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7/27/2019 Deep Venous Thrombosis and Thrombophlebitis
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Deep Venous Thrombosis and
Thrombophlebitis
Author: Donald Schreiber, MD, CM, Assistant Professor of Surgery,
Stanford University School of Medicine; Research Director, Division
of Emergency Medicine, Stanford University Hospital
Donald Schreiber, MD, CM, is a member of the following medical
societies: American College of Emergency Physicians
Editor(s): Francis Counselman, MD, Program Director, Chair,
Professor, Department of Emergency Medicine, Eastern Virginia Medical
School; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor,
Pharmacy, eMedicine; Gary Setnik, MD, Chair, Department of Emergency
Medicine, Mount Auburn Hospital; Assistant Professor, Division of
Emergency Medicine, Harvard Medical School; John Halamka, MD, Chief
Information Officer, CareGroup Healthcare System, Assistant Professor
of Medicine, Department of Emergency Medicine, Beth Israel Deaconess
Medical Center; Assistant Professor of Medicine, Harvard Medical
School; and Barry Brenner, MD, PhD, Chairman, Department of Emergency
of Medicine, Professor, Departments of Emergency Medicine and
Internal Medicine, University of Arkansas for Medical Sciences
INTRODUCTION Section 2 of 10
Author Information Introduction Clinical Differentials Workup
Treatment Medication Follow-up Miscellaneous Bibliography
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Background: Deep venous thrombosis (DVT) and its sequela, pulmonary
embolism, is the leading cause of preventable in-hospital mortality
in the US. Although pulmonary embolism is discussed elsewhere in this
text, it must be emphasized that it is primarily a complication of
DVT.
The first reference to peripheral venous disease is recorded on the
Ebers papyrus in 1550 BC, which documents the potential 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 pulmonary
embolism. Heparin only was introduced to clinical practice in 1937.
Over the last 25 years, considerable progress has been made in the
pathophysiology, diagnosis, and treatment of DVT.
Pathophysiology: Virchow triad as first formulated (venous stasis,
vessel wall injury, and a hypercoagulable state) is still the primary
mechanism for the development of venous thrombosis. The relative
importance of each factor still is debated. The formation,
propagation, and dissolution of venous thrombi represent a balance
between thrombogenesis and the body's protective mechanisms,
specifically the circulating inhibitors of coagulation and the
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fibrinolytic system.
In practical terms, the development of venous thrombosis is best
understood as the activation of coagulation in areas of reduced blood
flow. This explains why the most successful prophylactic regimens are
anticoagulation and minimizing venous stasis. DVT of the lower
extremity usually begins in the deep veins of the calf around the
valve cusps or within the soleal plexus. A minority of cases arise
primarily in the ileofemoral system as a result of direct vessel wall
injury, as seen with hip surgery or catheter-induced DVT. The vast
majority of calf vein thrombi dissolve completely without therapy.
Approximately 20% propagate proximally. Propagation usually occurs
before embolization. The process of adherence and organization of the
venous thrombus does not begin until 5-10 days after thrombus
formation. Until this process has been established fully, the
nonadherent, disorganized thrombus may propagate and/or embolize.
Not all venous thrombi pose equal embolic risk. Studies have shown
that isolated calf vein thrombi carry a limited risk of pulmonary
embolism. Furthermore, studies have suggested that isolated calf vein
thrombi are smaller and do not cause significant morbidity or
mortality if they embolize. Contradictory evidence from several other
studies has indicated that isolated calf vein thrombi do embolize and
suggests that propagation proximally may occur rapidly and that fatal
pulmonary embolism arising from isolated calf vein DVT is a
significant risk.
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The current diagnostic and therapeutic management of DVT is
influenced strongly by the different risks assigned to proximal and
calf vein thrombi. The propagation and organization of the venous
thrombus usually result in destruction of venous valves and produce
varying degrees of venous outflow obstruction. Spontaneous lysis and
complete recanalization of established proximal DVT occurs in fewer
than 10% of patients, even with anticoagulation. These factors are
the most important pathogenic mechanisms in the development of
chronic venous insufficiency.
Frequency:
In the US: The exact incidence of DVT is unknown because most studies
are limited by the inherent inaccuracy of clinical diagnosis. More
importantly, most DVT is occult and usually resolves spontaneously
without complication. Existing data that underestimate the true
incidence of DVT suggest that about 80 cases per 100,000 persons
occur annually. Approximately 1 person in 20 develops DVT over her or
his lifetime, and 600,000 hospitalizations for DVT occur annually in
the US.
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
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complications of DVT, affect 0.5% of the entire population.
Extrapolation of this data reveals that as many as 5 million people
suffer from venous stasis and varying degrees of venous
insufficiency.
Mortality/Morbidity: Death from DVT is attributed to massive
pulmonary embolism, which causes 200,000 deaths annually in the US.
Pulmonary embolism is the leading cause of preventable in-hospital
mortality.
Sex: Male-to-female ratio is 1.2:1.
Age: DVT usually affects individuals older than 40 years. CLINICAL
Section 3 of 10
Author Information Introduction Clinical Differentials Workup
Treatment Medication Follow-up Miscellaneous Bibliography
History:
The signs and symptoms of DVT are related to the degree of
obstruction to venous outflow and inflammation of the vessel wall.
