Deep Venous Thrombosis

Author: Kaushal (Kevin) Patel, MD; Chief Editor: Barry E Brenner, MD, PhD, FACEP
Updated: Mar 30, 2016

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.

CT venography showing bilateral deep

venous thrombosis. Arrows indicate bilateral deep venous thrombosis.

Signs and symptoms

Symptoms of deep venous thrombosis (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 pulmonary embolism (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)
See Clinical Presentation for more detail.

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 venous thromboembolism (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
See Workup for more detail.

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

See Treatment and Medication for more detail.

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.

Venous thrombus.

Pulmonary embolus.

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. (SeeMedication.)

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 calfs 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 handpump 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 calfs 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 coagulationfibrinolysis 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).

Coagulation pathway.

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).

Postoperative antithrombin III levels.

Furthermore, patients who have positive venograms postoperatively tend to be those in

whom circulating levels of ATIII are diminished (see the image below).

Antithrombin III levels and deep venous

thrombosis formation.

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 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]

Lower-extremity venogram shows outlining of an acute deep venous

thrombosis in the popliteal vein with contrast enhancement.

Lower-extremity venogram shows a nonocclusive chronic thrombus. The superficial

femoral vein (lateral vein) has the appearance of 2 parallel veins, when in fact, it is 1 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.

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 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
Schrtter syndrome) and (2) secondary thrombosis.
Effort induced thrombosis, or Paget-von Schrtter syndrome, accounts for 25% of cases.
[48]
Paget in England and von Schrtter 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.

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.

Superior vena cava syndrome in a patient

with lung cancer. CT scan demonstrates a hypoattenuating thrombus that fills the superior vena cava. The patient was treated
with anticoagulation alone.

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 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. 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.[60, 61]

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%.[62]
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.[63]
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.[64, 65]

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.[66] 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).[67, 68] This was the largest review of the

incidence, patterns, and risk for 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).[68] 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[69] :

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, 70] Obesity also appears to increases the risk
of anticoagulation reversal failure with prothrombin complex concentrate in those with
intracranial hemorrhage.[71]
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.[72] 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.[73]
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.[72, 74] 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.[75]

Malignancy is noted in as many as 30% of patients with venous thrombosis.[72, 76]The

thrombogenic mechanisms involve abnormal coagulation, as evidenced by 90% of cancer
patients having some abnormal coagulation factors.[77]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.[78] Additionally, DVT complicates 29% of surgical
procedures done for malignancy.[79]
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.[80] 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.
[81]
For more information, seeDeep Venous Thrombosis Prophylaxis.
Based on radioactive labeled fibrinogen, about half of lower extremity thrombi develop
intraoperatively.[82] Perioperative immobilization, coagulation abnormalities, and venous
injury all contribute to the development of surgical venous thrombosis.

Genetic factors
Genetic mutations within the bloods 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.[83, 84, 85] 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.[86] 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.[87]
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.[84]
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.[88]

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.[89]

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
Behet 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
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 4-fold. The in-hospital case-fatality rate for
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. [90]

Thromboembolism and recurrent thromboembolism appear to be serious complications of

inflammatory bowel disease.[91] 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). [91]

History
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 PE 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, 92] 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 DVT.
The classic finding of calf pain on dorsiflexion of the foot (Homans sign) is specific but
insensitive and present in one half of patients with DVT.[93] Discomfort in the calf muscles
on forced dorsiflexion of the foot with the knee straight has been a time-honored sign of
DVT. 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 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 legto-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 PE when symptomatic 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 (PaO ) 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.)
2

Lung scan

Spiral CT scan shows a pulmonary

thrombus.

Normal pulmonary angiogram.

Positive pulmonary angiogram.

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 DVT.

Recurrent Deep Venous Thrombosis

Without treatment, one half of patients 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 estrogencontaining 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.[94] However, it was noted that abnormal uterine
bleeding occurred more frequently with rivaroxaban than with enoxaparin/vitamin K
antagonists.

