Deep Vein Thrombosis

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Previous Volume 331:1630-1641 December 15, 1994 Number 24 Next
Deep-Vein Thrombosis
Eran E. Weinmann, and Edwin W. Salzman

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Credit for fundamental studies leading to our current understanding

of deep-
vein thrombosis should be given to Bauer, who used phlebography

to
diagnose deep-vein thrombosis complicating fractures of the

tibia,
1
and to
Sevitt and Gallagher for their autopsy-based

studies of the prevalence of
venous thromboembolism in patients

with other injuries
2,3
. The development
of objective methods

for the diagnosis of deep-vein thrombosis has
facilitated the

investigation of its natural history and has provided a rational

basis for its prevention and treatment.

Diagnosis
Most venous thrombi are clinically silent when they are first

detectable by
objective methods,
2,4
probably because they do

not totally obstruct the
vein
1,5
and because of collateral circulation
6
.

Even among the fraction of
patients with deep-vein thrombosis

who have symptoms in the lower
extremities, fewer than a third

present with the classic syndrome of calf
discomfort, edema,

venous distension, and pain on forced dorsiflexion of the
foot

(Homans's sign)
7,8
. When symptoms are initially attributed to

deep-vein
thrombosis, reassessment by objective methods shows

that this attribution is
correct less than half the time
9,10
.

The differential diagnosis of deep-vein thrombosis includes

many afflictions of the knee or calf that cause a
painful, swollen

leg. Among 87 consecutive patients with clinically suspected

deep-vein thrombosis but a normal
phlebogram, 37 had a musculoskeletal

cause, 12 had impaired venous or lymphatic flow, and 4 had popliteal

file:///A|/eHealth%20fot%20TED%20Registry/DVT.htm (1 of 25)9/20/2004 4:41:15 PM
inflammatory cysts (Baker's cysts)
11
. Thus, a diagnosis suspected

on clinical grounds must be confirmed by a
sensitive and specific

diagnostic test (Table 1).

View this table:
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Table 1. Tests Used in the Diagnosis of Deep-Vein
Thrombosis.

At one time, scanning with [
125
I]-labeled fibrinogen was widely

used for the objective confirmation of the
diagnosis of deep-vein

thrombosis. However, the test has serious flaws,
14
including

low sensitivity for venous
thrombi above the midthigh. This

point is moot, since [
125
I]-labeled fibrinogen has been withdrawn

from the
market for fear of transmission of infectious agents

by the transfusion of blood products. Recombinant fibrinogen

would be an attractive alternative, should it become available.

The standard diagnostic test for deep-vein thrombosis of the

lower extremities is ascending phlebography
performed according

to the method of Rabinov and Paulin
15
. Phlebography can detect

both distal thrombi (in the
calf veins, a common site of inception

of deep-vein thrombosis) and proximal thrombi (in the popliteal,

femoral,
and iliac veins), which are the source of most large

pulmonary emboli
3
. Regrettably, phlebography has
uncomfortable

side effects, including contrast medium-induced thrombosis of

peripheral veins in 2 or 3 percent
of patients, a particularly

unwelcome complication in patients who would otherwise not require

treatment for
deep-vein thrombosis
11,16
.

Recent studies have not confirmed the anticipated superiority

of the new iso-osmolar non-ionic contrast agents
for phlebography

over ionic contrast agents with respect to thrombotic side effects
17,18
.

Phlebography is costly,
especially in terms of technicians'

and radiologists' time, and cannot be readily repeated; it is

a poor choice for
monitoring patients with serial examinations.

Even so, its use has been judged cost effective
19
when the
diagnosis

of deep-vein thrombosis requires confirmation in symptomatic

patients, when recurrent deep-vein
thrombosis is suspected,

or when patients who have undergone hip operations require screening

for postoperative
deep-vein thrombosis but less invasive methods

lack sensitivity
20
. In such cases, the cost of phlebography

is
substantially less than the cost of hospitalization and treatment

for an incorrectly diagnosed illness.

Other objective diagnostic methods include impedance plethysmography
21
and various forms of real-time B-
mode ultrasonography,
22
most

of which are more sensitive for the detection of proximal than

distal thrombosis.
With impedance plethysmography, one measures

the electrical impedance between two electrodes wrapped
around

the calf. Venous obstruction proximal to the electrodes decreases

the impedance as the leg becomes
engorged with blood, an electrical

conductor, and delays the characteristic increase in calf impedance

when a
thigh tourniquet is deflated
21,23
.