The bedside diagnosis of venous thrombosis is insensitive and
inaccurate. Many thrombi do not produce significant obstruction to
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venous flow; venous collaterals may develop rapidly, and venous wall
inflammation may be minimal. Conversely, many nonthrombotic
conditions produce signs and symptoms suggestive of DVT. Studies
repeatedly have documented this inherent difficulty of the clinical
diagnosis of lower extremity DVT.
Many patients are asymptomatic, however, the history may include the
following:
Edema, principally unilateral, is the most specific symptom. Massive
edema with cyanosis and ischemia (phlegmasia cerulea dolens) is rare.
Leg pain occurs in 50%, but this is entirely nonspecific. Pain can
occur on dorsiflexion of the foot (Homans sign).
Tenderness occurs in 75% of patients, but it also is found in 50% of
patients without objectively confirmed DVT.
Clinical signs and symptoms of pulmonary embolism as the primary
manifestation occur in 10% of patients with confirmed DVT.
The pain and tenderness associated with DVT usually does not
correlate with the size, location, or extent of the thrombus.
Warmth or erythema of skin can be present over the area of thrombosis.
Physical: No single physical finding or combination of symptoms and
signs is sufficiently accurate to establish the diagnosis of DVT. The
following is a list outlining the most sensitive and specific
physical findings in DVT:
Edema, principally unilateral
Tenderness, if present, usually is confined to the calf muscles or
over the course of the deep veins in the thigh.
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Pain and/or tenderness away from these areas is not consistent with
venous thrombosis and usually indicates another diagnosis.
Homans sign
Discomfort in the calf muscles on forced dorsiflexion of the foot
with the knee straight has been a time-honored sign of DVT. However,
this sign is present in less than one third of patients with
confirmed DVT.
It also is found in more than 50% of patients without DVT. It is
therefore very nonspecific.
Venous distension and prominence of the subcutaneous veins
Superficial thrombophlebitis is characterized by the finding of a
palpable, indurated, cordlike, tender subcutaneous venous segment.
Patients with superficial thrombophlebitis without coexisting
varicose veins and with no other obvious etiology (eg, IV catheters,
IV drug abuse, soft tissue injury) are at high risk because
associated DVT is found in as many as 40% of these patients.
Patients with superficial thrombophlebitis extending to the
saphenofemoral junction are also at higher risk for associated DVT.
Fever: Fever, usually low grade, may be present. High fever is
usually indicative of an infectious process such as cellulitis or
lymphangitis.
Phlegmasia cerulea dolens
Patients with venous thrombosis may develop variable discoloration of
the lower extremity. The most common abnormal hue is reddish purple
from venous engorgement and obstruction.
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In rare cases, the leg is cyanotic from massive ileofemoral venous
obstruction. This ischemic form of venous occlusion originally was
described as phlegmasia cerulea dolens or painful blue inflammation.
The leg is usually markedly edematous, painful, and cyanotic.
Petechiae are often present.
Phlegmasia alba dolens
Painful white inflammation originally was used to describe massive
ileofemoral venous thrombosis and associated arterial spasm. 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.
Clinical findings of pulmonary embolism
These findings are the primary manifestation of about 10% of patients
with DVT.
In patients with angiographically proven pulmonary embolism, DVT is
found in 45-70%. In the vast majority of these patients, the DVT is
clinically silent.
Causes:
The clinical evaluation of patients with suspected DVT is facilitated
by an assessment of risk factors. The diagnosis of DVT is confirmed
in only 20-30% of ED patients with clinically suspected DVT. The
prevalence of DVT in the ED patient population correlates with the
number of risk factors present. In patients with no identified risk
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factors, DVT is confirmed in only 11%. In patients with 3 risk
factors, the number rises to 50%.
The following risk factors for DVT have been identified in many
different epidemiologic studies:
General
Age
Immobilization longer than 3 days
Pregnancy and the postpartum period
Major surgery in previous 4 weeks
Long plane or car trips (>4 h) in previous 4 weeks
Medical
Cancer
Previous DVT
Cerebrovascular accident
Acute myocardial infarction (AMI)
Congestive heart failure (CHF)
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Sepsis
Nephrotic syndrome
Ulcerative colitis
Trauma
Multiple trauma
CNS/spinal cord injury
Burns
Lower extremity fractures
Vasculitis
Systemic lupus erythematosus (SLE) and the lupus anticoagulant
Behet syndrome
Homocystinuria
Hematologic
Polycythemia rubra vera
Thrombocytosis
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Inherited disorders of coagulation/fibrinolysis
Antithrombin III deficiency
Protein C deficiency
Protein S deficiency
Factor V Leyden
Dysfibrinogenemias and disorders of plasminogen activation
Drugs/medications
IV drug abuse
Oral contraceptives
Estrogens
Heparin-induced thrombocytopenia
The clinical assessment of patients with suspected DVT is often
difficult because of the interplay between risk factors and the
nonspecific nature of the physical findings. Clinicians have observed
that often a discordance is present between the clinical assessment
and the results of objective testing. For example, patients deemed to
be at high risk for DVT may have a negative duplex ultrasound study.
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In this case, the probability of DVT is still greater than 20% when
the known sensitivity, specificity, and negative likelihood ratio of
duplex ultrasound are considered. It was recognized that having an
objective method to determine pretest probability would simplify
clinical management.
A clinical prediction guide that quantifies the pretest probability
was developed. The model enables physicians to reliably stratify
their patients into high, moderate, 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.