Postthrombotic Syndrome
PTS is a chronic complication of 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.[95]
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%. [96,
97]
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 postDVT, PTS-related venous ulcers is estimated to be $45 million per year, and 300,000 work
days are lost.[98]

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

Septic Thrombophlebitis

Thrombophlebitis, Superficial

Approach Considerations
A clinical practice guideline from the American Academy of Family Physicians and the
American College of Physicians provides 4 recommendations for the workup of patients
with probable DVT.[5] First, validated clinical prediction rules should be used to estimate
the pretest probability of 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.
Venous thromboembolism (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 recent
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.[99, 100]
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).[101] 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.[101]
Laboratory analysis has also been used in aiding the diagnosis of venous thrombosis.
Protein S, protein C, antithrombin III (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 deep venous thrombosis (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.
[102]
Many of these conditions are associated with higher risk for 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 Ddimer. 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%)[103] 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 Ddimer test require no further clinical evaluation. Similarly, subjects with an elevated Ddimer test at 1 month following anticoagulant cessation have a significantly higher risk of
recurrent venous thromboembolism (VTE).[104]
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%.[105, 106] 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 hospitals D-dimer
assay.
All D-dimer assays have been evaluated in various validation studies that determine the
assays 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 timeconsuming 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.[107]

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 Ddimer result rules out DVT. Ultrasonography was not required in these patients.[108]

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 DVT and PE can occur despite full therapeutic anticoagulation in 13% of patients.

Imaging in Deep Venous Thrombosis

Imaging studies used in DVT include ultrasonography, venography, impedance
plethysmography, 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 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.
Please go to the main article on Deep Venous Thrombosis Risk Stratification to see complete
information on this topic.

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.[109] Other anticoagulation drugs have subsequently been added to the
treatment armamentarium over the years, such as vitamin K antagonists and lowmolecular-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.
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 catheterdirected 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.[110]

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).

General Principles of Anticoagulation

Anticoagulant therapy remains the mainstay of medical therapy for 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.

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.
[111]
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.[109]
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 LMWH for the initial treatment of deep venous thrombosis 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 bodys
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.
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 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. HIT has not been reported. Therapeutic monitoring of laboratory
parameters such as the prothrombin time or 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.
Buller and his coauthors on behalf of the Matisse Investigators conducted a randomized
double-blind international study of fondaparinux versus enoxaparin on 2205 patients with

objectively confirmed acute 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 vitamin K antagonist until a therapeutic INR was achieved.
Anticoagulation with a vitamin K antagonist 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.
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%).
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.
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.[112]

Rivaroxaban
Rivaroxaban (Xarelto) is an oral factor Xa inhibitor approved by the FDA in November
2012 for treatment of DVT or 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 vitamin K antagonist (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.[113, 114]

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.[115, 116, 117] 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.[118] 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 DeepVein 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.[119, 120]
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.[121]

Dabigatran
Dabigatran (Pradaxa) inhibits free and clot-bound thrombin and thrombin-induced
platelet aggregation. This agent was 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.[122, 123, 124] 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.[122, 123]
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.[124]

Duration of Anticoagulation
For the first episode of DVT, patients should be treated for 3-6 months. Recurrent
episodes should be treated for at least 1 year.
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 fixedduration 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.[125]
Patients with cancer have a particularly higher rate of DVT recurrence than noncancer
patients. Long-term therapy for DVT is strongly recommended. Recent studies have
shown a lower rate of VTE recurrence without increasing the risk of bleeding with
LMWH therapy. Reports also describe that the LMWH compounds may decrease the allcause mortality rate. The author recommends LMWH therapy alone without crossover to
warfarin if the patients 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 4year follow-up period was reduced from 21% to 3% with continued anticoagulation.
However, the incidence of major bleeding increased from 3% to 9%.[126]
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.[127, 128] Initial
studies have also shown LMWH to be effective in pregnant patients, but long-term, large
randomized trials have yet to be completed.[129]

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.[130] High-risk populations (>65 y with a history of stroke, 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 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 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 drugs effects.
The risk of bleeding on warfarin is not linearly related to the elevation of the 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 CNS hemorrhage.
Additional complications include the following:

Systemic embolism
Chronic venous insufficiency
PTS (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 halflife, 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 DVT, anticoagulation remains the cornerstone of treatment. The recent
development of novel oral anticoagulants has provided clinicians with an expanding set
of options for DVT treatment.[131]
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 nonvitamin 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 6090 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.[132, 133]

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).[134]
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 Kdependent 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.

Nonvitamin K antagonist oral anticoagulants (NOACs)

The new oral anticoagulant factor Xa or IIa inhibitors have numerous advantages over
traditional vitamin K antagonists, 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.[135,
136]

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 (Pradbind)
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.
[137, 138, 139, 140]

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 ribaroxaban. Andexanet alfa has been shown to
reverse the anticoagulant effects of apixaban and rivroxaban in human volunteers, and
more studies are ongoing.[141]
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.[142]

Pharmacologic Thrombolysis
Use of thrombolytic medications to lyse DVT 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, GI 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 catheterdirected 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.[143]
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. Currently, 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.
For more information, see Inferior Vena Caval Thrombosis.
Percutaneous mechanical thrombectomy devices are a popular adjunct to catheterdirected 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.[144]
Table. Surgical Thrombectomy with Temporary Arteriovenous Fistula in Early Iliac Vein
Patency[145] (Open Table in a new window)
Study and Number of Patients Patent Iliac Vein
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 were developed in an attempt to trap emboli and minimize
venous stasis. In most patients with 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 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 shortterm 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 2year 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.[146]
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 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 PTS 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 DVT.

