Practice Essentials

Deep venous thrombosis (DVT) is a manifestation of venous

thromboembolism (VTE). Although most DVT is occult and resolves
spontaneously without complication, death from DVT-associated
massive pulmonary embolism (PE) causes as many as 300,000 deaths
annually in the United States. [1] See the image below.

Deep venous thrombosis

(DVT). The computed tomography venogram shows bilateral deep venous
thrombosis (arrows).

Signs and symptoms

Symptoms of DVT may include the following:
 Edema - Most specific symptom
 Leg pain - Occurs in 50% of patients but is nonspecific
 Tenderness - Occurs in 75% of patients
 Warmth or erythema of the skin over the area of thrombosis
 Clinical symptoms of PE as the primary manifestation
As many as 46% with patients with classic symptoms have negative
venograms, [2] and as many as 50% of those with image-documented venous
thrombosis lack specific symptoms. [2, 3]
No single physical finding or combination of symptoms and signs is sufficiently
accurate to establish the diagnosis of DVT, but physical findings in DVT may
include the following:
 Calf pain on dorsiflexion of the foot (Homans sign)
 A palpable, indurated, cordlike, tender subcutaneous venous segment
 Variable discoloration of the lower extremity
 Blanched appearance of the leg because of edema (relatively rare)
Potential complications of DVT include the following:
 As many as 40% of patients have silent PE when symptomatic DVT is
diagnosed [4]
 Paradoxic emboli (rare)
 Recurrent DVT
 Postthrombotic syndrome (PTS)

Diagnosis
The American Academy of Family Physicians (AAFP)/American College of
Physicians (ACP) recommendations for workup of patients with probable DVT
are as follows [5] :
 Validated clinical prediction rules (eg, Wells) should be used to estimate
the pretest probability of VTE and interpret test results
 In appropriately selected patients with low pretest probability of DVT or
PE, it is reasonable to obtain a high-sensitivity D-dimer
 In patients with intermediate to high pretest probability of lower-extremity
DVT, ultrasonography is recommended
 In patients with intermediate or high pretest probability of PE, diagnostic
imaging studies (eg, ventilation-perfusion scan, multidetector helical CT,
and pulmonary angiography) are required
The main laboratory studies to be considered include the following:
 D-dimer testing
 Coagulation studies (eg, prothrombin time and activated partial
thromboplastin time) to evaluate for a hypercoagulable state

Management
Treatment options for DVT include the following:
 Anticoagulation (mainstay of therapy) - Heparins, warfarin, factor Xa
inhibitors, and various emerging anticoagulants
 Pharmacologic thrombolysis
 Endovascular and surgical interventions
 Physical measures (eg, elastic compression stockings and ambulation)
Heparin products used in the treatment of DVT include the following:
 Low-molecular-weight heparin (LMWH; eg, enoxaparin)
 Unfractionated heparin (UFH)
Factor Xa inhibitors used in the treatment of DVT include the following:
 Fondaparinux – This agent appears to be comparable to enoxaparin with
respect to efficacy and safety [6]
 Rivaroxaban – This agent appears to prevent VTE recurrence as
effectively as enoxaparin followed by a vitamin K antagonist and may be
associated with less bleeding [7, 8, 9] ; in addition, it appears to be usable in
high-risk groups
Endovascular therapy is performed to reduce the severity and duration of
lower-extremity symptoms, prevent PE, diminish the risk of recurrent VTE,
and prevent PTS. Percutaneous transcatheter treatment of DVT includes the
following:
 Thrombus removal with catheter-directed thrombolysis – American
College of Chest Physicians (ACCP) recommends thrombolytic therapy
only for patients with massive iliofemoral vein thrombosis associated with
limb ischemia or vascular compromise
 Mechanical thrombectomy
 Angioplasty
 Stenting of venous obstructions
American Heart Association (AHA) recommendations for inferior vena cava
filters include the following [10] :
 Confirmed acute proximal DVT or acute PE in patients contraindicated for
anticoagulation
 Recurrent thromboembolism while on anticoagulation
 Active bleeding complications requiring termination of anticoagulation
therapy
Background
Deep venous thrombosis (DVT) and pulmonary embolism (PE) are
manifestations of a single disease entity, namely, venous thromboembolism
(VTE). The earliest known reference to peripheral venous disease is found on
the Eber papyrus, which dates from 1550 BC and documents the potentially
fatal hemorrhage that may ensue from surgery on varicose veins. In 1644,
Schenk first observed venous thrombosis when he described an occlusion in
the inferior vena cava. In 1846, Virchow recognized the association between
venous thrombosis in the legs and PE.
DVT is the presence of coagulated blood, a thrombus, in one of the deep
venous conduits that return blood to the heart. The clinical conundrum is that
symptoms (pain and swelling) are often nonspecific or absent. However, if left
untreated, the thrombus may become fragmented or dislodged and migrate to
obstruct the arterial supply to the lung, causing potentially life-threatening PE
See the images below.
 Deep venous thrombosis
(DVT). The image shows venous thrombi.
View Media Gallery

Deep venous thrombosis

(DVT). A pulmonary embolus is shown.
DVT most commonly involves the deep veins of the leg or arm, often resulting
in potentially life-threatening emboli to the lungs or debilitating valvular
dysfunction and chronic leg swelling. Over the past 25 years, the
pathophysiology of DVT has become much better understood, and
considerable progress has been made in its diagnosis and treatment.
DVT is one of the most prevalent medical problems today, with an annual
incidence of 80 cases per 100,000. Each year in the United States, more than
200,000 people develop venous thrombosis; of those, 50,000 cases are
complicated by PE. [11] Lower-extremity DVT is the most common venous
thrombosis, with a prevalence of 1 case per 1000 population. In addition, it is
the underlying source of 90% of acute PEs, which cause 25,000 deaths per
year in the United States (National Center for Health Statistics [NCHS], 2006).
Conclusive diagnosis has historically required invasive and expensive
venography, which is still considered the criterion standard. The diagnosis
may also be obtained noninvasively by means of ultrasonographic
examination. (See Workup.)
Early recognition and appropriate treatment of DVT and its complications can
save many lives. (See Treatment and Management.) The goals of
pharmacotherapy for DVT are to reduce morbidity, prevent postthrombotic
syndrome (PTS), and prevent PE. The primary agents include anticoagulants
and thrombolytics. (See Medication.)
Other than the immediate threat of PE, the risk of long-term major disability
from postthrombotic syndrome is high. [12, 13, 14, 15, 16]
For patient education resources, see the Lung Disease & Respiratory Health
Center, as well as the patient education articles Deep Vein Thrombosis (Blood
Clot in the Leg, DVT), Phlebitis, and Pulmonary Embolism.
Anatomy
The peripheral venous system functions both as a reservoir to hold extra
blood and as a conduit to return blood from the periphery to the heart and
lungs. Unlike arteries, which possess 3 well-defined layers (a thin intima, a
well-developed muscular media, and a fibrous adventitia), most veins are
composed of a single tissue layer. Only the largest veins possess internal
elastic membranes, and this layer is thin and unevenly distributed, providing
little buttress against high internal pressures. The correct functioning of the
venous system depends on a complex series of valves and pumps that are
individually frail and prone to malfunction, yet the system as a whole performs
remarkably well under extremely adverse conditions.
Primary collecting veins of the lower extremity are passive, thin-walled
reservoirs that are tremendously distensible. Most are suprafascial,
surrounded by loosely bound alveolar and fatty tissue that is easily displaced.
These suprafascial collecting veins can dilate to accommodate large volumes
of blood with little increase in back pressure so that the volume of blood
sequestered within the venous system at any moment can vary by a factor of
2 or more without interfering with the normal function of the veins.
Suprafascial collecting veins belong to the superficial venous system.
Outflow from collecting veins is via secondary conduit veins that have thicker
walls and are less distensible. Most of these veins are subfascial and are
surrounded by tissues that are dense and tightly bound. These subfascial
veins belong to the deep venous system, through which all venous blood must
eventually pass through on its way back to the right atrium of the heart. The
lower limb deep venous system is typically thought of as 2 separate systems,
one below the knee and one above.
The calf has 3 groups of paired deep veins: the anterior tibial veins, draining
the dorsum of the foot; the posterior tibial veins, draining the sole of the foot;
and the peroneal veins, draining the lateral aspect of the foot. Venous
sinusoids within the calf muscle coalesce to form soleal and gastrocnemius
intramuscular venous plexuses, which join the peroneal veins in the mid calf.
These veins play an important role in the muscle pump function of the calf.
Just below the knee, these tibial veins join to become the popliteal vein, which
too can be paired on occasion.
Together, the calf’s muscles and deep vein system form a complex array of
valves and pumps, often referred to as the “peripheral heart,” that functions to
push blood upward from the feet against gravity. The calf-muscle pump is
analogous to the common hand-pump bulb of a sphygmomanometer filling a
blood pressure cuff. Before pumping has started, the pressure is neutral and
equal everywhere throughout the system and the calf fills with blood, typically
100-150 mL. When the calf contracts, the feeding perforator vein valves are
forced closed and the outflow valves are forced open driving the blood
proximally. When the calf is allowed to relax, the veins and sinusoids refill
from the superficial venous system via perforating veins, and the outflow valve
is then forced shut, preventing retrograde flow. With each “contraction,” 40-
60% of the calf’s venous volume is driven proximally. [17]
The deep veins of the thigh begin distally with the popliteal vein as it courses
proximally behind the knee and then passes through the adductor canal, at
which point its name changes to the femoral vein. (This important deep vein is
sometimes incorrectly referred to as the superficial femoral vein in a
misguided attempt to distinguish it from the profunda femoris, or deep femoral
vein, a short, stubby vein that usually has its origin in terminal muscle
tributaries within the deep muscles of the lateral thigh but may communicate
with the popliteal vein in up to 10% of patients.
The term superficial femoral vein should never be used, because the femoral
vein is in fact a deep vein and is not part of the superficial venous system.
This incorrect term does not appear in any definitive anatomic atlas, yet it has
come into common use in vascular laboratory practice. Confusion arising from
use of the inappropriate name has been responsible for many cases of clinical
mismanagement and death.) In theproximal thigh,the femoral vein and the
deep femoral vein unite to form the common femoral vein, which passes
upwards above the groin crease to become the iliac vein.
The external iliac vein is the continuation of the femoral vein as it passes
upward behind the inguinal ligament. At the level of the sacroiliac joint, it
unites with the hypogastric vein to form the common iliac vein. The left
common iliac is longer than the right and more oblique in its course, passing
behind the right common iliac artery. This anatomic asymmetry sometimes
results in compression of the left common iliac vein by the right common iliac
artery to produce May-Thurner syndrome, a left-sided iliac outflow obstruction
with localized adventitial fibrosis and intimal proliferation, often with
associated deep venous thrombosis. At the level of the fifth lumbar vertebra,
the 2 common iliac veins come together at an acute angle to form the inferior
vena cava.
Please go to the main article on Inferior Vena Caval Thrombosis for more
information.
Pathophysiology
Over a century ago, Rudolf Virchow described 3 factors that are critically
important in the development of venous thrombosis: (1) venous stasis, (2)
activation of blood coagulation, and (3) vein damage. These factors have
come to be known as the Virchow triad.
Venous stasis can occur as a result of anything that slows or obstructs the
flow of venous blood. This results in an increase in viscosity and the formation
of microthrombi, which are not washed away by fluid movement; the thrombus
that forms may then grow and propagate. Endothelial (intimal) damage in the
blood vessel may be intrinsic or secondary to external trauma. It may result
from accidental injury or surgical insult. A hypercoagulable state can occur
due to a biochemical imbalance between circulating factors. This may result
from an increase in circulating tissue activation factor, combined with a
decrease in circulating plasma antithrombin and fibrinolysins.
Over time, refinements have been made in the description of these factors
and their relative importance to the development of venous thrombosis. The
origin of venous thrombosis is frequently multifactorial, with components of the
Virchow triad assuming variable importance in individual patients, but the end
result is early thrombus interaction with the endothelium. This interaction
stimulates local cytokine production and facilitates leukocyte adhesion to the
endothelium, both of which promote venous thrombosis. Depending on the
relative balance between activated coagulation and thrombolysis, thrombus
propagation occurs.
Decreased vein wall contractility and vein valve dysfunction contribute to the
development of chronic venous insufficiency. The rise in ambulatory venous
pressure causes a variety of clinical symptoms of varicose veins, lower
extremity edema, and venous ulceration.
Development of thrombosis
Thrombosis is the homeostatic mechanism whereby blood coagulates or clots,
a process crucial to the establishment of hemostasis after a wound. It may be
initiated via several pathways, usually consisting of cascading activation of
enzymes that magnify the effect of an initial trigger event. A similar complex of
events results in fibrinolysis, or the dissolution of thrombi. The balance of
trigger factors and enzymes is complex. Microscopic thrombus formation and
thrombolysis (dissolution) are continuous events, but with increased stasis,
procoagulant factors, or endothelial injury, the coagulation-fibrinolysis balance
may favor the pathologic formation of an obstructive thrombus. Clinically
relevant deep venous thrombosis is the persistent formation of macroscopic
thrombus in the deep proximal veins.
For the most part, the coagulation mechanism consists of a series of self-
regulating steps that result in the production of a fibrin clot. These steps are
controlled by a number of relatively inactive cofactors or zymogens, which,
when activated, promote or accelerate the clotting process. These reactions
usually occur at the phospholipid surface of platelets, endothelial cells, or
macrophages. Generally, the initiation of the coagulation process can be
divided into 2 distinct pathways, an intrinsic system and an extrinsic system
(see the image below).

Deep venous thrombosis

(DVT). The coagulation pathway is shown.
View Media Gallery
The extrinsic system operates as the result of activation by tissue lipoprotein,
usually released as the result of some mechanical injury or trauma. The
intrinsic system usually involves circulating plasma factors. Both of these
pathways come together at the level of factor X, which is activated to form
factor Xa. This in turn promotes the conversion of prothrombin to thrombin
(factor II). This is the key step in clot formation, for active thrombin is
necessary for the transformation of fibrinogen to a fibrin clot.
Once a fibrin clot is formed and has performed its function of hemostasis,
mechanisms exist in the body to restore the normal blood flow by lysing the
fibrin deposit. Circulating fibrinolysins perform this function. Plasmin digests
fibrin and also inactivates clotting factors V and VIII and fibrinogen.
Three naturally occurring anticoagulant mechanisms exist to prevent
inadvertent activation of the clotting process. These include the heparin-
antithrombin III (ATIII), protein C and thrombomodulin protein S, and the
tissue factor inhibition pathways. When trauma occurs, or when surgery is
performed, circulating ATIII is decreased. This has the effect of potentiating
the coagulation process. Studies have demonstrated that levels of circulating
ATIII is decreased more, and stay reduced longer, after total hip replacement
(THR) than after general surgical cases (see the image below).

Deep venous thrombosis

(DVT). This chart shows postoperative antithrombin III levels.
View Media Gallery
Furthermore, patients who have positive venograms postoperatively tend to
be those in whom circulating levels of ATIII are diminished (see the image
below).