Wells Clinical Prediction Guide for DVT
Clinical Parameter Score
Active cancer (treatment ongoing, or within 6 months or palliative) 1
Paralysis or recent plaster immobilization 1
Recently bedridden for >3 days or major surgery 3 cm compared to the asymptomatic leg 1
Pitting edema (greater in the symptomatic leg) 1
Collateral superficial veins (nonvaricose) 1
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Alternative diagnosis (as likely or > that of DVT) -2
Total of Above Score
High probability: Score 3
Moderate probability: Score = 1 or 2
Low probability: Score 0
Adapted from Anand SS, et al. JAMA. 1998; 279 [14];1094
DIFFERENTIALS Section 4 of 10
Author Information Introduction Clinical Differentials Workup
Treatment Medication Follow-up Miscellaneous Bibliography
Cellulitis
Pulmonary Embolism
Thrombophlebitis, Septic
Thrombophlebitis, Superficial
Other Problems to be Considered:
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In approximately 70% of patients with clinically suspected DVT,
alternate diagnoses ultimately are found as follows:
Achilles tendonitis
Arterial insufficiency
Arthritis
Asymmetric peripheral edema secondary to CHF, liver disease, renal
failure, or nephrotic syndrome
Cellulitis, lymphangitis
Extrinsic compression of iliac vein secondary to tumor, hematoma, or
abscess
Hematoma
Lymphedema
Muscle or soft tissue injury
Neurogenic pain
Postphlebitic syndrome
Prolonged immobilization or limb paralysis
Ruptured Baker cyst
Stress fractures or other bony lesions
Superficial thrombophlebitis
Varicose veins
Quick Find
Author Information
Introduction
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Clinical
Differentials
Workup
Treatment
Medication
Follow-up
Miscellaneous
Bibliography
Click for related images.
Related Articles
Cellulitis
Pulmonary Embolism
Thrombophlebitis, Septic
Thrombophlebitis, Superficial
Continuing Education
CME available for this topic. Click here to take this CME.
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Patient Education
Click here for patient education.
WORKUP Section 5 of 10
Author Information Introduction Clinical Differentials Workup
Treatment Medication Follow-up Miscellaneous Bibliography
Lab Studies:
Hematologic and coagulation studies are not required prior to
confirming the diagnosis.
A number of studies have evaluated the use of D-dimer, a fibrin
degradation product, in the diagnosis of DVT. It has been shown to be
93% sensitive for proximal vein thrombosis, but it is relatively
nonspecific. In some centers, it has been used as a screening test
for DVT. Some authors have recommended incorporating D-dimer results
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into a management strategy.
Different D-dimer assays are available with considerable variation in
sensitivity and specificity. The older quantitative enzyme-linked
immunoassay (ELISA) is very accurate but time consuming and not
practical for use in the ED. A new rapid qualitative ELISA assay is
now available.
The older qualitative latex agglutination assay is not accurate and
should not be used for treating patients with suspected DVT.
A rapid bedside qualitative RBC agglutination assay (SimpliRED) is
available and is reasonably sensitive for proximal DVT but less so
for calf vein DVT.
All D-dimer assays are dependent on the size of the clot. D-dimer
assays are not "clot specific" and are positive in many other
conditions associated with DVT such as recent surgery, trauma, MI,
pregnancy, and metastatic cancer. This explains their lack of
specificity.
In patients with low pretest probability for DVT, a negative D-dimer
as measured by the whole blood RBC agglutination assay reduces the
probability of DVT to less than 1%. Some physicians may choose to
forego objective ultrasound testing in this scenario.
Protein S, protein C, antithrombin III, factor V Leyden, prothrombin
20210A mutation, and antiphospholipid antibodies can be measured.
Deficiencies of these factors produce a hypercoagulable state. These
are rare causes of DVT.
Laboratory investigations for these abnormalities primarily are
indicated when DVT is diagnosed in patients younger than 35 years or
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when venous thrombosis is detected in unusual sites.
Imaging Studies:
Due to the inherent inaccuracy of clinical diagnosis, the history,
physical examination, and assessment of risk factors should be used
to determine who requires further objective diagnostic testing.
Diagnosing DVT and committing patients to the risks of
anticoagulation without confirmatory objective testing are
unacceptable.
Contrast venography
The criterion standard for evaluating patients with suspected DVT has
been contrast venography. For many reasons, including allergic
reactions, contrast-induced DVT, technical difficulties, inadequate
studies, interobserver reliability, and lack of availability,
venography is either contraindicated or nondiagnostic in as many as
20-25% of patients. As a result, noninvasive studies essentially have
replaced venography as the initial diagnostic test of choice.
Duplex ultrasonography and impedance plethysmography (IPG) are the
noninvasive tests that have been investigated the most.
Duplex ultrasound
Technological advances in ultrasound have permitted the combination
of real-time ultrasonic imaging with Doppler flow studies (duplex
ultrasound). The major ultrasound criterion for detecting venous
thrombosis is failure to compress the vascular lumen, presumably
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because of the presence of occluding thrombus. The absence of the
normal phasic Doppler signals arising from the changes to venous flow
provides indirect evidence of venous occlusion.
Many studies have confirmed the diagnostic sensitivity and
specificity of duplex ultrasound for proximal vein thrombosis.
Sensitivity and specificity for Duplex ultrasound are 98%.
Duplex ultrasound is also helpful to differentiate venous thrombosis
from hematoma, Baker cyst, abscess, and other causes of leg pain and
edema.