In patients with suspected deep-vein thrombosis, the combination

of normal results on both impedance
plethysmography and fibrinogen

scanning
9
or simply repeatedly normal impedance plethysmographic

examinations
24,25,26
was reported to be so sensitive and specific

that patients with these findings could safely be
regarded as

not having deep-vein thrombosis and thus in no need of anticoagulant

treatment; confirmatory
phlebography was not necessary. Recently,

however, the sensitivity of impedance plethysmography for proximal

thrombi in symptomatic patients was found to be far less than

previously reported
12
. When used as a screening
test in asymptomatic

patients at high risk for deep-vein thrombosis, impedance plethysmography

lacks
sensitivity, because sizable thrombi can be overlooked

if they are not totally occlusive
20
. Then, too, the method
lacks

specificity, since any process that causes venous obstruction

in the pelvis (e.g., enlarged lymph nodes or
pregnancy) can

be interpreted on the plethysmogram as a venous thrombus. Impedance

plethysmography seems
best suited for the identification of

proximal thrombi in symptomatic patients whose condition can

be monitored
by repeated examinations.

The introduction of real-time B-mode ultrasonography has provided

a promising alternative to impedance
plethysmography, with a

sensitivity for proximal thrombi that approaches 100 percent

in patients with
symptomatic deep-vein thrombosis
22,27
. A helpful

review of vascular ultrasonography is available
28
.
Visualization

of a venous thrombus is often possible but is not essential

for diagnosis
29
. The most sensitive
finding is failure of the

vein to collapse under gentle external pressure, so-called compression

ultrasonography
29,30
. In symptomatic outpatients with suspected

deep-vein thrombosis, serial compression
ultrasonography had

a positive predictive value of 94 percent, superior to the positive

predictive value of 83
percent for serial impedance plethysmography
13
.

In duplex scanning, real-time B-mode ultrasonography is supplemented

by Doppler flow-detection ultrasonic
imaging, which allows detection

of blood flow in any vessel seen. In symptomatic patients with

proximal deep-
vein thrombosis, its overall sensitivity in a

meta-analysis of four well-designed studies was 93 percent,

with a
specificity of 98 percent
31
. The sensitivity of duplex

scanning for the detection of distal thrombi is far less
satisfactory

because of poor visualization of the calf veins. Greater accuracy

for color Doppler ultrasonography is
claimed but may only be

achievable in technically uncompromised studies
32
. Initial evaluation

of symptomatic
patients by duplex ultrasonography alone (i.e.,

without supplementary phlebography) is enough to confirm or

disprove suspected cases of deep-vein thrombosis, as long as

a negative examination is followed by repeated
noninvasive testing

to detect proximal extension
31,33
.

Like impedance plethysmography, real-time B-mode ultrasonography

is less satisfactory for screening
asymptomatic patients at

high risk of deep-vein thrombosis. Pooled results from six such

studies showed an
overall sensitivity for the detection of proximal

deep-vein thrombosis of only 59 percent, although the specificity

was 98 percent
6
. Likewise, in a prospective study of prophylactic

antithrombotic therapy in orthopedic patients,
color Doppler

ultrasonography was a poor detector (sensitivity, 38 percent)

of asymptomatic deep-vein
thrombosis of the proximal leg veins
34
.

The small size and nonocclusive nature of clots in such patients

might
account for the disappointing results. Apparently the

last word regarding the ultrasonographic diagnosis of deep-
vein

thrombosis has not been said.

Computer-assisted tomography can detect thrombosed veins in

the abdomen and pelvis
35
and is considered
superior to conventional

phlebography
36
in visualizing the great veins, identifying intraluminal

thrombi,
distinguishing new thrombi from older ones, and delineating

adjacent abnormalities (e.g., extrinsic compression
of the vein)
37
.

Two recent prospective trials
38,39
of magnetic resonance venography

have reported 100 percent sensitivity and
over 96 percent specificity

for the diagnosis of proximal deep-vein thrombosis. In one study
39
the sensitivity for
deep-vein thrombosis of the calf was 87

percent, and the specificity was 97 percent. Because of its

high cost and
limited availability,
40
magnetic resonance venography

is not suitable for the routine diagnosis of deep-vein
thrombosis

but may be helpful in exceptional cases, such as those in which

the fine anatomical detail that can be
shown with this method

may provide decisive information relevant to the choice of therapy.

Other diagnostic tools are under development. Radionuclide venography
41
can detect a thrombus labeled with
various proteins,
42
platelets,
43
or red cells
44
. Monoclonal antibodies specific for cross-linked

fibrin function both
as vehicles for plasminogen activators
45
and, if radiolabeled, as markers that can be detected externally.