Deep venous thrombosis

(DVT). This chart depicts perioperative antithrombin III levels and DVT
formation.
View Media Gallery
Under normal circumstances, a physiologic balance is present between
factors that promote and retard coagulation. A disturbance in this equilibrium
may result in the coagulation process occurring at an inopportune time or
location or in an excessive manor. Alternatively, failure of the normal
coagulation mechanisms may lead to hemorrhage.
Thrombus usually forms behind valve cusps or at venous branch points, most
of which begin in the calf. Venodilation may disrupt the endothelial cell barrier
and expose the subendothelium. Platelets adhere to the subendothelial
surface by means of von Willebrand factor or fibrinogen in the vessel wall.
Neutrophils and platelets are activated, releasing procoagulant and
inflammatory mediators. Neutrophils also adhere to the basement membrane
and migrate into the subendothelium. Complexes form of the surface of
platelets and increase the rate of thrombin generation and fibrin formation.
Stimulated leukocytes irreversibly bind to endothelial receptors and
extravasate into the vein wall by means of mural chemotaxis. Because mature
thrombus composed of platelets, leukocytes and fibrin develops, and an active
thrombotic and inflammatory process occurs at the inner surface of the vein,
and an active inflammatory response occurs in the wall of the vein. [18, 19]
Studies have shown that low flow sites, such as the soleal sinuses, behind
venous valve pockets, and at venous confluences, are at most risk for the
development of venous thrombi. [20, 21] However, stasis alone is not enough to
facilitate the development of venous thrombosis. Experimental ligation of
rabbit jugular veins for periods of up to 60 minutes have failed to consistently
cause venous thrombosis. [22, 23] Although, patients that are immobilized for
long periods of time seem to be at high risk for the development of venous
thrombosis, an additional stimulus is required to develop deep venous
thrombosis (DVT).
Evolution of venous insufficiency
Over time, thrombus organization begins with the infiltration of inflammatory
cells into the clot. This results in a fibroelastic intimal thickening at the site of
thrombus attachment in most patients and a fibrous synechiae in up to
11%. [24] In many patients, this interaction between vessel wall and thrombus
leads to valvular dysfunction and overall vein wall fibrosis. Histological
examination of vein wall remodeling after venous thrombosis has
demonstrated an imbalance in connective tissue matrix regulation and a loss
of regulatory venous contractility that contributes to the development of
chronic venous insufficiency. [25, 26] Some form of chronic venous insufficiency
develops in 29-79% of patients with an acute DVT, while ulceration is noted in
4-6%. [27, 28] The risk has been reported to be 6 times greater in those patients
with recurrent thrombosis. [29]
Over a few months, most acute DVTs evolve to complete or partial
recanalization, and collaterals develop (see the images
below). [30, 31, 32, 33, 34, 35] Although blood flow may be restored, residual evidence
of thrombus or stenosis is observed in half the patients after 1 year.
Furthermore, the damage to the underlying valves and those compromised by
peripheral dilation and insufficiency usually persists and may progress.
Venous stasis, venous reflux, and chronic edema are common in patients who
have had a large DVT. [36]

Deep venous thrombosis (DVT). This lower-

extremity venogram shows outlining of an DVT in the popliteal vein with
contrast enhancement.
View Media Gallery
 Deep venous thrombosis (DVT). The lower-extremity
venogram reveals a nonocclusive chronic thrombus. The superficial femoral
vein (lateral vein) has the appearance of two parallel veins, when in fact it is
one lumen containing a chronic linear thrombus. Although the chronic clot is
not obstructive after it recanalizes, it effectively causes the venous valves to
adhere in an open position, predisposing the patient to reflux in the involved
segment.
View Media Gallery
The acute effect of an occluded outflow vein may be minimal if adequate
collateral pathways exist. As an alternative, it may produce marked pain and
swelling if flow is forced retrograde. In the presence of deep vein outflow
obstruction, contraction of the calf muscle produces dilation of the feeding
perforating veins, it renders the valves nonfunctional (because the leaflets no
longer coapt), and it forces the blood retrograde through the perforator
branches and into the superficial system. This high-pressure flow may cause
dilation of the superficial (usually low-pressure) system and produce
superficial venous incompetence. In clinical terms, the increased incidence of
reflux in the ipsilateral greater saphenous vein increases 8.7-fold on follow-up
of DVT. [30] This chain of events (ie, obstruction to antegrade flow producing
dilation, stasis, further valve dysfunction, with upstream increased pressure,
dilation, and other processes) may produce hemodynamic findings of venous
insufficiency.
Another mechanism that contributes to venous incompetence is the natural
healing process of the thrombotic vein. The thrombotic mass is broken down
over weeks to months by inflammatory reaction and fibrinolysis, and the
valves and venous wall are altered by organization and ingrowth of smooth
muscle cells and production of neointima. This process leaves damaged,
incompetent, underlying valves, predisposing them to venous reflux. The
mural inflammatory reaction breaks down collagen and elastin, leaving a
noncompliant venous wall. [30, 31, 32, 33, 34, 35]
Persistent obstructive thrombus, coupled with valvular damage, ensures
continuation of this cycle. Over time, the venous damage may become
irreversible. Hemodynamic venous insufficiency is the underlying pathology of
postthrombotic syndrome (PTS), also referred to as postphlebitic syndrome. If
numerous valves are affected, flow does not occur centrally unless the leg is
elevated. Inadequate expulsion of venous blood results in stasis and a
persistently elevated venous pressure or venous hypertension. As fibrin
extravasates and inflammation occurs, the superficial tissues become
edematous and hyperpigmented. With progression, fibrosis compromises
tissue oxygenation, and ulceration may result. After venous insufficiency
occurs, no treatment is ideal; elevation and use of compression stockings may
compensate, or surgical thrombectomy or venous bypass may be
attempted. [37, 38, 39, 40]
With anticoagulation alone, as many as 75% of patients with symptomatic
DVT present with PTS at 5-10 years. [40, 41] However, the incidence of venous
ulceration is far less, at 5%. Of the half million patients with venous ulcers in
the United States, 17-45% report having a history of DVT. [42]
Lower-extremity deep venous thrombosis
Most small thrombi in the lower extremities tend to resolve spontaneously
after surgery. In about 15% of cases, however, these thrombi may extend into
the proximal femoral venous system of the leg. Untreated proximal thrombi
represent a significant source of clinically significant pulmonary emboli.
In the absence of rhythmic contraction of the leg muscles, as in walking or
moving, blood flow in the veins slows and even stops in some areas,
predisposing patients to thrombosis. [43]
In the postoperative patient, as many as one half of all isolated calf vein
thrombi resolve spontaneously within a few hours, whereas approximately
15% extend to involve the femoral vein. A many as one third of untreated
symptomatic calf vein DVT extend to the proximal veins. [44] At 1-month follow-
up of untreated proximal DVT, 20% regress and 25% propagate. Although calf
vein thrombi are rare sources of clinically significant pulmonary embolism
(PE), the incidence of PE with untreated proximal thrombi is 29-
50%. [44, 45] Most PEs are first diagnosed at autopsy. [46, 47]
Upper-extremity deep venous thrombosis
The 2 forms of upper-extremity DVT are (1) effort-induced thrombosis (Paget-
von Schrötter syndrome) and (2) secondary thrombosis.
Effort induced thrombosis, or Paget-von Schrötter syndrome, accounts for
25% of cases. [48] Paget in England and von Schrötter in Germany
independently described effort thrombosis more than 100 years ago. In this
primary form of the disease, an underlying chronic venous compressive
abnormality caused by the musculoskeletal structures in the costoclavicular
space is present at the thoracic inlet and/or outlet. See the images below.

