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Management of Deep Vein Thrombosis and Pulmonary Embolism

A Statement for Healthcare Professionals From the Council on Thrombosis (in
Consultation With the Council on Cardiovascular Radiology), American Heart
Association
Jack Hirsh and John Hoak
Originally published 15 Jun 1996 https://doi.org/10.1161/01.CIR.93.12.2212 Circulation. 1996;93:2212–2245

Deep vein thrombosis (DVT) is a common but elusive illness that can result in suffering
and death if not recognized and treated effectively. DVT occurs in ≈2 million Americans
each year. Death can occur when the venous thrombi break off and form pulmonary
emboli, which pass to and obstruct the arteries of the lungs. DVT and pulmonary
embolism (PE) most often complicate the course of sick, hospitalized patients but may
also affect ambulatory and otherwise healthy persons.1234 It is estimated that each year
600 000 patients develop PE and that 60 000 die of this complication.567 This number
exceeds the number of American women who die each year from breast cancer. PE is
now the most frequent cause of death associated with childbirth.8 Women are a prime
target for PE, being affected more often than men.

Deep vein thrombosis is a major complication in orthopedic surgical patients and

patients with cancer and other chronic illnesses. DVT can be a chronic disease.
Patients who survive the initial episode of DVT are prone to chronic swelling of the leg
and pain because the valves in the veins can be damaged by the thrombotic process,
leading to venous hypertension. In some instances skin ulceration and impaired
mobility prevent patients from leading normal, active lives. In addition, patients with
DVT are prone to recurrent episodes. In those instances in which DVT and PE develop
DVT are prone to recurrent episodes. In those instances in which DVT and PE develop
as complications of a surgical or medical illness, in addition to the mortality risk,
hospitalization is prolonged and healthcare costs are increased.

Purpose
Over the past 20 years results of clinical trials have provided information that has
revolutionized the approach to management of venous thromboembolic disease. New
diagnostic modalities and therapeutic agents have been developed that are more
effective, less expensive, and more convenient. Patients with venous thromboembolic
disease (VTE) are seen by a variety of medical specialists, including general physicians,
surgeons, obstetricians, hematologists, radiologists, and chest physicians. Because
thromboembolic disease forms only a small part of the practice of most of these
clinicians, it is difficult for them to keep abreast of advances that are important for
optimal patient care.

The purpose of this report is to provide medical trainees and clinicians with the
information required to manage venous thromboembolic problems that they are likely
to encounter in daily practice.

Pathogenesis of Venous Thromboembolism

Venous thrombi are intravascular deposits composed of fibrin and red cells with a
variable platelet and leukocyte component.9 They usually form in regions of slow or
disturbed flow in large venous sinuses and in valve cusp pockets in the deep veins of
the calf (Fig 1) or in venous segments that have been exposed to direct trauma.101112
Venous thrombi often break off to form PE. The formation, growth, and dissolution of
venous thrombi and PE reflect a balance between the effects of thrombogenic stimuli
and a variety of protective mechanisms.131415

The factors traditionally implicated in the pathogenesis of venous thrombosis are

activation of blood coagulation, venous stasis, and vascular injury.131415 Vascular
damage contributes to the genesis of venous thrombosis through either direct
trauma9121315 or activation of endothelial cells by cytokines (interleukin-1 and tumor
necrosis factor) released as a result of tissue injury and inflammation. Blood
coagulation can be activated by intravascular stimuli released at a remote site (eg,
products of injured or infarcted tissue) or it can be activated locally by vessel wall
damage (eg, damage to the femoral vein during hip surgery) or by cytokine-induced
nondenuding endothelial stimulation.1215161718 These cytokines stimulate endothelial
cells to synthesize tissue factor and plasminogen activator inhibitor-1 and lead to a
reduction in thrombomodulin, thereby reversing the protective properties of normal
endothelium.

The thrombogenic effects of activation of blood coagulation are amplified by stasis and
counteracted by rapid flow. Venous stasis predisposes the patient to local thrombosis
counteracted by rapid flow. Venous stasis predisposes the patient to local thrombosis
by impairing the clearance of activated coagulation factors and limiting the accessibility
of thrombin formed in veins to endothelial protein thrombomodulin, which is present in
greatest density in the capillaries.

