagulation parameters seems helpful, pa-
tient based outcomes are far more important. For example, improvement of an INR, PT,
or PTT value is meaningless if a patient suffers a catastrophic intracranial hemorrhage
that is not prevented or treated by use of the reversal agent. The availability of FFPs,
PCCs, and Vitamin K for reversal of an INR does not necessarily translate into efficacy
in terms of patient outcome. Even the most recent trials utilizing 4-factor PCCs have
focused on INR reduction or surrogate markers of bleeding as opposed to patient out-
comes.96,97 As the NOACs are more commonly used and specific antidotes are devel-
oped, trials assessing patient outcomes should be conducted in order to assess the
efficacy of reversal of the NOACs in comparison to traditional reversal of VKAs.
SUMMARY
VTE ranges from an isolated and self-limited disease, in the case of distal calf vein
thrombosis, to catastrophic disease in the setting of large DVTs that cause localized
reservados.
swelling and pain and place patients at high risk of pulmonary embolism that could ul-
timately prove fatal. Assessment for DVT begins with risk factors and utilizes adjunc-
tive testing based on the perceived level of risk. Most DVTs are managed with
anticoagulant therapy, the type and duration of which varies with the patient’s own his-
tory of VTE, cancer, or other risk factors. Adjunctive therapies to anticoagulation play a
limited role in the management of DVT. Recent advances in anticoagulant therapies
have allowed for more regular dosing, less need for monitoring, and decreased risks
of bleeding, which ultimately may prove more satisfactory for patients, in addition to
the obvious safety benefits. In the future, additional studies should continue to eval-
uate the efficacy of novel anticoagulants in comparison to traditional agents, refine
the role of these agents based on individual risk factors, and compare the efficacy
of reversal agents in circumstances of catastrophic bleeding in terms of patient
outcomes.
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D e e p Ven o u s T h ro m b o s i s

Deep venous thrombosis (DVT) is part of a spectrum of venous thromboembolic dis-

Emerg Med Clin N Am 35 (2017) 743–770

Condition Approximate Relative Risk

not thought to be an independent risk for DVT. However, it is considered prudent to

Estimated Relative Risk of Recurrent

DIAGNOSING DEEP VENOUS THROMBOSIS

As already indicated, physical examination and elements of a patient’s history are

The Wells Scoring System

Findings on History and Examination Point Value

Emergency Department Physician-Performed Imaging

Fig. 1. The two-tiered algorithmic approach to diagnosing DVT.

defined by the presence of heparin-dependent immunoglobulin G (IgG) antibodies,

Low Molecular Weight Heparins

Warfarin and Vitamin K Antagonists

Novel (Direct) Oral Anticoagulant Therapy

Direct Thrombin Inhibitors

differences in major GI bleeding between apixaban and warfarin and demonstrated

Thrombolysis for deep venous thrombosis

Recommendations by type of anticoagulant therapy

Upper extremity deep venous thrombosis management

COMPLICATIONS OF DEEP VENOUS THROMBOSIS

After diagnosis and treatment of VTE, monitoring of complications, evaluation of

In those patients with unprovoked DVT, undiagnosed malignancy is an additional

Time Transient Risk Factor Rate Nontransient Risk Factor Rate

Provoked Deep Venous Thrombosis

Malignancy-associated deep venous thrombosis

Unprovoked Deep Venous Thrombosis

Isolated Distal Deep Venous Thrombosis

1. Fields JM, Goyal M. Venothromboembolism. Emerg Med Clin North Am 2008;

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