Deep venous thrombosis (DVT). This

contrast-enhanced study was obtained through a Mediport placed through the
chest wall through the internal jugular vein to facilitate chemotherapy. A
thrombus has propagated peripherally from the tip of the catheter in the
superior vena cava into both subclavian veins.
View Media Gallery
 Deep venous thrombosis
(DVT). Superior vena cava syndrome is noted in a patient with lung cancer.
The computed tomography scan demonstrates a hypoattenuating thrombus
that fills the superior vena cava. The patient was treated with anticoagulation
alone.
View Media Gallery
In 75% of patients with secondary thrombosis, hypercoagulability and/or
indwelling central venous catheters are important contributing factors. In fact,
with the advent of central venous catheters, upper-extremity and
brachiocephalic venous thrombosis has become a more common
problem. [49, 50, 51, 52]
For more information on upper-extremity DVT, see Imaging in Deep Venous
Thrombosis of the Upper Extremity.
Pulmonary embolism
PE develops as venous thrombi break off from their location of origin and
travel through the right heart and into the pulmonary artery, causing a
ventilation perfusion defect and cardiac strain. PE occurs in approximately
10% of patients with acute DVT and can cause up to 10% of in hospital
deaths. [53, 54] However, most patients (up to 75%) are asymptomatic.
Traditionally, proximal venous thrombosis are thought to be at highest risk for
causing pulmonary emboli; however, the single largest autopsy series ever
performed to specifically to look for the source of fatal PE was performed by
Havig in 1977, who found that one third of the fatal emboli arose directly from
the calf veins. [55]
Superior vena cava syndrome
Superior vena cava syndrome is caused by gradual compression of the
superior vena cava (SVC). Patients can present with dyspnea, cough,
dysphagia, and swelling of the neck and upper extremities. SVC syndrome is
most commonly caused by extrinsic compression from a malignant process,
such as lung or breast cancer. However, thrombotic causes of SVC syndrome
are increasing due to the more widespread use of central venous catheters
and pacemakers. SVC syndrome is a clinical diagnosis, but it can be
confirmed with plain radiography, computed tomography (CT) scanning, and
venography. [56]
For cancer-related SVC syndrome, the treatment consists of chemotherapy
and radiation directed at the obstructing tumor. For thrombotic causes,
thrombolysis and anticoagulation may be used. [57] Increasingly, endovascular
treatment with balloon dilation and stenting are being used with rapid
resolution of symptoms. [58, 59]
For more information, see Superior Vena Cava Syndrome.
Etiology
Numerous factors, often in combination, contribute to deep venous thrombosis
(DVT). These may be categorized as acquired (eg, medication, illness) or
congenital (eg, anatomic variant, enzyme deficiency, mutation). A useful
categorization may be an acute provoking condition versus a chronic
condition, as this distinction affects the length of anticoagulant therapy.
The frequent causes of DVT are due to augmentation of venous stasis due to
immobilization or central venous obstruction. Immobility can be as transient as
that occurring during a transcontinental airplane flight or that during an
operation under general anesthesia. Thus, risk factors include obesity,
medications, pregnancy, trauma, malignancy, and genetic conditions. [60] It can
also be extended, as during hospitalization for pelvic, hip, or spinal surgery, or
due to stroke or paraplegia. Individuals in these circumstances warrant
surveillance, prophylaxis, and treatment if they develop DVT. [61, 62]
Reduced blood flow from increased blood viscosity or central venous pressure
Increased blood viscosity may decrease venous blood flow. This change may
be due to an increase in the cellular component of the blood in polycythemia
rubra vera or thrombocytosis or a decrease in the fluid component due to
dehydration.
Increased central venous pressure, either mechanical or functional, may
reduce the flow in the veins of the leg. Mass effect on the iliac veins or inferior
vena cava from neoplasm, pregnancy, stenosis, or congenital anomaly
increases outflow resistance.
Anatomic variants contributing to venous stasis
Anatomic variants that result in diminution or absence of the inferior vena
cava or iliac veins may contribute to venous stasis. In iliocaval thromboses, an
underlying anatomic contributor is identified in 60-80% of patients. The best-
known anomaly is compression of left common iliac vein at the anatomic
crossing of the right common iliac artery. The vein normally passes under the
right common iliac artery during its normal course.
In some individuals, this anatomy results in compression of the left iliac vein
and can lead to band or web formation, subsequent stasis, and left leg DVT.
The reasons are poorly understood. Compression of the iliac vein is also
called May-Thurner syndrome or Cockett syndrome.
Inferior vena cava variants are uncommon. Anomalous development is most
commonly detected and diagnosed on cross-sectional imaging or venography.
The embryologic evolution of the inferior vena cava is from an enlargement or
atrophy of paired supracardinal and subcardinal veins. Anomalous
embryologic development may result in absence of the normal cava. These
variations may increase the risk of symptoms because small-caliber vessels
may be most subject to obstruction. In patients younger than 50 years who
have deep venous thrombosis, the incidence of a caval anomaly is as high as
5%. [63]
A double or duplicated inferior vena cava results from lack of atrophy in part of
the left supracardinal vein, resulting in a duplicate structure to the left of the
aorta. The common form is a partial paired inferior vena cava that connects
the left common iliac and left renal veins. When caval interruption, such as
placement of a filter, is planned, these alternate pathways must be
considered. As an alternative, the inferior vena cava may not develop. The
most common alternate route for blood flow is through the azygous vein,
which enlarges to compensate. If a venous stenosis is present at the
communication of iliac veins and azygous vein, back pressure can result in
insufficiency, stasis, or thrombosis. [64]
In rare cases, neither the inferior vena cava nor the azygous vein develops,
and the iliac veins drain through internal iliac collaterals to the hemorrhoidal
veins and superior mesenteric vein to the portal system of the liver. Hepatic
venous drainage to the atrium is patent. Because this pathway involves small
hemorrhoidal vessels, thrombosis of these veins can cause severe acute
swelling of the legs.
Thrombosis of the inferior vena cava is a rare occurrence and is an unusual
result of leg deep venous thrombosis unless an inferior vena cava filter is
present and stops a large embolus in the cava, resulting in obstruction and
extension of thrombosis. Common causes of caval thrombosis include tumors
involving the kidney or liver, tumors invading the inferior vena cava,
compression of the inferior vena cava by extrinsic mass, and retroperitoneal
fibrosis. [65, 66]
Mechanical injury to vein
Mechanical injury to the vein wall appears to provide an added stimulus for
venous thrombosis. Hip arthroplasty patients with the associated femoral vein
manipulation represent a high-risk group that cannot be explained by just
immobilization, with 57% of thrombi originating in the affected femoral vein
rather than the usual site of stasis in the calf. [67] Endothelial injury can convert
the normally antithrombogenic endothelium to become prothrombotic by
stimulating the production of tissue factor, von Willebrand factor, and
fibronectin.
Injury may be obvious, such as those due to trauma, surgical intervention, or
iatrogenic injury, but they may also be obscure, such as those due to remote
deep venous thrombosis (perhaps asymptomatic) or minor (forgotten) trauma.
Previous DVT is a major risk factor for further DVT. The increased incidence
of DVT in the setting of acute urinary tract or respiratory infection may be due
to an inflammation-induced alteration in endothelial function.
According to the results of a meta-analysis of 64 studies encompassing
29,503 patients, peripherally inserted central catheters (PICCs) may double
the risk for DVT in comparison with central venous catheters (CVCs). [68, 69] This
was the largest review of the incidence, patterns, and risk for venous
thromboembolism (VTE) associated with PICCs yet published; however, the
findings were limited by the absence of any published randomized trials.
Compared with CVCs, PICCs were associated with an increased risk of DVT
(odds ratio [OR], 2.55; but not of pulmonary embolism (no events). [69] The
frequency of PICC-related DVT was highest in patients who were critically ill
(13.91%) and patients who had cancer (6.67%).
Common risk factors for deep venous thrombosis
The presence of risk factors plays a prominent role in the assessing the
pretest probability of DVT. Furthermore, transient risk factors permit
successful short-term anticoagulation, whereas idiopathic deep venous
thrombosis or chronic or persistent risk factors warrant long-term therapy.
In the MEDENOX study that evaluated 1102 acutely ill, immobilized admitted
general medical patients, multiple logistic regression analysis found the
following factors to be significantly and independently associated with an
increased risk for VTE, most of which were asymptomatic and diagnosed by
venography of both lower extremities [70] :
 Presence of an acute infectious disease
 Age older than 75 years
 Cancer
 History of prior VTE
The most common risk factors are obesity, previous VTE, malignancy,
surgery, and immobility. Each is found in 20-30% of patients. Hospitalized and
nursing home patients often have several risk factors and account for one half
of all DVT (with an incidence of 1 case per 100 population). [46, 71] Obesity also
appears to increases the risk of anticoagulation reversal failure with
prothrombin complex concentrate in those with intracranial hemorrhage. [72]
The single most powerful risk marker remains a prior history of DVT, with as
many as 25% of acute venous thrombosis occurring in such
patients. [73] Pathologically, remnants of previous thrombi are often seen within
the specimens of new acute thrombi. However, recurrent thrombosis may
actually be the result of primary hypercoagulable states. Abnormalities within
the coagulation cascade are the direct result of discrete genetic mutations
within the coagulation cascade. Deficiencies of protein C, protein S, or
antithrombin III account for approximately 5-10% of all cases of DVT. [74]
Age has been well studied as an independent risk factor for venous
thrombosis development. Although a 30-fold increase in incidence is noted
from age 30 to age 80, the effect appears to be multifactorial, with more
thrombogenic risk factors occurring in the elderly than in those younger than
40 years. [73, 75] Venous stasis, as seen in immobilized patients and paralyzed
limbs, also contributes to the development of venous thrombosis. Autopsy
studies parallel the duration of bed rest to the incidence of venous thrombosis,
with 15% of patients in those studies dying within 7 days of bedrest to greater
than 80% in those dying after 12 weeks. [20] Within stroke patients, DVT is
found in 53% of paralyzed limbs, compared with only 7% on the nonaffected
side. [76]
Malignancy is noted in as many as 30% of patients with venous
thrombosis. [73, 77] The thrombogenic mechanisms involve abnormal
coagulation, as evidenced by 90% of cancer patients having some abnormal
coagulation factors. [78] Chemotherapy may increase the risk of venous
thrombosis by affecting the vascular endothelium, coagulation cascades, and
tumor cell lysis. The incidence has been shown to increase in those patients
undergoing longer courses of therapy for breast cancer, from 4.9% for 12
weeks of treatment to 8.8% for 36 weeks. [79] Additionally, DVT complicates
29% of surgical procedures done for malignancy. [80]
Postoperative venous thrombosis varies depending on a multitude of patient
factors, including the type of surgery undertaken. Without prophylaxis, general
surgery operations typically have an incidence of DVT around 20%, whereas
orthopedic hip surgery can occur in up to 50% of patients. [81] The nature of
orthopedic illnesses and diseases, trauma, and surgical repair or replacement
of hip and knee joints predisposes patients to the occurrence of VTE disease.
These complications are predictable and are the result of alterations of the
natural equilibrium mechanisms in various disease states. [82] For more
information, see Deep Venous Thrombosis Prophylaxis.
Based on radioactive labeled fibrinogen, about half of lower extremity thrombi
develop intraoperatively. [83] Perioperative immobilization, coagulation
abnormalities, and venous injury all contribute to the development of surgical
venous thrombosis.
Genetic factors
Genetic mutations within the blood’s coagulation cascade represent those at
highest risk for the development of venous thrombosis. Genetic thrombophilia
is identified in 30% of patients with idiopathic venous thrombosis. Primary
deficiencies of coagulation inhibitors antithrombin, protein C, and protein S are
associated with 5-10% of all thrombotic events. [84, 85, 86] Altered procoagulant
enzyme proteins include factor V, factor VIII, factor IX, factor XI, and
prothrombin. Resistance of procoagulant factors to an intact anticoagulation
system has also recently been described with the recognition of factor V
Leiden mutation, representing 10-65% of patients with DVT. [87] In the setting of
venous stasis, these factors are allowed to accumulate in thrombosis prone
sites, where mechanical vessel injury has occurred, stimulating the
endothelium to become prothrombotic. [88]
Factor V Leiden is a mutation that results in a form of factor Va that resists
degradation by activated protein C, leading to a hypercoagulable state. Its
importance lies in the 5% prevalence in the American population and its
association with a 3-fold to 6-fold increased risk for VTE. Antiphospholipid
syndrome is considered a disorder of the immune system, where
antiphospholipid antibodies (cardiolipin or lupus anticoagulant antibodies) are
associated with a syndrome of hypercoagulability. Although not a normal
blood component, the antiphospholipid antibody may be asymptomatic. It is
present in 2% of the population, and it may be detected in association with
infections or the administration of certain drugs, including antibiotics, cocaine,
hydralazine, procainamide, and quinine. [85]
Tests for these genetic defects are often not performed in patients with
recurrent venous thrombosis because therapy remains symptomatic. In most
patients with these genetic defects, lifetime anticoagulation therapy with
warfarin or low molecular weight heparin (LMWH) is recommended after
recurrent DVT without an alternative identifiable etiology documented. The
risk of recurrent DVT is multiplied 1.4-2 times, with the most common genetic
polymorphisms predisposing individuals to DVT. However, the low incidence
of factor V Leiden and prothrombin G20210A may not warrant aggressive
prophylaxis. Therefore, genetic testing might not be warranted until a second
event occurs. [89]
Other conditions that can induce hypercoagulability
Other diseases and states can induce hypercoagulability in patients without
other underlying risks for DVT. They can predispose patients to DVT, though
their ability to cause DVT without intrinsic hypercoagulability is in question.
The conditions include malignancy, dehydration, and use of medications (eg,
estrogens). Acute hypercoagulable states also occur, as in disseminated
intravascular coagulopathy (DIC) resulting from infection or heparin-induced
thrombocytopenia. [90]
Summary of risk factors
A summary of risk factors is as follows:
 Age
 Immobilization longer than 3 days
 Pregnancy and the postpartum period
 Major surgery in previous 4 weeks
 Long plane or car trips (>4 hours) in previous 4 weeks
 Cancer
 Previous DVT
 Stroke
 Acute myocardial infarction (AMI)
 Congestive heart failure (CHF)
 Sepsis
 Nephrotic syndrome
 Ulcerative colitis
 Multiple trauma
 CNS/spinal cord injury
 Burns
 Lower extremity fractures
 Systemic lupus erythematosus (SLE) and the lupus anticoagulant
 Behçet syndrome
 Homocystinuria
 Polycythemia rubra vera
 Thrombocytosis
 Inherited disorders of coagulation/fibrinolysis
 Antithrombin III deficiency
 Protein C deficiency
 Protein S deficiency
 Prothrombin 20210A mutation
 Factor V Leiden
 Dysfibrinogenemias and disorders of plasminogen activation
 Intravenous (IV) drug abuse
 Oral contraceptives
 Estrogens
 Heparin-induced thrombocytopenia (HIT)
Epidemiology
Deep venous thrombosis (DVT) and thromboembolism remain a common
cause of morbidity and mortality in bedridden or hospitalized patients, as well
as generally healthy individuals. The exact incidence of DVT is unknown
because most studies are limited by the inherent inaccuracy of clinical
diagnosis. Existing data that probably underestimate the true incidence of
DVT suggest that about 80 cases per 100,000 population occur annually.
Approximately 1 person in 20 develops a DVT in the course of his or her
lifetime. About 600,000 hospitalizations per year occur for DVT in the United
States.
In elderly persons, the incidence is increased four-fold. The in-hospital case-
fatality rate for venous thromboembolism (VTE) is 12%, rising to 21% in
elderly persons. In hospitalized patients, the incidence of venous thrombosis
is considerably higher and varies from 20-70%. Venous ulceration and venous
insufficiency of the lower leg, which are long-term complications of DVT, affect
0.5% of the entire population. Extrapolation of these data reveals that as
many as 5 million people have venous stasis and varying degrees of venous
insufficiency.
Age distribution for deep venous thrombosis
Deep venous thrombosis usually affects individuals older than 40 years. The
incidence of VTE increases with age in both sexes. The age-standardized
incidence of first-time VTE is 1.92 per 1000 person-years.
Prevalence of deep venous thrombosis by sex
The male-to-female ratio is 1.2:1, indicating that males have a higher risk of
DVT than females.
Prevalence of deep venous thrombosis by race
From a demographic viewpoint, Asian and Hispanic populations have a lower
risk of VTE, whereas whites and blacks have a higher risk (2.5-4 times
higher).
Prognosis
Most cases of deep venous thrombosis (DVT) is occult and usually resolves
spontaneously without complication. The principal long-term morbidity from
DVT is postthrombotic syndrome (PTS), which complicates about a quarter of
cases of symptomatic proximal DVT; most cases develop within 2 years
afterward.
Death from DVT is attributed to massive pulmonary embolism (PE), which
causes as many as 300,000 deaths annually in the United States. [1] PE is the
leading cause of preventable in-hospital mortality. The Longitudinal
Investigation of Thromboembolism Etiology (LITE) that combined data from
two prospective cohort studies, the Atherosclerosis Risk in Communities
(ARIC) and the Cardiovascular Health Study (CHS) determined the incidence
of symptomatic DVT and pulmonary embolism in 21,680 participants aged 45
years or older who were followed for 7.6 years. [91]
Thromboembolism and recurrent thromboembolism appear to be serious
complications of inflammatory bowel disease. [92] In a study comprising 84
patients with inflammatory disease and a history of thromboembolism, of
whom, 30% had recurrent thromboembolism, 70 patients (83%) developed
venous thromboembolism (40% of which manifested as DVT and 23% as
PE). [92]
History
Deep venous thrombosis (DVT) classically produces pain and limb edema;
however, in a given patient, symptoms may be present or absent, unilateral or
bilateral, or mild or severe. Thrombus that does not cause a net venous
outflow obstruction is often asymptomatic. Edema is the most specific
symptom of DVT. Thrombus that involves the iliac bifurcation, the pelvic veins,
or the vena cava produces leg edema that is usually bilateral rather than
unilateral. High partial obstruction often produces mild bilateral edema that is
mistaken for the dependent edema of right-sided heart failure, fluid overload,
or hepatic or renal insufficiency. Massive edema with cyanosis and ischemia
(phlegmasia cerulea dolens) is rare.
Leg pain occurs in 50% of patients, but this is entirely nonspecific. Pain can
occur on dorsiflexion of the foot (Homans sign). Tenderness occurs in 75% of
patients but is also found in 50% of patients without objectively confirmed
DVT. When tenderness is present, it is usually confined to the calf muscles or
along the course of the deep veins in the medial thigh. Pain and/or tenderness
away from these areas is not consistent with venous thrombosis and usually
indicates another diagnosis. The pain and tenderness associated with DVT
does not usually correlate with the size, location, or extent of the thrombus.
Warmth or erythema of skin can be present over the area of thrombosis.
Clinical signs and symptoms of pulmonary embolism as the primary
manifestation occur in 10% of patients with confirmed DVT.
Even with patients with classic symptoms, as many as 46% have negative
venograms. [2] Furthermore, as many as 50% of those with image-documented
venous thrombosis lack specific symptoms. [3, 93] DVT simply cannot be
diagnosed or excluded based on clinical findings; thus, diagnostic tests must
be performed whenever the diagnosis of DVT is being considered. (See
Workup)
Physical Examination
No single physical finding or combination of symptoms and signs is sufficiently
accurate to establish the diagnosis of deep venous thrombosis (DVT).
The classic finding of calf pain on dorsiflexion of the foot with the knee straight
(Homans sign) has been a time-honored sign of DVT. [94] However, Homans
sign is neither sensitive nor specific: it is present in less than one third of
patients with confirmed DVT, and is found in more than 50% of patients
without DVT.
Superficial thrombophlebitis is characterized by the finding of a palpable,
indurated, cordlike, tender, subcutaneous venous segment. Forty percent of
patients with superficial thrombophlebitis without coexisting varicose veins
and with no other obvious etiology (eg, intravenous catheters, intravenous
drug abuse, soft tissue injury) have an associated DVT. Patients with
superficial thrombophlebitis extending to the saphenofemoral junction are also
at higher risk for associated DVT.
If a patient is thought to have pulmonary embolism (PE) or has documented
PE, the absence of tenderness, erythema, edema, or a palpable cord upon
examination of the lower extremities does not rule out thrombophlebitis, nor
does it imply a source other than a leg vein. More than two thirds of patients
with proven PE lack any clinically evident phlebitis. Nearly one third of patients
with proven PE have no identifiable source of DVT, despite a thorough
investigation. Autopsy studies suggest that even when the source is clinically
inapparent, it lies undetected within the deep venous system of the lower
extremity and pelvis in 90% of cases.
Patients with venous thrombosis may have variable discoloration of the lower
extremity. The most common abnormal hue is reddish purple from venous
engorgement and obstruction. In rare cases, the leg is cyanotic from massive
ileofemoral venous obstruction. This ischemic form of venous occlusion was
originally described as phlegmasia cerulea dolens (“painful blue
inflammation”). The leg is usually markedly edematous, painful, and cyanotic.
Petechiae are often present.
In relatively rare instances, acute extensive (lower leg–to-iliac) occlusion of
venous outflow may create a blanched appearance of the leg because of
edema. The clinical triad of pain, edema, and blanched appearance is
termed phlegmasia alba dolens (“painful white inflammation”), a term originally
used to describe massive ileofemoral venous thrombosis and associated
arterial spasm. This is also known as milk-leg syndrome when it is associated
with compression of the iliac vein by the gravid uterus. The affected extremity
is often pale with poor or even absent distal pulses. The physical findings may
suggest acute arterial occlusion, but the presence of swelling, petechiae, and
distended superficial veins point to this condition. As many as half the patients
with phlegmasia alba dolens have capillary involvement, which poses a risk of
irreversible venous gangrene with massive fluid sequestration. In severely
affectedpatients, immediate therapyisnecessarytoprevent limb loss.
Pulmonary Embolism
As many as 40% of patients have silent pulmonary embolism (PE) when
symptomatic deep venous thrombosis (DVT) is diagnosed. [4] Approximately
4% of individuals treated for DVT develop symptomatic PE. Almost 1% of
postoperative hospitalized patients develop PE. The 10-12% mortality rate for
PE in hospitalized patients underscores the need for prevention of this
complication. Treatment options include anticoagulation therapy and
placement of an inferior vena cava filter. If evidence of right heart failure is
present or if adequate oxygenation cannot be maintained, the thrombus may
be removed with pharmacomechanical thrombolytic intervention.
Electrocardiography may demonstrate ST-segment changes in patients with
PE. The arterial oxygen saturation (PaO2) level may be lowered. All or none of
these findings may be present, and the embolization may remain subclinical
or silent. (See the images below.)