The mechanisms that protect against thrombosis are inactivation of activated

coagulation factors by circulating inhibitors, dilution and clearance of activated
coagulation factors by flowing blood, inhibition of the coagulant activity of thrombin by
thrombomodulin, enhancement of the anticoagulant activity of thrombin by
thrombomodulin through activation of protein C, and dissolution of fibrin by the
fibrinolytic system.19202122232425

Natural History
Venous thrombosis in the lower limb can involve the superficial leg veins, the deep
veins of the calf (calf vein thrombosis), the more proximal veins, including popliteal
veins, the superficial femoral, common femoral, and iliac veins. Less commonly,
thrombosis involves other veins in the body. Thrombosis of the superficial veins of the
legs usually occurs in varicosities and is benign and self-limiting. Occasionally,
however, the thrombi in superficial veins extend into the deep veins and give rise to
major PE. Deep calf vein thrombosis is a less serious disorder than proximal vein
thrombosis because thrombi in calf veins are generally small and are therefore not
usually associated with clinical disability or major complications.

Most calf vein thrombi are asymptomatic,10 but these thrombi can extend proximally
and become dangerous. Venous thrombi produce symptoms because they obstruct
venous outflow, cause inflammation of the vein wall or perivascular tissue, or embolize
into the pulmonary circulation. Extension of thrombosis is more likely if the original
thrombogenic stimulus persists.

Complete spontaneous lysis of large venous thrombi is uncommon, and even when
patients with venous thrombosis are treated with heparin, complete lysis occurs in
fewer than 10% of cases.26 In contrast, complete dissolution of small, asymptomatic
calf vein thrombi occurs quite frequently.10

There is a strong association between DVT and PE. Pulmonary emboli are detected by
perfusion lung scanning in ≈50% of patients with documented DVT,327282930 and
asymptomatic venous thrombosis is found in ≈70% of patients with confirmed clinically
symptomatic PE. If the thrombus that embolizes is small (which is frequently the case
when it is located in the calf), the embolus is usually asymptomatic and clinically
insignificant, although the cumulative effect, if there are repeated showers of small
emboli, can cause cor pulmonale. If the thrombus is large and involves the proximal
veins, it often produces clinical manifestations; if it is very large or if the patient has a
compromised cardiorespiratory system, it can be fatal. Most clinically significant and
compromised cardiorespiratory system, it can be fatal. Most clinically significant and
virtually all fatal emboli arise from thrombi in the proximal veins.1

Venous thrombi usually organize slowly and can be complicated by the postthrombotic
syndrome.31 The residual abnormality can also act as a nidus for recurrent
thrombosis,32 which occurs in approximately one third of patients over an 8-year
follow-up period.33

Prognosis
Studies done before the introduction of anticoagulant therapy reported that the
mortality rate for PE was ≈20% in hospitalized patients with clinically obvious venous
thrombosis.34 In a small study, Kakkar and colleagues10 reported that without
treatment, ≈20% of silent calf vein thrombi extended into the popliteal vein and that
extension was associated with a 40% to 50% risk of clinically detectable PE.

In a study of patients with clinically suspected DVT, Huisman and associates35 reported
that 6.5% (20 of 307) who had negative impedance plethysmography at presentation
developed evidence of extension over the next 10 days. Others have reported a lower
frequency of impedance plethysmography (IPG) conversion during serial testing. The
estimated frequency of extension rate of untreated symptomatic calf vein thrombosis is
≈30%, based on the results of these serial IPG studies.

In contrast to untreated thrombosis, the short-term prognosis of patients with proximal

DVT treated with adequate doses of anticoagulants for 3 months is good.363738
Clinically significant recurrent events take place in ≈5% of patients with proximal vein
thrombosis treated with an initial course of heparin followed by oral anticoagulants or
intermediate doses of subcutaneous heparin for 3 months.373839404142 Thereafter, DVT
recurs in 5% to 10% of patients the year after anticoagulant therapy is
discontinued363738 and in ≈30% of patients after 8 years.33

Clinical Course in Symptomatic Patients

A comprehensive prospective follow-up study examining long-term prognosis in
consecutive patients with a first episode of documented symptomatic DVT of the leg
was recently completed by Prandoni and associates.33 The study assessed the long-
term incidence of recurrent venous thromboembolism and postthrombotic syndrome.

Patients were treated with an initial course of high dose–adjusted intravenous standard
heparin or low-molecular-weight heparin (LMWH) followed by oral anticoagulants,
which were started during the first week of treatment and continued for at least 3
months.42 The dose of oral anticoagulant therapy was adjusted daily to maintain the
International Normalized Ratio (INR) between 2.0 and 3.0. All patients were instructed
to wear graduated compression stockings (40 mm Hg at the ankle) for at least 2 years.
They were seen at 3 and 6 months after presentation and every 6 months thereafter for
They were seen at 3 and 6 months after presentation and every 6 months thereafter for
follow-up assessments. Patients were asked to return immediately if they developed
symptoms suggestive of recurrent venous thromboembolism. Follow-up continued for
up to 8 years.