The primary disadvantage of duplex ultrasound is its inherent
inaccuracy in the diagnosis of calf vein thrombosis. Venous thrombi
proximal to the inguinal ligament are also difficult to visualize.
Nonoccluding thrombi may be hard to detect. In patients with
suspected acute recurrent DVT, duplex ultrasound may not be able to
differentiate between old and new clots. Ultrasound equipment is
expensive, and accuracy may vary depending on local expertise.
Impedance plethysmography
In some countries, IPG has been the initial noninvasive diagnostic
test of choice. Plethysmography is derived from the Greek word
meaning "to increase." This procedure is based on recording changes
in blood volume of an extremity, which are related directly to venous
outflow. Several different techniques can be used to measure these
changes, including electrical impedance. In the setting of proximal
vein thrombosis, venous outflow from the lower extremity is slowed,
and the blood volume or venous capacitance is increased. Standardized
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graphs are used to discriminate normal IPG studies from abnormal
results.
In many studies, IPG has been shown to be sensitive and specific for
proximal vein thrombosis. It is insensitive for calf vein thrombosis,
nonoccluding proximal vein thrombus, and ileofemoral vein thrombosis
above the inguinal ligament. IPG cannot distinguish between
thrombotic occlusion and extravascular compression of the vein. False-
positive results occur in the setting of significant CHF and raised
central venous pressure as well as with severe arterial insufficiency.
MRI
MRI increasingly has been investigated for evaluation of suspected
DVT. In limited studies, the accuracy approaches that of the
criterion standard, contrast venography.
MRI is the diagnostic test of choice for suspected iliac vein or
inferior vena caval thrombosis.
In the second and third trimester of pregnancy, MRI is more accurate
than duplex ultrasound because the gravid uterus alters Doppler
venous flow characteristics.
In suspected calf vein thrombosis, MRI is more sensitive than any
other noninvasive study.
Expense, lack of general availability, and technical issues limit its
use.
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Nuclear medicine imaging studies: Nuclear medicine studies with I125-
labeled fibrinogen no longer are recommended for ED patients. It is
relatively insensitive for proximal vein thrombosis, takes longer
than 24 hours to obtain results, and a significant number of false-
positive studies are obtained. I125-labeled fibrinogen is no longer
available in the US.
Summary - Which test is best?
When directly compared, duplex ultrasound has superior sensitivity
and specificity over IPG.
Controversy still exists over the use of noninvasive studies such as
duplex ultrasound for the diagnosis of suspected DVT. Recognizing
that duplex ultrasound is relatively insensitive for calf vein
thrombosis only matters if the clinician is inclined to anticoagulate
patients with calf vein DVT. If the clinical algorithm for calf vein
thrombosis recommends clinical surveillance and serial studies to
detect proximal extension, the lack of sensitivity of the noninvasive
study is irrelevant.
Reports on the use of noninvasive studies for DVT in asymptomatic
hospitalized patients should not be used to determine the optimal
evaluation of ED patients with suspected DVT who are usually
ambulatory and symptomatic. A number of authors incorrectly recommend
the routine use of contrast venography rather than a noninvasive
study for suspected DVT on the basis of low sensitivity that has been
reported on studies of hospitalized patients posthip surgery.
In ambulatory outpatients with suspected DVT, the sensitivity of
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duplex ultrasound for proximal vein thrombosis is 98%, and it remains
the initial diagnostic test of choice.
Simplified Clinical Management Strategy for Patients with Suspected
DVT
Using the pretest probability score calculated from the Wells
Clinical Prediction rule, patients are stratified into 3 risk groups
high, moderate, or low.
The results from duplex ultrasound are incorporated as follows:
If the patient is high or moderate risk and the duplex ultrasound
study is positive, treat for DVT.
If the duplex study is negative and the patient is low risk, DVT has
been ruled out.
When discordance exists between the pretest probability and the
duplex study result, further evaluation is required.
If the patient is high risk but the ultrasound study was negative,
the patient still has a significant probability of DVT. Some authors
recommend a venogram to rule out a calf vein DVT that the ultrasound
study did not detect. Some authors recommend surveillance with repeat
clinical evaluation and ultrasound in 1 week. Others use the results
of a D-dimer assay to guide management. A negative D-dimer in
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combination with a negative ultrasound study significantly lowers the
probability of DVT.
If the patient is low risk but the ultrasound study is positive, some
authors recommend a second confirmatory study such as a venogram
before treating for DVT and committing the patient to the risks of
anticoagulation.
If the patient is moderate risk and the ultrasound study is negative,
repeat clinical evaluation and ultrasound in 1 week is recommended.
It is important to realize that the clinical prediction rule was
developed in a specific subgroup of patients. Excluded from the model
were patients with recurrent DVT, patients with suspected coexistent
pulmonary embolism, and patients already on anticoagulants.
Therefore, the evaluation and subsequent treatment of this last
subgroup of patients must be individualized.
TREATMENT Section 6 of 10
Author Information Introduction Clinical Differentials Workup
Treatment Medication Follow-up Miscellaneous Bibliography
Emergency Department Care: The primary objectives of the treatment of
DVT are to prevent pulmonary embolism, reduce morbidity, and prevent
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or minimize the risk of developing the postphlebitic syndrome.
Anticoagulation
Thrombolytic therapy for DVT
Surgery for DVT
Surgical therapy for DVT may be indicated when anticoagulant therapy
is ineffective, unsafe, or contraindicated. The major surgical
procedures for DVT are clot removal and partial interruption of the
inferior vena cava to prevent pulmonary embolism.