Concentrations of plasma d-dimer, a product of plasmin digestion

of mature cross-linked fibrin, are increased in
patients with

venous thrombosis
46
or pulmonary emboli
47
. The sensitivity of

d-dimer measured by enzyme-
linked immunosorbent assay is 97

percent. Venous thrombosis is unlikely to be present if d-dimer

concentrations
are not elevated,
48
but a positive result requires

confirmation by more specific tests based on imaging
49
.

In a nutshell, the definitive objective diagnostic test for

both symptomatic and asymptomatic deep-vein
thrombosis continues

to be phlebography. In patients with suspected deep-vein thrombosis,

if the results of real-
time B-mode ultrasonography are normal

on repeated examinations, anticoagulant therapy can be withheld.

An
abnormal ultrasound study justifies treatment. Screening

of asymptomatic patients is unsatisfactory with the
available

noninvasive tests. The diagnosis of recurrent deep-vein thrombosis

depends to a large extent on the
availability of the results

of previous noninvasive studies for comparison. Unfortunately,

noninvasive methods
for the detection of pulmonary embolism

are not as sensitive or specific as techniques for the diagnosis

of deep-
vein thrombosis
50,51
.

Clinical Epidemiology of Venous Thromboembolism
At least 30 cases of deep-vein thrombosis identifiable by phlebography
10
can be expected among 100 patients
who have undergone general

surgical operations of moderate severity if they are not given

perioperative
antithrombotic prophylaxis
52
. Most postoperative

thrombi arise in the calves,
1,10
especially in soleal sinuses

or
in large veins draining the gastrocnemius muscles, but in

at least 20 percent of patients who have undergone
general surgical

procedures
10
and 40 to 50 percent of patients with skeletal

trauma,
3,53,54,55
thrombi can originate
in more proximal veins.

Isolated calf thrombi are often asymptomatic
8
. If untreated,

20 to 30 percent may extend
into the larger, more proximal veins,
10,56,57
an event that accounts for most clinically important pulmonary

emboli and virtually all fatal ones
3,58
. Among these 100 patients,

four cases of pulmonary emboli will be
recognized
10
; one or

two may be fatal
59
. One or two additional cases of pulmonary

emboli will probably be
detected within the first month after

discharge from hospital
60
. Many more patients will have silent,

clinically
unrecognized pulmonary emboli
61,62,63
. The true incidence

of pulmonary emboli is unknown, but the fact that
Freiman et

al.
64
found evidence of subclinical pulmonary emboli in 64 percent

of consecutive autopsies among
persons with various causes of

death implies that this is a common condition
65
. In a more recent

study using
intraoperative transesophageal echocardiography,

showers of intravascular echogenic material that presumably

reflected embolization were seen in 29 consecutive high-risk

patients who were undergoing total knee
arthroplasty
66
.

In a retrospective review, Dalen and colleagues concluded that

in 1968 pulmonary emboli caused about 200,000
deaths in the

United States, a figure that would be compatible with an estimated

total of 630,000 cases of
symptomatic pulmonary emboli
67,68
.

Meanwhile, in a retrospective survey of a defined community,

Anderson et
al.
69
found an average annual incidence of 48 initial

cases and 36 recurrent cases of deep-vein thrombosis (86
percent

confirmed objectively) plus 23 cases of pulmonary emboli per

100,000 population (54 percent confirmed
objectively). Extrapolation

from their data yields an estimated total of 170,000 initial

episodes and 90,000
recurrent episodes of venous thromboembolism

in the United States each year. Because of underdiagnosis, the

true incidence is probably higher, perhaps 600,000 cases per

year.

Improved diagnostic methods have also made it possible to verify

the association of many proposed risk factors
with venous thromboembolism

(Table 2). Their recognition should help to identify high-risk

patients who would
be particularly likely to benefit from prophylactic

antithrombotic therapy
52,76,109,110,111
.

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Table 2. Risk Factors for Deep-Vein
Thrombosis.

Treatment
Thanks to modern diagnostic methods, it is now possible to reevaluate

many aspects of the treatment of deep-
vein thrombosis that have

become part of clinical lore, often without ever being subjected

to controlled trials. In a
patient with proximal deep-vein thrombosis,

the goals of therapy are the prevention of pulmonary embolism

and
the restoration of venous patency and valvular function

in order to prevent the postphlebitic syndrome. In patients

with deep-vein thrombosis confined to the calf, the purpose

of treatment is not different, but it is used in a
different

stage of the disease. Anticoagulation should be the first-line

treatment for patients with distal deep-vein
thrombosis as well

as for those with proximal-vein involvement. In a landmark prospective,

controlled trial of
anticoagulant therapy for clinically diagnosed

pulmonary emboli, no treated patients died, as compared with

26
percent of the patients who did not receive anticoagulation
112
.