A total of 355 consecutive patients with a first episode of DVT confirmed by

venography were included in the study. Seventy-eight patients experienced one or
more episodes of objectively confirmed recurrent venous thromboembolic events. Of
the first recurrences, 35 (44.9%) occurred in a leg that was initially involved, 28 (35.9%)
in the contralateral leg, and 15 (19.2%) were PE, which was fatal in 9 patients (11.5%).
The cumulative incidence of recurrent VTE after 3 months was 4.9%; after 6 months it
was 8.6%. The incidence of recurrent events gradually increased to 17.5% after 2
years, 24.6% after 5 years, and 30.3% after 8 years of follow-up (Fig 2).

The risk of recurrent VTE was increased by the presence of malignancy and
coagulation abnormalities and reduced in patients who had a reversible risk factor (eg,
surgery and trauma or fracture).

Of the 355 patients, 83 developed postthrombotic syndrome and 24 developed severe

postthrombotic manifestations. The cumulative incidence of postthrombotic syndrome
was 17.3% after 1 year and 22.8% after 2 years. Thereafter, the incidence of
postthrombotic syndrome rose very gradually to 28.0% after 5 years and 29.1% at 8
years. Thus, in more than 80% of patients manifestations of postthrombotic syndrome
became apparent in the first 2 years after acute thrombosis. The cumulative incidence
of severe postthrombotic manifestations increased gradually from 2.6% after 1 year to
9.3% after 5 years. Thereafter, the cumulative incidence of severe postthrombotic
manifestations did not increase further. It is likely that the use of compression
stockings contributed to this low incidence of postthrombotic syndrome, as indicated
by a recent controlled study.43 Ipsilateral recurrent DVT was associated with a strong
increase in risk for postthrombotic syndrome (risk ratio 6:4).

Surprisingly, there were no significant associations between occurrence of

postthrombotic syndrome and size or location of the thrombus. Twenty-six of the 297
patients without a malignancy at baseline developed cancer. This occurred mainly in
patients with idiopathic DVT at presentation.44

Of the 355 patients, 90 died during follow-up. The causes of death included
malignancy (n=52), ischemic stroke (n=8), acute myocardial infarction (n=4), PE (n=9),
heart failure (n=3), anticoagulant-related hemorrhage (n=2), and miscellaneous (n=6). In
6 patients who died suddenly, a definite cause of death was not established.

Other studies have also reported that most recurrences take place in patients who
have idiopathic venous thrombosis or who are exposed to a continuing risk factor
(such as cancer). In these groups, the rate of recurrence is ≈15% in the 12 months after
(such as cancer). In these groups, the rate of recurrence is ≈15% in the 12 months after
treatment is stopped. In contrast, the long-term prognosis in patients who develop
venous thrombosis following exposure to a predisposing cause such as surgery or
trauma is very good.45 Thus, provided they are treated with anticoagulants for 3
months,363738 fewer than 4% of these patients develop recurrences in the following
year.454647

Acute Recurrent Venous Thrombosis

The label of recurrent venous thrombosis carries important prognostic implications.
Patients are usually treated with anticoagulants for life and may suffer considerable
mental anguish. Therefore, it is important to ensure that the diagnosis of recurrent DVT
is correct. In many patients with clinically suspected recurrence, the diagnosis of
recurrence is not confirmed by objective tests. For example, in a prospective study of
patients with clinically suspected acute DVT, almost two thirds did not have this
diagnosis confirmed by objective tests, and these patients did very well without
anticoagulant therapy.48

The diagnosis of recurrent venous thrombosis can be difficult because venography, the
diagnostic standard for acute venous thrombosis, is less reliable for diagnosis of
recurrent venous thrombosis.48 However, the accuracy of diagnosis of acute
recurrence has been improved by the introduction of noninvasive techniques (see
below).