The rationale for thrombectomy is to restore venous patency and
valvular function. Thrombectomy alone is not indicated, because
rethrombosis occurs very frequently. Heparin therapy is a necessary
adjunct. Thrombectomy is best reserved for patients with massive
ileofemoral vein thrombosis (phlegmasia cerulea dolens) when limb
viability is at risk.
Filters for DVT
The concept of inferior vena cava filters arose from the recognition
of the late complications of surgical ligation of the inferior vena
cava as first proposed by Homans in 1934. Today, intracaval devices
introduced intravenously at a remote site and floated into position
using fluoroscopy is the procedure of choice. The Kim-Ray-Greenfield
filter is preferred because the long-term patency rates are much
higher.
Indications for a filter are severe hemorrhagic complications on
anticoagulant therapy, other absolute contraindications to
anticoagulation, new or recurrent venous thrombosis, or pulmonary
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embolism despite adequate anticoagulation.
Compression stockings (routinely recommended)
Ambulation: Controversy exists regarding the role of ambulation in
the therapy of DVT. In North America, bed rest and decreased
ambulation usually are recommended theoretically to prevent
embolization. In Europe, increased ambulation usually is recommended
to avoid further venous stasis and propagation of the thrombus.
Consultations:
Hematology
Vascular surgery
Radiology
Nuclear medicine
MEDICATION Section 7 of 10
Author Information Introduction Clinical Differentials Workup
Treatment Medication Follow-up Miscellaneous Bibliography
Goals of pharmacotherapy in treating venous thrombosis are to reduce
morbidity, prevent the postphlebitic syndrome, prevent the
development of pulmonary embolism, and to attain these goals with a
minimum number of adverse effects and cost.
Drug Category: Anticoagulants -- Anticoagulation remains the mainstay
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of initial treatment for DVT. Regular unfractionated heparin was the
standard of care until the recent introduction of low molecular
weight heparin (LMWH). Heparin prevents extension of the thrombus and
has been shown to significantly reduce but not eliminate the
incidence of fatal and nonfatal pulmonary emboli, as well as
recurrent thrombosis. The primary reason for this is that heparin has
no effect on preexisting nonadherent thrombus. Heparin does not
affect the size of existing thrombus and has no intrinsic
thrombolytic activity.
Heparin therapy is associated with complete lysis in fewer than 10%
of patients studied with venography after treatment.
Heparin therapy has little effect on the risk of developing
postphlebitic syndrome. The original thrombus causes venous valvular
incompetence and altered venous return leading to a high incidence of
chronic venous insufficiency and postphlebitic syndrome.
Heparin's anticoagulant effect is related directly to its activation
of antithrombin III. Antithrombin III, the body's primary
anticoagulant, inactivates thrombin and inhibits the activity of
activated factor X in the coagulation process.
Heparin is a heterogeneous mixture of polysaccharide fragments with
varying molecular weights but with similar biological activity. The
larger fragments primarily interact with antithrombin III to inhibit
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thrombin. 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.
The optimal regimen for the treatment of DVT is anticoagulation with
heparin or an LMWH followed by full anticoagulation with oral
warfarin for 3-6 months. Some evidence exists that even longer
anticoagulation with warfarin is appropriate in certain cases.
Warfarin therapy is overlapped with heparin for 4-5 days until the
INR is therapeutically elevated to between 2-3. It is necessary to
overlap heparin with oral warfarin because of the initial transient
hypercoagulable state induced by warfarin. This effect is related to
the differential half-lives of protein C, protein S, and the vitamin
K-dependent clotting factors II, VII, IX, and X. Long-term
anticoagulation definitely is indicated for patients with recurrent
venous thrombosis and/or persistent or irreversible risk factors.
When IV unfractionated heparin is initiated for DVT, the goal is to
achieve and maintain an elevated aPTT of at least 1.5 times control.
Heparin pharmacokinetics are complex, with a half-life of 60-90
minutes. After an initial bolus of 80 U/kg, a constant maintenance
infusion of 18 U/kg is initiated. The aPTT is checked 6 hours after
the bolus and adjusted accordingly. The aPTT is repeated every 6
hours until 2 successive aPTTs are therapeutic. Thereafter, the aPTT
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is monitored every 24 hours as well as the hematocrit and platelet
count.
Heparin-induced thrombocytopenia is not infrequent. In this
condition, platelet aggregation induced by heparin may trigger venous
or arterial thrombosis with significant morbidity and mortality.
Unfortunately, the subset of patients who develop thrombosis is
unpredictable. All patients who develop thrombocytopenia while on
heparin are at risk. Alternatives include the substitution of porcine
for bovine heparin, the use of LMWH, or initiation of therapy with
warfarin alone.
LMWH is prepared by selectively treating unfractionated heparin to
isolate the low (
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for outpatient treatment of DVT using once or twice daily SC
treatment regimens. Outpatient treatment of acute DVT using LMWH has
been evaluated successfully in a number of studies and is currently
the treatment option of choice if the patient meets the necessary
criteria. Outpatient management is not recommended if the patient has
proven or suspected concomitant pulmonary embolism, significant
comorbidities, extensive ileofemoral DVT, morbid obesity, renal
failure, or poor follow-up.Drug Name
Heparin (Hep-Lock) -- Augments activity of antithrombin III and
prevents conversion of fibrinogen to fibrin. Does not actively lyse
but is able to inhibit further thrombogenesis. Prevents
reaccumulation of a clot after a spontaneous fibrinolysis.