Despite many shortcomings in design, this study
seems decisive

and will probably never be repeated.

Therapy for deep-vein thrombosis should start with an agent

that has an immediate anticoagulant effect (e.g.,
heparin),
113
and it should be given at an adequate dosage
114
. Failure to

reach the prescribed intensity of
anticoagulation in the first

24 hours of treatment increases the risk of recurrent venous

thromboembolism by 15
times
114
.

Treatment can be initiated with either a continuous intravenous

infusion or subcutaneous injections of heparin
114
.
The subcutaneous

route is more convenient for outpatients
115,116
. As long as

the activated partial-thromboplastin
time is maintained in the

prescribed therapeutic range (1.5 to 2.5 times the control value),

the two routes of
administration are equally effective
117,118
.

With continuous intravenous infusions or subcutaneous injections

of
heparin, serious bleeding occurred in fewer than 6 percent

of patients, as compared with 14 percent of patients
given intermittent

intravenous injections
117,118
.

Recently, heparin preparations of relatively low molecular weight

were tested in the treatment of proximal-vein
thrombosis
119,120,121
and in submassive pulmonary emboli
122
. Low-molecular-weight

heparin was as effective as
standard heparin for the prevention

of the extension of an existing thrombus
121,122
or of recurrent

thromboembolism,
119,120
and it resulted in the same or a lower

degree of serious bleeding
120
. Other aspects of
low-molecular-weight

heparin will be discussed later.

Five days of heparin therapy followed by an oral vitamin K antagonist

(e.g., warfarin) is usually effective against
deep-vein thrombosis

and is generally regarded as conventional therapy
123
. However,

asymptomatic extension of
deep-vein thrombosis to proximal veins

or pulmonary emboli can be expected in 8 percent of the patients

so
treated
113
. Symptomatic pulmonary emboli might occur in 0.5

percent
124
. Extending the course of heparin (e.g.,
10 days)

before warfarin therapy is begun is not beneficial
124,125
. On

the contrary, the shorter the heparin
treatment, the less often

it is followed by heparin-induced thrombocytopenia
126
. However,

treatment of deep-vein
thrombosis by oral anticoagulants alone

(without heparin) is not a satisfactory alternative. It is followed

by
symptomatic extension or recurrence of venous thrombosis

in 20 percent of patients
113
.

Warfarin treatment is usually adjusted according to the one-stage

prothrombin time, which can now be expressed
with reference

to an international standard. The international normalized ratio

(INR) is the result of an
international effort to improve the

uniformity of results
127
. Although the goals of the INR system

are laudable, its
success is still in dispute. An INR value

between 2.0 and 3.0 is recommended for the treatment of venous

thromboembolic disease,
123,128
but substantially less intense

anticoagulation may be enough
129
.

Oral anticoagulation should be continued for at least three

months to minimize the risk of recurrent
thromboembolism
123
.

If patients with deep-vein thrombosis are treated with a fixed

low dose of subcutaneous,
unfractionated heparin instead of

warfarin,
130
or if they receive no long-term anticoagulation

at all, up to a third
may have recurrent thrombosis
56
. Shorter

periods of treatment are probably sufficient in certain patients

at low
risk,
131,132
but the ability to identify such patients

is uncertain.

Continuing anticoagulant therapy beyond three months has not

been proved worthwhile in routine practice, but
neither is it

likely to be particularly harmful, since most hemorrhagic complications

of such therapy occur early,
when coexisting problems that increase

the likelihood of bleeding become apparent. Landefeld and Goldman
133
reported that the monthly risk of serious bleeding decreased

from an initial 3 percent to 0.3 percent after the first
year

of warfarin therapy in a heterogeneous group of outpatients

treated for various disorders. Prolonged
treatment with anticoagulant

agents is probably warranted when major underlying risk factors

for a thrombotic
event persist, such as lengthy immobilization,

a hypercoagulable state (as part of a malignant condition),

and
recurrent deep-vein thrombosis.

On the other hand, the risk of bleeding is strongly related

to the intensity of anticoagulant therapy. In a
randomized trial,
134
patients receiving less intense warfarin therapy (target INR,

2.0) had a 4 percent incidence of
bleeding, as compared with

an incidence of 22 percent among patients treated with a higher

dose (INR, 2.5 to
4.5).

