Deep Vein Thrombosis

Deep vein thrombosis
Straight to the point of care
Last updated: Apr 22, 2021

Table of Contents
Overview 3
Summary 3
Definition 3
Theory 4
Epidemiology 4
Aetiology 4
Pathophysiology 5
Classification 5
Case history 7
Diagnosis 8
Approach 8
History and exam 13
Risk factors 14
Investigations 19
Differentials 23
Criteria 24
Screening 25
Management 27
Approach 27
Treatment algorithm overview 35
Treatment algorithm 37
Emerging 58
Primary prevention 58
Secondary prevention 59
Patient discussions 60
Follow up 62
Monitoring 62
Complications 63
Prognosis 65
Guidelines 67
Diagnostic guidelines 67
Treatment guidelines 70
Online resources 74
References 75
Images 98
Disclaimer 101
Deep vein thrombosis Overview
Summary
Deep vein thrombosis (DVT) is the development of a blood clot within a vein deep to the muscular tissue
planes. DVT most commonly affects the legs, but can also affect the arms, and other sites in the body.
OVERVIEW
Patients who develop DVT commonly have risk factors, such as cancer, trauma, major surgery,
hospitalisation, immobilisation, pregnancy, or oral contraceptive use. DVT may also be unprovoked
(idiopathic) and occur in the absence of any identifiable extrinsic risk factors.
DVTs commonly cause asymmetrical leg swelling, unilateral leg pain, dilation or distension of superficial
veins, and red or discolored skin, but can also be asymptomatic.
Diagnosis requires documentation of a blood clot in a deep vein in the leg, pelvis, or vena cava by venous
duplex ultrasound imaging or computed tomography scan. However, patients suspected of DVT should
undergo an algorithmic diagnostic approach to avoid unnecessary imaging when the likelihood of DVT is low.
DVT is usually treated with anticoagulants such as unfractionated heparin, low molecular weight heparin,
fondaparinux, rivaroxaban, apixaban, edoxaban, dabigatran, and/or warfarin. Interventional therapies,
including thrombolysis, are rarely indicated.
Generally, anticoagulant therapy for at least 3 months is required for patients with DVT. Thereafter, continued
anticoagulant therapy for secondary prevention is indicated in selected patients to reduce the risk of recurrent
events.
Post-thrombotic syndrome may occur with symptoms of chronic pain, swelling, skin discoloration, or venous
ulcers following chronic obstruction of venous outflow and/or incompetence of venous valves.
Definition
Deep vein thrombosis (DVT) is the development of a blood clot in a major deep vein in the leg, thigh, pelvis,
or abdomen. It may also occur in less common locations such as the arm veins; the portal, mesenteric,
ovarian, or retinal veins; or the veins and venous sinuses of the brain. DVT can result in impaired venous
blood flow and consequent swelling and pain. DVT is rarely life-threatening on its own, but has the potential
to cause pulmonary embolism (PE), which can be fatal. Venous thromboembolism is the broad term that
includes DVT and PE. Superficial vein thrombosis, a common related condition, affects veins superficial to
the musculature. This topic focuses on lower and upper extremity DVT.
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 22, 2021.
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Deep vein thrombosis Theory
Epidemiology
Venous thromboembolism (VTE) is a relatively common medical problem with a yearly incidence of
approximately 1 in every 1000 adults.[1] [2] [3] Approximately two-thirds of all cases present as DVT alone,
THEORY
and one third present as pulmonary embolism (with or without concomitant symptoms of DVT).[2] It is
estimated that in the US as many as 300,000 deaths per year arise due to VTE (principally due to pulmonary
embolism).[4] The incidence increases with age for both men and women.[5] Overall incidence is higher in
men than in women, although incidence is higher in women during childbearing years.[5] Compared with
people of European ancestry in the US, VTE incidence is higher in African-American people and lower in
Asian and American Indian people.[5]
The incidence of DVT during pregnancy or the postnatal period is approximately 1 case per 1000 live
births.[6] Other clinical characteristics confer widely variable incidences of DVT. For instance, orthopaedic
surgical patients have a DVT incidence ranging from approximately 1% to 4% depending upon the utilisation
of pharmacological prophylaxis, while the incidence in acutely ill medical patients is approximately 0.5% to
6%, depending heavily upon the method of diagnosis, inclusion of asymptomatic versus only symptomatic
VTE, utilisation of pharmacological prophylaxis, and duration of follow-up.[7] In critically ill patients an
incidence as high as 37.2% has been reported.[8] The population incidence is increasing slowly as the
proportion of the population that is older increases, and as testing for DVT using ultrasound and testing
for pulmonary embolism using multi-detector chest computed tomographic angiography increases. The
prevalence of VTE is expected to reach over 1.8 million in the US by 2050.[9]
Aetiology
The coagulation system in blood is complex and highly regulated. Slight perturbations in the systems that
regulate coagulation can lead to bleeding or thrombosis.[10] The three factors that, individually or together,
lead to most DVT are vessel injury, venous stasis, and activation of the clotting system (known as Virchow's
triad). Thus, patients who develop DVT typically experience a trigger that leads to blood coagulation
(e.g., surgery or trauma that activates the coagulation system), prolonged immobility that leads to stasis,
or medications or illnesses (e.g., cancers, antiphospholipid syndrome) that can stimulate clotting.[11]
Susceptibility to thrombosis is genetically mediated. Several genetic variants in the coagulation system
itself (e.g., the factor V Leiden mutation) as well as outside the coagulation system (e.g., non-O blood type)
increase the risk of thrombosis. All of these factors may interact, further increasing the risk of DVT.
There is a clear association between DVT and the following:
• Active malignancy
• Recent major surgery (especially major orthopaedic procedures)
• Recent hospitalisation
• Recent trauma
• Medical illness (especially diseases associated with inflammation, such as acute infection)
• Hormone replacement and oral contraceptive oestrogen therapy.
Coronavirus disease 2019 (COVID-19), an infection caused by the novel coronavirus severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with risk for VTE.[12] See our topic
Coronavirus disease 2019 (COVID-19) for more information.
The presence or absence and timing of risk factors relative to the diagnosis of DVT has a major impact
on determining the duration of anticoagulant therapy.[13] The International Society on Thrombosis and
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 22, 2021.
Haemostasis has published a 4-category system of classification (presented in order of increasing risk of
recurrent venous thromboembolism after an initial episode), which is consistent with American College of
Chest Physicians and National Institute for Health and Clinical Excellence (UK) guidance:[14] [15] [16]
THEORY
• Major transient risk factors (e.g., surgery lasting >60 minutes), occurring within 3 months prior to
thrombosis
• Minor transient risk factors (e.g., oral contraceptives, medical hospitalisation), occurring within 2
months prior to thrombosis
• Unprovoked (no identifiable risk factor)
• Persistent risk factors (e.g., active cancer).
The American Society of Hematology and the European Society of Cardiology guidelines employ a similar
framework, with some differences in terminology.[17] [18] [19]
Pathophysiology
Most blood clots that develop in the deep venous system of the leg begin to form just above and behind a
venous valve.[20] [21]
Clots often resolve spontaneously. When propagation of the thrombus does occur, it expands and grows
proximally and across the lumen of the vein. A clot might occlude the entire lumen, but it is more commonly
located on one peripheral aspect of the lumen. Even when the entire lumen appears to be occluded, a
small amount of flow may continue on the extreme periphery of the clot. Many DVTs arise in the calf veins
and propagate proximally. However, in some instances, such as during pregnancy or following total hip
arthroplasty, the clot might form initially in the groin or iliac vein region.[21] These DVTs may propagate into
the more distal veins. DVTs may arise in more than one separated venous segment at the same time.
Acute thrombus begins to be dissolved by the body's fibrinolytic system as soon as a clot begins to form.
Thus, elevated levels of breakdown products of cross-linked fibrin, particularly the fragment called D-
dimer, appear in the blood soon after a clot begins to form. Therefore, testing for D-dimer is an important
component of the evidence-based approach to diagnosing suspected DVT.[22] [23]
Classification
DVT: lower extremity
The following is an informal clinical classification.
(a) Superficial versus deep
• Superficial vein thrombosis (SVT)
• Palpable thrombi in subcutaneous veins just below the skin (e.g., in a varicose vein) are
classified as SVT; also referred to as superficial thrombophlebitis.
• Most SVT confer less risk of complications than DVT and are managed differently. However,
thrombi in the proximal portion of the greater saphenous vein (especially if within a few
centimetres of the sapheno-femoral junction) may pose some risk of propagation and pulmonary
5
embolisation because the greater saphenous vein joins the common femoral vein in the groin.
SVT in the proximal greater saphenous vein are often managed in the same way as DVT.
• Deep vein thrombosis
THEORY
• Thrombi form within veins deep to the muscular tissue planes.
(b) Proximal versus distal
• Proximal venous thrombosis
• DVTs in the popliteal or more proximal (femoral, deep femoral, common femoral, iliac, and vena
cava) deep veins are classified as proximal.
• Distal or calf vein thrombosis
• DVTs in the three major axial calf veins (posterior tibial, anterior tibial, peroneal) below
the popliteal vein and clots in the muscular vein branches (gastrocnemius and soleus) are
considered distal deep calf vein thrombi. Some people may have anatomical variation of the
distal deep veins, including paired peroneal veins, or a tibial-peroneal trunk rather than an
immediate trifurcation distal to the popliteal vein. Thrombi in these areas are also distal DVTs.
DVT isolated to the distal veins have a lower risk of causing pulmonary embolism and post-
thrombotic syndrome, and are sometimes managed differently than proximal DVT.
(c) Acute versus subacute, or chronic
• Acute venous thrombosis confirmed by duplex ultrasound has the following characteristics: vein width
at site of the thrombus is wider than the unaffected vein on the contralateral side (i.e., dilated vessel),
and ultrasound echos are not prominent (i.e., the clot is not echogenic). Acute DVT often correlates
with recent onset of symptoms. Acute clots may totally or partially obstruct flow.
• Subacute or chronic DVTs are associated with some narrowing of the vein, partial but incomplete
compressibility of the vessel, and hyperechogenicity in the vein lumen. The involved vein is normal-
sized or contracted. Chronic clots may totally or partially obstruct flow. Chronic DVT can occur with or
without anticoagulant treatment in symptomatic or asymptomatic DVT.
• The time over which an acute DVT takes on subacute or chronic characteristics on ultrasound has not
been well validated, and likely varies between people. Distinguishing a new acute DVT from a prior
DVT is best accomplished by direct comparison with prior imaging studies.
DVT: upper extremity

The following is an informal clinical classification.
(a) Superficial versus deep thrombosis
• Thrombi in subcutaneous veins just below the skin that are palpable on the forearm or upper arm (i.e.,
basilic and cephalic veins) are classified as superficial.
• Brachial, axillary, subclavian, or innominate (or brachiocephalic) veins, and the superior vena cava are
classified as deep. The internal jugular vein is also considered to be a deep vein.
(b) Proximal versus distal
• The distinction of proximal versus distal DVT is not clearly defined for the upper extremity.
Management studies of upper extremity DVT have often included cases involving the axillary and more
proximal veins. The risk of embolisation, and management of DVT in the brachial vein, is less certain.
(c) Acute versus subacute, or chronic
THEORY
• Criteria are similar to lower-extremity venous thrombosis. However, inability to compress the
subclavian and other centrally located veins makes diagnosis and classification more difficult.
Case history
Case history #1
A 65-year-old woman presents with unilateral leg pain and swelling of 5 days' duration. There is a history
of hypertension, congestive heart failure, and recent hospitalisation for pneumonia. She had been
recuperating at home but on beginning to walk, her right leg became painful, tender, and swollen. On
examination, there is pitting oedema on the right and the right calf is 4 cm greater in circumference than
the left when measured 10 cm below the tibial tuberosity. Superficial veins on the right foot are more
dilated than on the left and easily visible. The right leg is slightly redder than the left. There is tenderness
on palpation in the popliteal fossa behind the right knee.
Other presentations
Other presentations include symptoms of shortness of breath, chest pain, and dyspnoea combined with
leg pain and swelling. Pulmonary embolism should be considered in any patient with an acute DVT and
respiratory symptoms. In severe DVT, massive swelling can obstruct superficial venous return as well
as arterial inflow, leading to a condition known as phlegmasia cerulea dolens. Here, the leg is not only
severely swollen and painful, but also appears ischaemic. Most patients who present with superficial
venous thrombosis (SVT) have a tender palpable cord under the skin. However, it should be appreciated
that about one quarter of patients with signs and symptoms of SVT on examination will also be found to
have DVT when ultrasound is performed.
7
Deep vein thrombosis Diagnosis
Approach
Contemporary management of DVT is based on an algorithmic diagnostic approach. History and physical
examination are relatively insensitive and non-specific, so must be combined with other diagnostic tests in
the clinical decision-making process. Confirmation of the diagnosis requires documentation of a blood clot
in a deep vein in the leg, pelvis, or vena cava by an imaging study (duplex ultrasound or a vascular contrast
study such as a computed tomographic [CT] venography). However, suspected DVT can often be excluded
without an imaging test, avoiding the expense (and the risks of radiation and contrast of venography).
Therefore, the first step in making the diagnosis of DVT is to establish the probability that a DVT is present
using a risk assessment model such as one based on the Wells' score in combination with a D-dimer
level. Using this approach, more than one third of patients suspected of DVT can have the diagnosis safely
excluded without imaging.[88]
History
Key information includes the presence or absence of a prior history of DVT or pulmonary embolism (PE)
as well as recent exposure to any of the common provoking risk factors (see the Risk factors section).
The patient may report symptoms of calf swelling (or, more rarely, swelling of the entire leg), localised
pain along the deep venous system, oedema, or dilated superficial veins over the foot and leg. Symptoms
range from severe to very subtle, and patients can be asymptomatic.
Signs and physical examination

Unilateral leg swelling can be assessed by measuring the circumference of the leg 10 cm below the tibial
tuberosity. Any difference between the symptomatic and asymptomatic leg increases the probability of
DVT, and a difference of >3 cm between the extremities further increases the probability.
There may be oedema and dilated collateral superficial veins on the affected side. Tenderness along the
path of the deep veins (posterior calf compression, compression of the popliteal fossa, and compression
along the inner anterior thigh from the groin to the adductor canal) might be present.
DIAGNOSIS
Two physical examination manoeuvres that have been taught historically – tenderness with dorsiflexion of
the foot (Homans' sign) or calf pain on palpation (Pratt's sign) – may be present; however, they have poor
sensitivity and specificity, and are not a component of current risk assessment models.[89]
With a high burden of thrombosis, especially in the iliac and femoral veins, the swelling can obstruct deep
and superficial venous outflow as well as arterial inflow, leading to phlegmasia cerulea dolens. Here, the
leg is swollen and painful and appears ischaemic.
The signs of DVT are not specific and may also occur in other conditions, such as large or ruptured
popliteal cyst (Baker's cyst), cellulitis, and musculoskleletal trauma or injury (calf bleeding or haematoma,
ruptured Achilles' tendon, or ruptured plantaris tendon).[90] In many patients, the diagnosis of cellulitis or
a musculoskeletal injury is straightforward, but DVT may co-exist with these conditions.
Pretest probability (Wells' score)

There are a number of risk assessment models available to assess the clinical probability of DVT;
however, the Wells' score provides a method to determine the clinical probability of DVT and is the most
widely accepted pretest probability tool used in diagnostic algorithms for DVT.[91] [92]
DIAGNOSIS
Wells' Score
Mazzolai L, et al. Diagnosis and management of acute deep
vein thrombosis. Eur Heart J. 2018 Dec 14;39(47):4208-18
Quantitative D-dimer level

D-dimer level is indicated in all patients with a Wells' score of <2. D-dimer is a breakdown product of
cross-linked fibrin; hence, if there is an acute clot, D-dimer level is likely to be elevated. A quantitative or
highly sensitive D-dimer test is therefore a useful test to exclude the presence of an acute DVT. However,
an elevated D-dimer level is non-specific and is frequently abnormal in patients who are older, are acutely
ill, have underlying hepatic disease, have an infection, or are pregnant. There are many tests available
for D-dimer, but the best are highly sensitive enzyme-linked immunosorbent assay tests. Each of the
multiple tests that are available on the market has its own normal cut-off value. D-dimer can be reported
in different units, so the specific cut-off value for the test being used should be noted.[93]
A normal value excludes the diagnosis of DVT in a patient who has a low clinical probability of having
DVT (i.e., a Wells' score of <2). This high negative predictive value is useful to reduce the need for further
9
wasteful imaging or immediate anticoagulation with its associated risks. An elevated, abnormal D-dimer
test, when combined with a low clinical probability for DVT, should prompt the clinician to proceed with
imaging.
Regardless of the patient group, D-dimer has a low positive predictive value. Approaches to mitigate
the low specificity of D-dimer have included adjusting the cut-off value based on the patient’s age
(e.g., age [years] × 10 micrograms/L [using D-dimer assays with a cut-off of 500 micrograms/L] in
patients >50 years old) or by the pretest probability of DVT (if using a risk assessment model with three
categories).[94] [95]
Venous duplex ultrasound (DUS)