Use of Elastic Compression Stockings

PTS affects approximately 50% of patients with 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.[147]
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. With the adoption of outpatient therapy for
proximal DVT, the initial management of DVT increasingly becomes the responsibility
of the emergency physician.

Ambulation
Controversy exists regarding the role of ambulation in the therapy of DVT. The study by
Partsch reviews the myths surrounding immediate ambulation and compression in the
patient with newly diagnosed DVT and concludes that early ambulation and compression
is not associated with any significant risk of PE.[148]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
PTS.
The authors cite 2 small previous studies that demonstrated that the incidence of a new
PE after initiation of anticoagulant therapy with a 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.[149]
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 VTE
also recommends ambulation as tolerated for patients with DVT. 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 DVT in 2 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,
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 Schrtter in 1884 and is sometimes
referred to as Pagetvon Schrtter syndrome. The pathophysiology is similar to that of
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. 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.[150,
151]
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.
[152]
Kolluri et al showed no benefit of prophylactic postoperative fondaparinux
following after coronary artery bypass graft (CABG) surgery.[152]
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.

Activity
Consultations with the following are indicated:

Hematologist
Vascular surgeon

Radiologist
Interventional radiologist

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.

Anticoagulants
Class Summary
These agents prevent recurrent or ongoing thrombolytic occlusion of the vertebrobasilar circulation.
View full drug information

Rivaroxaban (Xarelto)
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
treatment of DVT or PE, and to reduce risk of recurrent DVT and PE following initial treatment. It is
also indicated for prophylaxis of DVT in patients undergoing knee or hip replacement surgery.
View full drug information

Apixaban (Eliquis)
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 DVT or 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).
View full drug information

Fondaparinux sodium (Arixtra)

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.
View full drug information

Heparin
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 UFH to isolate the low
molecular weight (< 9000 Da) fragments. Its activity is measured in units of factor X inactivation, and
monitoring of the 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 DVT in the United States. Enoxaparin is approved for inpatient and outpatient
treatment of DVT.
View full drug information

Dalteparin (Fragmin)
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 LMWH. Average duration of treatment is 7-14
days.Average duration of treatment is 7-14 d.
View full drug information

Enoxaparin (Lovenox)
Enoxaparin is an LMWH used in treatment of DVT and 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. Average duration of treatment is
7-14 days.
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Tinzaparin (Innohep)
Tinzaparin enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In
addition, it preferentially increases inhibition of factor Xa. 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.
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Warfarin (Coumadin)
Warfarin interferes with hepatic synthesis of vitamin Kdependent coagulation factors. It is used for
prophylaxis and treatment of venous thrombosis, PE, and thromboembolic disorders. The dose must
be individualized and adjusted to maintain INR at 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.
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Tenecteplase (TNKase)
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.

Urokinase (Abbokinase)
Urokinase is a direct plasminogen activator isolated from human fetal kidney cells grown in culture. It
acts on endogenous fibrinolytic system and converts plasminogen to enzyme plasmin. Plasmin
degrades fibrin clots, fibrinogen, and other plasma proteins. Urokinase is nonantigenic but more
expensive than streptokinase, which limits its use. When used for purely local fibrinolysis, it is

administered as local infusion directly into area of thrombus and with no bolus. The dose must be
adjusted to achieve clot lysis or patency of the affected vessel.

Streptokinase (Kabikinase, Streptase)

Streptokinase acts with plasminogen to convert plasminogen to plasmin. Plasmin degrades fibrin clots
as well as fibrinogen and other plasma proteins. An increase in fibrinolytic activity that degrades
fibrinogen levels for 24-36 hours takes place with intravenous (IV) infusion of streptokinase.
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Alteplase, tPA (Activase)

Alteplase is a thrombolytic agent for DVT or 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.
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Reteplase (Retavase)
Reteplase is a tPA produced by recombinant DNA and used in the management of acute myocardial
infarction, acute ischemic stroke, and PE. Heparin and aspirin are usually given concomitantly and
after reteplase.