Postthrombotic Syndrome
In early descriptive studies, postthrombotic syndrome was reported to occur in ≈50%
of patients with symptomatic venous thrombosis. More recently and possibly as a
consequence of better initial anticoagulation and the use of graduated compression
stockings, the incidence of postthrombotic syndrome after 8 years of follow-up was
reported to be no more than ≈25%.33 The postthrombotic syndrome is caused by
venous hypertension, which occurs as a consequence of recanalization of major
venous thrombi leading to patent but scarred and incompetent valves or, less
frequently, persistent outflow obstruction produced by large proximal vein
thrombi.31495051 Recanalization and valve destruction result in a malfunction of the
muscular pump mechanism, which leads to increased pressure in the deep veins of the
calf. This high pressure results in progressive incompetence of the valves of the
perforating veins of the calf, and when this occurs, flow is directed from the deep vein
into the superficial system during muscle contraction, leading to edema and impaired
viability of subcutaneous tissues and, in its most severe form, ulceration of venous
origin. Follow-up studies of patients with proximal vein thrombosis have demonstrated
that outflow obstruction (measured by IPG) is relieved either by recanalization or
collateral flow in 30% of patients at 3 weeks and in 70% of patients at 3 months.52
Valvular incompetence is a more important cause of postthrombotic syndrome than is
Valvular incompetence is a more important cause of postthrombotic syndrome than is
outflow obstruction.53

In patients with extensive thrombosis in the iliofemoral veins, swelling may never
disappear, while in patients with less severe proximal vein thrombosis, swelling may
subside after the initial event but return in the next few years. Other manifestations of
postthrombotic syndrome are pain in the calf relieved by rest and elevation of the leg,
pigmentation and induration around the ankle and the lower third of the leg, and, less
commonly, ulceration and venous claudication, a bursting calf pain that occurs during
exercise.

Patients with extensive thrombosis involving the iliofemoral vein have a higher
frequency of venous claudication and frequently have greater disability than patients
with more distal vein thrombosis.50 However, incompetence of perforating veins may
follow thrombosis confined to calf veins and may lead to stasis changes. In a follow-up
study of calf vein thrombosis in Sweden, the frequency of postthrombotic syndrome
was reported to be 13 of 79 or 16% in 2 years’ follow-up.54 There is evidence from
recent studies that recurrent venous thrombosis is an important risk factor for
development of postthrombotic syndrome33 and that risk of developing postthrombotic
syndrome is reduced by the use of graduated compression stockings.43 The role of
thrombolytic therapy in prevention of postthrombotic syndrome is uncertain. Clinical
trials in acute DVT evaluating the effect of thrombolytic therapy on subsequent
development of postthrombotic syndrome have produced equivocal results,55 although
on balance, it is probable that the incidence of clinical symptoms is reduced in patients
who receive thrombolysis.55

The prevalence of postthrombotic syndrome in the general population has been

estimated in several countries. In Sweden it has been reported to occur in 2% of the
population, and in a study of more than 4000 chemical-industry workers in Switzerland,
the frequency of severe venous insufficiency with venous ulceration was reported to be
between 1% and 1.5%.5456 In an investigation in Michigan involving more than 9000
adults older than 20 years, the prevalence of active or healed venous ulcers was 5 per
1000.2 Extrapolation of this figure to the general population in the United States
suggests that about 500 000 Americans have or have had venous ulceration.

The diagnosis of postthrombotic syndrome is sometimes obvious on clinical grounds if

the symptoms are gradual in onset. However, patients can have subacute symptoms of
leg pain and swelling, which may mimic acute recurrence of DVT. Although these
symptoms are usually superimposed on a background of chronic pain and swelling, it
may be difficult to exclude acute recurrence on clinical grounds alone, and a diagnosis
of postthrombotic syndrome as the cause of the patient’s symptoms can be made only
after acute recurrent venous thrombosis has been excluded.
The diagnosis of postthrombotic syndrome should include demonstration of deep
venous incompetence using Doppler ultrasound or plethysmography575859 and more
recently by techniques such as volume plethysmography and duplex ultrasound.

In some patients with recurrent leg pain not due to acute recurrent venous thrombosis
or postthrombotic syndrome, an alternative cause is not found, and symptoms may be
due to thromboneurosis. This clinical syndrome tends to occur in patients who have a
morbid fear of the complications of DVT/PE. These patients may have had a previous
episode of DVT and some have evidence of postthrombotic syndrome, but some have
never had objectively documented episodes of venous thrombosis. These patients
usually present with pain and tenderness that may be disproportionate to physical
signs of swelling. In its most severe form, patients may be incapacitated by fear of
recurrence, loss of the leg, or death. Patients frequently have a history of multiple
hospital admissions for treatment of alleged recurrent venous thrombosis. Many are on
long-term anticoagulant therapy or antiplatelet drugs, and some have undergone caval
interruption procedures. Unfortunately, thromboneurosis is often iatrogenic, and fear of
recurrence is reinforced each time the attending physician admits the patient to the
hospital and orders treatment based on clinical suspicion alone. Thromboneurosis is
best prevented by ensuring that a clinical suspicion of acute venous thrombosis (either
first episode or recurrence) is always confirmed by appropriate objective tests.

