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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
Credit for fundamental studies leading to our current understanding of deep-

vein thrombosis should be given to Bauer, who used phlebography to Return to Search
diagnose deep-vein thrombosis complicating fractures of the tibia,1 and to Result
Sevitt and Gallagher for their autopsy-based studies of the prevalence of
venous thromboembolism in patients with other injuries2,3. The development
of objective methods for the diagnosis of deep-vein thrombosis has Letters
facilitated the investigation of its natural history and has provided a rational
basis for its prevention and treatment.
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Diagnosis
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Most venous thrombi are clinically silent when they are first detectable by Notify a Friend
objective methods,2,4 probably because they do not totally obstruct the E-mail When Cited
vein1,5 and because of collateral circulation6. 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 Find Similar Articles
discomfort, edema, venous distension, and pain on forced dorsiflexion of the
PubMed Citation
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 time9,10.
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: Table 1. Tests Used in the Diagnosis of Deep-Vein

[in this window] Thrombosis.
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At one time, scanning with [125I]-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 [125I]-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 Paulin15. 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 emboli3. 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 thrombosis11,16.
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 effects17,18. 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 effective19 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 sensitivity20. 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 plethysmography21 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 deflated21,23.
In patients with suspected deep-vein thrombosis, the combination of normal results on both impedance
plethysmography and fibrinogen scanning9 or simply repeatedly normal impedance plethysmographic
examinations24,25,26 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 reported12. 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 occlusive20. 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 thrombosis22,27. A helpful review of vascular ultrasonography is available28.
Visualization of a venous thrombus is often possible but is not essential for diagnosis29. The most sensitive
finding is failure of the vein to collapse under gentle external pressure, so-called compression
ultrasonography29,30. 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 plethysmography13.
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 percent31. 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 studies32. 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 extension31,33.
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 percent6. 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 veins34. 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 pelvis35 and is considered
superior to conventional phlebography36 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 trials38,39 of magnetic resonance venography have reported 100 percent sensitivity and

over 96 percent specificity for the diagnosis of proximal deep-vein thrombosis. In one study39 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 venography41 can detect a thrombus labeled with
various proteins,42 platelets,43 or red cells44. Monoclonal antibodies specific for cross-linked fibrin function both
as vehicles for plasminogen activators45 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 thrombosis46 or pulmonary emboli47. 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 imaging49.
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 thrombosis50,51.
Clinical Epidemiology of Venous Thromboembolism
At least 30 cases of deep-vein thrombosis identifiable by phlebography10 can be expected among 100 patients
who have undergone general surgical operations of moderate severity if they are not given perioperative
antithrombotic prophylaxis52. 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 procedures10 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 asymptomatic8. 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 ones3,58. Among these 100 patients, four cases of pulmonary emboli will be
recognized10; one or two may be fatal59. One or two additional cases of pulmonary emboli will probably be
detected within the first month after discharge from hospital60. Many more patients will have silent, clinically
unrecognized pulmonary emboli61,62,63. 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 condition65. 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
arthroplasty66.
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 emboli67,68. 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 therapy52,76,109,110,111.
View this table: Table 2. Risk Factors for Deep-Vein

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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 anticoagulation112. 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 dosage114. Failure to reach the prescribed intensity of
anticoagulation in the first 24 hours of treatment increases the risk of recurrent venous thromboembolism by 15
times114.
Treatment can be initiated with either a continuous intravenous infusion or subcutaneous injections of heparin114.
The subcutaneous route is more convenient for outpatients115,116. 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 effective117,118. 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 injections117,118.