Venous DUS is the first-line test recommended in all patients with a Wells' score of 2 or more, or in
patients with a Wells' score <2 who have an elevated D-dimer level. Diagnosis of an acute clot is based
on the inability to completely collapse the walls of the vein in the transverse plane by pressing down on
the vein with a transducer probe (the presence of thrombus prevents compression).
DIAGNOSIS
Short-axis ultrasound view showing the femoral vein and profunda femoris vein
adjacent to the femoral artery before compression (left) and compressed (right)
From the collection of Jeffrey W. Olin; used with permission
There are two well-validated techniques to perform venous ultrasound of the leg. Whole-leg ultrasound
assesses the veins of both the upper leg and calf. It takes longer to perform, is technically more
demanding, and identifies calf-vein DVT, which might resolve without treatment (thus can lead to over-
diagnosis and potentially over-treatment with anticoagulation, subjecting the patient to possible bleeding
complications). However, it is able to reach a diagnostic conclusion in a single session. Proximal DUS
assesses only the veins above the calf. While faster and simpler, if negative, it must be repeated 5 to 7
days later to exclude any undetected calf-vein DVTs that have propagated proximally.
The subsequent rate of VTE following a negative diagnostic evaluation does not appear to meaningfully
differ between whole-leg ultrasound and serial proximal ultrasound.[96]
Diagnostic algorithm for DVT
At the present time, the best way to exclude a DVT is by establishing that the clinical probability of DVT
is low combined with a normal D-dimer level using a highly sensitive test. A single negative whole-leg
ultrasound or two negative proximal DUS safely exclude the diagnosis if D-dimer is elevated, or the Wells'
score is ≥2. Imaging confirms the diagnosis of DVT.
DIAGNOSIS
Algorithm for the diagnosis of deep vein thrombosis
Created by the BMJ Knowledge Centre
Other tests
Other laboratory tests are seldom of any value in the diagnosis of an acute DVT. Occasionally, laboratory
tests may point to an underlying cause of a newly diagnosed DVT, such as abnormalities suggesting the
presence of a malignancy (e.g., anaemia or leucopenia on full blood count). A high platelet count may
suggest essential thrombocytosis or a myeloproliferative disorder. Baseline platelet count, activated partial
thromboplastin time, international normalised ratio, urea, and creatinine are important before commencing
anticoagulation, depending upon the anticoagulant agent chosen for therapy. Liver function tests may
detect abnormalities, precluding the use of certain anticoagulants because some are not approved in
varying degrees of hepatic dysfunction.
Colour flow Doppler and pulse-wave are sometimes done in conjunction with B-mode image
ultrasonography. Findings can include reduced or absent spontaneous flow, lack of respiratory variation,
intraluminal echoes, or colour flow patency abnormalities. A curvilinear probe may be used to attempt
11
to visualise the iliac veins, but this modality does not allow for compression. The absence of respiratory
variations on pulse-wave Doppler raises the suspicion of a proximal venous obstruction. It has low
sensitivity (75%) and medium specificity (85%).[97] [98] CT with contrast (CT venography) may be more
accurate than ultrasound at detecting thrombosis in larger veins of the abdomen and pelvis, and may be
utilised when more proximal thrombosis is clinically suspected or suggested by flow patterns on Doppler
ultrasound.[97]
Pregnancy
Clinical suspicion of DVT in pregnant women is challenging due to the overlap of symptoms associated
with pregnancy and thrombosis. Furthermore, there is a higher prevalence of iliac vein thrombosis
in pregnant compared with non-pregnant patients that can render an accurate diagnosis even more
challenging.[99] The D-dimer assay plays a limited role in pregnancy due to its natural rise with each
trimester.[100] However, a negative D-dimer test may be useful in ruling out a diagnosis of DVT in these
patients.[101] The Wells' score has not been validated in the pregnant population and, therefore, should
not be routinely used to risk stratify a pregnant patient with a suspected DVT. A clinical prediction rule,
termed the LEFt score, has been developed specifically for the pregnant population. This rule has yet
to be rigorously validated and should not be used routinely.[102] The correct diagnosis will thus rely
on a high index of suspicion and close follow-up. Venous DUS remains the initial test of choice for a
pregnant woman suspected of having a DVT. Several studies investigating the role of a single, whole-leg
ultrasound or serial, proximal compression ultrasonography for the diagnosis of DVT have been pooled
in a meta-analysis.[103] [104] [105] [106] [107] The false-negative rate of this approach is low, but the
absolute number of patients enrolled in trials is modest. Due to a higher prevalence of isolated, pelvic vein
thrombi in these patients, guidelines also recommend a low threshold to obtain additional imaging (such
as an iliac vein ultrasound or abdominal magnetic resonance venography) in patients with a suspected
abdominal/pelvic vein thrombosis (i.e., swelling of the entire leg, buttock, or back pain).[23]
Tests for underlying conditions

In a patient with objectively documented DVT, it is important to stratify the patient as having either a
provoked (secondary to known, identified risk factors) or an unprovoked (idiopathic, thus no known risk
DIAGNOSIS
factor identified) DVT. Patients with an unprovoked DVT present with no clear history of a provocation
(e.g., major leg trauma, recent surgery, active cancer, recent immobilisation). It is easier to define a
provoked DVT as a number of risk factors are known and widely used to define a provocation. Strong and
weak risk factors (provocations) for DVT are detailed in the Risk factors section.
Occult cancer is present in approximately 3% to 5% of patients with an unprovoked DVT.[108] However,

extensive investigations (beyond routine laboratory tests and age-appropriate routine screening) for
cancer in patients with a first unprovoked DVT are not routinely indicated, because they have not been
shown to improve prognosis or mortality.[109] [110] [111] Signs or symptoms that suggest a possible
malignancy should be pursued, if present.
Thrombophilia commonly refers to five hereditary conditions (factor V Leiden, prothrombin gene 20210A,
deficiencies in antithrombin, protein C deficiency, and protein S deficiency), and antiphospholipid
syndrome (an acquired condition). However, many gene variants and acquired conditions modify
thrombosis risk.[112] Indications for screening are controversial.[112] [113] Hereditary thrombophilia
does not sufficiently modify the predicted risk of recurrent thrombosis to affect treatment decisions, and
a conservative approach to testing is reasonable.[15] Some guidelines suggest testing only in situations
where the result is likely to change a clinical decision (such as in patients with unprovoked DVT who are
considering stopping anticoagulants).[114] However, the presence of a hereditary thrombophilia does not
significantly increase the predicted risk of recurrent VTE after a provoked DVT, and guidelines discourage
testing in this setting.[115]
Antiphospholipid antibodies may predict a higher risk of future thrombosis following an initial VTE event,
and may impact selection of anticoagulant therapy.[116] It is controversial whether broad screening,
or screening only on the basis of clinical suspicion, is preferred.[117] [118] Some guidelines suggest
testing only in situations where the result is likely to change a clinical decision (such as in patients with
unprovoked DVT who are considering stopping anticoagulants).[114]
Screening is not indicated in all cases of incident venous thromboembolic events; however, it may be
useful if the site of thrombus is unusual, if there is a large clot burden, or if there are recurrent events.
If a hereditary thrombophilia screen is indicated, it should be deferred until a minimum of 3 months of
anticoagulant therapy has been completed because some thrombophilia tests are influenced by the
presence of acute thrombosis or anticoagulant therapy.[119] For antiphospholipid antibody screening,
cardiolipin and beta-2 glycoprotein-I antibodies can be performed without regard to the presence of
anticoagulants, but most anticoagulants interfere with assays for lupus anticoagulant.[116]
Suspected PE
In patients with documented DVT who will be, or are being, treated in a standard fashion with heparin or
low molecular weight heparin followed by warfarin or with a direct oral anticoagulant such as apixaban,
rivaroxaban, edoxaban, or dabigatran for a total duration of at least 3 months, documenting the presence
of PE is not routinely indicated. However, tests for PE should be considered if there are clinical signs or
symptoms that raise the possibility of PE and there is clinically important cardiopulmonary compromise,
including hypotension, syncope, symptoms of right heart failure, or worsening hypoxia, as additional
therapies (e.g., reperfusion therapies) might be indicated.
The most common tests to diagnose PE are rapid-sequence CT pulmonary angiography or ventilation/
perfusion lung scanning. The latter is most often used in patients with renal impairment or allergy to
iodinated contrast.
DIAGNOSIS
See our topic Pulmonary embolism for detailed information regarding diagnosis and management.
History and exam

Key diagnostic factors
calf swelling (uncommon)
• Unilateral leg and thigh swelling can be assessed by measuring the circumference of the leg 10 cm
below the tibial tuberosity. If there is a difference in circumference, especially of >3 cm between the
extremities, DVT is more likely.
localised pain along deep venous system (uncommon)

• Localised pain can be assessed by gently palpating along the path of the deep venous system from
groin to adductor canal and in the popliteal fossa.
13
Other diagnostic factors

asymmetric oedema (common)
• Presence of oedema worse on leg with suspected DVT.
prominent superficial veins (common)

• Dilated superficial veins over foot and leg (not varicose veins) are a sign of DVT.
swelling of the entire leg (uncommon)

• Increases pretest probability of diagnosis of DVT.
phlegmasia cerulea dolens (uncommon)

• When DVT is massive, the swelling can obstruct not only venous outflow but arterial inflow, leading to
phlegmasia cerulea dolens due to ischaemia. Here, the leg is usually blue and painful.
Risk factors
Strong
major surgery within the preceding 3 months
• Approximately 18% of all incident venous thromboembolism occurs within 3 months of major surgery.
Reasons include postoperative immobilisation, inflammation, underlying comorbidity, and injury to the
venous system in selected cases (e.g., total knee replacement).[3]
medical hospitalisation within the preceding 2 months

• Approximately 20% of all incident venous thromboembolism (VTE) occurs either during a medical
hospitalisation or within 2 months of a hospitalisation of 4 or more days.[1] [2]
• Reasons are the combination of immobilisation with acute and chronic medical comorbidities that are
associated with VTE development, such as acute infection, heart failure, stroke, respiratory failure, and
DIAGNOSIS
inflammatory conditions.[24] [25] [26] [27] The use of intravenous catheters predisposes to hospital-
associated DVT, both in the upper and lower extremities.[28]
active cancer
• Many malignancies increase the risk for thrombosis through a variety of mechanisms, including
activation of the coagulation system and restriction of flow due to vein compression. DVT rates are
likely to be 4- to 7.5-fold higher in patients with cancer than in the general population,[29] and patients
with metastatic cancer at the time of diagnosis are at especially increased risk.[30] Cancer-related
therapies including surgery, some chemotherapeutic and biological agents, and use of vascular
access devices also increase the risk of DVT.
previous venous thromboembolic event

• Previous venous thromboembolism predicts the risk for future events, with the magnitude of the risk
being dependent on the presence or absence of provoking factors at the time of the initial event, sex
of the patient, and other factors. Recurrence risk may be as high as 15% per year or more in some
patients.[15]
recent trauma or fracture
• Patients with severe trauma are at increased risk of DVT even when the lower extremities are not
involved.[31] [32]
• Patients with lower-extremity injuries that require surgery, such as leg, femur, or hip fracture, are at
particularly increased risk, owing to vein injury coupled with effects of immobilisation and surgery.[33]
• Non-surgical injuries (e.g., a fracture that requires casting) also increases the risk.
increasing age
• The risk of venous thromboembolism, especially of a first episode, increases exponentially with age.[1]
[3] [34] Reasons likely include increased medical comorbidities, declining mobility, and perhaps age-
related changes in coagulation.
pregnancy and the postnatal period

• There is a more than 4-fold increased risk of thrombosis throughout gestation, and this risk may
increase during the postnatal period.[35] [36] [37] While the relative risk for DVT during pregnancy and
the postnatal period is substantially elevated, the absolute risk remains low.
paralysis of the lower extremities

• Venous stasis and prolonged bed rest are known to increase the risk of venous thromboembolism.[38]
factor V Leiden
• The factor V Leiden (FVL) mutation creates a variant factor V that is resistant to activated protein C.
The relative risk of developing venous thromboembolism (VTE; particularly DVT) is approximately 3
to 4 times greater in patients who carry 1 copy of the FVL mutation (heterozygotes) compared with
patients without this mutation. However, the absolute lifetime risk of developing VTE is low.
• There is a strong interaction between use of oral contraceptives or hormone replacement therapy
containing oestrogen and presence of FVL, likely because oestrogen also confers resistance to
activated protein C. The relative risk increase of VTE is approximately 12-fold that of a non-carrier who
does not use oestrogen.[39]
DIAGNOSIS
• Homozygous carriers have a substantially higher risk of developing VTE compared with heterozygotes.
• FVL carriers appear to have increased risk for DVT only, not for pulmonary embolism, an observation
called the 'factor V Leiden paradox'.[40]
• While predictive of an initial VTE event, the presence of hereditary thrombophilia carries little risk
prediction for recurrent VTE and is not considered an important factor in determining whether a patient
should continue anticoagulation for secondary prevention following the initial course of treatment.[15]
Guidelines recommend against testing for hereditary thrombophilia in the presence of a strong
transient risk factor (such as preceding surgery.[41]
prothrombin gene G20210A mutation

• The prothrombin gene mutation is caused by a single nucleotide polymorphism (G20210A).
Affected patients produce an excess amount of prothrombin. The relative risk of developing venous
thromboembolism (VTE) is approximately 4 times greater than the unaffected population, but the
absolute risk of thrombosis remains low.
• There is a strong interaction between use of oral contraceptives or hormone replacement therapy
containing oestrogen and presence of the prothrombin variant, with an approximately 7-fold increase in
the risk of VTE.[39]
15
• Homozygous carriers of the prothrombin gene mutation have substantially greater risk of developing
VTE compared with heterozygotes.
protein C or protein S deficiency

• Patients with a well-defined deficiency in protein C or protein S have a 5- to 6-fold greater risk of
developing venous thromboembolic events, although the magnitude of this risk varies according
to the degree of functional loss present.[39] The absolute risk of first pregnancy-associated
venous thromboembolism (VTE) is 7.8% in protein C-deficient women and 4.8% in protein S-
deficient women.[42] Thrombosis risk increases in a multiplicative fashion in the presence of other
thrombophilic disorders. Both disorders are rare.
antithrombin deficiency
• The prevalence of antithrombin deficiency disorders is low in cohorts of patients with venous
thromboembolism (VTE; <1%). The magnitude of thrombosis risk varies depending on the degree of
functional loss present. The absolute risk of first pregnancy-associated VTE in antithrombin-deficient
women is 16.6%.[43]
DIAGNOSIS
antiphospholipid antibody syndrome

• Defined as an association of persistently detectable antiphospholipid antibodies with specified clinical
features consisting of thrombosis and/or pregnancy-related morbidity, antiphospholipid antibody
syndrome is often over-diagnosed, likely due to the relatively complex criteria for diagnosis and the
possibility of false-positive laboratory tests. Criteria have been updated and clarified.[44]
• In contrast to the hereditary thrombophilias, antiphospholipid syndrome likely predicts a higher risk for
both initial and recurrent venous thromboembolism (VTE), and may be useful in informing decisions
regarding use of anticoagulation for secondary prevention after the initial treatment of a VTE event.[45]
Antiphospholipid antibodies have been reported in up to 14% of patients presenting with a VTE.[46]
medical comorbidity
• Underlying mechanisms vary with the type of comorbidity, but there is usually vascular inflammation or
stasis, alone or in combination.
• Increased venous thromboembolism risk occurs especially with inflammation, infection, and immobility.
• Case reports and small series show greater incidence in patients with sickle cell anaemia,
inflammatory bowel disease, Behcet's disease, HIV, primary pulmonary hypertension, hyperlipidaemia,
diabetes mellitus, myeloproliferative diseases, and others, including systemic lupus erythematosus.[47]
• Several medical disorders, especially heart failure, respiratory disease, acute ischaemic stroke, and
acute infections, are associated with hospital-acquired DVT, though the incidence of DVT continues to
accumulate for about 2 months after hospital admission.[24] [25] [26] [27]
• Liver disease, even when causing prolongation of coagulation times, increases the risk for
thrombosis.[48]
• Mechanical ventilation has been associated with increased DVT in many studies of critically ill patients,
though may be a marker of disease severity and underlying respiratory disease.[8] [49] [50]
• Coronavirus disease 2019 (COVID-19), an infection caused by the novel coronavirus severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with risk for VTE, though the
risk for PE may predominate over the risk for DVT.[51]
use of specific drugs

• The absolute risk of developing a DVT in women who take oestrogen-containing oral contraceptives
is low. The risk of developing an oral contraceptive-related DVT is associated with the presence of a
classic thrombophilia and is also associated with obesity and smoking. Risk is greatest in the first year
of use.
• For contraceptives, all preparations that contain oestrogen are associated with risk for venous
thromboembolism (VTE). Mechanism of delivery (oral, transdermal, transvaginal) and the 'generation'
of oral combined contraceptives are associated with broadly similar risks.[52] [53] However, oral
contraceptive pills containing third-generation progestins (such as desogestrel) or fourth-generation
progestins (such as drospirenone) may be associated with greater risk of VTE compared with
levonorgestrel.[54] [55] When used for the indication of hormone replacement, the transdermal route
appears to confer less risk than the oral route.[52] [53]
• Tamoxifen and raloxifen are associated with a 2- to 3-fold relative risk of developing DVT, particularly in
patients with a thrombophilic condition, such as factor V Leiden.
• Thalidomide most commonly causes DVT when used as a cancer chemotherapeutic agent. Many
other chemotherapeutic agents can also increase the risk. Concomitant prophylaxis is suggested for
DIAGNOSIS
certain diseases and regimens.[56]
• Erythropoietin is associated with an increased risk of DVT in cancer patients.
• Patients who develop antibodies to adalimumab (a tumour necrosis factor alpha inhibitor) frequently
develop venous thrombosis.[57]
• Androgen-deprivation therapies used in prostate cancer increase VTE risk between about 1.5- and
2.5-fold depending upon the agent.[58]
• Testosterone replacement therapy, both in men with and without demonstrable hypogonadism, has
been associated with a 2-fold increased VTE risk.[59]
• Non-steroidal anti-inflammatory drugs (NSAIDs), as a class, are associated with an increased rate of
VTE. Risk attributable to individual NSAIDs is unknown.[60] [61]
Weak
obesity
• Randomised clinical trials and retrospective cohort studies have shown that high body mass index
(especially >30 kg/m²) is associated significantly with DVT development.[34] [62]
17
• Mechanisms may include relative immobilisation, reduced venous flow rates, underlying inflammatory
state, and greater frequency of co-existing comorbidities.
cigaret te smoking
• The Emerging Risk Factors Collaboration (ERFC; 731,728 participants) found a correlation between
current smoking and the risk of VTE, with a hazard ratio of 1.38.[34]
recent long-distance air travel