Prophylaxis
The most effective way of reducing death from PE and morbidity from postthrombotic
syndrome is to institute a comprehensive institutional policy of primary prophylaxis in
patients at risk for VTE. Patients can be classified as being at low, moderate, or high
risk for developing VTE on the basis of well-defined clinical criteria60 (Tables 1 and 2),
and the choice of prophylaxis should be tailored to the patient’s risk. In the absence of
prophylaxis, the frequency of postoperative fatal PE ranges from 0.1% to 0.8% in
patients undergoing elective general surgery, 0.3% to 1.7% in patients undergoing
elective hip surgery, and 4% to 7% in patients undergoing emergency hip surgery.60
Safe and effective forms of prophylaxis are available for patients at high risk, and
primary prophylaxis is cost-effective.61

Prophylaxis is achieved by either modulating activation of blood coagulation or

preventing venous stasis. The following prophylactic approaches are of proven value:
low-dose subcutaneous heparin,6162 intermittent pneumatic compression of the
legs,6061 oral anticoagulants,6061 adjusted doses of subcutaneous heparin,63 graduated
compression stockings,64 and LMWHs65 (Table 3). Antiplatelet agents such as aspirin
are less effective for preventing VTE.60

Low-dose heparin is given subcutaneously at a dose of 5000 U 2 hours before surgery

and is then given postoperatively at a dose of 5000 U every 8 or 12 hours. Low-dose
and is then given postoperatively at a dose of 5000 U every 8 or 12 hours. Low-dose
heparin prophylaxis is the method of choice for moderate-risk general surgical and
medical patients.60 Low-dose heparin reduces the risk of VTE by 50% to 70%62 ; it
does not require laboratory monitoring and is simple, inexpensive, convenient, and
safe. However, because of the potential for minor bleeding, it should not be used in
patients undergoing cerebral, ocular, or spinal surgery. Low-dose heparin is less
effective than warfarin,60 adjusted-dose heparin,63 and LMWH in patients undergoing
major orthopedic surgical procedures.6566 Intermittent pneumatic compression of the
legs enhances blood flow in the deep veins and increases blood fibrinolytic activity.60
This method of prophylaxis is free of clinically important side effects and is particularly
useful in patients with a high risk of serious bleeding. Therefore, it is the method of
choice for preventing venous thrombosis in patients undergoing neurosurgery,64 is
effective in patients undergoing major knee surgery,67 and is as effective as low-dose
heparin in patients undergoing abdominal surgery.60

Graduated compression stockings reduce venous stasis and are effective for
preventing postoperative venous thrombosis in general surgical patients60 and in
medical or surgical patients with neurological disorders, including paralysis of the lower
limbs.64 In surgical patients the combination of graduated compression stockings and
low-dose heparin is significantly more effective than low-dose heparin alone.6869
Graduated compression stockings are relatively inexpensive and should be considered
for all high-risk surgical patients, even if other forms of prophylaxis are used.

Moderate-dose warfarin (INR, 2.0) is effective for preventing postoperative VTE in all
risk categories.60 Warfarin can be started preoperatively, at the time of operation, or in
the early postoperative period. Although the full, measurable anticoagulant effect is not
achieved until the third or fourth postoperative day, when treatment is started at the
time of surgery or in the early postoperative period, warfarin is still effective in very
high–risk patient groups, including patients with hip fractures.70 Prophylaxis with
warfarin is less convenient than low-dose heparin or LMWHs because of the need for
careful laboratory monitoring.

Adjusted-dose heparin is given subcutaneously in a dose of 3500 U three times daily,

starting 2 days before surgery. The dose is then adjusted to maintain the activated
partial thromboplastin time (aPTT) at the upper limit of the normal range. Adjusted-
dose heparin is more effective than fixed low-dose heparin in patients undergoing
elective hip surgery63 but is less effective in preventing proximal vein thrombosis than
LMWH following elective hip surgery.71 Adjusted-dose heparin is inconvenient because
it requires careful laboratory monitoring.