Surgical Treatment of Acute Deep-Vein Thrombosis
In selected cases of deep-vein thrombosis, it may be possible

to restore venous patency by surgical
thrombectomy, with dramatic

early results (e.g., complete clearance of the iliofemoral system

in 62 percent of
patients and partial clearance in 38 percent)
135
.

Because of incomplete removal of thrombus and injury to the

venous endothelium, the vein often eventually reoccludes,
136
but such an event is frequently well tolerated, as
long as it

does not occur before the collateral venous circulation has

enlarged enough to decompress the
obstructed distal venous tree.

Surgical thrombectomy has been recommended for the treatment

of phlegmasia
cerulea dolens,
137
a state of extensive venous

occlusion with compromised arterial circulation in which even

a
small improvement in venous return may save the limb
138,139
.

Surgery may also have a role in occasional cases of deep-vein

thrombosis that are less than massive
140
. Plate et
al.
139
reported

the persistence of patency of proximal veins in 76 percent of

patients and symptoms of stasis in
only 7 percent, six months

after acute iliofemoral venous thrombosis in patients treated

by thrombectomy
supplemented with a temporary arteriovenous

fistula and heparin for six months. For comparison, in patients

treated nonoperatively, the patency rate was 35 percent and

42 percent had symptoms of stasis. The potential
benefits of

venous thrombectomy, reported anecdotally, require assessment

in controlled trials
141
. Meanwhile,
venous thrombectomy should

probably be reserved for selected patients in whom the viability

of a limb is
threatened by an acute iliofemoral thrombosis
142
.

Thrombolytic Treatment
Thrombolytic treatment with plasminogen activators such as streptokinase

or recombinant tissue plasminogen
activator (alteplase), followed

by anticoagulation, is more effective than anticoagulation alone

for the early
restoration of patency of a thrombosed vein
143,144
.

Thrombolytic treatment should be continued until both
venous

patency and normal valvular anatomy are restored
145,146
. A recent

review of selected clinical trials that
compared streptokinase

with heparin for the treatment of deep-vein thrombosis
147
revealed

complete lysis of
thrombi in 70 percent of patients treated

with streptokinase, with long-term venous patency in 49 percent

after 3
to 102 months and normal valvular function in 41 percent

after 1 to 24 months, as compared with values of 4
percent and

15 percent, respectively, in patients treated with heparin.

However, earlier studies found that
pathologic stasis changes

characteristic of the postphlebitic syndrome were as severe

after thrombolytic therapy
as after conventional anticoagulation
148
.

Furthermore, thrombolysis does not afford more protection against

pulmonary emboli than does anticoagulation
149
. The more-than-doubled

hazard of bleeding with streptokinase
143

or alteplase,
150
including

a twofold to fourfold increase in the risk of intracranial bleeding,

has removed some of
the allure that originally surrounded therapeutic

thrombolysis.

New thrombolytic agents, such as anisoylated plasminogen-streptokinase

activator complex
151
or single-chain
urokinase-like plasminogen

activator,
152
are under investigation. Whether they will reduce

the late sequelae of
deep-vein thrombosis remains to be seen.

So far, there is little evidence that they are associated with

fewer
hemorrhagic complications than earlier agents, such as

streptokinase.

Prevention of Venous Thromboembolism
The goal of prophylactic therapy in patients with risk factors

for deep-vein thrombosis is to prevent both its
occurrence and

its consequences, pulmonary emboli and the postphlebitic syndrome.

Affected patients often have
no symptoms, and the detection

of deep-vein thrombosis is therefore apt to be delayed. Of the

patients who will
eventually die of pulmonary emboli, two thirds

survive less than 30 minutes after the event, not long enough

for
most forms of treatment to be effective
153
. Preventing deep-vein

thrombosis in patients at risk is clearly
preferable to treating

the condition after it has appeared,
154
a view that is supported

by cost-effectiveness
analysis
154,155,156,157
. The presence

of clinical risk factors identifies patients with the most to

gain from
prophylactic measures,
158
as well as patients who

should receive antithrombotic prophylaxis during periods of

increased susceptibility, such as postoperatively or post partum.

The blood concentration of certain hemostatic elements (e.g.,

platelets, antithrombin III, protein C, protein S, von
Willebrand

factor, and d-dimer) and other features such as age and euglobulin

lysis time have been correlated
with the subsequent development

of deep-vein thrombosis and have provided the basis for a predictive

index
100
.
However, reliance on laboratory tests to select patients

for antithrombotic prophylaxis has not been more
accurate and

certainly is not more economical than the use of clinically

defined risk factors for this purpose.

Risk factors may combine synergistically to increase the incidence

of venous thromboembolism in various
circumstances (Table 3).