• The absolute risk with air travel appears to be small. The risk appears to be increased in patients
with an elevated baseline risk of venous thromboembolism (VTE) such as those with a previous
VTE, recent surgery or trauma, obesity, limited mobility, or advanced age. The duration of flight
associated with increased risk is uncertain, but flights longer than about 4 hours are likely associated
with elevated risk.[63]
family history
• Family history of DVT or pulmonary embolism may increase the risk.[62] The strength of
the association varies dependent on the number of affected family members and degree of
relatedness.[64]
central venous catheterisation

• Studies of cancer patients have estimated the overall rate of catheter-related thrombosis to be between
14% and 18%.[65]
• Among non-metastatic invasive breast cancer patients, an incidence rate of 2.18/100 patient-months
has been reported for central venous catheter-related venous thromboembolism (VTE).[66]
• Central venous catheters are also associated with VTE in non-cancer patients. VTE is increased in
intensive care unit patients with central venous catheters and the risk is further increased with multiple
catheters.[67] Different types of central venous catheters, catheter size, and location of placement
affect the risk of catheter-associated VTE.[28]
DIAGNOSIS
Investigations
1st test to order
Test Result
Wells' score score ≥2: DVT likely
(proceed to imaging);
• Not a definitive test but should be determined in all patients with
score <2: DVT unlikely
suspected DVT. Wells' score provides a method to determine the
(proceed to D-dimer)
clinical probability of DVT and is the most widely accepted pretest
probability tool used in diagnostic algorithms for DVT.[91] [92] If
the Wells' score is 2 or greater, condition is likely (absolute risk is
approximately 40%).[91] [92] People with a score of <2 are unlikely to
have a DVT (probability <15%).[91] [92]
• The criteria are as follows:
• Active cancer (any treatment within past 6 months): 1 point
• Calf swelling where affected calf circumference measures >3 cm
more than the other calf (measured 10 cm below tibial tuberosity): 1
point
• Prominent superficial veins (non-varicose): 1 point
• Pitting oedema (confined to symptomatic leg): 1 point
• Swelling of entire leg: 1 point
• Localised pain along distribution of deep venous system: 1 point
• Paralysis, paresis, or recent cast immobilisation of lower extremities:
1 point
• Recent bed rest for >3 days or major surgery requiring regional or
general anaesthetic within past 12 weeks: 1 point
• Previous history of DVT or pulmonary embolism: 1 point
• Alternative diagnosis at least as probable: subtract 2 points.
• This test has not been validated in the pregnant population and,
therefore, should not be routinely used to risk stratify a pregnant
woman with a suspected DVT. A clinical prediction rule, termed
the LEFt score, has been developed specifically for the pregnant
population; however, this rule has yet to be rigorously validated and
should also not be used routinely.[102]
DIAGNOSIS
quantitative D-dimer level normal (DVT excluded if
Wells' score <2); elevated
• Indicated if the pretest probability of DVT is classified as unlikely
(proceed to imaging)
(Wells' score <2). If the D-dimer is normal, DVT is excluded in low-
probability patients.[120] If elevated, a venous duplex ultrasound is
indicated for further investigation.
• In outpatients with suspected venous thromboembolic event, point-
of-care tests can contribute important information and guide patient
management in patients with a low-probability score on a clinical
decision rule.[121] For example, a negative test excludes DVT when
the pretest probability is low.
• Not a definitive test. Elevated levels are highly sensitive but non-
specific.[91] [122] [123] It is frequently abnormal in patients who
are older, are acutely ill, have underlying hepatic disease, have an
infection, or are pregnant.
• Regardless of the patient group, D-dimer has a low positive predictive
value. Approaches to mitigate the low specificity of D-dimer have
included adjusting the cut-off value based on the patient’s age (e.g.,
age [years] × 10 micrograms/L [using D-dimer assays with a cut-
off of 500 micrograms/L] in patients >50 years old) or by the pretest
probability of DVT (if using a risk assessment model with three
categories).[94]
19
Test Result
• The D-dimer assay plays a limited role in pregnancy due to its natural
rise with each trimester.[100] However, a negative D-dimer test may
be useful in ruling out a diagnosis of DVT in these patients.[101]
proximal duplex ultrasound abnormal: inability to
fully compress lumen of
• Assesses venous flow by the use of Doppler and vein compression.
• First-line test in all high-probability patients (Wells' score of 2 or more) vein using ultrasound
transducer; normal:
or in low-probability patients (Wells' score <2) with an elevated D-
all vein segments fully
dimer level to assess popliteal, deep femoral, femoral, and common
compressible, non-
femoral veins.[98]
diagnostic
Short-axis ultrasound view showing the femoral vein

and profunda femoris vein adjacent to the femoral
artery before compression (left) and compressed (right)
• High sensitivity and specificity of over 95%.[124] Venous ultrasound
has a high sensitivity because: 1) deep veins in the lower extremities
are easily visualised; 2) it scans multiple areas, making it likely that
at least a portion of a clot is detected; and 3) compression readily
identifies intravascular thrombus.
• Ultrasound cannot provide the exact age of a vein clot, but it is better
than all current imaging techniques in differentiating acute, subacute,
chronic, and age-indeterminant venous thrombi.
DIAGNOSIS
• In high-probability patients, a repeat ultrasound is indicated in 5 to 7

days if the initial ultrasound test is normal.
• In low-probability patients, a repeat ultrasound is indicated in 5 to 7
days if D-dimer level is elevated and initial ultrasound is normal.
• Ultrasound testing can be limited to only the proximal deep venous
system, so long as patients with a positive D-dimer or high probability
and who have an initially normal proximal ultrasound undergo a
repeat ultrasound in 5 to 7 days.[96] A serial ultrasound strategy may
be necessary to exclude proximal extension of the thrombus into the
popliteal veins or beyond.
• The subsequent rate of venous thromboembolism following a
negative diagnostic evaluation does not appear to meaningfully differ
between whole-leg ultrasound and serial proximal ultrasound.[96]
• The initial test of choice for a pregnant woman suspected of having a
DVT. The American College of Chest Physicians advocates the use
of serial, proximal ultrasonography if a DVT is suspected in pregnant
women.[23]
whole-leg ultrasound abnormal: inability to
fully compress lumen of
• Assesses venous flow by the use of Doppler and vein compression.
vein using ultrasound
transducer, reduced or
Test Result
• First-line test in all high-probability patients (Wells' score ≥2) or in absent spontaneous
low-probability patients (Wells' score <2) with an elevated D-dimer flow, lack of respiratory
level to assess the deep veins of the entire leg (including the calf). variation, intraluminal
echoes, colour flow
patency abnormalities;
normal: all vein segments
fully compressible, non-
diagnostic
Short-axis ultrasound view showing the femoral vein

and profunda femoris vein adjacent to the femoral
artery before compression (left) and compressed (right)
• High sensitivity and specificity of over 95%.[124] Venous ultrasound
has a high sensitivity because: 1) deep veins in the lower extremities
are easily visualised; 2) it scans multiple areas, making it likely that
at least a portion of a clot is detected; and 3) compression readily
identifies intravascular thrombus. Sensitivity for DVT isolated to the
calf veins is lower than for proximal DVT.
• Nonetheless, management studies based on a single, negative
whole-leg ultrasound reveal very low rates of subsequent venous
thromboembolism (VTE) when treatment is withheld.[125]
• Ultrasound cannot provide the exact age of a vein clot, but it is better
than all current imaging techniques in differentiating acute, subacute,
chronic, and age-indeterminate venous thrombi.
• Whole-leg ultrasound does not require repetition if negative and of
good quality. However, it identifies calf-vein DVT, some of which may
not benefit from treatment.
DIAGNOSIS
• The subsequent rate of VTE following a negative diagnostic
evaluation does not appear to meaningfully differ between whole-leg
ultrasound and serial proximal ultrasound.[96]
• The initial test of choice for a pregnant woman suspected of having a
DVT. The American College of Chest Physicians advocates the use
of serial, proximal ultrasonography if a DVT is suspected in pregnant
women.[23] A few small studies have investigated the role of a single,
whole-leg ultrasound or serial, proximal compression ultrasonography
for the diagnosis of DVT.[103] [104] [105] [106]
INR and activated partial thromboplastin time (aPTT) baseline values
• INR is required before starting warfarin and aPTT is required before
starting intravenous heparin.
urea and creatinine baseline values
• Doses of some anticoagulants (e.g., low molecular weight heparin,
fondaparinux, apixaban, rivaroxaban, dabigatran, edoxaban) may
need to be adjusted or discontinued in patients with renal impairment,
so baseline values should be obtained.
LFTs baseline values
21
Test Result
• May detect abnormalities associated with underlying provoking factor
(e.g., cancer). Some anticoagulants are not approved for varying
degrees of hepatic dysfunction.
FBC baseline values
• A component of the assessment of bleeding risk while using
an anticoagulant. Very low values are a contraindication to
anticoagulation.
• May detect abnormalities such as underlying haematological
malignancy (e.g., anaemia, leucopenia).
• A high platelet count may suggest essential thrombocytosis or a
myeloproliferative disorder. Exceedingly low platelet count may
preclude the use of some anticoagulants.
• Heparin therapy can be associated with heparin-induced
thrombocytopenia; platelet counts should be measured at baseline
and regularly throughout treatment.
Other tests to consider
Test Result
Doppler venous flow testing reduced or absent
spontaneous flow, lack
• Colour flow Doppler and pulse-wave are sometimes done in
of respiratory variation,
conjunction with B-mode image ultrasonography. The absence of
respiratory variations on pulse-wave Doppler raises the suspicion of a intraluminal echoes,
proximal venous obstruction. or colour flow patency
abnormalities
• Low sensitivity (75%) and medium specificity (85%).[97] [98]
CT abdomen and pelvis with contrast presence of an
intraluminal filling defect
• More accurate than ultrasound for visceral veins and deep veins of
abdomen and pelvis.
• CT has a similar sensitivity and specificity to ultrasound in patients
with suspected pulmonary embolism where investigation of
suspected DVT of the legs and pelvis is required.[126]
DIAGNOSIS
thrombophilia screen positive in inherited

thrombophilias; elevated
• Hereditary thrombophilia does not sufficiently modify the predicted
titres/abnormal result
risk of recurrent thrombosis to affect treatment decisions, and a
in antiphospholipid
conservative approach to testing is reasonable.[15] Some guidelines
syndrome
suggest testing only in situations where the result is likely to change
a clinical decision (such as in patients with unprovoked DVT who are
considering stopping anticoagulants).[114]
• It is controversial whether broad screening for antiphospholipid
antibodies, or screening only on the basis of clinical suspicion, is
preferred.[127] [128]
Differentials
Condition Differentiating signs / Differentiating tests

symptoms
Cellulitis • Patients with cellulitis usually • Leukocytosis is common,
manifest redness, heat, and with a WBC count >10 × 10⁹/
swelling in the dermis of the L (10,000 cells/microlitre).
affected leg. The affected • Fluid collection seen if
area is likely to be smaller abscess present.
than in DVT (which may • Ultrasound differentiates
involve the entire foot, calf, diagnoses.
or thigh), but the signs more
pronounced.
• The demarcation of the skin
margins affected by cellulitis
is more defined than in DVT.
• Portal of infection entry may
be identified.[129]
• Fever and prior history of
cellulitis is common.
• May occur with a concurrent
DVT.
Calf muscle tear/Achilles' • History of trauma or sudden • No DVT seen on MRI or

tendon tear onset of calf pain. ultrasound.
• Muscle tear is difficult to • Oedema associated with
differentiate from DVT on muscle tear makes it very
exam. Although defect or difficult to visualise the calf
spasm of calf muscles is veins using ultrasonography.
noted on examination, calf Furthermore, extreme
DVT may occasionally be tenderness associated
associated with spasm. with a muscle tear makes it
difficult to compress with the
ultrasound probe.
DIAGNOSIS
Calf muscle haematoma • Calf injury or sudden onset • Venous ultrasound shows no
of calf pain. There may be thrombosis, and there may
ecchymosis on the skin. be ultrasound evidence of a
• Calf haematoma, calf muscle haematoma.
tear, and calf muscle tendon
tear frequently occur in the
absence of injury or trauma.
Large or ruptured • Sudden onset of calf pain. • Ultrasound shows fluid in

popliteal cyst (Baker's • Tenderness in popliteal the soft tissues of the calf or
cyst) fossa. visualises cyst.
Pelvic/thigh mass/tumour • Oedema usually occurs • Venous ultrasound, CT scan,

compressing venous without pain in venous outlet or MRI of abdomen, pelvis,
out flow from the leg obstruction. and thigh with contrast,
• Difficult to distinguish from may show obstructing mass
iliac or caval DVT (which impinging on the femoral,
may co-exist). iliac, or vena cava vessels.
23
Criteria
Wells' score
• Active cancer (any treatment within past 6 months): 1 point
• Calf swelling where affected calf circumference measures >3 cm more than the other calf (measured
10 cm below tibial tuberosity): 1 point
• Prominent superficial veins (non-varicose): 1 point
• Pitting oedema (confined to symptomatic leg): 1 point
• Swelling of entire leg: 1 point
• Localised pain along distribution of deep venous system: 1 point
• Paralysis, paresis, or recent cast immobilisation of lower extremities: 1 point
• Recent bed rest for >3 days or major surgery requiring regional or general anaesthetic within past 12
weeks: 1 point
• Previous history of DVT or pulmonary embolism: 1 point
• Alternative diagnosis at least as probable: subtract 2 points.
If the Wells' score is 2 or greater, the condition is likely (absolute risk is approximately 40%).[91] [92] People
with a Wells' score of <2 are unlikely to have DVT (probability <15%).[91] [92]
Ultrasonography criteria
The radiologist or technician who performs lower-extremity ultrasound first locates the femoral artery and
vein in the groin region. The artery and its associated pulsatility can be identified readily; the femoral vein is
adjacent. Compression of the femoral vein using the ultrasound probe is easy. Inability to compress the vein
indicates the presence of a clot, but provides no information on the age of the clot.[130]
All of the deep veins in the leg must be identified and compressed in a deliberate and systematic fashion
(including the deep veins of the calf if whole-leg ultrasound is chosen). There must be a careful search for a
duplicated femoral vein and a duplicated popliteal vein.
DIAGNOSIS
Secondary criteria include a larger vein diameter on the affected side, and absent or scant echoes within the
clot. In acute DVT, the vein is non-compressible and dilated. In subacute DVT, the vein is non-compressible
and marginally dilated or of normal size. In chronic DVT, the affected vein is non-compressible and small.
Acute DVT is frequently easy to determine on the ultrasound, but where the vein is normal-sized or the vein
is partially compressible or partially non-compressible, it is more difficult to determine the age of the DVT. In
these cases, the DVT is referred to as age-indeterminant.
Compression ultrasound is used to assess the presence of DVT in the deep veins of the upper extremity.
Compression cannot be performed on the intrathoracic veins (subclavian and innominate veins and superior
vena cava). The presence of a DVT in these centrally located veins of the chest is suggested by the absence
of flow on colour flow Doppler and the absence of respiratory variations on pulse-wave Doppler in a more
distal vein.[131] The Wells' score does not apply to upper-extremity DVT; however, there is one prospective
management study of a risk assessment model for suspected upper-extremity DVT.[132]
Warkentin Probability Scale for heparin-induced thrombocytopenia

(HIT)[133]
The Warkentin Probability Scale for HIT (the '4T score') can be used to estimate the probability of a patient
having HIT. Points are scored (0, 1, or 2) for each of the 4 categories (maximum possible score = 8).
Thrombocytopenia
• 2 points if >50% fall in platelet count to a platelet count nadir of ≥20 × 10⁹/L (≥20,000/mm³ or 20 × 10³/
microL)
• 1 point if 30% to 50% fall in platelet count, or if the nadir is 10-19 × 10⁹/L (10-19,000/mm³ or 10-19 ×
10³/microL)
• 0 points if <30% fall in the platelet count, or if the nadir is <10 × 10⁹/L (<10,000/mm³ or 10 × 10³/
microL).
Timing* of onset of platelet fall (or other sequelae of HIT)
• 2 points if onset is 5 to 10 days after starting heparin, or <1 day if there has been recent heparin
(within past 30 days)
• 1 point if onset is more than 10 days after starting heparin or if timing unclear; or if <day 1 after starting
heparin with recent heparin (past 31-100 days)
• 0 points if onset is within 4 days of first time heparin exposure (no recent heparin).
Thrombosis or other sequelae
• 2 points if there is a proven new thrombosis, or skin necrosis, or acute systemic reaction after
intravenous unfractionated heparin bolus
• 1 point if there is progressive or recurrent thrombosis, or erythematous skin lesions, or suspected
thrombosis (not proven)
• 0 points if no thrombosis or other finding.
Other cause(s) of platelet fall
• 2 points if none evident

