Deep Venous Thrombosis and Thrombophlebitis

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



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



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



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



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



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


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


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



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



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


44/48

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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Deep Venous Thrombosis and Thrombophlebitis