LMWHs have recently been approved for use as prophylactic agents in North America.
LMWHs are safe and effective for prophylaxis in the following high-risk areas65 :
elective hip surgery, hip fracture, major general surgery, major knee surgery, spinal
injury, and stroke. LMWH has been reported to be more effective than standard low-
dose heparin in general surgical patients,65 patients undergoing elective hip
surgery,6566 and patients with stroke65 or spinal injury.65 In addition, LMWHs have also
been more effective than warfarin in patients undergoing hip66 or major knee
surgery,6566676869707172 and better than adjusted-dose heparin at preventing proximal
vein thrombosis after elective hip surgery.71

Choice of Prophylaxis
General Surgery and Illness

Patients at moderate risk should be given prophylaxis (Table 3) with low-dose heparin.
If anticoagulants are contraindicated because of an unusually high risk of bleeding,
intermittent pneumatic compression should be used.

Hip Surgery

LMWH, oral anticoagulants, or adjusted-dose heparin is effective following hip surgery.

Of these three approaches, LMWH is the most convenient because laboratory
monitoring is not required.

Major Knee Surgery

Both LMWHs and intermittent pneumatic compression are effective in preventing

venous thrombosis in patients undergoing major knee surgery. LMWH is more
convenient and is the prophylactic method of choice.

Genitourinary Surgery, Neurosurgery, and Ocular Surgery

Intermittent pneumatic compression, with or without static graduated compression

stockings, is effective and does not increase the risk of bleeding.

Diagnosis of Venous Thrombosis

A clinical suspicion of venous thrombosis should always be confirmed by objective
tests because patients with minimal leg symptoms may have extensive venous
thrombosis, whereas the classic symptoms and signs of pain, tenderness, and swelling
of the leg can be caused by nonthrombotic disorders.117273747576 In most
contemporary studies of ambulatory patients with symptoms compatible with venous
thrombosis, the diagnosis of venous thrombosis is confirmed in only approximately one
third when reliable objective tests are performed.767778 Alternative diagnoses include
superficial thrombophlebitis, cellulitis, ruptured muscle or tendon, muscle strain,
internal derangement of the knee, ruptured popliteal cyst, cutaneous vasculitis, and
lymphedema.79

Despite the nonspecificity of clinical features, history and physical examination are
important components of the diagnostic process because they may uncover an
important components of the diagnostic process because they may uncover an
alternative cause of the patient’s symptoms and because they allow patients to be
classified as having a high, intermediate, or low probability for venous thrombosis.80
With a simple clinical scoring system that included three main components (symptoms
and signs at presentation, presence or absence of risk factors, and presence or
absence of a possible alternative diagnosis), Wells and associates80 showed that
≈80% of patients with high clinical probability have venous thrombosis, while only 5%
of patients with low clinical probability have venous thrombosis. When combined with
the results of noninvasive tests, these pretest probabilities can be used to both simplify
and reduce costs of the diagnostic process (Table 4).

Methods of Testing
Although a number of tests have been evaluated over the years, only three have been
shown to be accurate for diagnosing venous thrombosis in symptomatic patients:
venography,818283 IPG,34357784858687888990 and venous
ultrasonography.77919293949596979899100101102103104105

If used properly, any one of these methods is acceptable, although venous

ultrasonography (also known as B-mode imaging) is the diagnostic method of choice in
most patients with clinically suspected venous thrombosis.7799 In addition, the Simpli-
red D-dimer test, which is performed on blood obtained by finger prick at the patient’s
side and which has high sensitivity and moderate specificity, shows considerable
promise as a test to rule out venous thrombosis.106 The D-dimer test is often false-
positive after surgery or trauma, thereby limiting its value in these clinical situations.

Performance of Testing
Venography is performed by injecting radiographic material into a superficial vein on
the dorsum of the foot. The contrast material mixes with the blood and flows
proximally. An x-ray image of the leg and pelvis will show the calf and thigh veins,
which drain into the external iliac vein. With good technique, the entire deep venous
system of the leg, including the external iliac and common iliac veins, may be imaged.
A thrombus is diagnosed by the presence of an intraluminal filling defect.818283

Impedance plethysmography is performed by placing two sets of electrodes around the

patient’s calf and an oversized blood pressure cuff around the thigh. The electrodes
sense a change in blood volume (increased blood volume decreases electrical
impedance) in the calf veins, which is recorded on a strip chart. Changes in venous
filling are produced by inflating the thigh cuff to obstruct venous return and then
reestablishing blood flow by deflating the cuff and assessing the time taken for venous
volume in the calf to return to baseline. If an occlusive thrombus is present in the
popliteal or more proximal veins, venous emptying is delayed. The test may also detect
extensive calf vein thrombosis if venous outflow is obstructed, but it fails to detect the
majority of calf vein thrombi.848687
majority of calf vein thrombi.848687