Deep venous thrombosis

(DVT). Lung scans are shown. LPO = left posterior oblique.
View Media Gallery
 Deep venous thrombosis
(DVT). Spiral computed tomography scan showing a pulmonary thrombus.
View Media Gallery

Deep venous thrombosis

(DVT). This is the appearance of a normal pulmonary angiogram.
View Media Gallery
 Deep venous thrombosis
(DVT). This is a positive pulmonary angiogram.
View Media Gallery
PE is most often diagnosed by means of ventilation/perfusion lung scanning,
which is reported as having a low, moderate, or high probability of depicting
PE. When the results of these studies are equivocal, the use of spiral CT
scans may be able to demonstrate intravascular thrombosis. In many
institutions, the criterion standard for diagnosing PE is pulmonary
angiography.
Paradoxic Emboli
Although rare, paradoxic emboli can occur in patients with cardiac defects
(usually atrial septal defect), who are at risk for the passage of emboli to the
arterial circulation and resultant stroke or embolization of a peripheral artery.
Patients can present after cardiac failure occurs late in life, with resultant
bedrest that increases the risk for deep venous thrombosis.
Recurrent Deep Venous Thrombosis
Without treatment, one half of patients with deep venous thrombosis (DVT)
have a recurrent, symptomatic venous thromboembolism (VTE) event within 3
months. After anticoagulation for an unprovoked VTE event is discontinued,
the incidence is 5-15% per year. Presentations are similar, with pain and
edema. However, the diagnosis may be difficult (ie, differentiating acute from
chronic thrombus). Recurrence increases the risk of postthrombotic syndrome
(PTS).
A review by Martinelli et al indicates that hormonal therapy, including
estrogen-containing agents, does not appear to be associated with recurrent
VTE in women younger than 60 years receiving anticoagulation with
rivaroxaban or enoxaparin/vitamin K antagonists for confirmed
VTE. [95] However, it was noted that abnormal uterine bleeding occurred more
frequently with rivaroxaban than with enoxaparin/vitamin K antagonists.
Postthrombotic Syndrome
Postthrombotic syndrome (PTS) is a chronic complication of deep venous
thrombosis (DVT) that manifests months to many years after the initial event.
Symptoms range from mild erythema and localized induration to massive
extremity swelling and ulceration, usually exacerbated by standing and
relieved by elevation of the extremity. Evaluations of the incidence or of
improvements with therapy have been problematic because reporting is not
standardized. Furthermore, correlation between objectively measured
hemodynamic changes and the severity of PTS is poor. [96]
After symptomatic DVT is treated with anticoagulation, the incidence of PTS at
2 years is 25-50% despite long-term anticoagulation for iliofemoral DVT, and
after 7-10 years, the incidence is 70-90%. [97, 98] The only current treatment is
use of a compression hose and elevation. In many patients, this is only partly
effective in relieving swelling, pain, and venous ulcers. In the United States,
the annual direct cost of post–DVT, PTS-related venous ulcers is estimated to
be $45 million per year, and 300,000 work days are lost. [99]

Differential Diagnoses

Diagnostic Considerations
Of patients evaluated for deep venous thrombosis (DVT) of the lower
extremity, only a quarter of them have the disease. DVT is characterized by
pain and swelling of the limb, which are not specific. Numerous patients with
DVT are asymptomatic.
Severe venous congestion produces a clinical appearance that can be
indistinguishable from the appearance of cellulitis. Patients with a warm,
swollen, tender leg should be evaluated for both cellulitis and DVT because
patients with primary DVT often develop a secondary cellulitis, while patients
with primary cellulitis often develop a secondary DVT. Superficial
thrombophlebitis, likewise, is often associated with a clinically inapparent
underlying DVT.
Other problems to be considered include the following:
 Achilles tendonitis
 Arthritis
 Muscle strain or tear
 Hematoma
 Soft-tissue injury
 Stress fracture
 Pain
 Swelling in a paralyzed limb
 Arterial insufficiency
 Peripheral occlusive disease
 Thromboembolism
 Superficial thrombophlebitis
 Postphlebitic syndrome
 Varicose veins
 Dependent edema
 Hepatic disease
 Renal failure
 Nephritic syndrome
 Lymphedema
Differential Diagnoses
 Baker Cyst Imaging
 Budd-Chiari Syndrome Imaging
 Cellulitis
 Heart Failure, Congestive
 Pulmonary Embolism (PE)
 Septic Thrombophlebitis
 Thrombophlebitis, Superficial