• 1 point if there is another possible cause
• 0 points if there is another definite cause.
Pretest probability score
DIAGNOSIS
• High = 6 to 8 points (probability of HIT approximately 50%)
• Intermediate = 4 to 5 points (probability of HIT approximately 10%)
• Low = 0 to 3 points (<1% probability of HIT).
*First day of immunising heparin exposure is considered day 0.
Screening
Ultrasound screening
Compression ultrasound looking for evidence of acute DVT is an excellent screening test in high-risk
patients, such as patients who have sustained major trauma and patients who have recently undergone total
hip or knee replacement. There is no convincing evidence, however, that screening reduces the incidence of
adverse outcomes, particularly the incidence of fatal pulmonary embolism. The overall accuracy of screening
ultrasound in asymptomatic patients is not clear but it is lower than in symptomatic patients.[124] Because
less than half of patients who develop pulmonary embolism have ultrasound evidence of DVT in the legs,
the value of detecting asymptomatic DVT in preventing pulmonary embolism is uncertain. Guidelines conflict
regarding whether screening ultrasound should be performed in hospitalised trauma patients.[134] The
American College of Chest Physicians suggests against such screening.[68]
25
Thrombophilia screening
Screening for thrombophilia in patients who have not yet had a DVT is not likely to be beneficial except in
very rare circumstances (such as a known family history of antithrombin deficiency in a woman planning
pregnancy).[135]
Cancer screening
Routine screening for cancer, apart from assuring that all age-appropriate screening has been completed,
is not currently recommended in patients with an unprovoked DVT.[109] The prevalence of occult cancer
was low among patients with a first unprovoked venous thromboembolism. Routine screening with computed
tomography of the abdomen and pelvis did not provide a clinically significant benefit.[111]
DIAGNOSIS
Deep vein thrombosis Management
Approach
Anticoagulation is the mainstay of therapy for the treatment of DVT. Patients are treated with anticoagulants
to:
• Prevent propagation/progression of the thrombus in the deep veins in the legs

• Reduce the risk of pulmonary embolism (PE)
• Reduce the risk of recurrent DVT.
Anticoagulant therapy for DVT has been described in three phases: initiation, treatment (also referred to as
'long-term'), and extended.[136] [137] [138]
• Initiation (5-21 days following diagnosis): goals of care are to arrest the active prothrombotic state and
to inhibit thrombus propagation and embolisation.
• Treatment (initiation to 3 months): goals are to prevent new thrombus while the original clot is
stabilised and intrinsic thrombolysis is under way.
• Extended (3 months to indefinite): goal is secondary prevention of new venous thromboembolism
(VTE).
The recommended treatment regimens for patients with DVT have changed rapidly as new anticoagulants
have become available. Care should be taken to minimise the risk of major haemorrhage throughout the
treatment period and monitor for the development of heparin-induced thrombocytopenia (HIT) if heparin or
low molecular weight heparin (LMWH) is used.[20] [62]
[IHI: reducing adverse drug events involving anticoagulants] (http://www.ihi.org/knowledge/pages/tools/

anticoagulanttoolkitreducingades.aspx)
Hospitalisation
Criteria for hospitalisation:
• DVT that is best treated with intravenous unfractionated heparin (UFH)

• Suspected or confirmed concomitant PE, especially with cardiopulmonary compromise
(tachycardia, tachypnoea, signs of right heart failure); in many centres, patients with PE are
hospitalised only if there is a high Pulmonary Embolism Severity Index (86 or greater)[139] [140]
[141] [142]
• DVT that will undergo interventional therapy (e.g., catheter-directed thrombolysis)
• Highly symptomatic DVT (e.g., severe pain and oedema in the presence of acute DVT requiring
inpatient analgesia)
• Inability to educate the patient adequately in the outpatient or accident and emergency department
setting regarding ongoing anticoagulant therapy
• Co-existing comorbidity requiring hospital management
• Presence of risk factors for bleeding that requires close observation in the hospital (e.g., chronic
liver disease with or without varices, recent or prior gastrointestinal bleeding, chronic renal stones
with recurrent haematuria, bleeding disorder, malignancy, recent stroke, or prior intracranial
MANAGEMENT
haemorrhage).
27
Home treatment
Most cases of DVT are amenable to treatment at home, rather than in the hospital. Patients who meet
no criteria for hospitalization can be safely treated in the home setting. Outcomes are at least as good as
those achieved with hospitalization, with lower cost and improved patient satisfaction.[143]
Initiation phase of anticoagulation (5 to 21 days)

Recommendations from the American College of Chest Physicians (ACCP) are that patients with proximal
DVT of the leg and some patients with distal DVT of the leg should generally receive anticoagulation for at
least 3 months.[15]
Proximal DVT of the leg
• For patients with a proximal DVT of the leg, anticoagulant therapy is recommended.[15]
Isolated distal DVT of the leg
• For patients with severe symptoms or risk factors for extension, anticoagulation is recommended.
Risk factors for extension include:[15]
• Positive D-dimer
• Extensive thrombosis (e.g., >5 cm long; involving multiple veins; >7 mm in maximum
diameter)
• Thrombosis close to the proximal veins
• Absence of any reversible provoking factor
• Active cancer
• Past history of VTE
• Inpatient status.
• For patients with an acute isolated distal DVT of the leg but without severe symptoms or risk
factors for extension, or with a high risk for bleeding, serial imaging of the deep veins for 2 weeks is
suggested over anticoagulation.[15] [144] Anticoagulation is given only if the thrombus propagates
on serial ultrasound examinations.
Recommendations for choice of antithrombotic therapy
• The choice of agent depends on patient factors such as hepatic function, renal function, pregnancy,
presence of cancer, obesity, concomitant medications and the ability to monitor drug-drug
interactions, and the risk of bleeding. Choice may also depend on individual physician or patient
preference or recommendations in local guidelines.
• Generally, anticoagulation with direct oral anticoagulants (DOACs) – dabigatran, rivaroxaban,
apixaban, or edoxaban – is recommended over vitamin K antagonist therapy (usually warfarin),
which is in turn recommended over LMWH. Fondaparinux is generally reserved for patients with
HIT or those with a history of this condition.
Increased risk of bleeding
MANAGEMENT
• It is preferable to treat patients who are at increased risk of bleeding (e.g., recent surgery, peptic
ulceration) with intravenous UFH initially because it has a short half-life and its effect can be
reversed quickly with protamine.[138] Once it is clear anticoagulation is tolerated, selection of an
appropriate anticoagulation regimen can take place.
Active cancer
• In patients with VTE and active cancer (cancer-associated thrombosis [CAT]) LMWH has
historically been recommended.[15] [145] [146] However, randomised trials have now been
conducted comparing the oral factor Xa inhibitors (edoxaban, rivaroxaban, and apixaban) in CAT
patients, and results of these studies have been pooled into meta-analyses.[147] Oral factor Xa
inhibitors are associated with a lower risk of recurrent VTE but a higher risk of bleeding than
LMWH, particularly in gastrointestinal cancers. Guidelines from the American Society of Clinical
Oncology now suggest oral factor Xa inhibitors as alternatives to LMWH in patients with CAT.[148]
Guidelines from the UK National Institute for Health and Care Excellence recommend oral factor Xa
inhibitors as the preferred option in patients with CAT.[114]
Renal impairment
• For patients with renal impairment (i.e., creatinine clearance <30 mL/minute), intravenous or
subcutaneous UFH, followed by warfarin, is the preferred anticoagulant regimen.
• LMWH has unpredictable renal clearance among patients with renal failure. For patients on LMWH,
laboratory monitoring of the anticoagulant effect (i.e., by anti-factor Xa assay) is generally not
necessary, but should be considered in patients with severe renal impairment and those with
moderate renal impairment if LMWH use is prolonged (i.e., >10 days).[149]
• Fondaparinux, rivaroxaban, apixaban, edoxaban, and dabigatran are generally not recommended
in people with severe renal impairment, and patients with creatinine clearance <25 to 30 mL/minute
were excluded from large randomised controlled trials. Apixaban, edoxaban, and rivaroxaban
may be used in some patients with renal impairment; however, consult local guidance as
recommendations vary between countries.
Hepatic impairment
• LMWH or UFH are recommended in these patients. Both LMWH and UFH should be overlapped
with warfarin, unless cancer is present.[15] Warfarin should be used cautiously if the baseline INR
is elevated; extended-duration LMWH may be preferred.[150]
• Rivaroxaban, apixaban, edoxaban, and dabigatran are generally not recommended in patients with
hepatic impairment, especially those with moderate-to-severe impairment (Child-Pugh class B or
C).[15] [138]
Obesity
• LMWH or UFH are options in these patients. The use of actual body weight is appropriate when
calculating the therapeutic dose in obese patients. Laboratory monitoring of the anticoagulant effect
of LMWH (i.e., by anti-factor Xa assay) is generally not necessary, but should be considered in
patients with class III obesity (BMI 40 or above).[17] [149]
• There is no known weight limit for the use of DOACs; however, they have not been extensively
studied in patients with extreme weights. The Scientific and Standardization Committee of the
International Society on Thrombosis and Haemostasis recommends avoiding DOACs in patients
with body mass index >40 kg/m² or weight >120 kg given the lack of clinical outcomes data in
MANAGEMENT
these patients.[151] Since then, two large, retrospective, matched cohort studies have been
published showing similar outcomes in patients receiving rivaroxaban, apixaban, or dabigatran
versus warfarin, though no prospective comparative evidence exists.[152] [153] If DOACs are used
29
in these patients, appropriate drug-specific monitoring may be considered, though there is limited
evidence that drug-specific levels predict important clinical outcomes.
Pregnancy
• Women who develop DVT and who are pregnant or may become pregnant can be treated with
subcutaneous UFH or LMWH monotherapy.[154] Because of changes in the pharmacodynamics of
subcutaneous UFH during pregnancy, LMWH is preferred.[15] [155] Routine measurement of peak
anti-Xa activity for pregnant or postnatal patients on LMWH is not recommended except in women
at extremes of body weight (i.e., <50 kg or >90 kg) or with other complicating factors (e.g., renal
impairment or recurrent VTE) that put them at high risk.
• Warfarin is known to cause teratogenic effects when used in pregnancy and should be avoided.
• If breastfeeding is planned, then LMWH is the agent of choice. Warfarin is an alternative; it is
minimally secreted in breast milk, but there is extensive clinical experience suggesting no ill effect
in the breastfeeding infant.[135] [156]
• The safety of apixaban, rivaroxaban, dabigatran, and edoxaban in pregnancy and lactation is not
known, and these should be avoided in both situations (but can be used in the postnatal period if
the patient is not breastfeeding).
Considerations for specific anticoagulants
• UFH, LMWH, and fondaparinux
• UFH treatment is usually initiated with an intravenous weight-based loading bolus followed
immediately by initiation of a weight-based continuous infusion. It also requires monitoring of
activated partial thromboplastin time or heparin-calibrated anti-Xa activity, which is used to
titrate dosing to the target range.
• LMWH and fondaparinux are dosed subcutaneously, according to patient weight.
• Platelet count is regularly measured during treatment with any heparin (e.g., UFH, LMWH)
therapy because of the possibility of HIT as a complication.
• Warfarin
• In patients who will transition from UFH, LMWH, or fondaparinux to warfarin, warfarin
should be started the same day that UFH, LMWH, or fondaparinux is started, unless there is
a very high risk for bleeding. If bleeding risk is high, observing the patient for 1 to 2 days on
intravenous heparin alone is advisable.
• Three strategies can be used to select the initial dose of warfarin: a clinical algorithm
calculates the estimated stable and starting dose based on several patient characteristics;
a genetic algorithm calculates the estimated stable and starting dose based on the results
of genetic tests such as CYP450-2C9 genotype and VKOR-C1 haplotype, as well as clinical
variables; a fixed-dose approach uses initiation nomograms based on starting doses of 5 mg/
day or 10 mg/day.[157] [158]
• Use of an individualised nomogram for selecting the initial warfarin dose, and for
MANAGEMENT
subsequent titrations, is likely to result in better outcomes than a fixed-dose initiation, and
is preferred.[158] [159] Tests are available that determine the genotype of the patient for
cytochrome 2C9 variants and vitamin K epoxide reductase variants. However, overall, this
information has not led to more rapid or safe anticoagulation compared with routine dosing.
Genotyping is expensive and it takes several days to receive results.[160] [161] [162] [163]
• When available, employing an individualised approach to warfarin initiation may be preferred.
An online tool is available to assist with warfarin initiation dosing, which utilises clinical
variables with or without the addition of genetic information. [Warfarin dosing] (http://
www.warfarindosing.org/Source/Home.aspx)
• Once warfarin is started, it is continued concomitantly with the parenteral anticoagulant
while the dose is titrated. Subsequent dosing of warfarin is based on the INR response to
each dose. The therapeutic INR range is 2 to 3 (target 2.5, unless concomitantly being used
for anticoagulation of mechanical heart valves). UFH, LMWH, or fondaparinux should be
continued for a minimum of 5 days, and until INR is 2 or greater for at least 24 hours, at
which point the UFH, LMWH, or fondaparinux can be discontinued.[15] [164]
• DOACs
• Rivaroxaban, apixaban, edoxaban, and dabigatran are as effective as UFH, LMWH, and
warfarin for the treatment of DVT, and are generally recommended over warfarin, UFH, and
LMWH outside of special populations.[165] No monitoring of coagulation profile is necessary,
and bleeding complications are similar to those of warfarin, but there is a lower or similar
incidence of major bleeding with pulmonary embolism. All have a longer half-life than UFH or
LMWH and a shorter half-life than warfarin, and all have a rapid onset of action.
• Unlike warfarin, DOACs do not interact with food. However, rivaroxaban at doses ≥15 mg/day
should be given with the largest meal of the day (most often the evening meal) to maximise
absorption.
• DOACs do, however, have some drug-drug interactions. DOAC-specific notable drug
interactions: strong P-glycoprotein inducers and inhibitors (dabigatran and edoxaban); strong
inhibitors or inducers of P-glycoprotein and CYP3A4 (apixaban and rivaroxaban).
• Specific reversal agents for dabigatran (idarucizumab) and the oral factor Xa inhibitors
apixaban and rivaroxaban (recombinant coagulation factor Xa [andexanet alfa]) have
been approved. Reversal of warfarin, in the setting of major or life-threatening bleeding, is
recommended with vitamin K and prothrombin complex concentrates.[166]
• Dabigatran and edoxaban require lead-in therapy with a parenteral anticoagulant such as
UFH or LMWH for 5 to 10 days before switching to oral monotherapy.
• Rivaroxaban and apixaban are initiated at a higher initial dose (for 7-21 days) with no need
for lead-in therapy with parenteral anticoagulants.
• Argatroban (a thrombin inhibitor) may also be used if the patient currently has, or has had
a prior history of, HIT; it is the preferred agent in these patients. Fondaparinux, apixaban,
rivaroxaban, and dabigatran have also been suggested, though they do not have regulatory
approval for patients with active HIT.[167] [168]
Treatment phase of anticoagulation (initiation to 3 months)

Once the initiation phase of anticoagulation has been completed, the patient remains on the anticoagulant
agent for a minimum of 3 months.[138] During this time, follow-up and re-evaluation are based on the
patient’s level of risk for bleeding, comorbidities, and the anticoagulant agent selected.
MANAGEMENT
• Patients treated with warfarin continue to report for INR measurements. The frequency of
measurements depends on the stability of INR values at each visit. Commonly INR is measured
1 to 2 times weekly after initial dose titration, with the time between measurements progressively
31
extending if values remain in range. The target range of 2 to 3 (target INR 2.5) is maintained,
unless concomitantly being used for anticoagulation of mechanical heart valves.[138]
• Patients taking dabigatran or edoxaban remain on the same dose started following the
initiation with a parenteral agent, unless renal function substantially declines, warranting
discontinuation.[138]
• Apixaban and rivaroxaban doses are adjusted following the initiation phase (7 days for apixaban, 21
days for rivaroxaban).[138]
• If extended LMWH is used, the dose depends upon the agent:
• If dalteparin is chosen, the dose is reduced after 1 month

• If enoxaparin is chosen, some experts suggest reducing the initial dose after 1 month though
this is based on opinion only, and the initial dose can be continued.
• LMWH dose should be adjusted to change in the patient’s weight or creatinine clearance.
Extended phase of anticoagulation (3 months to indefinite)

Recommendations for continuation of anticoagulant therapy beyond 3 months vary by patient group. In
patients who receive extended anticoagulation therapy, there is usually no need to change the choice of
anticoagulant.[15] Some agents change dose when used in the extended phase.
Provoked (minor or major transient risk factors) DVT
• Anticoagulation is discontinued after a course of at least 3 months. There is consensus that

patients who have an index DVT that occurs in the setting of a major transient provocation have
a relatively low risk of developing recurrent VTE in the next 5 years, with estimates in the range
of 15%.[15] In these patients, a time-limited course of anticoagulation of at least 3 months is
suggested.[15] The presence of a hereditary thrombophilia does not alter this recommendation,
and guidelines recommend against testing for thrombophilias in patients with a DVT occurring
following a major transient provocation.[115] [Choosing Wisely: Society for Vascular Medicine
– five things physicians and patients should question] (http://www.choosingwisely.org/societies/
society-for-vascular-medicine) While the risk of recurrent VTE is modestly higher in patients who
sustain DVT in the setting of a minor transient provocation, the same time-limited course of therapy
is suggested.[14]
Unprovoked (no identifiable risk factor) DVT
• Patients with an unprovoked DVT of the leg who have been started on anticoagulation therapy
should be assessed after 3 months for continued treatment.[15]
• For patients with a first proximal DVT that is unprovoked who have a low or moderate bleeding risk,
extended anticoagulant therapy is recommended (with no scheduled stop date and reassessment
of ongoing therapy at regular intervals, such as annually). For those patients with a high bleeding
risk, 3 months’ treatment only is recommended.
• For patients with a second unprovoked DVT who have a low or moderate bleeding risk, extended
anticoagulant therapy is recommended (with no scheduled stop date) over 3 months' treatment. In
MANAGEMENT
patients with a high bleeding risk, 3 months’ treatment only is recommended.