Venous ultrasound imaging of the venous system is obtained with high-resolution

equipment to produce two-dimensional images by real-time computation of reflected
signals from an array of ultrasound sources.77949599102 The ultrasound probe is first
placed over the common femoral vein in the groin. The transducer is then moved
distally to visualize the superficial femoral vein over its course. The entire popliteal vein
is then visualized in the popliteal fossa and traced distally to its trifurcation with the
deep veins of the calf. Gentle pressure is applied with the probe to determine whether
the vein under examination is compressible. The most accurate ultrasonic criterion for
diagnosing venous thrombosis is noncompressibility of the venous lumen under gentle
probe pressure.7799 Vein compressibility is best evaluated in the transverse plane.
Visualization of the proximal portion of calf veins can often be achieved by experienced
operators,95 but resolution can be suboptimal, and the sensitivity and specificity of
venous ultrasonography is much lower for calf vein thrombosis than for proximal vein
thrombosis. Duplex ultrasound, which combines real-time imaging with pulsed gated
Doppler and color-coded Doppler technology, facilitates identification of veins, and as
technology improves, diagnostic accuracy for calf vein thrombosis may
increase.919293103104105106107 Although it has been claimed that color-coded Doppler is
accurate for calf vein thrombosis, this contention has not been demonstrated by an
appropriately designed clinical study.

Venography is the reference standard, but it is invasive; the other two tests are
noninvasive. All three tests are sensitive and specific for proximal vein thrombosis
(thrombi in the popliteal and more proximal veins) in symptomatic patients, although
IPG is less sensitive and less specific than venous ultrasound.108109110 Venography
detects calf vein thrombosis. Venous ultrasonography detects ≈50% of symptomatic
calf vein thrombosis; sensitivity is said to be higher in the hands of some experts, but
this impression awaits confirmation in large clinical trials. Impedance plethysmography
is insensitive to calf vein thrombosis, detecting <20%. Venous ultrasonography is now
the diagnostic method of choice in patients with symptoms suggestive of DVT.

Venography can be painful, it is relatively expensive and inconvenient to perform, and,

on rare occasions, can be complicated by phlebitis. In addition, when performed by
nonexpert radiologists, up to 30% of venograms are technically inadequate and
therefore impossible to interpret. In contrast, venous ultrasonography is readily
available, painless, and can be performed at bedside. However, like venography, this
test is operator dependent.

There is evidence from diagnostic studies using serial noninvasive testing in patients
with symptoms of DVT that calf vein thrombi are not dangerous, provided that they
remain confined to calf veins.33585111 However, calf vein thrombi can extend and do so
in ≈30% of cases.74 Because only ≈5% of patients with symptoms of DVT have calf
in ≈30% of cases.74 Because only ≈5% of patients with symptoms of DVT have calf
vein thrombosis (Fig 3),78 it is safe to exclude clinically important venous thrombosis if
the venous ultrasonography is negative at presentation in patients who have low
pretest clinical probability, because the negative predictive value of a negative venous
ultrasound is more than 99%.80 In patients at moderate or high clinical probability,
however, it would be prudent to repeat the test once after 5 to 7 days to detect the
small percentage of patients with calf vein thrombosis that extends (Fig 4).

The safety of withholding treatment when either the IPG or venous ultrasound test
result is negative at presentation and subsequently on repeated testing over the next
week has been demonstrated in a number of well-designed studies.33585111 Between
1% and 2% of patients with negative IPG at presentation and <1% of patients with
negative venous ultrasonography develop clinically important events during the first 7
days of serial testing. When these patients with negative venous ultrasonography (or
IPG) are followed up after 6 months, 99% have had no recurrences (Fig 5).111112