At one extreme, the risk of deep-vein thrombosis in the course

of daily activities may be
so low that no specific preventive

measures are necessary. A patient at low risk needs only minimal

prophylactic
measures, such as early ambulation after surgery

and the use of elastic stockings, augmenting the propulsion

of
blood from ankle to knee
159,160
.

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Table 3. Incidence of Thromboembolic Events after Surgery or Trauma or in the Presence
of Certain Medical Conditions and Recommended Prophylaxis, According to Risk Group.

The risk may be much higher in a patient older than 40 years

of age who is undergoing an operation that lasts
longer than

an hour, who has congestive heart failure, who has been taking

an oral contraceptive, or who has had
multiple traumatic injuries.

Unless prophylactic measures are used, the incidence of deep-vein

thrombosis can
exceed 60 percent
2,55
after an orthopedic operation

on the lower extremities, especially if there is a lengthy
convalescence

involving bed rest
55
. During a total hip replacement, mechanical

trauma to the femoral or iliac
veins,
161
thermal damage from

the heat of polymerization of the acrylic cement,
162
and a possible

chemical
effect of circulating absorbed monomer contribute to

the hazard. The implantation of a hip prosthesis without
plastic

adhesive is complicated by deep-vein thrombosis less often than

when a polymeric cement is used
162,163
.
The presence of malignant

disease is also a serious risk factor for deep-vein thrombosis

and pulmonary
emboli
86,87
. The way in which cancer increases

the risk of thrombotic complications has recently been
reviewed
86,164
.

Antithrombotic Drugs
For the prevention of deep-vein thrombosis, there are a number

of antithrombotic agents with important
differences in efficacy

and in the gravity and frequency of their principal side effect,

bleeding. For example, in a
patient with a pertrochanteric fracture

of the hip (reported incidence of deep-vein thrombosis, 75 percent),
165
the
substantial risk of a hemorrhagic complication posed by

warfarin would be offset by its superior antithrombotic
efficacy
111
.

A different agent might be preferred in transurethral resection

of the prostate for benign hypertrophy,
in which the incidence

of deep-vein thrombosis is only 7 to 10 percent,
166,167
but

bleeding is a major concern
(incidence, 6 percent)
81
.

Although sometimes eschewed because of fear of hemorrhagic side

effects, the vitamin K antagonists, such as
warfarin, remain

valuable, especially in high-risk patients,
133
such as those

with malignant disease. An advantage
of warfarin is that the

dose recommended to prevent deep-vein thrombosis is adequate

to treat an established but
undetected thrombus, which is not

uncommon in such patients
123,168
.

The one-stage prothrombin time can be misleading for the regulation

of oral anticoagulant therapy if performed
with an insensitive

thromboplastin reagent. When this problem was recognized, the

prescribed dose of warfarin
was reduced, with a resultant reduction

in bleeding complications
168,169
. Persistence of the antithrombotic

effectiveness of the lower dose of warfarin was affirmed by

clinical trials
54
.

Small subcutaneous doses of heparin (minidose heparin, given

in a dose of 5000 U two or three times daily)
prevent deep-vein

thrombosis in patients at moderate risk as a result of general,

mainly abdominal, surgery
59,170
.
Several meta-analyses in the

1980s found minidose heparin to be a good general-purpose prophylactic

agent,
even in orthopedic patients, in whom anecdotal evidence

had supported the contrary view
59,160,170
. More
recently, a

subcutaneous dose of standard heparin adjusted to produce a

high-normal activated partial-
thromboplastin time
171
and a subcutaneous

dose of low-molecular-weight heparin based on body weight without

laboratory control
172
have also been highly effective in comparative

trials in orthopedic patients.

Hemorrhagic side effects are uncommon with subcutaneous heparin,

about 2 percent on average, and serious
bleeding is rare, as

long as there is no other systemic hemorrhagic diathesis
59
.

Such postoperative complications
are often predictable preoperatively

from a careful analysis of the patient's history, particularly

regarding the use
of aspirin and other drugs that affect hemostasis
173
.

Another important side effect of heparin is an allergic thrombocytopenia

(heparin-induced thrombocytopenia)
that is sometimes complicated

by thromboembolism
126
. A review of patients with heparin-induced

thrombocytopenia revealed a strong association with postoperative

venous thrombosis
174
. Heparin-induced
thrombocytopenia has recently

been reviewed critically
175
.

The combination of heparin with a purified concentrate of antithrombin

III was recently studied. It was more
effective in preventing

deep-vein thrombosis after orthopedic operations than was heparin

alone,
176
perhaps
because the combination could compensate for

the decline in plasma concentrations of antithrombin III that

has
been observed after hip arthroplasty and other major operations
92
.