• The decision to proceed to extended-phase anticoagulation should be shared with the patient and
be responsive to the patient’s values and preferences.
• In all patients who receive extended anticoagulant therapy, its continued use should be reassessed
at periodic intervals (such as annually).[15]
• Many studies have attempted to identify subgroups of patients with unprovoked VTE who do not
need to be treated indefinitely with oral anticoagulation. There is strong evidence that the risk of
recurrent VTE is higher in the following patients: male sex; those with a diagnosis of a proximal
DVT (versus isolated calf DVT); those with ultrasound evidence of residual clot; those who have an
elevated D-dimer 1 month after stopping a 3- to 6-month course of oral anticoagulation; and those
who had an unprovoked DVT.[15] [138] Several risk assessment models have been developed for
this purpose, including the DASH score, the Vienna Prediction Model, and the 'Men Continue and
HER-DOO2' model.[169] The latter model identifies a subset of women with low risk for recurrent
VTE after an initial unprovoked event, and a prospective validation study of this model has been
published.[170]
• When apixaban or rivaroxaban is used for extended therapy, the dose may be reduced (following 6
months at the treatment dose).
Cancer-associated DVT
• Cancer represents a persistent provocation for VTE until cured. Among patients who are diagnosed
with DVT and have an active cancer (e.g., cancer under any form of active therapy or palliation)
there is a very high risk for recurrent VTE and indefinite anticoagulation is recommended.
Guidelines recommend using an oral factor Xa inhibitor (e.g., apixaban, edoxaban, rivaroxaban) or
LMWH for at least the initial 6 months of therapy.[114]
• LMWH is the preferred agent for patients with a higher risk of bleeding, especially those
with gastrointestinal (GI) cancers, or drug-drug interactions with apixaban, rivaroxaban, or
dabigatran.[171] [172] [173]
Bleeding risk
• When assessing bleeding risk, the following factors should be considered:[15]
• Age >65 years

• Previous bleeding
• Cancer (especially GI cancer with oral factor Xa inhibitors)
• Renal failure
• Liver failure
• Thrombocytopenia
• Previous stroke
• Diabetes mellitus
• Anaemia
• Antiplatelet therapy
• Poor anticoagulant control
• Comorbidity with reduced functional capacity
• Recent surgery
• Frequent falls
• Alcohol misuse
• Use of non-steroidal anti-inflammatory drugs
MANAGEMENT
• Uncontrolled hypertension.
• Patients with none of these risk factors are considered low risk; one risk factor renders a patient
moderate risk; and two or more risk factors renders a patient high risk.
33
• Risk assessment models to assess bleeding risk derived from atrial fibrillation populations are not
known to be accurate in patients with DVT. VTE-specific bleeding risk assessment models are in
development.
• Drug-drug interactions may increase the risk of bleeding in patients receiving anticoagulants,
and both the pharmacodynamic (e.g., non-steroidal anti-inflammatory drugs, selective serotonin-
reuptake inhibitors) and pharmacokinetic (e.g., amiodarone, rifampicin) interactions should be
thoroughly evaluated prior to initiation.
Pregnancy
• The treatment phase of anticoagulation differs in pregnant patients. Patients with pregnancy-
associated VTE undergo treatment-phase anticoagulation for at least 3 months, or until 6 weeks
postnatal, whichever is longer.[154] [155] At the conclusion of this phase in the postnatal period,
decisions are made according to whether the patient is planning to breastfeed.
Aspirin
Long-term aspirin therapy to prevent VTE recurrence should be considered for patients with an
unprovoked proximal DVT who are stopping anticoagulant therapy and in whom aspirin is not
contraindicated.[15] Aspirin should not, however, be considered a reasonable alternative for patients who
are willing to undergo extended anticoagulation therapy, as aspirin is much less effective. The use of
aspirin should in any case be reassessed when patients stop anticoagulant therapy because it might have
been stopped when anticoagulant therapy was started.[15]
Gradient stockings and physical activity

Gradient (graduated compression) stockings are not recommended for the purpose of preventing post-
thrombotic syndrome by the ACCP guidelines.[15] However, they remain useful for patients with acute
or chronic symptoms of DVT, and in these patients a trial of graduated compression stockings is often
justified.[15]
Early walking exercise is considered safe in patients with acute DVT and may actually help to reduce
symptoms. It does not increase leg symptoms acutely in patients with a previous DVT, and may help to
reduce post-thrombotic syndrome.[174] [175] [176] [177]
Bleeding patients
Use of a retrievable inferior vena cava (IVC) filter is recommended in patients with acute proximal DVT
who have a contraindication to anticoagulation therapy because of active bleeding.[138] Presence of an
IVC filter is associated with a doubling of the long-term risk of recurrent lower-extremity DVT. There is no
evidence that presence of a filter in the IVC by itself is an indication for long-term oral anticoagulation.
However, the presence of a filter should be considered a risk factor that increases the long-term risk of
recurrent DVT. Once bleeding has resolved, the patient may be assessed for initiation of anticoagulation
and removal of the IVC filter.[138]
Patients with recurrent VTE on anticoagulant therapy

MANAGEMENT
Recurrent VTE is unusual among patients receiving therapeutic-dose anticoagulant therapy, except
in cancer (7% to 9% on-therapy recurrence with LMWH).[15] [136] [178] In addition to definitively
establishing the presence of recurrent VTE, consideration should be given to compliance with
anticoagulant therapy or the presence of underlying malignancy and the presence of any medications that
may diminish the anticoagulant effect of therapy.[15]
ACCP guidelines recommend a temporary switch to LMWH (for at least 1 month) for patients with
recurrent VTE who are thought to be compliant with a non-LMWH anticoagulant (or within the therapeutic
range if receiving vitamin K antagonist therapy).[15] An increased dose of LMWH is appropriate for
patients with recurrent VTE who have been receiving LMWH.[15]
Treatment algorithm overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Initial ( summary )
initiation-phase therapy: no active
bleeding
proximal DVT of the leg: 1st anticoagulation

non-pregnant
plus physical activity
adjunct gradient stockings
distal DVT of the leg: non- 1st serial imaging of the deep veins and/or
pregnant anticoagulation
pregnant 1st low molecular weight heparin or

subcutaneous unfractionated heparin
initiation-phase therapy: active

bleeding
1st IVC filter
Acute ( summary )
MANAGEMENT
treatment-phase therapy
1st maintain anticoagulation
35
Ongoing ( summary )
extended-phase therapy (3 months’
anticoagulation therapy completed):
not postnatal, no recurrence
1st consideration of extended

anticoagulation
extended-phase therapy: postnatal

(planning to breast feed)
1st low molecular weight heparin or

subcutaneous unfractionated heparin ±
warfarin

(not planning to breast feed)
1st anticoagulation
extended-phase therapy: recurrent

VTE
1st further investigation

MANAGEMENT
Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
MANAGEMENT
37
Initial
initiation-phase therapy: no active
bleeding
proximal DVT of the leg: 1st anticoagulation

non-pregnant
Primary options
» rivaroxaban: 15 mg orally twice daily initially

for 3 weeks, followed by 20 mg once daily
OR
» apixaban: 10 mg orally twice daily for 7

days, followed by 5 mg twice daily
OR
» edoxaban: body weight ≤60 kg: 30 mg

orally once daily, starting 5-10 days after
treatment with a parenteral anticoagulant;
body weight >60 kg: 60 mg orally once daily,
starting 5-10 days after treatment with a
parenteral anticoagulant
OR
» dabigatran: 150 mg orally twice daily,

OR
» enoxaparin: 1 mg/kg/dose subcutaneously

twice daily; or 1.5 mg/kg/dose
subcutaneously once daily
-and-
» warfarin: 2-10 mg orally once daily initially,
adjust dose according to target INR
Starting dose can also be calculated
using an online tool that takes patient
characteristics and/or CYP2C9/VKORC1
genotype information (if available)
into account. Warfarin dosing http://
www.warfarindosing.org/Source/Home.aspx
Secondary options
» dalteparin: 200 units/kg/dose

subcutaneously once daily; or 100 units/kg/
MANAGEMENT
dose subcutaneously twice daily

-and-
Initial
OR
» fondaparinux: patients <50 kg body

weight: 5 mg subcutaneously once daily;
patients 50-100 kg body weight: 7.5 mg
subcutaneously once daily; patients >100 kg
body weight: 10 mg subcutaneously once
daily
-and-
OR
» heparin: 80 units/kg intravenous bolus

initially, followed by 18 units/kg/hour
intravenous infusion, adjust dose according
to aPTT or calibrated anti-Xa activity; or 333
units/kg subcutaneously initially, followed by
250 units/kg every 12 hours
-and-
OR
» argatroban: consult specialist for guidance

on dose
-and-
» warfarin: consult specialist for guidance on
initiating therapy in patients on argatroban
» For patients with a proximal DVT of the leg,

MANAGEMENT
anticoagulant therapy is recommended.[15]

Therapy is initially for 3 months; some patients
require extended therapy.
» Choice of agent depends on patient factors

such as hepatic/renal function, pregnancy,
39
Initial
cancer, obesity, other comorbidities, concomitant
medications and drug-drug interactions, and
bleeding risk. Choice may also depend on
patient preference or recommendations in local
guidelines.
» Generally, anticoagulation with direct

oral anticoagulants (DOACs) – dabigatran,
rivaroxaban, apixaban, or edoxaban – is
recommended over warfarin, which is in turn
recommended over low molecular weight
heparin (LMWH).[15] Fondaparinux is generally
reserved for patients with heparin-induced
thrombocytopenia (HIT) or those with a history of
this condition.
» In patients at increased risk of bleeding

(e.g., recent surgery, peptic ulceration):
anticoagulation with intravenous unfractionated
heparin (UFH) is recommended initially because
it has a short half-life and its effect can be
reversed quickly with protamine. An appropriate
anticoagulation regimen can be selected once it
is clear anticoagulation is being tolerated.
» In patients with active cancer (regional spread

or metastatic, especially adenocarcinomas
or haematological malignancies): guidelines
recommend using an oral factor Xa inhibitor
(apixaban, edoxaban, rivaroxaban) or LMWH for
at least the initial 6 months of therapy.[114] [179]
» In renal impairment (creatinine clearance <30

mL/minute): intravenous or subcutaneous UFH
followed by warfarin is recommended. Apixaban,
edoxaban, and rivaroxaban may be used in
some patients with renal impairment; however,
consult local guidance as recommendations vary
between countries.
» In hepatic impairment: LMWH or UFH are

recommended. Both LMWH and UFH should
be overlapped with warfarin, unless cancer
is present, in which case LMWH should be
continued. DOACs should generally be avoided,
especially in those with moderate-to-severe
impairment (Child-Pugh class B or C). Warfarin
should be used cautiously if the baseline
international normalised ratio (INR) is elevated,
in which case LMWH may be preferred.[15]
» In obese patients: LMWH or UFH are options.

MANAGEMENT
DOACs can also be considered; however, they

have not been extensively studied in patients
with extreme weights (body mass index >40
kg/m² or >120 kg).[151] If DOACs are used
in these patients, appropriate drug-specific
monitoring may be considered, though there is
Initial
limited evidence that drug-specific levels predict
important clinical outcomes.
» Warfarin is started at the same time as UFH,

LMWH, or fondaparinux and is continued,
overlapping with the parenteral agent for at least
5 days and until INR is 2 or greater for at least
24 hours, at which point the UFH, LMWH, or
fondaparinux can be discontinued.[15] [164]
» Use of an individualised nomogram for

selecting the initial warfarin dose, and for
subsequent titrations, results in improved
outcomes compared with use of a fixed initiation
dose.[158] [159] When available, employing an
individualised approach to warfarin initiation may
be preferred. An online tool is available to assist
with warfarin initiation dosing, which utilises
clinical variables with or without the addition of
genetic information. [Warfarin dosing] (http://
» With intravenous UFH, activated partial

thromboplastin time (aPTT) or calibrated
anti-Xa activity should be monitored every 6
hours, adjusting the dose as needed. Once
a therapeutic level is reached without dose
change, then aPTT or calibrated anti-Xa can be
performed once daily. The goal is to maintain
a therapeutic range, which is specific for each
laboratory based on the reagent used. It is
imperative to achieve a therapeutic heparin
effect within the first 24 hours in order to reduce
the incidence of recurrent VTE. Platelet count
should be measured at baseline, then on days 3
and 5, to observe for the development of HIT.
» Monitoring of anticoagulant efficacy is not

required with LMWH, subcutaneous UFH,
fondaparinux, rivaroxaban, apixaban, edoxaban,
or dabigatran.
» Dabigatran and edoxaban require lead-in

therapy with a parenteral anticoagulant such as
UFH or LMWH for 5 to 10 days before switching
to oral therapy. Rivaroxaban and apixaban are
initiated with a higher dose with no need for
lead-in therapy.
» Argatroban (a thrombin inhibitor) may also

be used if the patient currently has, or has had
a prior history of, HIT; it is the preferred agent
MANAGEMENT
in these patients. Fondaparinux, apixaban,

rivaroxaban, and dabigatran have also been
suggested, but they do not have regulatory
approval for active HIT.
41
Initial
Treatment recommended for ALL patients in
selected patient group
» Early ambulation is considered safe in
patients with acute DVT.[174] [180] [181] It does
not increase leg symptoms acutely in patients
with a previous DVT, and may help to reduce
post-thrombotic syndrome.[174] [175] [176] [177]
Treatment recommended for SOME patients in
» While routinely suggested as unhelpful for
the prevention of post-thrombotic syndrome,
gradient stockings may be useful for patients
with acute or chronic symptoms of DVT, in whom
a trial is often justified.[15]
» Not recommended for other patients.[15]

distal DVT of the leg: non- 1st serial imaging of the deep veins and/or
pregnant anticoagulation
Primary options
» rivaroxaban: 15 mg orally twice daily initially

for 3 weeks, followed by 20 mg once daily
OR
» apixaban: 10 mg orally twice daily for 7

days, followed by 5 mg twice daily
OR

orally once daily, starting 5-10 days after
treatment with a parenteral anticoagulant;
body weight >60 kg: 60 mg orally once daily,
OR
» dabigatran: 150 mg orally twice daily,

OR

MANAGEMENT

-and-
Initial
Secondary options
» dalteparin: 200 units/kg/dose

subcutaneously once daily; or 100 units/kg/
dose subcutaneously twice daily
-and-
OR
» fondaparinux: patients <50 kg body

weight: 5 mg subcutaneously once daily;
patients 50-100 kg body weight: 7.5 mg
subcutaneously once daily; patients >100 kg
body weight: 10 mg subcutaneously once
daily
-and-
OR
» heparin: 80 units/kg intravenous bolus

initially, followed by 18 units/kg/hour
intravenous infusion, adjust dose according
to aPTT or calibrated anti-Xa activity; or 333
units/kg subcutaneously initially, followed by
250 units/kg every 12 hours
-and-
MANAGEMENT

43
Initial
OR
» argatroban: consult specialist for guidance

on dose
-and-
initiating therapy in patients on argatroban
» For patients with an acute isolated distal

DVT of the leg but without severe symptoms
or risk factors for extension, serial imaging of
the deep veins for 2 weeks is suggested over
anticoagulation.[15] [144] Anticoagulation is
given only if the thrombus propagates on serial
ultrasound examinations.
» However, for patients with severe symptoms

or risk factors for extension, anticoagulation is
recommended. Anticoagulation is initially for 3
months.
» Risk factors for extension include:[15] positive

D-dimer, extensive thrombosis (e.g., >5 cm long;
involving multiple veins; >7 mm in maximum
diameter), thrombosis close to the proximal
veins, absence of any reversible provoking
factor, active cancer, past history of venous
thromboembolism (VTE), or hospital inpatient
status.
» Choice of agent depends on patient factors

such as hepatic/renal function, pregnancy,
cancer, obesity, other comorbidities, concomitant
medications and drug-drug interactions, and
bleeding risk. Choice may also depend on
patient preference or recommendations in local
guidelines.
» Generally, anticoagulation with direct

oral anticoagulants (DOACs) – dabigatran,
rivaroxaban, apixaban, or edoxaban – is
recommended over warfarin, which is in turn
recommended over low molecular weight
heparin (LMWH). Fondaparinux is generally
reserved for patients with heparin-induced
thrombocytopenia (HIT) or those with a history of
this condition.
» In patients at increased risk of bleeding

MANAGEMENT
(e.g., recent surgery, peptic ulceration):

anticoagulation with intravenous unfractionated
heparin (UFH) is recommended initially because
it has a short half-life and its effect can be
reversed quickly with protamine. An appropriate
Initial
anticoagulation regimen can be selected once it
is clear anticoagulation is being tolerated.
» In patients with active cancer (regional spread

or metastatic, especially adenocarcinomas
or haematological malignancies): guidelines
recommend using an oral factor Xa inhibitor
or LMWH for at least the initial 6 months of
therapy.[114] [179]
» In renal impairment (creatinine clearance <30

mL/minute): intravenous or subcutaneous UFH
followed by warfarin is recommended. Apixaban,
edoxaban, and rivaroxaban may be used in
some patients with renal impairment; however,
consult local guidance as recommendations vary
between countries.
» In hepatic impairment: LMWH or UFH are

recommended. Both LMWH and UFH should
be overlapped with warfarin, unless cancer
is present, in which case LMWH should be
continued. DOACs should generally be avoided,
especially in those with moderate-to-severe
impairment (Child-Pugh class B or C). Warfarin
should be used cautiously if the baseline
international normalised ratio (INR) is elevated,
in which case LMWH may be preferred.[15]
» In obese patients: LMWH or UFH are options.