Adult Dose 80 U/kg IV bolus, followed by 18-U/kg/h maintenance
infusion
Monitor aPTT and titrate maintenance dose to effect
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; subacute bacterial
endocarditis; severe liver disease; hemophilia; active bleeding;
history of heparin-induced thrombocytopenia
Interactions Digoxin, nicotine, tetracycline, and antihistamines may
decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and
hydroxychloroquine may increase heparin toxicity
Pregnancy A - Safe in pregnancy
Precautions In neonates, preservative-free heparin is recommended to
avoid possible toxicity (gasping syndrome) by benzyl alcohol, which
is used as preservative; caution in severe hypotension and shock
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Drug Name
Warfarin (Coumadin) -- Interferes with hepatic synthesis of vitamin
K-dependent coagulation factors. Used for prophylaxis and treatment
of venous thrombosis, pulmonary embolism, and thromboembolic
disorders.
Dose must be individualized and adjusted to maintain INR between 2-3.
Adult Dose 2-10 mg/d PO
Pediatric Dose Weight-based dose of 0.05-0.34 mg/kg/d; adjust
according to desired INR
Infants may require doses at or near high end of this range
Contraindications Documented hypersensitivity; severe liver or kidney
disease; risk of CNS hemorrhage; cerebral aneurysms; open wounds or
bleeding of GI, GU, or respiratory tract
Interactions Drugs that may decrease anticoagulant effects include
griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin,
phenytoin, rifampin, barbiturates, cholestyramine, colestipol,
vitamin K, spironolactone, oral contraceptives, and sucralfate
Medications that may increase anticoagulant effects of warfarin
include oral antibiotics, phenylbutazone, salicylates, sulfonamides,
chloral hydrate, clofibrate, diazoxide, anabolic steroids,
ketoconazole, ethacrynic acid, miconazole, nalidixic acid,
sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram,
metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides,
gemfibrozil, acetaminophen, and sulindac
Pregnancy D - Unsafe in pregnancy
Precautions Do not switch brands after achieving therapeutic
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response; caution in active tuberculosis or diabetes; patients with
protein C or S deficiency are at risk of developing skin necrosis
Drug Name
Enoxaparin (Lovenox) -- LMWH used in treatment of DVT and pulmonary
embolism as well as DVT prophylaxis.
Enhances inhibition of factor Xa and thrombin by increasing
antithrombin III activity. Slightly affects thrombin and clotting
time and preferentially increases inhibition of factor Xa.
Average duration of treatment is 7-14 d.
Adult Dose 1 mg/kg SC bid; alternatively, administer 1.5 mg/kg SC qd
Pediatric Dose Not established
The following doses have been suggested:
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Drug Name
Tinzaparin (Innohep) -- Used in hospitalized patients. Enhances
inhibition of factor Xa and thrombin by increasing antithrombin III
activity. In addition, preferentially increases inhibition of factor
Xa.
Average duration of treatment is 7-14 d.
Adult Dose 175 U/kg SC qd, at same time each day for >6 d and until
patient is adequately anticoagulated with warfarin (INR >2 for 2
consecutive d)
Pediatric Dose Not established; adult dose suggested
Contraindications Documented hypersensitivity; major bleeding,
heparin-induced thrombocytopenia (current or history of)
Interactions Platelet inhibitors or oral anticoagulants such as
dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and
ticlopidine may increase risk of bleeding
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions If thromboembolic event occurs despite LMWH prophylaxis,
discontinue drug and initiate alternate therapy; elevation of hepatic
transaminases may occur but is reversible; heparin-associated
thrombocytopenia may occur with fractionated low-molecular-weight
heparins; 1 mg of protamine sulfate will reverse effect of
approximately 100 U of tinzaparin if significant bleeding
complications develop
Drug Category: Thrombolytics -- Offer significant advantages over
conventional anticoagulant therapy. Advantages include prompt
resolution of symptoms, prevention of pulmonary embolism, restoration
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of normal venous circulation, preservation of venous valvular
function, and prevention of postphlebitic syndrome. Thrombolytic
therapy does not prevent clot propagation, rethrombosis, or
subsequent embolization. Heparin therapy and oral anticoagulant
therapy always must follow a course of thrombolysis.
Unfortunately, the majority of patients with DVT have absolute
contraindications to thrombolytic therapy. Thrombolytic therapy is
also not effective once the thrombus is adherent and begins to
organize. Venous thrombi in the legs are often large and associated
with complete venous occlusion. The thrombolytic agent that acts on
the surface of the clot may not be able to penetrate and lyse the
thrombus.
Nevertheless, the data from many published studies indicate that
thrombolytic therapy is more effective than heparin in achieving vein
patency. The unproven assumption is that the degree of lysis seen on
the posttreatment venogram is predictive of future venous valvular
insufficiency and late (5-10 y) development of postphlebitic
syndrome. Preliminary evidence suggests the incidence of
postphlebitic syndrome at 3 years is reduced by half but certainly
not entirely eliminated.
The hemorrhagic complications of thrombolytic therapy are formidable
(about 3 times higher), including the small but potentially fatal
risk of intracerebral hemorrhage. The uncertainty regarding
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thrombolytic therapy likely will continue. Currently, thrombolytic
therapy is not recommended routinely for DVT at most centers but
should be considered in patients with massive ileofemoral vein
thrombosis or in young patients with acute onset of extensive
DVT.Drug Name
Urokinase (Abbokinase) -- Direct plasminogen activator isolated from
human fetal kidney cells grown in culture. Acts on endogenous
fibrinolytic system and converts plasminogen to enzyme plasmin.