Workup

Approach Considerations
Routine blood tests that have the potential to help clinicians stratify patients
with the risk for deep venous thrombosis (DVT) include D-dimer assay; levels
of antithrombin III (ATIII), N-terminal pro-brain natriuretic peptide (NT-
proBNP), and C-reactive protein (CRP); and erythrocyte sedimentation rate
(ESR). [100]
A clinical practice guideline from the American Academy of Family Physicians
(AAFP) and the American College of Physicians (ACP) provides four
recommendations for the workup of patients with probable DVT). [5] First,
validated clinical prediction rules should be used to estimate the pretest
probability of venous thromboembolism (VTE) and interpret test results. The
Wells prediction rules for DVT and for pulmonary embolism meet this
standard, although the rule performs better in younger patients without
comorbidities or a history of VTE than it does in other patients.
Second, in appropriately selected patients with low pretest probability of DVT
or pulmonary embolism, it is reasonable to obtain a high-sensitivity D-dimer. A
negative result indicates a low likelihood of VTE. Third, in patients with
intermediate to high pretest probability of lower-extremity DVT,
ultrasonography is recommended.
Fourth, patients with intermediate or high pretest probability of pulmonary
embolism require diagnostic imaging studies. Options include a ventilation-
perfusion (V/Q) scan, multidetector helical computed axial tomography (CT),
and pulmonary angiography; however, CT alone may not be sufficiently
sensitive to exclude pulmonary embolism in patients who have a high pretest
probability of pulmonary embolism.
VTE remains an underdiagnosed disease, and most cases of pulmonary
embolism (PE) are diagnosed at autopsy. Diagnosis depends on a high level
of clinical suspicion and the presence of risk factors that prompt diagnostic
study. Because the presentation is nonspecific and because the consequence
of missing the diagnosis is serious, it must be excluded whenever it is a
feasible differential diagnosis. Because the prevalence of the disease is 15-
30% in the population at clinical risk, a widely applicable (inexpensive and
simple) screening test is required.
Conclusive diagnosis historically required invasive and expensive
venography, which is still considered the criterion standard. Since 1990, the
diagnosis has been obtained noninvasively by means of (still expensive)
sonographic examination. The validation of the simpler and cheaper D-dimer
test as an initial screening test permits a rapid, widely applicable screening
that may reduce the rate of missed diagnoses. Algorithms are based on
pretest probabilities and D-dimer results. As many of 40% of patients with a
low clinical suspicion and a negative D-dimer result require no further
evaluation. [101, 102]
Kleinjan et al have proposed a diagnostic algorithm that uses a combination of
a clinical decision probability, D-dimer testing, and ultrasonographic findings
to exclude upper extremity DVT (UEDVT). [103] The algorithm was feasible and
completed in 390 of 406 patients (96%), excluded UEDVT from 87 patients
(21%) with an unlikely clinical score and normal D-dimer levels, and identified
superficial venous thrombosis in 54 (13%) and UEDVT in 103 (25%)
patients. [103]
Laboratory analysis has also been used in aiding the diagnosis of venous
thrombosis. Protein S, protein C, ATIII, factor V Leiden, prothrombin 20210A
mutation, antiphospholipid antibodies, and homocysteine levels can be
measured. Deficiencies of these factors or the presence of these
abnormalities all produce a hypercoagulable state. These are rare causes of
DVT. Laboratory investigations for these abnormalities are primarily indicated
when DVT is diagnosed in patients younger than 50 years, when there is a
confirmed family history of a hypercoagulable state or a familial deficiency,
when venous thrombosis is detected in unusual sites, and in the clinical
setting of warfarin-induced skin necrosis.
D-Dimer Testing
D-dimers are degradation products of cross-linked fibrin by plasmin that are
detected by diagnostic assays. D-dimer level may be elevated in any medical
condition where clots form. D-dimer level is elevated in trauma, recent
surgery, hemorrhage, cancer, and sepsis. [104] Many of these conditions are
associated with higher risk for deep venous thrombosis (DVT).
D-dimer levels remain elevated in DVT for about 7 days. Patients presenting
late in the course, after clot organization and adherence have occurred, may
have low levels of D-dimer. Similarly, patients with isolated calf vein DVT may
have a small clot burden and low levels of D-dimer that are below the analytic
cutoff value of the assay. This accounts for the reduced sensitivity of the D-
dimer assay in the setting of confirmed DVT.
Current evidence strongly supports the use of a D-dimer assay in the setting
of suspected DVT. Most studies have confirmed the clinical utility of D-dimer
testing, and most clinical algorithms incorporate its use. The D-dimer assay
has a high sensitivity (up to 97%); however, it has a relatively poor specificity
(as low as 35%) [105] and therefore should only be used to rule out DVT, not to
confirm the diagnosis of DVT.
A negative D-dimer assay result rules out DVT in patients with low-to-
moderate risk (Wells DVT score < 2). (See Risk Stratification.) A negative
result also obviates surveillance and serial testing in patients with moderate-
to-high risk and negative ultrasonographic findings. All patients with a positive
D-dimer assay result and all patients with a moderate-to-high risk of DVT
(Wells DVT score >2) require a diagnostic study (duplex ultrasonography).
Studies indicate that the D-dimer test can be used as a rapid screening
measure in cases where leg swelling exists in the face of equivocal or
negative clinical or radiologic findings. Forty percent of patients with a
negative clinical examination and negative D-dimer test require no further
clinical evaluation. Similarly, subjects with an elevated D-dimer test at 1 month
following anticoagulant cessation have a significantly higher risk of recurrent
venous thromboembolism (VTE). [106]
A randomized, multicenter, controlled trial involving 1723 patients found that
selective testing of D-dimer levels lowered the proportion of patients who
underwent ultrasonography and decreased the percentage of patients who
needed D-dimer testing by 21.8%. [107, 108] This suggests that a selective D-
dimer testing strategy based on clinical pretest probability (C-PTP), as
opposed to testing all patients presenting with symptoms of a first DVT
episode, can exclude DVT in more patients without increasing the rate of
missed diagnoses.
Characteristics of different D-dimer assays
Many different D-dimer assays are available, with varying sensitivities and
specificities. These assays are not standardized. They incorporate different
monoclonal antibodies to the D-dimer fragment. Results may be reported
quantitatively or qualitatively. Different units may be used; some assay results
are reported as fibrinogen equivalent units (FEU) and others in nanograms
per milliliter (ng/mL). The results of one assay cannot be extrapolated to
another. Accordingly, physicians should know their hospital’s D-dimer assay.
All D-dimer assays have been evaluated in various validation studies that
determine the assay’s sensitivity, specificity, and negative predictive value
(NPV). Unfortunately, fewer management studies have been conducted to
determine the safety of withholding anticoagulant therapy on the basis of a
negative test result. Furthermore, the NPV of a specific assay falls as the
pretest probability of the study population at risk for DVT increases. An assay
with a sensitivity of 80% has an NPV of 97.6% in a low-risk patient. However,
the NPV of the same assay is only 33% in high-risk patients with a pretest
probability of 90% for DVT.
Traditional enzyme-linked immunosorbent assays (ELISAs), although
accurate, are time-consuming and not practical for use in the emergency
department. A rapid ELISA assay (VIDAS) with high sensitivity was validated
in a large European trial. In that study a negative VIDAS D-dimer assay
essentially ruled out DVT. All patients with a negative D-dimer result did not
require further diagnostic testing with ultrasonography. [109]
The older qualitative latex agglutination assay is not accurate and should not
be used for making treatment decisions in patients with suspected DVT.
Newer latex-enhanced immunoturbidimetric and immunofiltration assays have
high sensitivity and are available.
A rapid qualitative red blood cell agglutination assay (SimpliRED) is available.
It is sensitive for proximal vein DVT but less so for calf vein DVT. A large
study confirmed that, in low-risk patients with low pretest probability for DVT, a
negative SimpliRED D-dimer result rules out DVT. Ultrasonography was not
required in these patients. [110]
Coagulation Profile
Additional blood work should include coagulation studies to evaluate for a
hypercoagulable state, if clinically indicated. A prolonged prothrombin time or
activated partial thromboplastin time does not imply a lower risk of new
thrombosis. Progression of deep venous thrombosis and pulmonary embolism
can occur despite full therapeutic anticoagulation in 13% of patients.
Imaging in Deep Venous Thrombosis
Imaging studies used in deep venous thrombosis (DVT) include
ultrasonography, venography, impedance plethysmography, magnetic
resonance imaging (MRI), and nuclear imaging. Ultrasonography is the
current first-line imaging examination for DVT because of its relative ease of
use, absence of irradiation or contrast material, and high sensitivity and
specificity in institutions with experienced sonographers.
The criterion standard to diagnostic imaging for DVT remains venography with
pedal vein cannulation, intravenous contrast injection, and serial limb
radiographs. However, the invasive nature and significant consumption of
resources are only 2 of its many limitations.
In some countries, impedance plethysmography (IPG) has been the initial
noninvasive diagnostic test of choice and has been shown to be sensitive and
specific for proximal vein thrombosis. However, IPG also has several other
limitations; among them are insensitivity for calf vein thrombosis,
nonoccluding proximal vein thrombus, and iliofemoral vein thrombosis above
the inguinal ligament.
MRI has increasingly been investigated for evaluation of suspected DVT.
Limited studies suggest the accuracy approaches that of contrast venography.
MRI is the diagnostic test of choice for suspected iliac vein or inferior vena
caval thrombosis when CT venography is contraindicated or technically
inadequate. Radiolabeled peptides that bind to various components of a
thrombus have been investigated. The cost of the tests and the inability to
visualize the anatomy of the area of involvement (which many clinicians
prefer) has lead to the underuse of scintigraphy.
For more information, see Imaging in Deep Venous Thrombosis.
Additionally, note that imaging modalities, techniques, and findings may be
specific to the upper extremities and lower extremities.
For more information, see Imaging in Deep Venous Thrombosis, Lower
Extremity.
Risk Stratification
The Wells clinical prediction guide quantifies the pretest probability of deep
venous thrombosis (DVT). The model enables physicians to reliably stratify
their patients into high-risk, moderate-risk, or low-risk categories. Combining
this with the results of objective testing greatly simplifies the clinical workup of
patients with suspected DVT. The Wells clinical prediction guide incorporates
risk factors, clinical signs, and the presence or absence of alternative
diagnoses.
Predictors of venous thromboembolism (VTE) in a Japanese study comprising
data from 3,578 patients diagnosed with VTE over 6 years (2008-2013)
included the presence of malignancies and the use of antipsychotic agents
and/or nonsteroidal anti-inflammatory agents. [111]
Approach Considerations
The primary objectives for the treatment of deep venous thrombosis (DVT) are
to prevent pulmonary embolism (PE), reduce morbidity, and prevent or
minimize the risk of developing the postthrombotic syndrome (PTS).
The mainstay of medical therapy has been anticoagulation since the
introduction of heparin in the 1930s. [112] Other anticoagulation drugs have
subsequently been added to the treatment armamentarium over the years,
such as vitamin K antagonists and low-molecular-weight heparin (LMWH).
More recently, mechanical thrombolysis has become increasingly used as
endovascular therapies have increased. Absolute contraindications to
anticoagulation treatment include intracranial bleeding, severe active
bleeding, recent brain, eye, or spinal cord surgery, pregnancy, and malignant
hypertension. Relative contraindications include recent major surgery, recent
cerebrovascular accident, and severe thrombocytopenia.
The immediate symptoms of DVT often resolve with anticoagulation alone,
and the rationale for intervention is often reduction of the 75% long-term risk
of PTS. Systemic IV thrombolysis once improved the rate of thrombosed vein
recanalization; however, it is no longer recommended because of an elevated
incidence of bleeding complications, slightly increased risk of death, and
insignificant improvement in PTS. The lack of a significantly reduced
incidence of PTS after systemic thrombolysis (40-60%) likely reflects the
inadequacy of the relatively low threshold volume of thrombus removal that
was considered successful.
Thrombolytic therapy is recommended (systemic preferred over catheter
directed) in hypotensive individuals with an acute PE. [113] Those with high-risk
PE presenting in shock should undergo systemic thrombolysis; when
thrombolysis is contraindicated owing to a high risk of bleeding, consider
surgical thrombectomy or catheter direct thrombolysis. [114]
The bleeding risk of systemic thrombolysis is similar to that of catheter-
directed thrombolysis, and the risk of PTS may further decrease risk.
However, whether catheter-directed thrombolysis is preferred to
anticoagulation has not been examined. The addition of percutaneous
mechanical thrombectomy to the interventional options may facilitate decision-
making, because recanalization may be achieved faster than before and with
a decreased dose of lytic; therefore, the bleeding risk may be decreased.
Inpatient Versus Outpatient Treatment
Acute DVT may be treated in an outpatient setting with LMWH. Patients with
low-risk PE may be safely discharged early from hospital or receive only
outpatient treatment with LMWH, followed by vitamin K antagonists, although
nonvitamin K-dependent oral anticoagulants may be as effective but safer
than the LMWH/vitamin K antagonist regimen. [115]
Anticoagulant therapy is recommended for 3-12 months depending on site of
thrombosis and on the ongoing presence of risk factors. If DVT recurs, if a
chronic hypercoagulability is identified, or if PE is life threatening, lifetime
anticoagulation therapy may be recommended. This treatment protocol has a
cumulative risk of bleeding complications of less than 12%.
Most patients with confirmed proximal vein DVT may be safely treated on an
outpatient basis. Exclusion criteria for outpatient management are as follows:
 Suspected or proven concomitant PE
 Significant cardiovascular or pulmonary comorbidity
 Iliofemoral DVT
 Contraindications to anticoagulation
 Familial or inherited disorder of coagulation: antithrombin III (ATIII)
deficiency, prothrombin 20210A, protein C or protein S deficiency, or
factor V Leiden
 Familial bleeding disorder
 Pregnancy
 Morbid obesity (>150 kg)
 Renal failure (creatinine >2 mg/dL)
 Unavailable or unable to arrange close follow-up care
 Unable to follow instructions
 Homeless
 No contact telephone
 Geographic (too far from hospital)
 Patient/family resistant to outpatient therapy
Admitted patients may be treated with a LMWH, fondaparinux, or
unfractionated heparin (UFH). Warfarin 5 mg PO daily is initiated and
overlapped for about 5 days until the international normalized ratio (INR) is
therapeutic >2 for at least 24 hours.
For admitted patients treated with UFH, the activated partial thromboplastin
time (aPTT) or heparin activity level must be monitored every 6 hours while
the patient is taking intravenous (IV) heparin until the dose is stabilized in the
therapeutic range. Patients treated with LMWH or fondaparinux do not require
monitoring of the aPTT.
Platelets should be monitored. Heparin or LMWH should be discontinued if
the platelet count falls below 75,000. Fondaparinux is not associated with
hepatin-induced thrombocytopenia (HIT).
Consultations
Consultations with the following specialists are indicated:
 Hematologist
 Vascular surgeon
 Radiologist
 Interventional radiologist
General Principles of Anticoagulation
Anticoagulant therapy remains the mainstay of medical therapy for deep
venous thrombosis (DVT) because it is noninvasive, it treats most patients
(approximately 90%) with no immediate demonstrable physical sequelae of
DVT, it has a low risk of complications, and its outcome data demonstrate an
improvement in morbidity and mortality. Long-term anticoagulation is
necessary to prevent the high frequency of recurrent venous thrombosis or
thromboembolic events. Anticoagulation does have problems. Although it
inhibits propagation, it does not remove the thrombus, and a variable risk of
clinically significant bleeding is observed.
First-line therapy for non-high risk venous thromboembolism (VTE)
or pulmonary embolism (PE) consists of direct oral anticoagulants
(dabigatran, rivaroxaban, apixaban, or edoxaban) over vitamin K antagonists
(VKAs). [113, 114] VKAs are also recommended over low-molecular-weight
heparin (LMWH), unless VTE is associated with malignancy, in which case
LMWH is preferred over VKAs or any direct oral anticoagulants. [113]
When the risk of VTE recurrence is high in patients with subsegmental PE
without DVT, the American College of Chest Physicians (ACCP) recommends
anticoagulation over surveillance; when the VTE recurrence risk is low in
these patients, surveillance over anticoagulation is suggested. [113]
Inferior vena cava filters are not recommended in patients with acute VTE on
anticoagulant therapy. [113]
Barring contraindications to aspirin therapy, aspirin is recommended to
prevent recurrent VTE in patients with an unprovoked proximal DVT or PE
following anticoagulation cessation. [113]
Park and Byun indicate that possibilities for advances in anticoagulant delivery
systems include expansion of new oral agents and their antidotes, reducing
the size of heparins, developing oral or topical heparins, and modifying
physical or chemical formulations. [116] For example, Ita suggests that
transdermal delivery may potentially bypass known issues with heparin use,
such as short half-life and unpredictable bioavailability, and offer improved
patient compliance, convenience, ease of dosing termination, as well as avoid
the first-pass effect. [112]
For more information, see General Principles of Anticoagulation in Deep
Venous Thrombosis.
Heparin Use in Deep Venous Thrombosis
Heparin products used in the treatment of deep venous thrombosis (DVT)
include unfractionated heparin and low molecular weight heparin (LMWH) The
efficacy and safety of low-molecular-weight heparin (LMWH) for the initial
treatment of DVT have been well established in several trials. Traditionally,
heparin has been used only for admitted patients with DVT. Regular
unfractionated heparin was the standard of care until the introduction of
LMWH products. Heparin prevents extension of the thrombus and has been
shown to significantly reduce (but not eliminate) the incidence of fatal and
nonfatal pulmonary embolism and recurrent thrombosis.
Heparin is a heterogeneous mixture of polysaccharide fragments with varying
molecular weights but with similar biological activity. The larger fragments
exert their anticoagulant effect by interacting with antithrombin III (ATIII) to
inhibit thrombin. ATIII, the body’s primary anticoagulant, inactivates thrombin
and inhibits the activity of activated factor X in the coagulation process. The
low-molecular-weight fragments exert their anticoagulant effect by inhibiting
the activity of activated factor X. The hemorrhagic complications attributed to
heparin are thought to arise from the larger higher-molecular-weight
fragments. LMWH is prepared by selectively treating unfractionated heparin to
isolate the low-molecular-weight (< 9000 Da) fragments.
Patients with recurrent venous thromboembolism (VTE) while on treatment
with a non-LMWH anticoagulant should be switched to LMWH
therapy. [113] Those who suffer recurrent VTE while on LMWH therapy should
receive an increased dose of LMWH. [113]
For more information, see Heparin Use in Deep Venous Thrombosis.
Factor Xa and Direct Thrombin Inhibitors
Fondaparinux
Fondaparinux, a direct selective inhibitor of factor Xa, overcomes many of the
aforementioned disadvantages of low-molecular-weight heparins (LMWHs).
Pharmacokinetic studies of fondaparinux reveal that only a single-daily
subcutaneous dose is required. Furthermore, a single dose of 7.5 mg is
effective over a wide range of patient weights between 50 and 100 kg. Daily
doses of 5 mg or 10 mg are appropriate for patients who weigh less or more
than that weight range. Heparin-induced thrombocytopenia (HIT) has not been
reported. Therapeutic monitoring of laboratory parameters such as the
prothrombin time or activated partial thromboplastin time (aPTT) is also not
required. In some regions, the cost of therapy with fondaparinux is less than
enoxaparin when it is being used to bridge therapy to a vitamin K antagonist
(VKA).
The combination of two factor Xa inhibitors may be an effective treatment
strategy for acute venous thromboembolism (VTE). [117] In an observational
study, 80 of 87 consecutive Japanese patients with VTE who received SC
fondaparinux for 7-10 days and then were switched to oral rivaroxaban for 7-
14 days had treatment success. Both D-dimer levels and quantitative
ultrasound thrombosis (QUT) scores were improved with the use of
fondaparinux, and further reductions were achieved using rivaroxaban. [117]
Buller and his coauthors on behalf of the Matisse Investigators conducted a
randomized, double-blind, international study of fondaparinux versus
enoxaparin on 2,205 patients with objectively confirmed acute deep venous
thrombosis (DVT) and found the two agents to be comparable in safety and
efficacy. [6] Patients were randomly assigned to receive fondaparinux or
enoxaparin therapy. Fondaparinux was administered as a single 7.5-mg
subcutaneous daily dose, with adjustments made for those patients weighing
less than 50 kg (5 mg) or greater than 100 kg (10 mg). Enoxaparin was given
1 mg/kg subcutaneously twice daily. Both agents were bridged with a VKA
until a therapeutic international normalized ratio (INR) was achieved.
Anticoagulation with a VKA was continued for 3 months. Efficacy was
measured by the rate of recurrent VTE in the 3-month follow-up period after
enrollment. Safety was assessed by the incidence of major bleeding and
mortality over the same interval. [6]
The recurrence rate showed a nonsignificant trend in favor of fondaparinux
(3.9%) compared with enoxaparin (4.1%) (absolute difference = 0.15%; 95%
CI, 1.8% to -1.5%). [6] The conservative noninferiority margin was attained, and
fondaparinux was determined to be equally as effective as enoxaparin for the
treatment of DVT. Major bleeding rates were essentially identical, and
mortality rates were also comparable. In a subgroup analysis, the authors also
evaluated the relationship between the recurrence rate, the bleeding risks,
and the patients’ body weight. In general, the safety and efficacy of
fondaparinux were independent of body weight. However, patients with mild
renal insufficiency and a low creatinine clearance had the same risk of
bleeding in both the LMWH and fondaparinux groups. Overall, the authors
concluded that once-daily fondaparinux was as effective and as safe as twice-
daily, weight-adjusted enoxaparin. [6]
The Matisse DVT trial confirmed that fondaparinux and enoxaparin have
similar safety and efficacy for the initial treatment of DVT. Only one fixed-
dosage regimen for fondaparinux is required for patients who weigh between
50 kg and 100 kg, and only one subcutaneous dose per day is required. This
greatly simplifies the treatment of DVT and facilitates outpatient therapy. In
the original study, about one third of the patients were treated partially or
entirely as outpatients without any increased risk when compared with those
treated as inpatients.
In renal insufficiency with a creatinine clearance less than 30 mL/min, major
bleeding occurred in 2 of 25 patients (8%) on fondaparinux versus 1 of 18