DOACs can also be considered; however, they
have not been extensively studied in patients
with extreme weights (body mass index >40
kg/m² or >120 kg).[151] If DOACs are used
in these patients, appropriate drug-specific
monitoring may be considered, though there is
limited evidence that drug-specific levels predict
important clinical outcomes.
» Warfarin is started at the same time as UFH,

LMWH, or fondaparinux and is continued,
overlapping with the parenteral agent for at least
5 days and until INR is 2 or greater for at least
24 hours, at which point the UFH, LMWH, or
fondaparinux can be discontinued.[15] [164]
» Use of an individualised nomogram for

selecting the initial warfarin dose, and for
subsequent titrations, results in improved
outcomes compared with use of a fixed initiation
dose.[158] [159] When available, employing an
individualised approach to warfarin initiation may
MANAGEMENT
be preferred. An online tool is available to assist

with warfarin initiation dosing, which utilises
clinical variables with or without the addition of
genetic information. [Warfarin dosing] (http://
45
Initial
» With intravenous UFH, activated partial
thromboplastin time (aPTT) or calibrated
anti-Xa activity should be monitored every 6
hours, adjusting the dose as needed. Once
a therapeutic level is reached without dose
change, then aPTT or calibrated anti-Xa can be
performed once daily. The goal is to maintain
a therapeutic range, which is specific for each
laboratory based on the reagent used. It is
imperative to achieve a therapeutic heparin
effect within the first 24 hours in order to reduce
the incidence of recurrent VTE. Platelet count
should be measured at baseline, then on days 3
and 5, to observe for the development of HIT.
» Monitoring of anticoagulant efficacy is not

required with LMWH, subcutaneous UFH,
fondaparinux, rivaroxaban, apixaban, edoxaban,
or dabigatran.
» Dabigatran and edoxaban require lead-in

therapy with a parenteral anticoagulant such as
UFH or LMWH for 5 to 10 days before switching
to oral monotherapy. Rivaroxaban and apixaban
are initiated with a higher dose with no need for
lead-in therapy.
» Argatroban (a thrombin inhibitor) may also

be used if the patient currently has, or has had
a prior history of, HIT; it is the preferred agent
in these patients. Fondaparinux, apixaban,
rivaroxaban, and dabigatran have also been
suggested, but they do not have regulatory
approval for active HIT.
» Early ambulation is considered safe in patients
with acute DVT.[174] [180] [181] It does not
increase leg symptoms acutely in patients with
a previous DVT, and may help to reduce post-
thrombotic syndrome.[174] [175] [176] [177]
MANAGEMENT


pregnant 1st low molecular weight heparin or
subcutaneous unfractionated heparin
Initial
Primary options
» enoxaparin: consult specialist for guidance

on dose
OR
» dalteparin: consult specialist for guidance

on dose
Secondary options
» heparin: consult specialist for guidance on

dose
» Women who develop DVT during pregnancy

can be treated with subcutaneous unfractionated
heparin (UFH) or low molecular weight
heparin (LMWH). LMWH is preferred because
of changes in the pharmacodynamics of
subcutaneous UFH during pregnancy.[15] [154]
» Routine measurement of peak anti-Xa

activity for pregnant patients on LMWH is not
recommended. It may, however, be considered
in women at extremes of body weight (i.e., <50
kg or >90 kg) or with other complicating factors
(e.g., renal impairment or mechanical heart
valve) that put them at high risk.
» For patients with severe renal impairment

(i.e., creatinine clearance <30 mL/minute)
subcutaneous UFH with appropriate activated
partial thromboplastin time adjustment is the
preferred treatment.
» Other anticoagulants are not recommended

in pregnant women for the treatment of venous
thromboembolism. Direct oral anticoagulants are
not recommended in pregnancy.
MANAGEMENT

47
Initial

initiation-phase therapy: active
bleeding
1st IVC filter
» When possible, retrievable inferior vena cava

(IVC) filters are preferable to older models.
Presence of an IVC filter is associated with a
doubling of the long-term risk of recurrent lower-
extremity DVT, owing to both the presence of
thrombosis and the mechanical effects of the
filter. There is no evidence that presence of a
filter in the IVC by itself is an indication for long-
term oral anticoagulation. However, the presence
of a filter should be considered a risk factor that
increases the long-term risk of recurrent DVT.
Once bleeding has resolved, the patient may
be assessed for initiation of anticoagulation and
removal of the IVC filter.[138]
» The US Food and Drug Administration (FDA)

recommends that implanting physicians and
clinicians responsible for the ongoing care of
patients with retrievable IVC filters consider
removing the filter as soon as protection from
pulmonary embolism is no longer needed (e.g.,
once anticoagulant therapy has been started
and is tolerated). The FDA encourages all
physicians involved in the treatment and follow-
up of patients receiving IVC filters to consider
the risks and benefits of filter removal for each
patient. The FDA states that a patient should
be referred for IVC filter removal when the risk/
benefit profile favours removal and the procedure
is feasible given the patient's health status.[182]
MANAGEMENT

Initial
MANAGEMENT
49
Acute
treatment-phase therapy
1st maintain anticoagulation
» Once the initiation phase of anticoagulation

has been completed, the patient remains on the
anticoagulant agent for a minimum of 3 months
(treatment phase).[138] During this time, follow-
up and re-evaluation are based on the patient’s
level of risk for bleeding, comorbidities, and the
anticoagulant agent selected.
» Patients treated with warfarin continue to

report for international normalised ratio (INR)
measurements. The target range of 2 to 3 (target
INR 2.5) is maintained, unless concomitant
anticoagulation for mechanical heart valves is
required.[138]
» Patients taking dabigatran or edoxaban

remain on the same dose started following
the initiation with a parenteral agent, unless
renal function substantially declines, warranting
discontinuation.[138]
» Apixaban and rivaroxaban doses are adjusted

following the initiation phase (7 days for
apixaban, 21 days for rivaroxaban). If extended
low molecular weight heparin (LMWH) is used,
the dose depends upon the agent.[138] If
dalteparin is chosen, the dose is reduced after
1 month. If enoxaparin is chosen, some experts
suggest reducing the initial dose after 1 month
though this is based on opinion only, and the
initial dose can be continued. The dose of
LMWH should be adjusted to change in the
patient’s weight or creatinine clearance.
MANAGEMENT

Acute
MANAGEMENT
51
Ongoing
extended-phase therapy (3 months’
anticoagulation therapy completed):
not postnatal, no recurrence
1st consideration of extended anticoagulation

Primary options
» rivaroxaban: 20 mg orally once daily; 10 mg

orally once daily after completing at least 6
months treatment
OR
» apixaban: 5 mg orally twice daily; 2.5 mg

orally twice daily after completing at least 6
months treatment
OR

orally once daily; body weight >60 kg: 60 mg
orally once daily
OR
» dabigatran: 150 mg orally twice daily
OR

OR

Secondary options
» aspirin: 100 mg orally once daily
» Recommendations for continuation of

MANAGEMENT
anticoagulant therapy beyond 3 months vary by

patient group. In patients who receive extended
anticoagulation therapy, there is usually no need
to change the choice of anticoagulant.[15] Some
agents change dose in the extended phase of
therapy.
Ongoing
» In patients with DVT following a major transient
provocation, anticoagulation is discontinued
after a course of at least 3 months. There is
consensus that patients who have an index
DVT that occurs in the setting of a major
transient provocation have a relatively low risk of
developing recurrent venous thromboembolism
(VTE) in the next 5 years, with estimates in
the range of 15%. In these patients, a time-
limited course of anticoagulation of at least
3 months is suggested.[15] The presence of
a hereditary thrombophilia does not alter this
recommendation, and guidelines recommend
against testing for thrombophilias in patients
with a DVT occurring following a major
transient provocation.[115] [Choosing Wisely:
Society for Vascular Medicine – five things
physicians and patients should question]
(http://www.choosingwisely.org/societies/
society-for-vascular-medicine) While the risk of
recurrent VTE is modestly higher in patients who
sustain DVT in the setting of a minor transient
provocation, the same time-limited course of
therapy is suggested.[14]
» Patients with an unprovoked (no identified risk

factors) DVT of the leg who have been started
on anticoagulation therapy should be assessed
after 3 months for continued treatment.[15]
For patients with a first proximal DVT that is
unprovoked (no identified risk factors) who
have a low or moderate bleeding risk, extended
anticoagulant therapy is recommended (with
no scheduled stop date though reassessed at
regular intervals, such as annually). For those
patients with a high bleeding risk, 3 months’
treatment only is recommended.
» For patients with a second unprovoked DVT

who have a low or moderate bleeding risk,
extended anticoagulant therapy is recommended
(with no scheduled stop date) over 3 months.
In patients with a high bleeding risk, 3 months’
treatment only is recommended.
» The decision to proceed with extended

anticoagulation should be a shared decision with
the patient and respect the patient’s values and
preferences.
» In all patients who receive extended

anticoagulant therapy, its continued use should
MANAGEMENT
be reassessed at periodic intervals (such as

annually).[15]
» Patients with an unprovoked proximal DVT who

are not proceeding to extended anticoagulation
should be considered for long-term aspirin
53
Ongoing
therapy to prevent recurrence.[15] Aspirin should
not, however, be considered a reasonable
alternative for patients who are willing to undergo
extended anticoagulation therapy, as aspirin is
less effective.
» The use of aspirin should in any case be

reassessed when patients stop anticoagulant
therapy because it might have been stopped
when anticoagulant therapy was started.[15]
» The treatment phase of anticoagulation differs

in pregnant patients. Patients with pregnancy-
associated VTE undergo treatment-phase
anticoagulation for at least 3 months, or until 6
weeks postnatal, whichever is longer.[154] [155]
At the conclusion of this phase in the postnatal
period, decisions are made according to whether
the patient is planning to breastfeed (see below).
(planning to breast feed)
1st low molecular weight heparin or

subcutaneous unfractionated heparin ±
warfarin
Primary options

on dose
OR

on dose
OR

on dose
-or-
on dose
--AND--
dose
Secondary options

dose
MANAGEMENT
OR

dose
Ongoing
-and-
dose
» Low molecular weight heparin (LMWH)

or subcutaneous unfractionated heparin is
generally continued in the postnatal period. If
breastfeeding is planned, then LMWH is the
agent of choice and is continued because it
does not cross into the breast milk. Patients can
either be continued on LMWH or transitioned to
warfarin. Warfarin is secreted in breast milk, but
long experience with this agent has suggested
lack of harm to the infant.
» For patients on LMWH, no monitoring of

the activated partial thromboplastin time is
needed. Platelet count should be measured
at baseline, then on days 3 and 5 to observe
for the development of heparin-induced
thrombocytopenia.
» Other anticoagulants are not recommended.

Direct oral anticoagulants are not recommended
in pregnancy and the postnatal period if patients
are breastfeeding.
» These patients should only be treated under

specialist supervision.
(not planning to breast feed)
1st anticoagulation
Primary options

on dose
-or-
on dose
--AND--
dose
OR
» apixaban: consult specialist for guidance on

dose
OR
MANAGEMENT
» edoxaban: consult specialist for guidance

on dose
OR
55
Ongoing
» rivaroxaban: consult specialist for guidance
on dose
OR
» dabigatran: consult specialist for guidance

on dose
Secondary options

dose
-and-
dose
» If warfarin is started, the international

normalised ratio (INR) should be in the
therapeutic range (2-3) at the time that
low molecular weight heparin (LMWH) or
unfractionated heparin (UFH) is discontinued.
Some experts suggest that the INR needs to be
in the therapeutic range for 48 hours before the
LMWH or UFH is discontinued.
» Although not studied in postnatal patients,

apixaban, rivaroxaban, dabigatran, and
edoxaban can be considered for use in
accordance with their their prescribing
information so long as the mother is not currently
and does not plan on breastfeeding.
» These patients should only be treated under

specialist supervision.
extended-phase therapy: recurrent
VTE
1st further investigation
» Recurrent venous thromboembolism

(VTE) is unusual among patients receiving
therapeutic-dose anticoagulant therapy,
except in cancer (7% to 9% on-therapy
recurrence with low molecular weight heparin
[LMWH]).[15] [136] [183] In addition to
definitively establishing the presence of
recurrent VTE, consideration should be given
to compliance with anticoagulant therapy or
the presence of underlying malignancy and the
presence of any medications that may diminish
the anticoagulant effect of therapy.[15]
MANAGEMENT
» American College of Chest Physicians

guidelines recommend a temporary switch to
LMWH (for at least 1 month) for patients with
recurrent VTE who are thought to be compliant
with a non-LMWH anticoagulant (or within
Ongoing
the therapeutic range if receiving vitamin K
antagonist therapy).[15] An increased dose of
LMWH is appropriate for patients with recurrent
VTE who have been receiving LMWH.[15]
MANAGEMENT
57
Emerging
Catheter-directed or pharmacomechanical thrombolysis
Catheter-directed and pharmacomechanical interventions attempt to accelerate the resolution of DVT through
invasive methods that dissolve or remove existing thrombus (anticoagulant therapy does not dissolve existing
thrombosis; healing relies on the patient’s innate intrinsic thrombolysis). The ATTRACT study assessed
whether pharmacomechanical catheter-directed thrombolysis lowers the incidence of post-thrombotic
syndrome and improves the quality of life.[184] [185] Results from the ATTRACT trial showed no net benefit
for primary end point of lowering the incidence of post-thrombotic syndrome and, in fact, had more bleeding
complications.[184] Intravenous stents have been used to address residual obstruction following catheter-
directed thrombolysis of acute DVT, and to address refractory symptoms of the post-thrombotic syndrome in
patients with persistent venous obstruction. At present, little data are available on the impact of stenting on
patient outcomes, the rate of stent thrombosis, duration of subsequent antithrombotic therapy, and whether
antiplatelet agents should be added to anticoagulants following the procedure. The CAVA trial utilised
ultrasound-assisted catheter-directed thrombolysis in patients with proximal DVT, but did not demonstrate
an improvement in the rate of post-thrombotic syndrome (PTS); however, the subgroup of patients defined
as having 'successful' thrombolysis had fewer symptoms at 1 year.[186] A Cochrane review comparing
the effects of thrombolytic clot removal and anticoagulation to anticoagulation alone for the management
of people with acute DVT of the lower limb found that complete clot lysis occurred more frequently after
thrombolysis and the incidence of PTS was reduced.[187] Thrombolysis was associated with an increased
risk of bleeding, but this mainly occurred in older studies and the risk has decreased over time. Presently, the
indication for interventional therapies for patients with DVT who do not have limb-threatening phlegmasia is
unclear.
Primary prevention
A large body of literature shows that the incidence of venous thromboembolism (VTE) can be reduced in the
medically ill, surgical, and traumatic non-surgical populations.
Risk stratification
• Risk assessment models (RAMs) have been proposed to risk stratify patients for VTE and guide
prophylactic strategies.[63] [68] Such models include the Caprini RAM, the Geneva Risk Score,
IMPROVE-RAM, IMPROVEDD (which included D-dimer), the Kucher Model, and the Padua
Prediction Score.[69] [70] Externally validated models that have been shown to either improve rates
of pharmacological prophylaxis or clinical outcomes include the Kucher Model, the Padua Prediction
Score, and the Geneva Risk Score. Early, frequent ambulation is recommended in all patients, as
feasible. Pharmacological prophylaxis should be given to all hospitalised patients with an increased
risk of VTE, a low risk for bleeding, and no contraindications. Mechanical prophylaxis (generally
with intermittent pneumatic compression devices) should be given to patients at risk for DVT but
with a high risk for bleeding, or a contraindication to pharmacological prophylaxis. It is important to
re-evaluate these patients frequently, and begin pharmacological prophylaxis if the bleeding risk or
contraindication remits, or if the risk of VTE increases (e.g., placement of a central venous catheter
while hospitalised). Very-high-risk patients should receive both pharmacological and mechanical
prophylaxis if bleeding risk is low.[63] [68] [71] Hospital-associated VTE rates are a publicly reported
hospital quality measure in the US.
Pharmacological prophylaxis
• Options for pharmacological prophylaxis for the medically ill and surgical populations include low-dose
unfractionated heparin, low molecular weight heparin, and fondaparinux. Betrixaban, a direct factor
MANAGEMENT
Xa inhibitor, has been approved in the US by the Food and Drug Administration for the prophylaxis of
VTE in adults (with restricted mobility and other risk factors for VTE) hospitalised for an acute medical
illness. Betrixaban has not been approved for the prevention of VTE in Europe. Apixaban, rivaroxaban,
dabigatran, aspirin, and vitamin K antagonists (warfarin) are also endorsed for VTE prophylaxis in
patients undergoing joint replacement procedures, along with low molecular weight heparin and
fondaparinux.[71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] Emerging evidence suggests that
apixaban may prevent VTE in intermediate-to-high risk ambulatory patients with cancer; risk of major
bleeding with apixaban was, however, greater than with placebo.[83]
Extended-duration pharmacological prophylaxis
• Extended-duration pharmacological prophylaxis (i.e., continued prophylaxis after hospital discharge)