Pharmaceutical-grade heparin is a mixture of polysaccharide

molecules of 5 to 30 kd that vary widely in
anticoagulant potency.

Experiments in animals suggested that heparin species below

7 kd have fewer
hemorrhagic side effects than conventional heparin,
177
thus providing the impetus for the interest in preparations

of low-molecular-weight heparin that are less active against

platelets
178
. This activity is believed to be causally
related

to the hemorrhagic side effects of heparin. Several preparations

of low-molecular-weight heparin and
other glucose aminoglycans

with heparin-like properties have been superior to a placebo

in preventing
postoperative deep-vein thrombosis, especially

in orthopedic patients
179,180
. There are also claims of fewer

episodes of bleeding with low-molecular-weight heparin than

with standard heparin
181,182
. The cost effectiveness
of prophylaxis

with low-molecular-weight heparin was addressed in a recent

meta-analysis of randomized trials
of total hip arthroplasty
183
.

However, not all reports on low-molecular-weight heparin have

been entirely favorable. In elective surgery of the
hip and

knee, a once-daily dose of low-molecular-weight heparin (Logiparin)

was more effective than less
intense warfarin prophylaxis with

an INR of 2.0 to 3.0 (incidence of deep-vein thrombosis, 31

percent vs. 37
percent; P = 0.03), but was associated with a

higher incidence of serious bleeding complications (2.8 percent

vs.
1.2 percent, P = 0.04)
184
. Furthermore, an unexpectedly

high rate of deep-vein thrombosis (24 percent, proved by
phlebography)

followed abdominal surgery, despite daily doses of low-molecular-weight

heparin at
recommended levels
185
. The explanation is not clear.

The results, overall, suggest a small therapeutic advantage

for low-molecular-weight heparin
119,186,187
. The long biologic

half-life and predictable plasma concentrations of
low-molecular-weight

heparin allow it to be administered once or twice daily in a

fixed dose without the need for
laboratory tests,
119,179
which

should facilitate outpatient management and result in considerable

savings.

More detailed reviews of the clinical use and side effects of

heparin and oral anticoagulants can be found in
previous issues

of the Journal
188,189
.

Antiplatelet Agents
Since the usual venous thrombus is a fibrin-rich clot formed

within the circulation in dead waters, recirculating
eddies,

valve sinuses, and other areas of relative stasis,
190
it is

not surprising that inhibition of thrombin
generation and fibrin

formation can prevent deep-vein thrombosis. Platelets might

also be involved, especially if
there is direct trauma to the

vein
161
. Aspirin has been studied extensively as prophylaxis

against deep-vein
thrombosis, and its use has given rise to

intense controversy
111,191
. In a recent large meta-analysis,
192
prophylactic aspirin reduced both proximal and distal deep-vein

thrombosis by 30 to 40 percent and pulmonary
emboli by 60 percent

in patients undergoing general surgical, orthopedic, and medical

procedures. The
physician's familiarity with the drug is an

asset, but aspirin appears to provide less protection than can

be
achieved safely with more modern programs of anticoagulation.

Other antiplatelet agents have been prescribed to prevent deep-vein

thrombosis. The dextrans, which are
branched-chain polysaccharides

of 40 to 70 kd, increase flow in the microcirculation by various

mechanisms,
193,194
and they have prevented deep-vein thrombosis

in clinical trials
195
. Their ability to protect
against pulmonary

emboli is about the same as that of low-dose heparin
170
. Bleeding

complications are dose
related and are uncommon at doses customarily

given to prevent deep-vein thrombosis
170
. Allergic reactions

including anaphylaxis, the need for intravenous administration,

and high cost have curtailed the use of dextrans
for prophylaxis

against deep-vein thrombosis in the United States. They are

of no value in the treatment of
established deep-vein thrombosis.

Recombinant-DNA techniques have been used to reproduce the parent

compound and express biologically active
relatives of hirudin,

a natural anticoagulant constituent of the saliva of the medicinal

leech
196
. These substances
are potent inhibitors of thrombin,

but unlike that of heparin, their action is independent of antithrombin

III and
they have little effect on platelets, save for their

profound ability to block interactions between thrombin and

platelets. Preliminary clinical trials have demonstrated their

safety and efficacy,
197
and they appear to deserve
further trials.

Other antithrombotic agents are in early stages of development,

such as 7E3, a murine monoclonal-antibody
fragment that competes

with fibrinogen for its platelet receptor (glycoprotein IIb/IIIa),
198
and recombinant
human factor Xa,
199
which blocks prothrombinase

activity.