patients (5.6%) treated with enoxaparin (P = NS). Because of the small
sample size and the higher risk of bleeding, fondaparinux is contraindicated in
patients with renal insufficiency and a creatinine clearance less than 30
mL/min.
In the event of a major bleed, protamine sulfate partially reverses the
anticoagulant effect of enoxaparin. However, no specific antidote to
fondaparinux is available. A recent study revealed that a bolus dose of 90
mcg/kg of recombinant factor VIIa reversed the anticoagulant effect of
fondaparinux, at least in healthy volunteers given a larger 10-mg dose. [118]
Rivaroxaban
Rivaroxaban (Xarelto) is an oral factor Xa inhibitor approved by the FDA in
November 2012 for treatment of DVT or pulmonary embolism (PE) and for
reduction of the risk of recurrent DVT and PE after initial
treatment. [7, 8, 9] Approval for this indication was based on studies totaling 9478
patients with DVT or PE. Participants were randomly assigned to receive
rivaroxaban, a combination of enoxaparin and a VKA (eg, warfarin), or a
placebo. Study endpoints were designed to measure the number of patients
who experienced recurrent symptoms of DVT, PE, or death after receiving
treatment.
Data from a pooled analysis of the EINSTEIN-DVT [7] and EINSTEIN-PE [8] trials
suggested that rivaroxaban is as effective in preventing VTE recurrence as
enoxaparin followed by a VKA and may be associated with less bleeding [9] ; in
addition, the data suggested that there are no grounds for avoiding
rivaroxaban use in high-risk groups (eg, fragile patients, cancer patients, and
patients with a large clot).
Approximately 2.1% of patients treated with rivaroxaban experienced
recurrent DVT or PE, compared with 1.8-3% treated with the enoxaparin and
VKA combination. [7, 8]
Additionally, results from extended treatment demonstrated a reduced risk of
recurrent DVT and PE. Approximately 1.3% in the rivaroxaban group
experienced recurrent DVT or PE, compared with 7.1% in the placebo
group. [119, 120]
Apixaban
In March 2014, the FDA approved apixaban (Eliquis) for the additional
indication of prophylaxis of DVT and PE in adults who have undergone hip- or
knee-replacement surgery. Support for this new indication was a result of the
ADVANCE 1, 2, and 3 clinical trials that enrolled nearly 12,000
patients. [121, 122, 123] Apixaban was originally approved by the FDA in December
2012 for the prevention of stroke and systemic embolism in patients with
nonvalvular atrial fibrillation.
In August 2014, apixaban was approved for treatment of DVT and PE. [124] The
approval for treatment of PE and prevention of recurrence was based on the
outcome of the AMPLIFY (Apixaban for the Initial Management of Pulmonary
Embolism and Deep-Vein Thrombosis as First-Line Therapy) and AMPLIFY-
EXT (extended treatment) studies, in which apixaban therapy was compared
with enoxaparin and warfarin treatment. The AMPLIFY study showed that, in
comparison with the standard anticoagulant regimen, apixaban therapy
resulted in a 16% reduction in the risk of a composite endpoint that included
recurrent symptomatic venous thromboembolism (VTE) or VTE-associated
death. [125, 126]
Data from the AMPLIFY-EXT trial showed that extended anticoagulation (12
months) with apixaban shortened hospital stays, reduced symptomatic
recurrent venous thromboembolism or all-cause death without an associated
increase in major episodes of hemorrhage when compared with placebo. [127]
Dabigatran
Dabigatran (Pradaxa) inhibits free and clot-bound thrombin and thrombin-
induced platelet aggregation. This agent was FDA approved in 2010 to reduce
the risk of stroke and systemic embolism in patients with nonvalvular atrial
fibrillation. In April 2014, it was approved for the treatment of DVT and PE in
patients who have been treated with a parenteral anticoagulant for 5-10 days.
Additionally, it was approved to reduce the risk of DVT and PE recurrence in
patients who have been previously treated. Approval was based on results
from 4 global phase III trials that showed dabigatran was noninferior to
warfarin and had a lower risk of major or clinically relevant bleeding compared
with warfarin. [128, 129, 130] There have been reports of severe and fatal bleeding in
users of the drug.
The RE-COVER and RE-COVER II trials included patients with DVT and PE
who were treated with parenteral anticoagulant therapy for 5-10 days. Results
showed dabigatran was noninferior to warfarin in reducing DVT and PE after a
median of 174 days of treatment with a lower risk of bleeding compared with
warfarin. [128, 129]
The RE-SONATE trial and RE-MEDY trials included patients (n=2856) with
acute DVT and PE who had completed at least 3 months of anticoagulant
therapy. Results from this trial showed dabigatran was noninferior to warfarin
in the extended treatment of VTE and carried a lower risk of major or clinically
relevant bleeding than warfarin. [130]
Edoxaban
Edoxaban (Savaysa) was approved by the FDA in January 2015 for the
treatment of DVT and PE in patients who have been initially treated with a
parenteral anticoagulant for 5-10 days. [131] Approval was based on the
Hokusai-VTE study that included 4,921 patients with DVT and 3,319 patients
with PE. [131, 132]
Among patients with PE, 938 had right ventricular dysfunction, as assessed
by measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP)
levels. [132] There was a 3.3% rate of recurrent VTE in this subgroup in those
who received edoxaban compared to 6.2% in the group that received warfarin.
The investigators concluded that edoxaban was not only noninferior to high-
quality standard warfarin therapy but also caused significantly less bleeding in
a broad spectrum of patients with VTE, including those with severe PE. [132]
Betrixaban
Betrixaban (Bevyxxa), a FXa inhibitor, was approved by the FDA in June
2017. [133] It is indicated for the prophylaxis of VTE in adults hospitalized for
acute medical illness who are at risk for thromboembolic complications owing
to moderate or severe restricted mobility and other risk factors that may cause
VTE. [133]
Approval of betrixaban was based on data from the phase 3 APEX
studies. [134, 135] These randomized, double-blind, multinational clinical trials
compared extended-duration betrixaban (35-42 days) to short-duration
enoxaparin (6-14 days) for VTE in 7,513 acutely medically ill hospitalized
patients with VTE risk factors. [133, 134, 135] Patients in the betrixaban group
received an initial dose of 160 mg orally on day 1, followed by 80 mg once
daily for 35-42 days, and received a placebo injection once daily for 6-14
days. Patients in the enoxaparin group received 40 mg subcutaneously once
daily for 6-14 days and took an oral placebo once daily for 35-42
days. [133, 134, 135]
Efficacy was measured in 7,441 patients using a composite outcome score
composed of the occurrence of asymptomatic or symptomatic proximal DVT,
nonfatal PE, stroke, or VTE-related death. [133, 134, 135] Those who received
betrixaban showed significant decreases in VTE events (4.4%) compared with
patients in the enoxaparin group (6%).
Duration of Anticoagulation
For the first episode of deep venous thrombosis (DVT), patients should be
treated for 3-6 months. Recurrent episodes should be treated for at least 1
year.
The American College of Chest Physicians (ACCP) recommends cessation of
anticoagulant therapy after 3 months of treatment in those with (1) surgery-
associated acute proximal DVT, (2) an acute proximal DVT or PE provoked by
a nonsurgical transient risk factor, and (3) a first unprovoked VTE and a high
risk of bleeding. [113] (In those with a low or moderate bleeding risk, extend
anticoagulation without a scheduled stop date.) [113]
Prandoni et al found that the use of ultrasonography to determine the duration
of anticoagulation can reduce recurrences of venous thromboembolism after a
first episode of acute proximal DVT. In the study, 538 consecutive outpatients
who had completed an uneventful 3-month period of anticoagulation were
randomized to receive either fixed-duration anticoagulation (< 9 months for
secondary DVT and up to 21 months for unprovoked thrombosis) or flexible-
duration anticoagulation, with treatment discontinued once ultrasound showed
recanalization of the affected veins. Recurrent venous thromboembolism
developed in 17.2% of the patients allocated to fixed-duration anticoagulation
and 11.9% of the patients allocated to flexible-duration anticoagulation; no
significant difference was noted in the rate of major bleeding. [136]
Patients with cancer have a particularly higher rate of DVT recurrence than
noncancer patients. Long-term therapy for DVT is strongly recommended.
Studies have shown a lower rate of venous thromboembolism (VTE)
recurrence without increasing the risk of bleeding with low-molecular-weight
heparin (LMWH) therapy. Reports also describe that the LMWH compounds
may decrease the all-cause mortality rate. The author recommends LMWH
therapy alone without crossover to warfarin if the patient’s insurance covers it.
Indefinite therapy is recommended for patients with recurrent episodes of
venous thrombosis regardless of the cause. The risk of recurrent
thromboembolism during a 4-year follow-up period was reduced from 21% to
3% with continued anticoagulation. However, the incidence of major bleeding
increased from 3% to 9%. [137]
Long-term therapy with LMWH has been shown to be as effective as warfarin
in the treatment of venous thrombosis, except in those patients with a
concurrent malignancy. In this subgroup, LMWH was shown to be more
effective than oral therapy. [138, 139] Initial studies have also shown LMWH to be
effective in pregnant patients, but long-term, large randomized trials have yet
to be completed. [140]
Complications of Anticoagulant Therapy
Hemorrhagic complications are the most common adverse effects of
anticoagulant therapy. Anticoagulation therapy for 3-6 months results in major
bleeding complications in 3-10% of patients. [141] High-risk populations (>65 y
with a history of stroke, gastrointestinal [GI] bleed, renal insufficiency, or
diabetes) have a 5-23% risk of having major hemorrhage at 90 days. Patients
who require yearlong or indefinite anticoagulation (because of chronic risk
factors) have double the risk of hemorrhage. Significant bleeding (ie,
hematemesis, hematuria, GI hemorrhage) should be thoroughly investigated
because anticoagulant therapy may unmask a preexisting disease (eg,
cancer, peptic ulcer disease, arteriovenous malformation).
The treatment of hemorrhage while taking heparin depends on the severity of
the bleeding and the extent to which the activated partial thromboplastin time
(aPTT) is elevated above the therapeutic range. Patients who hemorrhage
while receiving heparin are best treated by discontinuing the drug. The half-life
is relatively short, and the aPTT usually returns to the reference range within a
few hours. Treatment with fresh frozen plasma or platelet infusions is
ineffective. For severe hemorrhage, such as intracranial or massive
gastrointestinal bleeding, heparin may be neutralized by protamine at a dose
of 1 mg for every 100 units. Protamine should be administered at the same
time that the infusion is stopped.
The treatment of major hemorrhage associated with low-molecular-weight
heparin (LMWH) is similar to heparin. However, the half-life of these agents is
longer (4-6 h). As with heparin, fresh frozen plasma or platelet transfusions
are ineffective. Protamine may be used, but it only reverses 60% of the drug’s
effects.
The risk of bleeding on warfarin is not linearly related to the elevation of the
international normalized ratio (INR). The risk is conditioned by other factors,
including poor follow-up, drug interactions, age, and preexisting disorders that
predispose to bleeding.
Patients who hemorrhage while receiving oral warfarin are treated by
withholding the drug and administering vitamin K. Severe life-threatening
hemorrhage is managed with fresh frozen plasma in addition to vitamin K.
Recombinant factor VIIa is another option especially for central nervous
system hemorrhage.
Additional complications include the following:
 Systemic embolism
 Chronic venous insufficiency
 Postthrombotic syndrome (ie, pain and edema in the affected limb without
new clot formation)
 Soft tissue ischemia associated with massive clot and very high venous
pressures - phlegmasia cerulea dolens
Emerging Anticoagulant Agents
The qualities desired in the ideal anticoagulant are ease of administration,
efficacy and safety (with minimal complications or adverse effects), rapid
onset, a therapeutic half-life, and minimal or no monitoring. Predictable and
reversible action, with few drug or dietary interactions, and cost also are
important. Achieving all these criteria in a single agent has not yet been
achieved. Each of the anticoagulant agents available today has generally
been able to incorporate some, but not all, of these characteristics.
In patients with deep venous thrombosis (DVT), anticoagulation remains the
cornerstone of treatment. The relatively recent development of novel oral
anticoagulants has provided clinicians with an expanding set of options for
DVT treatment. [142]
Current research in anticoagulants involves investigations into drugs that act
on various phases of the coagulation cascade. Drugs under investigation that
act in the initiation phase include tissue factor pathway inhibitors (TFPIs) and
nematode anticoagulant peptide (NAPc2). Drugs that act on the third stage of
the coagulation cascade, the thrombin activity phase, include the direct
thrombin inhibitors. A partial listing of these emerging new anticoagulants
includes razaxaban, idraparinux, bivalirudin, lepirudin, and ximelagatran.
For more information, see Emerging Anticoagulant Agents in Deep Venous
Thrombosis.
Reversal of Anticoagulation
Anticoagulation-related major bleeding is associated with an increased risk of
death and thrombotic events, independent of the class of anticoagulant used.
Although older agents of anticoagulation and their reversal are well studied,
the newer agents lack similar antidotes. With the increasing use of non–
vitamin K antagonist oral anticoagulants (NOAC), the number of patients who
require reversal of their anticoagulant effects can be expected to rise. The
following section describes the reversal agents for both older and new
anticoagulants.
Heparin
Heparin has a relatively short half-life of about 60–90 minutes and, therefore,
the anticoagulant effect of therapeutic doses of heparin will mostly be
eliminated at 3-4 hours after termination of continuous intravenous
administration.
For a more immediate neutralization of heparin, protamine sulfate can be
administered at a dose of 1 mg for every 100 units of heparin. Protamine was
originally isolated from fish sperm and binds to heparin to form a stable,
biologically inactive complex. [143, 144]
Lower molecular weight heparins
Currently, there are no specific antidotes to low molecular weight heparins.
Recombinant FVIIa (rVIIA) has been shown to stop bleeding in patients
anticoagulated with fondaparinux; however, no randomized controlled trials on
such patients have been conducted.
Warfarin
Vitamin K
In patients with clinically significant bleeding, vitamin K can be used to reverse
the anticoagulant effect of vitamin K antagonists (VKA). Vitamin K can be
given orally or intravenously. The parenteral route has a more rapid onset;
however, it is associated with a slightly increased risk of allergic reaction.
Fresh frozen plasma (FFP)
In case of a life-threatening emergency, FFP can be used for the reversal of
VKA. FFP contains all the coagulation factors in normal concentrations.
However, FFP should be used with caution, as it has the potential to cause
volume overload, allergic reaction, and transfusion-related reactions
(eg, transfusion-related acute lung injury). [145]
Prothrombin complex concentrates (PCCs)
In the case of serious and life-threatening bleeding, immediate correction of
the international normalized ratio (INR) can be achieved by the administration
of PCCs. These contain 3 or 4 of the vitamin K–dependent coagulation
factors, as well as proteins C and S. In a prospective study, administration of
PCCs has been shown to result in sustained hemostasis in patients using
VKA.
Non–vitamin K antagonist oral anticoagulants (NOACs)
The new oral anticoagulant factor Xa or IIa inhibitors have numerous
advantages over traditional VKAs, including rapid therapeutic effectiveness,
ease of dosing, and lack of monitoring. Until recently, there were no approved
drug-specific reversal agents for the NOACs. A number of drugs are currently
under development. [146, 147]
Due to the short half-life of FXa inhibitors, discontinuation of the drugs suffice
in clinical situations in which there is time to await spontaneous clearance.
Currently, PCCs can be used to address severe bleeding in patients taking
NOACs when administered in high enough dosages. Some guidelines
suggest an initial dose of 25 to 50 U/kg of PCCs in life-threatening
emergencies, to be repeated if necessary.
Idarucizumab (Praxbind)
Idarucizumab is a humanized antibody fragment directed against dabigatran.
This agent has been shown to completely reverse the anticoagulant effect of
dabigatran within minutes; on October 16, 2015, it was approved by the FDA
as an antidote for dabigatran. [148, 149, 150, 151]
Andexanet alfa
Andexanet alfa is a recombinant, modified FXa molecule that acts as a decoy
protein that is catalytically inactive but has a high affinity for FXa inhibitors. It
is being developed as an antidote for apixaban, edoxaban, and rivaroxaban.
Andexanet alfa has been shown to reverse the anticoagulant effects of
apixaban and rivaroxaban in human volunteers, and more studies are
ongoing. [152]
Aripazine (PER977, ciraparantag)
Aripazine is a synthetic small molecule that has broad activity against both old
(heparin, low molecular weight heparin) and new oral anticoagulants
(dabigatran, rivaroxaban, apixaban, edoxaban). A 2014 study of human
volunteers demonstrated that administration of aripazine reversed the
prolonged clotting time caused by edoxaban. Further human trials are
ongoing. [153]
Pharmacologic Thrombolysis
Use of thrombolytic medications to lyse deep venous thrombosis can cause
intracranial bleeding, though this is infrequent, and death or impairment can
result. Accordingly, careful assessment of the indications for lysis against the
possibility of bleeding must be carried out before pharmacologic thrombolysis
is attempted.
The need should be compelling when thrombolysis is considered in a setting
of known contraindications. Factors such as recent surgery, stroke,
gastrointestinal or other bleeding, and underlying coagulopathy increase the
bleeding risk when the thrombolytic medication is administered. The process
of obtaining informed consent should include a discussion of these risks.
General Principles of Endovascular Intervention
Percutaneous transcatheter treatment of patients with deep venous
thrombosis (DVT) consists of thrombus removal with catheter-directed
thrombolysis, mechanical thrombectomy, angioplasty, and/or stenting of
venous obstructions. Consensus has been reached regarding indications for
the procedure, although it is based on midlevel evidence from nonrandomized
controlled trials. The goals of endovascular therapy include reducing the
severity and duration of lower-extremity symptoms, preventing pulmonary
embolism, diminishing the risk of recurrent venous thrombosis, and preventing
postthrombotic syndrome. A randomized controlled trial comparing catheter-
directed thrombolysis to conventional anticoagulation demonstrated a lower
incidence of postthrombotic syndrome and improved iliofemoral patency in
patients with a high proximal DVT and low risk of bleeding. [154]
Indications for intervention include the relatively rare phlegmasia or
symptomatic inferior vena cava thrombosis that responds poorly to
anticoagulation alone, or symptomatic iliofemoral or femoropopliteal DVT in
patients with a low risk of bleeding. Contraindications are the same as those
for thrombolysis in general. Absolute contraindications include active internal
bleeding or disseminated intravascular coagulation, a cerebrovascular event,
trauma, or neurosurgery within 3 months. Unfortunately, most patients with
DVT have absolute contraindications to thrombolytic therapy. The American
College of Chest Physicians (ACCP) consensus guidelines recommend
thrombolytic therapy only for patients with massive ileofemoral vein
thrombosis associated with limb ischemia or vascular compromise. [113, 155]
For more information, see Inferior Vena Caval Thrombosis.
Percutaneous mechanical thrombectomy devices are a popular adjunct to
catheter-directed thrombolysis. Although these devices may not completely
remove thrombus, they are effective for debulking and for minimizing the dose
and time required for infusing a thrombolytic. Percutaneous mechanical
thrombectomy has developed as an attempt to shorten treatment time and
avoid costly ICU stays during thrombolytic infusion. The most basic
mechanical method for thrombectomy is thromboaspiration, or the aspiration
of thrombus through a sheath. Mechanical disruption of venous thrombosis
has the potential disadvantage of damaging venous endothelium and valves,
in addition to thrombus fragmentation and possible pulmonary embolism.
For more information, see Percutaneous Transcatheter Treatment of Deep
Venous Thrombosis.
Surgical Thrombectomy
Surgical thrombus removal has traditionally been used in patients with
massive swelling and phlegmasia cerulea dolens. In many patients,
fibrinolysis alone is highly effective, and it has become the primary treatment
of choice for many forms of venous and arterial thrombosis. Unfortunately,
when thrombosis is extensive, fibrinolysis alone may be inadequate to
dissolve the volume of thrombus present. Even when the bulk of the thrombus
is not excessive, many patients with thrombosis are poor candidates for
fibrinolysis because of recent surgery or trauma involving the central nervous
system or other noncompressible areas.
Precisely defining the location and extent of thrombosis before considering
any surgical approach to the problem is important. Duplex ultrasonography
may sometimes be sufficient for this purpose, but venography (including
routine contralateral iliocavography) is a more reliable guide to the anatomy
and the particular pathology that must be addressed.
The patient must be heparinized before the procedure. Traditional venous
thrombectomy is performed by surgically exposing the common femoral vein
and saphenofemoral junction through a longitudinal skin incision. A Fogarty
catheter is passed through the clot, and the balloon is inflated and withdrawn,
along with the clot. However, care must be taken to avoid dislodging the clot
or breaking it into small fragments because pulmonary embolus will result.
A proximal balloon or a temporary caval filter may be used to reduce the
likelihood of embolization. Venography is mandatory to confirm the clearance
of the thrombus. Back bleeding does not indicate clot clearance because a
patent valve can block flow, or flow can be present with patent tributaries.
Venous valves may sometimes prevent the passage of a catheter in a
retrograde direction down the leg. When this happens, the leg may be
wrapped tightly with an Esmarch bandage in an attempt to force clot
extrusion. After the thrombus has been removed, construction of a small
arteriovenous fistula may assist in maintaining patency by increasing the flow
velocity through a thrombogenic iliofemoral venous segment and promoting
collateral development. The fistula is usually performed between the
saphenous vein and the femoral vein. To reduce the likelihood of
rethrombosis, heparin anticoagulation is usually initiated before surgery,
continued during the procedure, and maintained for 6-12 months afterward.
Leg compression devices are useful to maintain venous flow.
Outcomes from multiple studies have shown rethrombosis rates around 12%
when a temporary arteriovenous fistula is used. Optimal results were found in
thrombosis less than 7 days, clearance of thrombus from the external and
internal iliac veins, intraoperative venography, early ambulation, and religious
use of compression stockings. In a prospective randomized study from
Sweden comparing surgery with anticoagulation, at 5 years, 37% of operated
patients were asymptomatic, compared with just 18% in the anticoagulation
group. Vein patency was 77% in the surgical group compared with just 30% in
the anticoagulation group. [156]
Table. Surgical Thrombectomy with Temporary Arteriovenous Fistula in Early
Iliac Vein Patency [157] (Open Table in a new window)
Study and Number of
Patent Iliac Vein
Patients