Recently, heparin preparations of relatively low molecular weight were tested in the treatment of proximal-vein
thrombosis119,120,121 and in submassive pulmonary emboli122. Low-molecular-weight heparin was as effective as
standard heparin for the prevention of the extension of an existing thrombus121,122 or of recurrent
thromboembolism,119,120 and it resulted in the same or a lower degree of serious bleeding120. 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 therapy123. However, asymptomatic extension of
deep-vein thrombosis to proximal veins or pulmonary emboli can be expected in 8 percent of the patients so
treated113. Symptomatic pulmonary emboli might occur in 0.5 percent124. Extending the course of heparin (e.g.,
10 days) before warfarin therapy is begun is not beneficial124,125. On the contrary, the shorter the heparin
treatment, the less often it is followed by heparin-induced thrombocytopenia126. 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 patients113.
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 results127. 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 enough129.
Oral anticoagulation should be continued for at least three months to minimize the risk of recurrent
thromboembolism123. 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 thrombosis56. 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 Goldman133
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 limb138,139.
Surgery may also have a role in occasional cases of deep-vein thrombosis that are less than massive140. 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 trials141. Meanwhile,
venous thrombectomy should probably be reserved for selected patients in whom the viability of a limb is
threatened by an acute iliofemoral thrombosis142.
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 vein143,144. Thrombolytic treatment should be continued until both
venous patency and normal valvular anatomy are restored145,146. A recent review of selected clinical trials that
compared streptokinase with heparin for the treatment of deep-vein thrombosis147 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 anticoagulation148. Furthermore, thrombolysis does not afford more protection against
pulmonary emboli than does anticoagulation149. The more-than-doubled hazard of bleeding with streptokinase143
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 complex151 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 effective153. 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
analysis154,155,156,157. 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 index100.
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 knee159,160.
View this table: Table 3. Incidence of Thromboembolic Events after Surgery or Trauma or in the Presence
[in this window] of Certain Medical Conditions and Recommended Prophylaxis, According to Risk Group.
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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 percent2,55 after an orthopedic operation on the lower extremities, especially if there is a lengthy
convalescence involving bed rest55. 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 used162,163.
The presence of malignant disease is also a serious risk factor for deep-vein thrombosis and pulmonary
emboli86,87. The way in which cancer increases the risk of thrombotic complications has recently been
reviewed86,164.
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
efficacy111. 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 patients123,168.
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 complications168,169. Persistence of the antithrombotic
effectiveness of the lower dose of warfarin was affirmed by clinical trials54.
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, surgery59,170.
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 view59,160,170. More
recently, a subcutaneous dose of standard heparin adjusted to produce a high-normal activated partial-
thromboplastin time171 and a subcutaneous dose of low-molecular-weight heparin based on body weight without
laboratory control172 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 diathesis59. 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 hemostasis173.
Another important side effect of heparin is an allergic thrombocytopenia (heparin-induced thrombocytopenia)

that is sometimes complicated by thromboembolism126. A review of patients with heparin-induced
thrombocytopenia revealed a strong association with postoperative venous thrombosis174. Heparin-induced
thrombocytopenia has recently been reviewed critically175.
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 operations92.
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 platelets178. 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 patients179,180. There are also claims of fewer
episodes of bleeding with low-molecular-weight heparin than with standard heparin181,182. The cost effectiveness
of prophylaxis with low-molecular-weight heparin was addressed in a recent meta-analysis of randomized trials
of total hip arthroplasty183.
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 levels185. The explanation is not clear. The results, overall, suggest a small therapeutic advantage
for low-molecular-weight heparin119,186,187. 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 Journal188,189.
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 vein161. Aspirin has been studied extensively as prophylaxis against deep-vein
thrombosis, and its use has given rise to intense controversy111,191. 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 trials195. Their ability to protect
against pulmonary emboli is about the same as that of low-dose heparin170. Bleeding complications are dose
related and are uncommon at doses customarily given to prevent deep-vein thrombosis170. 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 leech196. 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 stockings200 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 surgical170 and urologic102 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 effects201,202. Pneumatic
compression prevents deep-vein thrombosis after major knee surgery,203 but its effectiveness in hip
replacement204 and its efficacy relative to that of warfarin are in dispute205,206. 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
thrombosis207.
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 sequence208. 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 bladder209.
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 groups210 that
received equally close surveillance (usually by 125I-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 heparin154. Such problems
may make surveillance worth considering for selected patients who are poor candidates for antithrombotic
drugs211.

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 time213. 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 fractures214 -- 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 recommended215.
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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Previous Volume 331:1630-1641 December 15, 1994 Number 24 Next

Credit for fundamental studies leading to our current understanding of deep-

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

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In duplex scanning, real-time B-mode ultrasonography is supplemented by Doppler flow-detection ultrasonic

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Clinical Epidemiology of Venous Thromboembolism

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View this table: Table 2. Risk Factors for Deep-Vein

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Surgical Treatment of Acute Deep-Vein Thrombosis

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New thrombolytic agents, such as anisoylated plasminogen-streptokinase activator complex151 or single-chain

Prevention of Venous Thromboembolism

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Another important side effect of heparin is an allergic thrombocytopenia (heparin-induced thrombocytopenia)

Pharmaceutical-grade heparin is a mixture of polysaccharide molecules of 5 to 30 kd that vary widely in

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ultrasonography. N Engl J Med 1989;320:342-345.[Abstract]

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system. Br J Surg 1979;66:687-690.[Medline]

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discharge: an underestimated risk. Arch Surg 1992;127:310-313.[Abstract]

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diagnosis. Clin Orthop 1989;242:212-231.[Medline]

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poor anticoagulant response to activated protein C. Lancet 1993;342:1503-1506.[Medline]

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Philadelphia: J.B. Lippincott, 1994:1346-66.

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on platelet aggregation. J Clin Invest 1980;65:64-73.[Medline]

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antithrombotic agent in a rabbit model of venous thrombosis. Circulation 1992;86:Suppl I:I-410.abstract

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