Plasmin degrades fibrin clots, fibrinogen, and other plasma proteins.
Advantage is that it is nonantigenic. More expensive than
streptokinase, which limits its use. When used for purely local
fibrinolysis, given as local infusion directly into area of thrombus
and with no bolus.
Dose should be adjusted to achieve clot lysis or patency of affected
vessel.
Adult Dose 4400 U/kg IV bolus followed by maintenance infusion at
4400 U/kg/h for 1-3 d
For regional thrombus-directed therapy, smaller bolus of 250,000 U IV
may be given followed by infusion at 500-2000 U/kg/h
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; internal bleeding;
recent trauma including cardiopulmonary resuscitation; history of
cerebrovascular accident; intracranial or intraspinal surgery or
trauma; intracranial neoplasm
Interactions Thrombolytic enzymes, alone or in combination with
anticoagulants and antiplatelets, may increase risk of bleeding
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complications
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Caution in patients receiving intramuscular
administration of medications and those with severe hypertension or
trauma or surgery in previous 10 d; avoid dislodging a possible deep
vein thrombi; do not measure blood pressure in lower extremities;
monitor therapy by performing PT, aPTT, TT, or fibrinogen
approximately 4 h after initiation of therapy
Drug Name
Streptokinase (Kabikinase, Streptase) -- 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 h takes place with
intravenous infusion of streptokinase.
Adult Dose 250,000 U IV bolus followed by an infusion at 100,000 U/h
for 1-3 d
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; active internal
bleeding; intracranial neoplasm; aneurysm; diathesis; severe
uncontrolled arterial hypertension
Interactions Antifibrinolytic agents may decrease effects of
streptokinase; heparin, warfarin, and aspirin may increase risk of
bleeding
Pregnancy C - Safety for use during pregnancy has not been
established.
Precautions Caution in severe hypertension, intramuscular
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administration of medications, and trauma or surgery in the previous
10 d; measure hematocrit, platelet count, aPTT, TT, PT, or fibrinogen
levels before therapy is implemented; either TT or aPTT should be
less than twice the normal control value following infusion of
streptokinase and before (re)instituting heparin; do not take blood
pressure in the lower extremities as it may dislodge a possible deep
vein thrombi; PT, aPTT, TT, or fibrinogen should be monitored 4 h
after initiation of therapy
Drug Name
Alteplase, t-PA (Activase) -- Thrombolytic agent for DVT or
pulmonary embolism. A tissue plasminogen activator (tPA) produced by
recombinant DNA and used in the management of acute ischemic stroke,
AMI, and pulmonary embolism.
Safety and efficacy of this regimen with coadministration of heparin
and aspirin during the first 24 h after symptom onset have not been
investigated.
Adult Dose Front-loaded regimen recommended
15 mg IV bolus initially followed by 50 mg IV over the next 30 min
and then 35 mg IV over the next 1 h
Pediatric Dose Not established
Contraindications Documented hypersensitivity; active internal
bleeding; intracranial or intraspinal surgery or trauma; intracranial
neoplasm; arteriovenous malformation or aneurysm;
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subarachnoid hemorrhage, or serious head trauma or recent previous
stroke; do not administer with a history of intracranial hemorrhage,
uncontrolled hypertension, intracranial neoplasm, seizure at onset of
stroke, active internal bleeding, arteriovenous malformation or
aneurysm, or bleeding diathesis
Interactions Drugs that alter platelet function (aspirin,
dipyridamole, abciximab) may increase risk of bleeding before,
during, or after alteplase therapy; may give heparin with and after
alteplase infusions to reduce risk of rethrombosis; either heparin or
alteplase may cause bleeding complications
Pregnancy C - Safety for use during pregnancy has not been
established.
Precautions Monitor for bleeding, especially at arterial puncture
sites, with coadministration of vitamin K antagonists; control and
monitor blood pressure frequently during and following alteplase
administration (when managing acute ischemic stroke); do not use >0.9
mg/kg to manage acute ischemic stroke; doses >0.9 mg/kg may cause ICH
FOLLOW-UP Section 8 of 10
Author Information Introduction Clinical Differentials Workup
Treatment Medication Follow-up Miscellaneous Bibliography
Further Inpatient Care:
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Most patients with confirmed proximal vein DVT may be treated safely
on an outpatient basis. Exclusion criteria for outpatient management
are as follows:
Suspected or proven concomitant pulmonary embolism
Significant cardiovascular or pulmonary comorbidity
Morbid obesity
Renal failure
Unavailable or unable to arrange close follow-up care
Patients are treated with a low molecular weight heparin and
instructed to initiate therapy with warfarin 5 mg PO the next day.
Low molecular weight heparin and warfarin are overlapped for about 5
days until the international normalized ratio (INR) is therapeutic.
If inpatient treatment is necessary, low molecular weight heparin is
effective and obviates the need for IV infusions or serial monitoring
of the PTT.
With the introduction of low molecular weight heparin, selected
patients qualify for outpatient treatment only if adequate home care
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and close medical follow-up care can be arranged.
At some centers, patients with isolated calf vein DVT are admitted
for full anticoagulant therapy. Many physicians do not treat calf
vein DVT with anticoagulation unless proximal extension is documented
objectively with close clinical surveillance.