Delin (13) 85%

Plate (31) 87%

Piquet (92) 80%

Einarsson (51) 88%

Juhan (42) 93%

Vollmar (93) 82%

Kniemeyer (185) 96%

Neglen (48) 89%

Total (555) 88%

Placement of Inferior Vena Cava Filters

Inferior vena cava filters are not recommended in patients with acute venous
thromboembolism (VTE) on anticoagulant therapy. [113] These filters were
developed in an attempt to trap emboli and minimize venous stasis. In most
patients with deep venous thrombosis (DVT), prophylaxis against the
potentially fatal passage of thrombus from the lower extremity or pelvic vein to
the pulmonary circulation is adequately accomplished with anticoagulation. An
inferior vena cava filter is a mechanical barrier to the flow of emboli larger than
4 mm.
In the past, inferior vena cava filters were placed in 4.4% of patients. Recent
use was documented in 14% of patients with DVT; this rate was perhaps due
to broadened indications with the introduction of removable filters. Temporary
or removable filters, all of which may also be left as permanent, permit
transient mechanical pulmonary embolism (PE) prophylaxis. This option may
be useful in the setting of polytrauma, head injury, hemorrhagic stroke, known
VTE, or major surgery when PE prophylaxis must be maintained during a
short-term contraindication to anticoagulation.
In a randomized trial, the addition of an inferior vena cava filter to
anticoagulation for DVT increased the risk of recurrent DVT (11.6% to 20.8%)
and did not improve the 2-year survival rate. However, the filter group had
significantly fewer PEs (1.1% vs 4.8%). Of note was the risk of major bleeding
at 3 months (10.5%). This result agrees with other reports and highlights the
usual trade-off of prophylaxis with a filter versus anticoagulation and the
respective complication risks of new DVT (peripheral to the filter) versus major
hemorrhage. In the elderly patient with an increased risk of bleeding, and
particularly if the patient is at risk for trauma, the risk and benefits may favor
use of a filter.
Catheter-directed thrombolysis does not add to the risk of PE to warrant
routine filter placement. However, for patients with contraindications to
pharmacologic lysis in whom a percutaneous mechanical thrombectomy
device is to be used, a filter may be a useful adjunct. [158]
The ideal vena cava filter would trap venous emboli while maintaining normal
venous flow. Many different filter configurations have been used, but the
current benchmark remains the Greenfield filter with the longest long-term
data. Patency rates greater than 95% and recurrent embolism rates of less
than 5% have been demonstrated by numerous studies. The conical shape
allows central filling of emboli while allowing blood on the periphery to flow
freely. Numerous other filters with similar track records have since been
developed, including filters that can be removed.
Regardless of the type of filter placed, the technique remains the same. Local
anesthetic is used to anesthetize either the groin for a femoral vein approach
or the neck for a jugular vein approach. A single wall needle is used under
ultrasonic guidance to enter the target vein, and a 0.035-inch guidewire is
passed into the inferior vena cava. A venogram is performed to identify the
renal veins and measure the diameter of the vena cava to ensure the cava is
not too big for the filter. Intravascular ultrasound (IVUS) can also be used for
this purpose. It has the added benefit of not only allowing for bedside filter
placement in sick intensive care unit (ICU) patients, but it also obviates the
need for IV contrast. The correct filter location traditionally entails an infra-
renal fixation with central filter extension to the level of the renal veins.
Placement in the suprarenal inferior vena cava or superior vena cava may be
indicated in some situations.
American Heart Association recommendations for inferior vena cava filters
include the following [10] :
 Confirmed acute proximal DVT or acute PE in patient with contraindication
for anticoagulation (this remains the most common indication for inferior
vena cava filter placement)
 Recurrent thromboembolism while on anticoagulation
 Active bleeding complications requiring termination of anticoagulation
therapy
Relative contraindications include the following:
 Large, free-floating iliofemoral thrombus in high-risk patients
 Propagating iliofemoral thrombus while on anticoagulation
 Chronic PE in patient with pulmonary hypertension and cor pulmonale
 Patient with significant fall risk
For more information, see Inferior Vena Caval Thrombosis and Inferior Vena
Cava Filters.
Replacement of Venous Valves
Percutaneously placed bioprosthetic venous valves are under development
and may provide a minimally invasive therapy to the long-term complication of
postthrombotic syndrome due to valve destruction. If successful, this
approach may provide a percutaneous therapeutic alternative for patients with
primarily palliative options to manage their venous reflux symptoms. An
effective therapy should diminish one of the primary indications for aggressive
thrombolytic therapy for acute deep venous thrombosis.
Use of Elastic Compression Stockings
Postthrombotic syndrome (PTS) affects approximately 50% of patients with
deep venous thrombosis (DVT) after 2 years. Elderly patients and patients
with recurrent ipsilateral DVT have the highest risk. Below-the-knee elastic
compression stockings (ECS) assist the calf muscle pump and reduce venous
hypertension and venous valvular reflux. This reduces leg edema, aids the
microcirculation, and prevents venous ischemia.
In a randomized controlled study from an Italian university setting involving
180 patients who presented with a first episode of symptomatic proximal DVT,
Prandoni and colleagues found below-the-knee ECS to have value for the
prevention of PTS. After conventional anticoagulation with heparin, patients
were discharged on therapeutic warfarin for 3-6 months and randomly
assigned to the control group (no ECS) or the ECS group. Graduated
compression stockings with ankle pressures of 30-40 mm Hg were given to
the participants, who were required to wear them daily on the affected leg or
legs over 2 years. Ninety percent of trial participants were compliant (wore the
stockings for at least 80% of daytime hours), and 5-year cumulative data was
evaluated to compare the incidence of PTS between the groups. [159]
A standardized validated scale was used to assess symptoms, severity,
and/or progression of PTS. PTS occurred in 26% of patients who wore ECS
compared with 49% of patients without ECS. All patients with PTS except one
developed manifestations of the syndrome within the first 2 years after the
initial diagnosis of DVT. The number of patients who need to be treated with
ECS was estimated at 4.3 to prevent one case of PTS. The adjusted hazard
ratio was 0.49 (CI 0.29-0.84, P = .011) in favor of ECS. Almost 50% of their
patients with proximal DVT developed PTS within 2 years.
The regular use of graduated elastic compression stockings reduced the
incidence of PTS by 50%. The authors also noted that the benefit conferred
by ECS was not related to the rate of recurrent DVT, which was identical in
both groups. The authors strongly recommended the early use and
widespread implementation of graduated elastic stockings with adequate
anticoagulant therapy for symptomatic proximal DVT to prevent the
development of PTS.
The Eighth ACCP Conference on Antithrombotic and Thrombolytic Therapy
observed that PTS occurs in 20-50% of patients with objectively confirmed
DVT and assigned a grade 1A recommendation for the use of graduated
elastic compression stockings for 2 years after the onset of proximal
DVT. [144, 160] With the adoption of outpatient therapy for proximal DVT, the initial
management of DVT increasingly becomes the responsibility of the
emergency physician.
More recently, the ACCP recommends against the routine use of compression
stockings in patients with acute DVT to prevent postthrombotic syndrome. [113]
Ambulation
Controversy exists regarding the role of ambulation in the therapy of deep
venous thrombosis (DVT). A study by Partsch reviewed the myths
surrounding immediate ambulation and compression in the patient with newly
diagnosed DVT and concluded that early ambulation and compression is not
associated with any significant risk of pulmonary embolism (PE). [161] It is well
recognized from the older literature that almost 50% of patients with acute
proximal DVT have evidence, based on V/Q pulmonary scanning, of
asymptomatic PE at baseline. Analyzing the effect of ambulation and
compression in this patient cohort focused on the development of a new PE,
the relief of pain and swelling, and the reduction in the incidence and severity
of postthrombotic syndrome (PTS).
The authors cited 2 small previous studies that demonstrated that the
incidence of a new PE after initiation of anticoagulant therapy with a low-
molecular-weight heparin (LMWH) did not increase significantly in patients
treated with early ambulation and compression. They had previously reported
their own prospective cohort study of 1289 patients with acute DVT treated as
outpatients with LMWH, early ambulation, and compression. Partsch et al
reported that only 77 of 1289 patients (5.9%) developed a new PE, only 6 of
1289 patients (0.4%) of these were symptomatic, and only 3 deaths (0.23%)
were attributed to the PE. This was not significantly different than historical
controls.
A systematic review by Kahn et al found that in patients with acute DVT, early
walking exercise is safe and may help to reduce acute symptoms and that in
patients with previous DVT, exercise training does not increase leg symptoms
acutely and may help to prevent or improve the postthrombotic syndrome. [162]
In Europe, early ambulation and compression has been the mainstay of
adjunctive treatment for DVT. In North America, the unsubstantiated fear of
dislodging clots by ambulation led clinicians to recommend bed rest and leg
elevation to their patients. The authors explained that bed rest promotes
venous stasis, which is a major risk factor for DVT and, therefore, may
actually enhance thrombus propagation and the risk of subsequent PE.
The authors also cited a number of other studies that revealed a significant
decrease in leg swelling (using leg circumference measures) and pain (analog
pain scales and quality of life scores) with early ambulation and compression.
They also recognized the limited data that are available to assess the effect of
early ambulation and compression on the subsequent development of PTS. In
their own small trial, they reported a trend toward a lower incidence of PTS.
They conceded that a larger, long-term study would be required.
Nevertheless, they strongly recommended early ambulation for their patients
in addition to elastic compression stockings.
The ACCP Consensus Conference on Antithrombotic and Thrombolytic
Therapy for venous thromboembolism also recommended ambulation as
tolerated for patients with DVT. [144, 160] Therefore, early ambulation on day 2
after initiation of outpatient anticoagulant therapy in addition to effective
compression is strongly recommended. Early ambulation without ECS is not
recommended. The fear of dislodging clots and precipitating a fatal PE is
unfounded.
Treatment of Superficial Thrombophlebitis
Superficial thrombophlebitis is often associated with deep venous thrombosis
(DVT) in two specific settings. The following high-risk groups require further
evaluation for DVT:
 Superficial thrombophlebitis in the absence of coexisting venous varices
and no other obvious etiology
 Involvement of the greater saphenous vein above the knee, especially if it
extends to the saphenofemoral junction (These latter patients should be
treated as having proximal vein DVT and treated with full anticoagulant
therapy.)
Uncomplicated superficial thrombophlebitis may be treated symptomatically
with heat, nonsteroidal anti-inflammatory agents (NSAIDs), and compression
hose. Bed rest is not recommended.
Some centers recommend full anticoagulation for high-risk patients with
isolated superficial thrombophlebitis. Some physicians may anticoagulate
high-risk patients with negative initial study results until follow-up surveillance
studies are completed. An alternative approach involves symptomatic care
alone with close follow-up and repeated noninvasive testing in 1 week. Full
anticoagulation is then reserved only for those patients with proven proximal
vein DVT.
Treatment of Axillary and Subclavian Vein Thrombosis
This was first described by Paget in 1875 and von Schrötter in 1884 and is
sometimes referred to as Paget–von Schrötter syndrome. The
pathophysiology is similar to that of deep venous thrombosis (DVT), and the
etiologies overlap. The incidence is lower than that of lower extremity DVT
because of decreased hydrostatic pressure, fewer venous valves, higher rates
of blood flow, and less frequent immobility of the upper arm.
Thoracic outlet compression from cervical ribs or congenital webs may
precipitate axillary/subclavian venous thrombosis. Catheter-induced
thrombosis is increasingly a common cause of this condition. The increased
use of subclavian catheters for chemotherapy and parenteral nutrition has
resulted in a dramatic increased incidence of proven thrombosis. Similarly,
pulmonary artery catheters are associated with a high incidence of internal
jugular and subclavian vein thrombosis. Pulmonary embolism (PE) occurs in
approximately 10% of patients. Fatal or massive PE is extremely rare.
Ultrasonography and venography are the diagnostic tests of choice.
Ultrasonographic findings may be falsely negative because of collateral blood
flow. Duplex ultrasonography is accurate for the evaluation of the internal
jugular vein and its junction with the subclavian vein where the innominate
vein begins.
Thrombolytic therapy is the treatment of choice for axillary/subclavian venous
thrombosis. Restoration of venous patency is more critical for the prevention
of chronic venous insufficiency in the upper extremity. Thrombolysis is best
accomplished with local administration of the thrombolytic agent directly at the
thrombus. After completion of a venographic study, a catheter is floated up to
the site of the clot, and the thrombolytic agent is administered as a direct
infusion. Venographic assessment for clot lysis is repeated every 4-6 hours
until venous patency is restored. Heparin is usually given concurrently to
prevent rethrombosis.
In the presence of anatomic abnormalities, surgical therapy is recommended
to minimize long-term morbidity and recurrence. Catheter-induced thrombosis
may require removal of the device. Locally infused thrombolytic agents have
been used successfully and are currently the treatment of choice.
Prophylaxis of Deep Venous Thrombosis
Prevention of deep venous thrombosis (DVT) has long been studied in various
clinical situations with varying degrees of success. Primary prophylaxis is
directed toward acting on one or more components of the Virchow triad,
affecting blood flow, coagulation, or vessel wall endothelium. Methods of
prophylaxis may be generally divided into mechanical and pharmacologic.
Many pharmacologic agents are currently available to prevent thrombosis.
Agents that retard or inhibit the process belong under the general heading of
anticoagulants. Agents that prevent the growth or formation of thrombi are
properly termed antithrombotics and include anticoagulants and antiplatelet
drugs, whereas thrombolytic drugs lyse existing thrombi.
Surgical patients undergoing general anesthesia have been extensively
studied. Studies of pneumatic compression in cardiac surgery and
neurosurgical patients have shown a distinct improvement in the incidence of
DVT without the added risk of bleeding. [163, 164] However, the effect is less
impressive in higher-risk patients, and compliance can be difficult. Routine
use of anticoagulant prophylaxis after cardiac surgery is
discouraged. [165] Kolluri et al showed no benefit of prophylactic postoperative
fondaparinux following after coronary artery bypass graft (CABG) surgery. [165]
Timing and duration of prophylactic agents has also been determined to have
a significant effect on the development of DVT. Early prophylaxis in surgical
patients with low molecular weight heparin has been associated with
significant reductions in postoperative venous thrombosis. If surgery is
delayed, then prophylaxis with low-dose unfractionated heparin or low
molecular weight heparin should be initiated at the time of admission and
discontinued prior to surgery.
Major surgical and high-risk orthopedic procedures place patients at risk for
deep venous thrombosis and venous thromboembolism, including pulmonary
embolism. Complications of DVT include postphlebitic syndrome or death
from pulmonary embolism. Therefore, prophylaxis with anticoagulant
medications, as well as the adjunct use of mechanical devices, is essential.
The most effective treatment protocol for a patient must be determined on a
case-by-case basis and account for the risk-benefit ratio in each situation. A
risk stratification protocol, such as that developed by the American College of
Chest Physicians (ACCP), is recommended to determine the appropriate level
and method of treatment.
For more information, see Deep Venous Thrombosis Prophylaxis.