may be appropriate in certain patient groups. Patients undergoing hip or knee replacement or hip
fracture surgery are suggested to continue prophylaxis for up to 10 to 35 days following surgery.
Patients undergoing abdominal-pelvic surgeries for a malignancy are recommended a 28-day regimen
of prophylactic low molecular weight heparin.[68] [71] Five randomized trials enrolling over 40,000
patients have examined extended-duration prophylaxis following hospitalization for medical illness.[24]
[25] [26] [27] [84] Regimens included low molecular weight heparin or oral factor Xa inhibitors at a
prophylactic-dose for 4-6 weeks following discharge. Inclusion criteria varied, but the most common
reason for hospitalization across studies was heart failure. A pooled analysis revealed that extended
prophylaxis reduced symptomatic VTE or VTE-related death compared with standard of care (0.8%
versus 1.2%; risk ratio [RR] 0.61, 95% confidence interval [CI] 0.44 to 0.83; P = 0.002) but increased
the risk of major or fatal bleeding (0.6% versus 0.3%; RR 2.04, 95% CI 1.42 to 2.91; P <0.001).[85]
Due to the very narrow margin of risks and benefits, further research is needed to appropriately select
medical patients for extended prophylaxis following hospital discharge. Currently in the US betrixaban
and rivaroxaban are approved for extended-duration or post-discharge pharmacological prophylaxis in
select patients.[84] [86] [87]
Long-distance travel
• The routine use of pharmacological prophylaxis in patients travelling long distances is not
recommended but can be considered on a case-by-case basis. Elastic compression stockings may
reduce the risk of VTE in these patients.[63]
Secondary prevention
The principal means of secondary prevention is the extended prescription (e.g., no planned stop date) of
an anticoagulant medication. The decision to offer extended anticoagulation arises from an assessment
of the risk for future thrombosis without a medication, balanced against projected risk of bleeding with a
medication, its cost, and burden to the patient. Guidelines recognise the importance of the patient’s values
and preferences in making this decision.[15] When extended anticoagulant therapy is offered, the decision
should be periodically re-evaluated, as the projected risks, benefits, and patient preferences may change
over time. Finally, it is notable that anticoagulants offer secondary prevention benefits only as long as they
are continued. There is no legacy effect of a longer time-limited course of treatment; the risk of recurrent
venous thromboembolism (VTE) re-emerges as soon as the anticoagulant is discontinued.[213] Apixaban
and rivaroxaban both have published studies utilising a lower dose for secondary prevention.[214] [215] [216]
Secondary prevention may also embrace interventions undertaken episodically, at times when thrombosis
risk is elevated. Such interventions include assuring prophylaxis at the time of hospitalisations and surgeries,
prophylactic measures during pregnancy and the postnatal period, and possibly prophylactic interventions
during long distance travel. Finally, maintenance of a healthy weight, regular exercise, avoidance of
oestrogens and smoking, and possibly use of a statin (when indicated for hyperlipidaemia) may all reduce
the risk of recurrent thrombosis.
Provoked DVT: there is consensus that patients who have an index DVT that occurs in the setting of a
major transient provocation have a relatively low risk of developing recurrent VTE in the next 5 years, with
estimates in the range of 15%.[15] In these patients, a time-limited course of anticoagulation of at least 3
MANAGEMENT
months is suggested.[15] The presence of a hereditary thrombophilia does not alter this recommendation,
and guidelines recommend against testing for thrombophilias in patients with a DVT occurring following a
major transient provocation.[115] [Choosing Wisely: Society for Vascular Medicine – five things physicians
and patients should question] (http://www.choosingwisely.org/societies/society-for-vascular-medicine) While
the risk of recurrent VTE is modestly higher in patients who sustain DVT in the setting of a minor transient
provocation, the same time-limited course of therapy is suggested.[15]
59
Unprovoked (no identified risk factors) DVT: among patients who present with an idiopathic or unprovoked
DVT, the 5-year recurrence rate is estimated to be approximately 30% or more.[15] Because of the high
recurrence rate, extended anticoagulation (no planned stop date) to reduce this risk is recommended
in patients at low risk of major bleeding, and suggested in patients at high risk for bleeding.[15] Shared
decision-making with the patient is suggested, and when extended anticoagulation is chosen, this decision
should be re-evaluated at least annually.
Cancer represents a persistent provocation for VTE until cured. Among patients who are diagnosed with DVT
and have an active cancer (e.g., cancer under any form of active therapy or palliation) there is a very high
risk for recurrent VTE, and indefinite anticoagulation is recommended. Guidelines have recommended using
an oral factor Xa inhibitor, which is supported by randomised controlled trials and subsequent meta-analyses
(e.g., apixaban , edoxaban, rivaroxaban), or low molecular weight heparin (LMWH) for at least the initial 6
months of therapy.[114] [217] [145] [218] [219] [220] [221] [222]
LMWH is the preferred agent for patients with a higher risk of bleeding, especially those with gastrointestinal
cancers, or drug-drug interactions with apixaban, rivaroxaban, or dabigatran.[223] [218] [224]
Many studies have attempted to identify subgroups of patients with unprovoked VTE who do not need to be
treated indefinitely with oral anticoagulation. There is strong evidence that the risk of recurrent VTE is higher
in the following patients: male sex; those with a diagnosis of a proximal DVT (versus isolated calf DVT); those
with ultrasound evidence of residual clot; those who have an elevated D-dimer 1 month after stopping a 3-
to 6-month course of oral anticoagulation; and those who had an unprovoked DVT.[15] [138] Several risk
assessment models have been developed for this purpose, including the DASH score, the Vienna Prediction
Model, and the 'Men Continue and HER-DOO2' model.[169] The latter model identifies a subset of women
with low risk for recurrent VTE after an initial unprovoked event, and a prospective validation study of this
model was published.[170]
Patient discussions
Patients must be instructed carefully about the proper use of warfarin and the need for regular follow-
up and monitoring of their international normalised ratio (INR). [Thrombosis Canada: warfarin point-
of-care INR monitoring] (http://thrombosiscanada.ca/wp-content/uploads/2017/07/Warfain-Point-of-
Care-2017Jul21-FINAL.pdf) Patients must understand the following:
• Warfarin makes the blood more difficult to clot and therefore carries a risk of bleeding.
• The effect of the drug is measured with a blood-clotting test called the INR.
• Warfarin dose frequently changes over time, and dosing that varies with the day of the week is very
common (e.g., 4 mg on Monday, Wednesday, Friday, and Sunday; 5 mg on Tuesday, Thursday, and
Saturday).
• Dosing is typically referred to in weekly dosing amounts given the day-to-day fluctuations in dose.
• The desired or target INR values are generally between 2 and 3.
• Many drugs interact with warfarin, so the physician/healthcare provider who oversees the warfarin
treatment must be notified whenever a new medicine (e.g., prescription or over-the-counter
medicine, supplement, or herbal therapy) is started for the first time, or when a current medication
is stopped or the dose is adjusted. Non-steroidal anti-inflammatory drugs (NSAIDs) should be
avoided or used with extreme caution under physician supervision.
• Even when medications do not interact with INR testing, they may still increase the risk of bleeding
through pharmacodynamic interactions (NSAIDs, selective serotonin-reuptake inhibitors).
• Diet changes can affect the INR, especially the intake of foods with high amounts of vitamin K (e.g.,
MANAGEMENT
spinach, broccoli); eating any amount of vegetables or food high in vitamin K is acceptable, so long
as the intake is consistent from week to week. Alcohol should be consumed with caution and only
in small amounts. Grapefruit juice should be avoided.
• Activities that carry a high risk of trauma or serious bleeding should be avoided, or if this is not
possible, additional safety precautions should be taken.
• The INR must be checked (monitored) frequently, with blood tests, often once or twice weekly until
the stable dose is reached, then on an extended interval (4-12 weeks) thereafter.
• Patients should be instructed on how to handle a missed dose (the approach may vary according to
the warfarin manager).
• Patients must be very clear about the daily dose of warfarin and the colours of their different
warfarin tablets.
• A pill organiser can help.
Although direct oral anticoagulants (DOACs) do not require coagulation assay laboratory monitoring and
drug-drug interactions are minimised when compared with warfarin, there are still some medications that
interact with DOACs and can lead to either increased risk of bleeding or increased risk of thrombosis
(e.g., primidone, amiodarone, diltiazem, verapamil, rifampicin, phenytoin, phenobarbital). Interactions are
most commonly mediated via cytochrome P450 enzyme (CYP450) and/or the transporter permeability
glycoprotein (P-gp).[212]
Patients should be taught about the range of signs and symptoms of bleeding and recurrent thrombosis in
order to be adequately prepared to make a decision about seeking immediate medical attention or not.
MANAGEMENT
61
Deep vein thrombosis Follow up
Monitoring
Monitoring
FOLLOW UP
For patients on intravenous heparin, activated partial thromboplastin time (aPTT) or calibrated anti-Xa
activity is measured:
• Prior to heparin initiation, to obtain a baseline

• 6 hours after initiation of the infusion
• 6 hours after each adjustment in the dose
• At least once daily thereafter when the therapeutic level is achieved (defined as 3 measurements in
the target range without interval dose adjustment).
Target values for aPTT are based on the local laboratory's standardised aPTT values, which should
correspond to a heparin level between 0.4 U/mL and 0.8 U/mL. Calibrated anti-Xa activity is an alternative
to aPTT. Platelet count should be measured at baseline, then on days 3 and 5, to observe for the
development of heparin-induced thrombocytopenia. Full blood count should be obtained to evaluate early
signs of bleeding through decreases in haematocrit/haemoglobin.
For patients treated with low molecular weight heparin (LMWH) or fondaparinux, no therapeutic
monitoring of anticoagulation is needed in most patients. Changes in patient weight may require
adjustment of the dose. Renal function indices, such as serum creatinine and urea, should be obtained to
determine initial and ongoing appropriateness of LMWH and fondaparinux as both require discontinuation
or dose adjustment in renal impairment.
Frequent international normalised ratio (INR) monitoring of patients who are treated with warfarin is
required. This is preferably done by experts or specialised anticoagulation clinics, whenever possible.
Anticoagulant therapy, although potentially life-saving, has inherent bleeding risks. A systematic approach
will reduce the likelihood of adverse events.[209] Patients can self-monitor their INR using portable point-
of-care instruments.[210]
The initial dose and titration of warfarin is more efficient and leads to better patient outcomes if an
estimating equation is used, rather than a fixed-dose initiation algorithm.[158] [159]
Rivaroxaban, apixaban, edoxaban, and dabigatran do not require laboratory monitoring for anticoagulant
effect. It is recommended that attention be directed to any changes in renal or liver function testing as
clinically indicated (e.g., at baseline then as indicated). With direct oral anticoagulants (DOACs), any
changes in concomitant medications (addition or discontinuation) should also be closely monitored
because this may require dose adjustment or discontinuation of the current DOAC for a change to another
DOAC or non-DOAC anticoagulant.
Patients who have pulmonary embolism should be evaluated clinically over time to determine whether
they have chronic thromboembolic pulmonary hypertension due to unresolved pulmonary emboli, which
may occur in up to 4% of patients.[211]
Complications
Complications Timeframe Likelihood
FOLLOW UP
pulmonary embolism (PE) short term high
The frequency, size, and symptoms of PE are variable. Among patients with proven thrombosis, lung
scans at the start of antithrombotic treatment showed a high probability of PE in 51% of patients.[198]
PE is treated in the same fashion as DVT unless there is cardiopulmonary compromise with hypotension
or evidence of right heart strain with significant pulmonary hypertension. In these cases, pulmonary
embolectomy or use of catheter-directed or systemic thrombolytic therapy should be considered. The
exact criteria for when to use thrombolysis have not been determined, but certain high-risk groups (e.g.,
patients with haemodynamic compromise) seem to confer greater benefit.[199] Selected patients with PE
are candidates for inferior vena cava filter.
bleeding during initial treatment short term medium
Most episodes of bleeding during anticoagulation result from a previously unknown pathological
lesion, such as duodenal ulcer, angiodysplasia in the colon, microvascular disease (such as a striatal
intracerebral bleed in a patient with hypertension), or rare conditions, such as amyloid angiopathy in the
central nervous system.[202]
If the patient is taking warfarin and experiences major bleeding, inactivated 4-factor prothrombin complex
concentrate (PCC) should be given promptly if clinically indicated. Oral or intravenous phytomenadione
(vitamin K) can also be given, either alone or in conjunction with PCC, but the effect of vitamin K on
warfarin is delayed and typically sustained for days. Intravenous administration is preferred in the setting
of intracranial haemorrhage.[203] The effect of the PCC can be assessed immediately by measuring the
international normalised ratio.[204] Fresh frozen plasma (FFP) has also been described as a means of
reversing the effect of warfarin, but carries greater risk, is much slower to administer, and confers a much
larger volume load than PCC. Guidelines favour PCC over FFP.[156]
Specific reversal agents are available for direct oral anticoagulants. Dabigatran can be reversed with
idarucizumab.[166] Recombinant coagulation factor Xa (andexanet alfa) has been approved for patients
with major or life-threatening bleeding on rivaroxaban and apixaban. Of note, andexanet alfa is not
approved for the reversal of edoxaban, likely due to low study enrollment of these patients.[205]
Protamine should be used to reverse unfractionated heparin and may be used to reverse low molecular
weight heparin, although it is not as effective.[206]
Non-specific reversal strategies have been tested for newer anticoagulants as well, but the level of
evidence for these is low. PCC has also been shown to normalise coagulation studies in normal volunteers
given high-dose rivaroxaban or apixaban. It is not known if this is the case with edoxaban. Dabigatran
does not appear to be reversed by PCC, though factor VIII inhibitor bypassing fraction (also known as
factor eight inhibitor bypass activity) may affect dabigatran, and about 60% of dabigatran can be removed
by dialysis. Activated charcoal may inhibit absorption of recently taken oral anticoagulants.
Inferior vena cava filter may be indicated in selected patients with acute bleeding during anticoagulation.
heparin-induced thrombocytopenia (HIT) short term low
Antibodies may develop to heparin-platelet factor IV complexes starting 5 to 7 days after initial exposure
to heparin or as early as <1 day in patients with recent (<30 days prior) heparin exposure.[196] The
antibodies aggregate platelets, lead to thrombocytopenia, and might result in acute arterial and venous
thrombosis as well as bleeding.
63

If there is a history of recent heparin exposure, development of HIT can be immediate. It develops in
between 1% to 2% of patients treated with therapeutic doses of heparin; however, it is rare when heparin
FOLLOW UP
is given subcutaneously to patients as a form of prophylaxis, but is possible and should be evaluated in
patients receiving prophylactic heparin with an elevated Warkentin Probability Scale ('4T score').
The incidence of HIT is lower in patients treated with low molecular weight heparin (LMWH). Although
there have been several reported cases of fondaparinux-associated HIT, it is a rare occurrence.
Due to the risk of HIT, platelet count should be measured at baseline, then on days 3 and 5, to observe for
the development of HIT.
Suspected HIT should be managed by promptly discontinuing heparin or LMWH, and substituting a direct
thrombin inhibitor such as argatroban, bivalirudin, or fondaparinux, or selecting apixaban, rivaroxaban, or
dabigatran. Anticoagulation may be transitioned to warfarin, if a parenteral anticoagulant is initially chosen,
when the platelet count returns to baseline.
When anticoagulation is clinically indicated in the presence of definite or moderate/high probability HIT,
a direct thrombin inhibitor (e.g., argatroban) is the generally recommended anticoagulant. Fondaparinux,
bivalirudin, apixaban, rivaroxaban, and dabigatran have been suggested, but they do not have regulatory
approval for active HIT.[167] [197]
The Warkentin Probability Scale ('4T score') for HIT can be used to estimate the pretest probability of
HIT.[133]
heparin resistance/aPTT confounding short term low
Patients might require very large doses of intravenous heparin and never achieve a therapeutic activated
partial thromboplastin time (aPTT).[207] This might be caused by very high levels of clotting factors, such
as fibrinogen.
In patients who require extremely large daily doses of unfractionated heparin (i.e., >2500 units/hour)
without achieving a therapeutic aPTT, it is recommended that the calibrated anti-Xa activity be measured
and used to guide heparin dosing.
In certain patients, such as those with antiphospholipid syndrome, the aPTT value may create a result
in the target range with only very low doses of heparin (or even no heparin). Calibrated anti-Xa activity
should be used to manage heparin in such cases if heparin is the drug chosen.
post-thrombotic syndrome long term medium
Caused by chronic obstruction of venous outflow and/or destruction of venous valves, resulting in venous
hypertension from venous insufficiency and/or venous outflow obstruction.[200]
Up to half of patients develop some signs or symptoms of post-thrombotic syndrome and this usually
occurs within 2 years of the acute DVT episode.[201]
bleeding during long-term/extended treatment variable low
The incidence is greatest in the first 3 months of treatment when on warfarin. Most bleeds are minor.
Fatality is relatively rare, and the rate is greatest for intracranial bleeds. Age over 75 years is associated
with an increase in the incidence of intracranial bleeding. Patients with renal impairment have a higher rate