The activated partial thromboplastin time (aPTT) must be monitored
every 6 hours while the patient is on IV heparin until the dose
stabilizes.
Platelets also should be monitored and heparin discontinued if
platelets fall below 75,000.
While on warfarin, the prothrombin time (PT) must be monitored daily
until target achieved, then weekly for several weeks. When the
patient is stable, monitor monthly. Inability to monitor INR
precludes outpatient treatment of DVT.
For the first episode, patients should be treated for 3-6 months.
Subsequent episodes should be treated for at least 1 year.
Significant bleeding (ie, hematemesis, hematuria, gastrointestinal
hemorrhage) should be investigated thoroughly since anticoagulant
therapy may unmask a preexisting disease (eg, cancer, peptic ulcer
disease, arteriovenous malformation).
Further Outpatient Care:
Treatment for isolated calf vein DVT is best individualized, taking
into account local preferences, patient reliability, the availability
of follow-up care, and an assessment of ongoing risk factors.
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Patients with suspected or diagnosed isolated calf vein DVT may be
discharged safely on a nonsteroidal anti-inflammatory drug (NSAID) or
aspirin with close follow-up care and repeat diagnostic studies in 3-
7 days to detect proximal extension.
At certain centers, patients with isolated calf vein DVT are admitted
for full anticoagulant therapy.
Patients with suspected DVT but negative noninvasive studies need to
be reassessed by their primary care provider within 3-7 days.
Patients with ongoing risk factors may need to be restudied at that
time to detect proximal extension because of the limited accuracy of
noninvasive tests for calf vein DVT.
Transfer:
Transfers may be necessary for patients with special concerns such as
those with inherited coagulation disorders.
Transfers may be required depending on local expertise for treatment
with thrombolytics, surgical therapy, or insertion of a filter.
Deterrence/Prevention:
Prophylaxis for DVT is required for all patients who develop risk
factors. DVT prophylaxis for patients scheduled to undergo major
surgery is well recognized.
Recently a large multicenter double-blind placebo-controlled trial
showed a 63% reduction in the incidence of DVT/pulmonary embolism in
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general medical patients admitted to the hospital.
Complications:
Acute pulmonary embolism still may occur despite adequate
anticoagulation.
Hemorrhagic complications are the most common adverse effects of
anticoagulant therapy. The risk of hemorrhage on heparin is
approximately 5%.
The treatment of hemorrhage while on 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 normal 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 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
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addition to vitamin K.
Additional complications include the following:
Systemic embolism
Chronic venous insufficiency
Postphlebitic syndrome (ie, pain and edema in the affected limb
without new clot formation)
Soft-tissue ischemia associated with massive clot and very high
venous pressures - Phlegmasia cerulea dolens (very rare but should be
considered a surgical emergency)
Prognosis:
All patients with proximal vein DVT are at long-term risk of
developing chronic venous insufficiency.
About 20% of untreated proximal (above the calf) DVTs progress to
pulmonary emboli, and 10-20% of these are fatal. With aggressive
anticoagulant therapy, the mortality is decreased 5- to 10-fold.
DVT confined to the calf virtually never causes clinically
significant emboli and thus does not require anticoagulation.
However, calf DVTs occasionally propagate into the proximal system.
Therefore, suspected calf DVTs should be observed every 3-5 days for
10 days and treated aggressively if they propagate into the popliteal
or femoral system.
Patient Education:
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Advise women taking estrogen of the risks and common symptoms of
thromboembolic disease.
Discourage prolonged immobility, particularly on plane rides and long
car trips.
MISCELLANEOUS Section 9 of 10
Author Information Introduction Clinical Differentials Workup
Treatment Medication Follow-up Miscellaneous Bibliography
Medical/Legal Pitfalls:
Failure to consider the diagnosis in patients with risk factors
Failure to recommend repeat noninvasive studies and reassessment in
high-risk patients with negative initial evaluations
Special Concerns:
Superficial thrombophlebitis
Superficial thrombophlebitis often is 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
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varices and no other obvious etiology
Involvement of the greater saphenous vein above the knee, especially
if it extends to the saphenofemoral junction
Uncomplicated superficial thrombophlebitis may be treated
symptomatically with heat, NSAIDs, and compression hose. Bed rest is
not recommended.
Some centers recommend full anticoagulation even with negative
noninvasive studies for the high-risk groups mentioned above. An
alternative approach involves symptomatic care alone with close
follow-up and repeat noninvasive testing in 24-72 hours. Full
anticoagulation then is reserved only for those patients with proven
proximal vein DVT.
Axillary/subclavian vein thrombosis
This first was described by Paget (1875) and von Schrtter (1884) and
is sometimes referred to as Paget-von Schrtter syndrome. The
pathophysiology is similar to that of DVT, and the etiologies
overlap. The incidence is lower than DVT, of the lower extremities
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
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thrombosis.
Similarly, pulmonary artery catheters are associated with a high
incidence of internal jugular and subclavian vein thrombosis.
Pulmonary embolism occurs in approximately 10% of patients. Fatal or
massive pulmonary embolism is extremely rare.
Ultrasonography and venography are the diagnostic tests of choice.
Ultrasonography may be falsely negative because of collateral blood
flow. Duplex ultrasound 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 usually is
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.
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Author Information Introduction Clinical Differentials Workup
Treatment Medication Follow-up Miscellaneous Bibliography
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