Physical Measures
The contribution of venous stasis to the pathogenesis of deep-vein

thrombosis can largely be overcome by
contraction or compression

of the calf muscles, which prevents pooling of blood in the

veins of the lower
extremities. Graduated-compression stockings
200
provide adequate prophylaxis in patients at low risk for deep-
vein

thrombosis (Table 3), but intermittent external pneumatic compression

of the legs and thighs with inflatable
cuffs has a greater effect,

being on a par with the better antithrombotic drugs in patients

at moderate risk (those
who have undergone general surgical
170
and urologic
102
procedures). Pneumatic compression is contraindicated

in patients with compromised arterial circulation, but it is

particularly attractive for prophylaxis in patients who
have

undergone neurosurgical procedures, since it is free of hemorrhagic

side effects
201,202
. Pneumatic
compression prevents deep-vein

thrombosis after major knee surgery,
203
but its effectiveness

in hip
replacement
204
and its efficacy relative to that of warfarin

are in dispute
205,206
. Improper application of
pneumatic-compression

devices, described in 22 percent of patients in an intensive

care unit and in 52 percent in
routine nursing units, could

be a frequent reason for the failure of this form of prophylaxis

against deep-vein
thrombosis
207
.

The effect of pneumatic devices on blood flow to the limbs can

be increased if circumferential bladders with
graded pressures

highest at the ankle are filled in sequence
208
. However, in

patients who had undergone
neurosurgical procedures, such optimization

of hemodynamics did not improve the antithrombotic efficacy

more
than uniform compression of the calves by a single circumferential

bladder
209
.

Surveillance
The practice of screening patients postoperatively to detect

deep-vein thrombosis early reduces the occurrence of
major pulmonary

emboli as well, for it leads to earlier diagnosis and treatment

of venous thrombosis before
pulmonary embolism supervenes. In

published trials in which prophylactic administration of an

antithrombotic
agent was compared with no treatment, major pulmonary

emboli were usually rare in both groups
210
that
received equally

close surveillance (usually by
125
I-labeled fibrinogen). The

problem with early surveillance is
not lack of efficacy, but

rather the high cost of the monitoring procedures. The marginal

cost in patients
undergoing general surgical procedures was

calculated to be $49,000 for each death from pulmonary emboli

averted (in 1980 dollars), as compared with a cost of $870 with

the use of low-dose heparin
154
. Such problems
may make surveillance

worth considering for selected patients who are poor candidates

for antithrombotic
drugs
211
.

Venous Interruption
Surgical procedures are sometimes undertaken to prevent the

recurrence of pulmonary emboli in patients with
deep-vein thrombosis,

if conventional anticoagulation has failed or if there is an

apparent contraindication to
anticoagulation (e.g., a major

risk factor for bleeding, such as intracranial trauma). Obstruction

or
compartmentalization of the inferior vena cava can be accomplished

by direct surgical ligation, plication, or the
application of

a clip. Compartmentalization into channels approximately 3 mm

in diameter is preferred to ligation
or total occlusion, since

it is less likely to be followed by acute circulatory instability

and since, paradoxically,
recurrent pulmonary emboli are slightly

less common (frequency, 6 percent) than after total occlusion

(7 percent)
212
. The latter is apt to be followed by dilatation

of retroperitoneal collateral veins, which are potential avenues

for large emboli.

Percutaneous insertion of intracaval devices has largely supplanted

the direct surgical approach. Caval patency
rates exceed 95

percent with the Greenfield filter, the most popular device,

and embolism recurs less than 4
percent of the time
213
. Other

complications, such as misplacement (4 percent) and migration

of the filter or
perforation of the caval wall, are infrequent.

The reputation for success of the vena caval filter has resulted

in its more frequent prophylactic use in patients at
very high

risk for deep-vein thrombosis and pulmonary emboli -- those

with multiple trauma, severe head injury,
spinal cord injury,

and long-bone fractures
214
-- particularly if there is a relative

contraindication to
antithrombotic therapy. Further clinical

trials and analyses of cost effectiveness are necessary to identify

patients
in whom the prophylactic insertion of intracaval devices

should be recommended
215
.

Supported by a grant from the National Heart, Lung, and Blood

Institute.

We are indebted to Sophia Movshovich for assistance in the preparation

of the manuscript.

Source Information
From the Department of Surgery, Beth Israel Hospital and Harvard Medical School, Boston.
Address reprint requests to Dr. Salzman at the Department of Surgery, Beth Israel Hospital, 330 Brookline Ave., Boston,
MA 02215.
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