of major bleeding. In general, bleeding is less with direct oral anticoagulants (e.g., apixaban, edoxaban,
dabigatran) when compared with warfarin for the management of venous thromboembolism.
FOLLOW UP
osteoporosis due to heparin treatment variable low
While the risk of osteoporotic fracture is as high as 2% if unfractionated heparin is given throughout
pregnancy, there are only a handful of cases published where osteoporotic fracture occurred in those on
low molecular weight heparin.[208]
There is conflicting evidence as to whether this develops in patients during chronic warfarin therapy.
Prognosis
Whether a DVT is due to major transient risk factors (e.g., trauma, surgery), minor transient risk factors
(prolonged hospitalisation or medical illness), major persisting risk factors (e.g., cancer), or no identified
risk factors (unprovoked) is a significant determinant of recurrence. The extent and location of the initial clot
influence the risk of post-thrombotic syndrome, which is the major sequela of DVT. Deep venous thrombosis
seldom alters the overall prognosis of the patient; the presence or absence of an underlying malignancy,
and the presence or absence of underlying medical comorbidity, such as liver disease or chronic kidney
disease, remain the major prognostic determinants among DVT patients. People with cancer have reduced
survival rates compared with people without cancer, and cancer patients who sustain DVT have a shorter life
expectancy than cancer patients without venous thromboembolism (VTE; though this appears to be related
to an association with more severe malignancy and VTE, rather than to the DVT itself). When a patient dies
from DVT, it is usually from pulmonary embolus (PE) or from a major haemorrhage as a complication of the
anticoagulation therapy.
In one systematic review, during the initial 3 months of anticoagulation, the rate of recurrent fatal VTE was
0.4% with a case-fatality rate of 11.3%. The rate of fatal major bleeding events was 0.2% with a case-fatality
rate of 11.3%. After anticoagulation, the rate of fatal recurrent VTE was 0.3 per 100 patient-years with a
case-fatality rate of 3.6%.[188]
In community cohort studies, the incidence of acute recurrent DVT within 60 days is as high as 25% to 30%.
The reasons for this acute recurrence are not known, but subtherapeutic anticoagulant therapy or patient
non-adherence to therapy may contribute.[189] [190]
In patients with acute DVT or PE enrolled in prospective cohort studies, only 5% of patients develop recurrent
VTE during the initial 6 months of anticoagulation; however, 30% of patients develop recurrent VTE between
6 months and 5 years after the initial event, if off anticoagulation.[191] [192]
Compared with patients with no thrombophilic defects, the rate of recurrence during warfarin therapy is not
increased in the presence of one or more defects.[193]
The incidence of major life-threatening haemorrhage owing to anticoagulant treatment is low, with the precise
risk varying by anticoagulant agent and patient characteristics.
Recurrence
Consensus guidelines recommend 3 months of oral anticoagulant therapy, unless contraindicated by
bleeding, in all patients with VTE with reassessment for possible extended therapy after the initial 3 months
65
of treatment.[194] Patients with DVT occurring in the setting of a major or minor transient provocation
will usually stop anticoagulants after completion of at least 3 months of therapy. Consideration should be
given to indefinite treatment among patients who have idiopathic or unprovoked DVT.[195] Patients with
cancer continue anticoagulants, as long as they are tolerated, while the cancer is active, and if the risk of
FOLLOW UP
bleeding remains low to moderate without any recent major bleeding episodes.[15] Regular reassessment is
necessary in patients with cancer as the risks of VTE and bleeding regularly change given modifications in
pharmacotherapeutic, surgical, and radiation therapies.[114] [179]
Many studies have attempted to identify subgroups of patients with unprovoked VTE who do not need to be
treated indefinitely with oral anticoagulation. There is strong evidence that the risk of recurrent VTE is higher
in the following patients: male sex; those with a diagnosis of a proximal DVT (versus isolated calf DVT); those
with ultrasound evidence of residual clot; those who have an elevated D-dimer 1 month after stopping a 3-
to 6-month course of oral anticoagulation; and those who had an unprovoked DVT.[15] [138] Several risk
assessment models have been developed for this purpose, including the DASH score, the Vienna Prediction
Model, and the 'Men Continue and HER-DOO2' model.[169] The latter model identifies a subset of women
with low risk for recurrent VTE after an initial unprovoked event, and a prospective validation study of this
model was published.[170]
Deep vein thrombosis Guidelines
Diagnostic guidelines
Europe
Venous thromboembolic diseases: diagnosis, management and

thrombophilia testing (ht tps://www.nice.org.uk/guidance/ng158)
Published by: National Institute for Health and Care Excellence Last published: 2020
Venous thromboembolism in over 16s: reducing the risk of hospital-acquired

deep vein thrombosis or pulmonary embolism (ht tps://www.nice.org.uk/
guidance/ng89)
Prevention and management of venous thromboembolism: a national clinical

guideline (ht tps://www.sign.ac.uk/our-guidelines)
GUIDELINES
Published by: Scottish Intercollegiate Guidelines Network Last published: 2014
Clinical guidelines for testing for heritable thrombophilia (ht tps://b-s-

h.org.uk/guidelines)
Published by: British Society for Haematology Last published: 2010
67
North America
NCCN clinical practice guidelines in oncology: cancer-associated venous

thromboembolic disease (ht tps://www.nccn.org)
Published by: National Comprehensive Cancer Network Last published: 2020
ACR-AIUM-SPR-SRU practice parameter for the performance of peripheral

venous ultrasound examination (ht tps://www.acr.org/Clinical-Resources/
Practice-Parameters-and-Technical-Standards/Practice-Parameters-by-
Modality)
Published by: American College of Radiology; American Institute Last published: 2019
of Ultrasound in Medicine; Society of Pediatric Radiology; Society of
Radiologists in Ultrasound
American Society of Hematology 2018 guidelines for management of

venous thromboembolism: diagnosis of venous thromboembolism (ht tps://
GUIDELINES
www.hematology.org/education/clinicians/guidelines-and-quality-care/
clinical-practice-guidelines/venous-thromboembolism-guidelines/diagnosis)
Published by: American Society of Hematology Last published: 2018
American Society of Hematology 2018 guidelines for management of venous

thromboembolism: venous thromboembolism in the context of pregnancy
(ht tps://www.hematology.org/education/clinicians/guidelines-and-quality-
care/clinical-practice-guidelines/venous-thromboembolism-guidelines/
pregnancy)
ACR appropriateness criteria: suspected lower extremity deep vein

thrombosis (ht tps://www.acr.org/Clinical-Resources/ACR-Appropriateness-
Criteria)
Published by: American College of Radiology Last published: 2018
Management of venous thromboembolism (ht tps://acforum.org/web/

education-guidance.php)
Published by: Anticoagulation Forum Last published: 2016
Diagnosis and management of iliofemoral deep vein thrombosis: clinical

practice guideline (ht tps://www.cmaj.ca/content/187/17/1288.long)
Published by: Interdisciplinary Expert Panel on Iliofemoral Deep Vein Last published: 2015
Thrombosis
Diagnosis of DVT: antithrombotic therapy and prevention of thrombosis, 9th

edition (ht tps://journal.chestnet.org/issue/S0012-3692(12)X6003-3)
Published by: American College of Chest Physicians Last published: 2012
Asia
Diagnosis and treatment of lower extremity deep vein thrombosis: Korean

practice guidelines (ht tps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045251)
Published by: Korean Society of Interventional Radiology; Korean Last published: 2016
Society for Vascular Surgery
GUIDELINES
69
Treatment guidelines
Europe
Venous thromboembolic diseases: diagnosis, management and

thrombophilia testing (ht tps://www.nice.org.uk/guidance/ng158)
Venous thromboembolism in over 16s: reducing the risk of hospital-acquired

deep vein thrombosis or pulmonary embolism (ht tps://www.nice.org.uk/
guidance/ng89)
Thromboembolic disease in pregnancy and the puerperium: acute

management (ht tps://www.rcog.org.uk/guidelines)
GUIDELINES
Published by: Royal College of Obstetricians and Gynaecologists Last published: 2015
Reducing the risk of venous thromboembolism during pregnancy and the

puerperium (ht tps://www.rcog.org.uk/guidelines)
Published by: Royal College of Obstetricians and Gynaecologists Last published: 2015
Ultrasound-enhanced, catheter-directed thrombolysis for deep vein

thrombosis (ht tps://www.nice.org.uk/guidance/ipg523)
Apixaban for the treatment and secondary prevention of deep vein

thrombosis and/or pulmonary embolism (ht tps://www.nice.org.uk/guidance/
ta341)
Postnatal care up to 8 weeks after birth (ht tps://www.nice.org.uk/guidance/

CG37)
Dabigatran etexilate for the treatment and secondary prevention of deep vein
thrombosis and/or pulmonary embolism (ht tps://www.nice.org.uk/guidance/
ta327)
Prevention and management of venous thromboembolism: a national clinical

guideline (ht tps://www.sign.ac.uk/our-guidelines)
Antithrombotics: indications and management - a national clinical guideline

(ht tps://www.sign.ac.uk/our-guidelines)
Europe
Guidelines on travel-related venous thrombosis (ht tps://b-s-h.org.uk/

guidelines)
Guidelines on use of vena cava filters (ht tps://b-s-h.org.uk/guidelines)

GUIDELINES
71
North America

thromboembolism: prevention and treatment in patients with cancer (ht tps://
www.hematology.org/education/clinicians/guidelines-and-quality-care/
clinical-practice-guidelines/venous-thromboembolism-guidelines/cancer)

thromboembolism: treatment of deep vein thrombosis and pulmonary
embolism (ht tps://www.hematology.org/education/clinicians/guidelines-
and-quality-care/clinical-practice-guidelines/venous-thromboembolism-
guidelines/treatment)
NCCN clinical practice guidelines in oncology: cancer-associated venous

GUIDELINES
thromboembolic disease (ht tps://www.nccn.org)

Published by: National Comprehensive Cancer Network Last published: 2020
Venous thromboembolism prophylaxis and treatment in patients with cancer

(ht tps://www.asco.org/research-guidelines/quality-guidelines/guidelines/
supportive-care-and-treatment-related-issues%20)
Published by: American Society of Clinical Oncology Last published: 2020

thromboembolism: optimal management of anticoagulation therapy (ht tps://
www.hematology.org/Clinicians/Guidelines-Quality/VTE/9178.aspx)

thromboembolism: venous thromboembolism in the context of pregnancy
(ht tps://www.hematology.org/education/clinicians/guidelines-and-quality-
care/clinical-practice-guidelines/venous-thromboembolism-guidelines/
pregnancy)
Published by: American Society of Hematology 2018 Last published: 2018
Management of venous thromboembolism (ht tps://acforum.org/web/

education-guidance.php)
Published by: Anticoagulation Forum Last published: 2016
Antithrombotic therapy for VTE disease: CHEST guideline and expert panel
report (ht tps://www.sciencedirect.com/science/article/pii/S0012369215003359)
North America
Diagnosis and management of iliofemoral deep vein thrombosis: clinical

practice guideline (ht tps://www.cmaj.ca/content/187/17/1288.long)
Published by: Interdisciplinary Expert Panel on Iliofemoral Deep Vein Last published: 2015
Thrombosis
Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy

and prevention of thrombosis, 9th edition (ht tps://journal.chestnet.org/issue/
S0012-3692(12)X6003-3)
Prevention of VTE in nonsurgical patients: antithrombotic therapy and

prevention of thrombosis, 9th edition (ht tps://journal.chestnet.org/issue/
S0012-3692(12)X6003-3)
GUIDELINES
Preventing venous thromboembolic disease in patients undergoing elective
hip and knee arthroplasty (ht tps://www.aaos.org/quality/quality-programs/
tumor-infection-and-military-medicine-programs/venous-thromboembolic-
disease-in-elective-tka-and-tha-prevention)
Published by: American Academy of Orthopaedic Surgeons Last published: 2011
Management of massive and submassive pulmonary embolism, iliofemoral

deep vein thrombosis, and chronic thromboembolic pulmonary hypertension
(ht tps://www.ahajournals.org/doi/full/10.1161/cir.0b013e318214914f)
Published by: American Heart Association Last published: 2011
Asia
Diagnosis and treatment of lower extremity deep vein thrombosis: Korean

practice guidelines (ht tps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045251)
Published by: Korean Society of Interventional Radiology; Korean Last published: 2016
Society for Vascular Surgery
73
Deep vein thrombosis Online resources
Online resources
1. IHI: reducing adverse drug events involving anticoagulants (http://www.ihi.org/knowledge/pages/tools/
anticoagulanttoolkitreducingades.aspx) (external link)
2. Warfarin dosing (http://www.warfarindosing.org/Source/Home.aspx) (external link)
3. Choosing Wisely: Society for Vascular Medicine – five things physicians and patients should question
(http://www.choosingwisely.org/societies/society-for-vascular-medicine) (external link)
4. Thrombosis Canada: warfarin point-of-care INR monitoring (http://thrombosiscanada.ca/wp-content/

uploads/2017/07/Warfain-Point-of-Care-2017Jul21-FINAL.pdf) (external link)
ONLINE RESOURCES
Deep vein thrombosis References
Key articles
• Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: Chest guideline and
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expert panel report. Chest. 2016 Feb;149(2):315-52. Full text (https://www.sciencedirect.com/
science/article/pii/S0012369215003359) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/26867832?
tool=bestpractice.bmj.com)
• Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: antithrombotic
therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-
based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e195S-226S. Full text (https://
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• Linnemann B, Bauersachs R, Rott H, et al. Diagnosis of pregnancy-associated venous

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ehx003) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/28329262?tool=bestpractice.bmj.com)
• Linnemann B, Scholz U, Rott H, et al. Treatment of pregnancy-associated venous thromboembolism

- position paper from the Working Group in Women's Health of the Society of Thrombosis
and Haemostasis (GTH). Vasa. 2016;45(2):103-18. Full text (http://econtent.hogrefe.com/doi/
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97
Deep vein thrombosis Images
Images
IMAGES
Figure 1: Wells' Score

Mazzolai L, et al. Diagnosis and management of acute deep vein thrombosis. Eur Heart J. 2018 Dec
14;39(47):4208-18
Deep vein thrombosis Images
IMAGES
Figure 2: Short-axis ultrasound view showing the femoral vein and profunda femoris vein adjacent to the
femoral artery before compression (left) and compressed (right)
99
IMAGES Deep vein thrombosis Images
Figure 3: Algorithm for the diagnosis of deep vein thrombosis

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Contributors:
// Authors:
Scot t M. Stevens, MD
Director
Thrombosis Clinic, Intermountain Medical Center, Murray, Professor of Medicine, Department of Medicine,
Intermountain Healthcare and University of Utah, Salt Lake City, UT
DISCLOSURES: SMS declares that he has no competing interests.
Scot t C. Woller, MD
Director
Thrombosis Clinic, Intermountain Medical Center, Murray, Professor of Medicine, Department of Medicine,
Intermountain Healthcare and University of Utah, Salt Lake City, UT
DISCLOSURES: SCW serves as co-chair of the American College of Chest Physicians (CHEST) guideline
on the treatment of venous thrombotic disease.
Gabriel V. Fontaine, PharmD, MBA, BCPS

Clinical Pharmacy Manager
Critical Care and Emergency Medicine, Advanced Clinical Pharmacist, Neuroscience Critical Care,
Intermountain Medical Center, Murray, UT
DISCLOSURES: GVF has received consulting fees and honoraria from Alexion Pharmaceuticals.
// Acknowledgements:
Dr Scott M. Stevens, Dr Scott C. Woller, and Dr Gabriel V. Fontaine would like to gratefully acknowledge Dr
Geno Merli, Dr Taki Galanis, Dr Luis Eraso, Dr Geoffrey Ouma, Dr Richard White, and Dr Windsor Ting, the
previous contributors to this topic.
DISCLOSURES: GM has received grant or research support from BMS, J&J, Sanofi-Aventis, Portola,
and Janssen; he has served as a Scientific Consultant for BMS, J&J, and Sanofi-Aventis. RW declares
participation in numerous multicentred clinical trials sponsored by companies: Agenix, Boehringer-
Ingleheim, Amgen, Bayer, Bristol-Meyer-Squibb, Novartis, Hemosense. TG, LE, GO, and WT declare that
they have no competing interests.
// Peer Reviewers:
Beverly Hunt, FRCP, FRCPath, MD

Professor of Thrombosis & Haemostasis
King's College, Consultant, Departments of Haematology, Pathology & Rheumatology, Lead in Blood
Sciences, Guy's & St Thomas' NHS Foundation Trust, London, UK
DISCLOSURES: BH declares that she has no competing interests.

Deep Vein Thrombosis

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Deep vein thrombosis

Straight to the point of care

Last updated: Apr 22, 2021

There is a clear association between DVT and the following:

(a) Superficial versus deep

• Superficial vein thrombosis (SVT)

• Thrombi form within veins deep to the muscular tissue planes.

(b) Proximal versus distal

• Proximal venous thrombosis

(c) Acute versus subacute, or chronic

DVT: upper extremity

(a) Superficial versus deep thrombosis

Signs and physical examination

Pretest probability (Wells' score)

Quantitative D-dimer level

Venous duplex ultrasound (DUS)

Tests for underlying conditions

Occult cancer is present in approximately 3% to 5% of patients with an unprovoked DVT.[108] However,

History and exam

localised pain along deep venous system (uncommon)

Other diagnostic factors

prominent superficial veins (common)

swelling of the entire leg (uncommon)

phlegmasia cerulea dolens (uncommon)

medical hospitalisation within the preceding 2 months

previous venous thromboembolic event

pregnancy and the postnatal period

paralysis of the lower extremities

prothrombin gene G20210A mutation

protein C or protein S deficiency

transient risk factor (such as preceding surgery.[41]

antiphospholipid antibody syndrome

use of specific drugs

recent long-distance air travel

central venous catheterisation

Short-axis ultrasound view showing the femoral vein

• In high-probability patients, a repeat ultrasound is indicated in 5 to 7

Short-axis ultrasound view showing the femoral vein

Other tests to consider

thrombophilia screen positive in inherited

Condition Differentiating signs / Differentiating tests

Calf muscle tear/Achilles' • History of trauma or sudden • No DVT seen on MRI or

Large or ruptured • Sudden onset of calf pain. • Ultrasound shows fluid in

Pelvic/thigh mass/tumour • Oedema usually occurs • Venous ultrasound, CT scan,

Warkentin Probability Scale for heparin-induced thrombocytopenia

Thrombosis or other sequelae

Other cause(s) of platelet fall

• 2 points if none evident

Pretest probability score

*First day of immunising heparin exposure is considered day 0.

• Prevent propagation/progression of the thrombus in the deep veins in the legs

[IHI: reducing adverse drug events involving anticoagulants] (http://www.ihi.org/knowledge/pages/tools/

• DVT that is best treated with intravenous unfractionated heparin (UFH)

Initiation phase of anticoagulation (5 to 21 days)

Proximal DVT of the leg

• UFH, LMWH, and fondaparinux

Treatment phase of anticoagulation (initiation to 3 months)

• If dalteparin is chosen, the dose is reduced after 1 month

Extended phase of anticoagulation (3 months to indefinite)

Provoked (minor or major transient risk factors) DVT

• Anticoagulation is discontinued after a course of at least 3 months. There is consensus that

patients with a high bleeding risk, 3 months’ treatment only is recommended.

• When assessing bleeding risk, the following factors should be considered:[15]