Diagnosis of Venous Thromboembolism

In November 2018, the American Society of Hematology (ASH) released
guidelines for the diagnosis of venous thromboembolism (VTE). [166] The
American Academy of Family Physicians endorsed these guidelines in March
2019 and provided the following key recommendations from the guidelines. [167]
D-dimer testing alone should not be used to rule in or diagnose a PE, and a
positive D-dimer alone should not be used to diagnose DVT.
Pulmonary Embolism (PE)
Individuals with a low or intermediate pretest probability or
prevalence: Clinicians should use a D-dimer strategy to rule out PE, followed
by a ventilation-perfusion (VQ) scan or computed tomography pulmonary
angiography (CTPA) in patients requiring additional testing. D-dimer testing
alone should not be used to rule in a PE.
Individuals with a high pretest probability or prevalence (≥50%): Clinicians
should start with CTPA to diagnose PE. If CTPA is not available, a VQ scan
should be used with appropriate follow-up testing.
Individuals with a high pretest probability/prevalence: D-dimer testing alone
should not be used to diagnose PE and should not be used as a subsequent
test after CT scanning.
Individuals with a positive D-dimer or likely pretest probability: CTPA should
be performed. D-dimer testing can be used to exclude recurrent PE in
individuals with an unlikely pretest probability.
Outpatients older than 50 years: Use of an age-adjusted D-dimer cutoff is safe
and improves the diagnostic yield. Age-adjusted cutoff = Age (years) × 10
µg/L (using D-dimer assays with a cutoff of 500 µg/L).
Lower Extremity (LE) Deep Vein Thrombosis (DVT)
Individuals with a low pretest probability or prevalence: Clinicians should use
a D-dimer strategy to rule out DVT, followed by proximal LE or whole-leg
ultrasonography in patients requiring additional testing.
Individuals with a low pretest probability or prevalence (≤10%): Positive D-
dimer alone should not be used to diagnose DVT, and additional testing
following negative proximal or whole-leg ultrasonography should not be
conducted.
Individuals with an intermediate pretest probability or prevalence
(~25%): Whole-leg or proximal LE ultrasonography should be used. Serial
proximal ultrasonographic testing is needed after a negative proximal
ultrasonogram. No serial testing is needed after a negative whole-leg
ultrasonogram.
Individuals with suspected DVT and a high pretest probability or prevalence
(≥50%): Whole-leg or proximal LE ultrasonography should be used. Serial
ultrasonography should be used if the initial ultrasonogram is negative and no
alternative diagnosis is identified.
Upper Extremity (UE) DVT
Individuals with a low prevalence/unlikely pretest probability: D-dimer testing
should be used to exclude UE DVT, followed by duplex ultrasonography if
findings are positive.
Individuals with a high prevalence/likely pretest probability: Either D-dimer
testing followed by duplex ultrasonography/serial duplex ultrasonography, or
duplex ultrasonography/serial duplex ultrasonography alone can be used for
assessing patients suspected of having a UE DVT.
A positive D-dimer alone should not be used to diagnose UE DVT.
Anticoagulation for Venous Thromboembolism
The guidelines on optimal management of anticoagulation therapy for venous
thromboembolism (VTE) were released on November 7, 2018, by the
American Society of Hematology (ASH). [168]
Initial Anticoagulant Dose Selection
In obese patients receiving low-molecular-weight heparin (LMWH) for
treatment of acute VTE, it is suggested that initial LMWH dose selection be
based on actual body weight rather than on a fixed maximum daily dose (ie,
capped dose).
Drug-Interaction Management
For patients requiring administration of inhibitors or inducers of P-glycoprotein
(P-gp) or strong inhibitors or inducers of cytochrome P450 (CYP) enzymes, it
is suggested to use an alternative anticoagulant (eg, a vitamin K antagonist
[VKA] or LMWH) rather than a direct oral anticoagulant (DOAC) to treat VTE.
Point-of-Care INR Testing
For patients receiving maintenance VKA therapy for VTE, home point-of-care
international normalized ratio (INR) testing (patient self-testing [PST]) is
suggested in preference to any other INR testing approach except patient self-
management (PSM) in suitable patients (those who have demonstrated
competency to perform PST and who can afford this option).
For patients receiving maintenance VKA therapy for VTE, point-of-care INR
testing by the patient at home with self-adjustment of VKA dose (PSM) is
suggested in preference to any other management approach, including PST in
suitable patients (those who have demonstrated competency to perform PSM
and who can afford this option).
Selection of Timing Between INR Measurements (INR Recall Interval)
For patients receiving VKA therapy for VTE, an INR recall interval of 4 weeks
or less is suggested rather than an interval longer than 4 weeks after VKA
dose adjustment due to an out-of-target-range INR.
For patients receiving maintenance VKA therapy for VTE, a longer (6-12
weeks) INR recall interval is suggested rather than a shorter (4 weeks)
interval during periods of stable INR control.
Laboratory Monitoring of Anticoagulant Response
For patients with renal dysfunction (creatinine clearance, < 30 mL/min) or
obesity receiving LMWH therapy for VTE, it is suggested not to use anti–factor
Xa concentration monitoring to guide LMWH dose adjustment.
For patients receiving DOAC therapy for VTE, it is suggested not to measure
the DOAC anticoagulant effect during management of bleeding.
Transitions Between Anticoagulants
For patients transitioning from DOAC to VKA, overlapping DOAC and VKA
therapy until the INR is within the therapeutic range is suggested in
preference to LMWH or unfractionated heparin (UFH) "bridging therapy."
Use of Specialized AMS
For patients receiving anticoagulation therapy for VTE, specialized
anticoagulation-management service (AMS) care is suggested in preference
to care provided by the patient's usual healthcare provider.
Structured Patient Education
For patients receiving oral anticoagulation therapy for VTE, supplementary
patient education is suggested in addition to basic education.
Efforts to Improve Adherence to Anticoagulant Regimen
For patients receiving anticoagulation therapy for VTE, it is suggested not to
use a daily lottery, electronic reminders, or a combination of the two to
improve medication adherence. It is also suggested not to use visual
medication schedules (provided to patients at each visit, along with brief
counseling) to improve medication adherence.
Invasive Procedure Management
For patients at low-to-moderate risk for recurrent VTE who require interruption
of VKA therapy for invasive procedures, VKA interruption alone is
recommended in preference to periprocedural bridging with LMWH or UHF.
For patients interrupting DOAC therapy for scheduled invasive procedures, it
is suggested not to perform laboratory testing for DOAC effect before
procedures.
Excessive Anticoagulation and Bleeding Management
For patients receiving VKA therapy for VTE with INR >4.5 but < 10 and
without clinically relevant bleeding, temporary cessation of VKA alone is
suggested, without the addition of vitamin K.
For patients with life-threatening bleeding during VKA therapy for VTE and an
elevated INR, use of four-factor prothrombin complex concentrates (PCCs) is
suggested in preference to fresh frozen plasma (FFP) as an addition to
cessation of VKA and IV vitamin K.
For patients with life-threatening bleeding during oral direct Xa inhibitor
therapy for VTE, it is suggested to use either four-factor PCC administration
as an addition to cessation of oral direct Xa inhibitor or cessation of oral direct
Xa inhibitor alone.
For patients with life-threatening bleeding during oral direct Xa inhibitor
therapy for VTE, it is suggested to use coagulation factor Xa (recombinant),
inactivated-zhzo in addition to cessation of oral direct Xa inhibitor rather than
no coagulation factor Xa (recombinant), inactivated-zhzo.
For patients with life-threatening bleeding during dabigatran therapy for VTE,
it is suggested to use idarucizumab in addition to cessation of dabigatran
rather than no idarucizumab.
For patients with life-threatening bleeding during LMWH or UFH therapy for
VTE, it is suggested to use protamine in addition to LMWH/UFH cessation
rather than no protamine.
Anticoagulant Resumption Following Bleeding
For patients receiving anticoagulation therapy for VTE who survive an episode
of major bleeding, resumption of oral anticoagulation therapy within 90 days is
suggested in preference to discontinuance of oral anticoagulation therapy.

Medication Summary
The goals of pharmacotherapy for deep venous thrombosis (DVT) are to
reduce morbidity, to prevent the postthrombotic syndrome (PTS), and to
prevent pulmonary embolism (PE), all with minimal adverse effects and cost.
The main agent classes include anticoagulants and thrombolytics. [169]
Anticoagulants
Class Summary
These agents prevent recurrent or ongoing thrombolytic occlusion of the
vertebrobasilar circulation.

Rivaroxaban (Xarelto)
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Rivaroxaban is an oral factor Xa inhibitor that inhibits platelet activation by
selectively blocking the active site of factor Xa without requiring a cofactor (eg,
antithrombin III) for activity. It is indicated for a variety of treatment and
prophylaxis VTE indications including the following:
Risk reduction of stroke and systemic embolism in nonvalvular atrial fibrillation
Treatment of DVT
Treatment of PE
Reduction in risk of recurrent DVT and/or PE
Prophylaxis of DVT following hip or knee replacement surgery
Prophylaxis of VTE in acutely ill medical patients at risk for thromboembolic
complications owing to restricted mobility (and who are not at high risk of
bleeding)
Risk reduction of major CV events with CAD or PAD
Apixaban (Eliquis)
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Apixaban is an oral factor Xa inhibitor that inhibits platelet activation by
selectively and reversibly blocking the active site of factor Xa without requiring
a cofactor (eg, antithrombin III) for activity. It inhibits free and clot-bound factor
Xa, and prothrombinase activity; no direct effect on platelet aggregation, but
indirectly inhibits platelet aggregation induced by thrombin. It is indicated for
prophylaxis of deep venous thrombosis (DVT) or pulmonary embolism (PE) in
adults undergoing knee or hip replacement surgery. It is also indicated for
treatment of DVT and PE and for prevention of recurrence (following the initial
6 months of the initial treatment).

Dabigatran (Pradaxa)
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Dabigatran inhibits free and clot-bound thrombin and thrombin-induced
platelet aggregation. It is indicated for the prevention of stroke and systemic
embolism associated with nonvalvular atrial fibrillation (NVAF). This agent is
also indicated for the prevention and treatment of deep venous thrombosis
(DVT) or pulmonary embolism (PE).

Edoxaban (Savaysa)
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Edoxaban is indicated to reduce the risk of stroke and systemic embolism
associated with nonvalvular atrial fibrillation (NVAF).

Betrixaban (Bevyxxa)
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Betrixaban is indicated for the prophylaxis of venous thromboembolism (VTE)
in adults hospitalized for acute medical illness who are at risk for
thromboembolic complications owing to moderate or severe restricted mobility
and other risk factors that may cause VTE.
Fondaparinux sodium (Arixtra)
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Fondaparinux sodium is a synthetic anticoagulant that works by inhibiting
factor Xa, a key component involved in blood clotting. It provides a highly
predictable response and has a bioavailability of 100%. The drug has a rapid
onset of action and a half-life of 14-16 hours, allowing for sustained
antithrombotic activity over 24-hour period. Fondaparinux sodium does not
affect prothrombin time or activated partial thromboplastin time, nor does it
affect platelet function or aggregation.

Heparin
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Heparin augments activity of antithrombin III and prevents conversion of
fibrinogen to fibrin. It does not actively lyse but is able to inhibit further
thrombogenesis. Heparin prevents reaccumulation of a clot after a
spontaneous fibrinolysis.
Low Molecular Weight Heparins
Class Summary
Low-molecular-weight-heparin (LMWH) is prepared by selectively treating
unfractionated heparin (UFH) to isolate the low molecular weight (<9000 Da)
fragments. Its activity is measured in units of factor X inactivation, and
monitoring of the activated partial thromboplastin time (aPTT) is not required.
The dose is weight adjusted. Enoxaparin (Fragmin), dalteparin (Lovenox), and
tinzaparin (Innohep) have received US Food and Drug Administration (FDA)
approval for the treatment of deep venous thrombosis (DVT) in the United
States. Enoxaparin is approved for inpatient and outpatient treatment of DVT.

Dalteparin (Fragmin)
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Dalteparin enhances inhibition of factor Xa and thrombin by increasing
antithrombin III activity. In addition, it preferentially increases inhibition of
factor Xa. Except in overdoses, no utility exists in checking prothrombin time
(PT) or activated partial thromboplastin time (aPTT) because aPTT does not
correlate with anticoagulant effect of fractionated low-molecular-weight
heparin (LMWH). The average duration of treatment is 7-14 days.
Enoxaparin (Lovenox)
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Enoxaparin is a low-molecular-weight (LMWH) used in treatment of deep
venous thrombosis (DVT) and pulmonary embolism (PE) as well as DVT
prophylaxis. It enhances inhibition of factor Xa and thrombin by increasing
antithrombin III activity, it slightly affects thrombin and clotting time, and it
preferentially increases inhibition of factor Xa. The average duration of
treatment is 7-14 days.

Tinzaparin (Innohep)
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Tinzaparin enhances inhibition of factor Xa and thrombin by increasing
antithrombin III activity. In addition, it preferentially increases inhibition of
factor Xa. The average duration of treatment is 7-14 days.
Vitamin K Antagonists
Class Summary
Coumarins are a class of oral anticoagulant drugs that act as antagonists to
vitamin K. The mechanism of action is to interfere with the interaction between
vitamin K and coagulation factors II, VII, IX, and X. Vitamin K acts as a
cofactor at these levels. Coumarins produce their anticoagulant effect by
inhibiting the carboxylation necessary for biologic activity.

Warfarin (Coumadin)
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Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation
factors. It is used for prophylaxis and treatment of venous thrombosis,
pulmonary embolism (PE), and thromboembolic disorders. The dose must be
individualized and adjusted to maintain an international normalized ratio (INR)
of 2-3.
Thrombolytics
Class Summary
These agents are used to dissolve a pathologic intraluminal thrombus or
embolus that has not been dissolved by the endogenous fibrinolytic system.
Also used for the prevention of recurrent thrombus formation and rapid
restoration of hemodynamic disturbances.

Tenecteplase (TNKase)
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Tenecteplase is a modified version of alteplase (tPA) made by substituting 3
amino acids of alteplase. It has a longer half-life and, thus, can be given as a
single bolus over 5 seconds infusion instead of 90 minutes with alteplase. It
appears to cause less non-intracranial bleeding but has similar risk of
intracranial bleeding and stroke as alteplase. The dose should be determined
on the basis of patient weight. Treatment should be initiated as soon as
possible after onset of acute myocardial infarction symptoms. Because
tenecteplase contains no antibacterial preservatives, it must be reconstituted
immediately before use.

Alteplase, tPA (Activase)

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Alteplase is a thrombolytic agent for deep venous thrombosis (DVT) or
pulmonary embolism (PE). It is a tissue plasminogen activator (tPA) produced
by recombinant DNA and used in the management of acute myocardial
infarction, acute ischemic stroke, and PE. The safety and efficacy of this
regimen with coadministration of heparin and aspirin during the first 24 hours
after symptom onset have not been investigated.

Reteplase (Retavase)
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Reteplase is a tissue plasminogen activator (tPA) produced by recombinant
DNA and used in the management of acute myocardial infarction, acute
ischemic stroke, and pulmonary embolism (PE). Heparin and aspirin are
usually given concomitantly and after reteplase.