Diagnosis of Recurrent Venous Thrombosis

The diagnosis of clinically suspected recurrent venous thrombosis is often more
difficult to establish than diagnosis of the first episode of venous thrombosis.48113 As
with patients with suspected acute venous thrombosis, most patients referred with a
diagnosis of recurrence do not have recurrent venous thrombosis. The clinical
diagnosis of recurrent venous thrombosis is less specific than the diagnosis of the first
episode of venous thrombosis48 because patients fear recurrence and physicians are
sensitized to the possibility of this diagnosis. As a consequence, there is a tendency to
overdiagnose recurrent venous thrombosis by attributing any new episodes of leg pain
or swelling to a recurrent episode. Any other cause of leg pain or swelling can be
confused with recurrence, but the most important mimic is postthrombotic syndrome,
particularly because this disorder occurs in ≈30% of patients who have experienced
proximal vein thrombosis.43114115116 The most common manifestations of
postthrombotic syndrome, chronic aching and swelling of the calf, are unlikely to be
confused with recurrent venous thrombosis. However, subacute exacerbations of pain
and swelling can occur after episodes of increased activity or sometimes without an
obvious precipitating cause and can be difficult to differentiate from recurrence.
Because of their fear of recurrent venous thrombosis, patients often become
concerned if they develop even minimal exacerbations of symptoms or signs. Finally,
some patients develop recurrent episodes of superficial phlebitis or local cellulitis,
which can be confused with recurrent DVT. For these reasons, and because
overdiagnosis of recurrent venous thrombosis often results in unnecessary
prolongation of anticoagulant treatment, every effort should be made to confirm a
diagnosis of suspected recurrence.

The diagnosis of recurrent venous thrombosis is made or excluded by a combination of

either IPG and venography113 or venous ultrasonography and venography (Fig 6). A
either IPG and venography113 or venous ultrasonography and venography (Fig 6). A
correct diagnosis of recurrent venous thrombosis is made by repeating the test used to
make the initial diagnosis when the patient presents with suspected recurrence. The
diagnostic process is facilitated by obtaining a baseline noninvasive test (either IPG or
venous ultrasonography) when anticoagulants are discontinued and repeating the test
if it is still abnormal at this time.48113 The negative test result can then be used as a
baseline against which future tests can be compared.113

The rate of conversion is different for IPG and venous ultrasonography. The IPG result
is negative in 60% of patients with proximal vein thrombosis by 3 months and in 90%
by 12 months.51113 The rates of conversion for venous ultrasonography are lower than
those for IPG.112117118 When the results of IPG or venous ultrasound are negative
before presentation with a suspected recurrence, a positive result can be used to make
a diagnosis of recurrent venous thrombosis. If the IPG performed at the previous visit
was abnormal and remains abnormal at presentation with suspected recurrence,
further testing with venography is required; if there is a new intraluminal filling defect, a
diagnosis of recurrence can be made. If the results of venous ultrasound were
abnormal at the previous visit, it is often possible to diagnose recurrence by
demonstrating extension into a previously normal venous segment or by an increase in
diameter of the venous lumen in a previously affected segment.112 Recurrence can be
excluded if venography shows either no change or improvement compared with the
previous examination or if a negative IPG or venous ultrasound remains negative on
serial testing over the next 7 days (Fig 6).

Diagnosis of Pulmonary Embolism

The clinical diagnosis of PE is also highly nonspecific because the clinical features may
be simulated by other cardiorespiratory or musculoskeletal
disorders.3119120121122123124125126 Accordingly, the diagnosis should always be
confirmed by objective tests.

Patients may present with clinical features of minor or major PE. Patients with minor PE
can have one or a combination of the following symptoms: transient shortness of
breath, sharp localized chest pain aggravated by inspiration (pleuritic-type pain), and
hemoptysis. The clinical features of minor PE are nonspecific and can also occur in
patients with viral or bacterial pulmonary infections, postoperative atelectasis and
pneumonia, acute bronchitis, and musculoskeletal chest wall pain. Esophageal spasm
can cause severe chest pain that is not usually aggravated by breathing but may be
confused with PE. Pleuritic-type chest pain may accompany pericarditis or immune
pleuritis. In addition, patients with a past history of VTE may suffer anxiety attacks that
are manifested as shortness of breath and occasionally as chest pain. These patients
often have fleeting attacks of sharp chest pain that last for seconds or a feeling that
they cannot take a deep breath.
they cannot take a deep breath.

Patients with chronic obstructive lung disease who become acutely short of breath or
develop pleuritic-type chest pain or hemoptysis present a difficult problem, because all
of these complications can be produced by chest infection as well as by PE. Likewise,
it can be difficult to differentiate between postoperative PE and postoperative
atelectasis and infection, because both of these disorders can cause shortness of
breath and pleuritic-type chest pain.

Patients with major PE usually have severe shortness of breath with or without
associated right-heart failure. Patients who sustain a massive embolism or have
impaired cardiorespiratory reserve and sustain a moderate-sized embolus may present
with hypotension, syncope, and peripheral circulatory failure. Sometimes there is
associated dull central chest pain.

Some of these features also occur in patients with acute myocardial infarction, a
fulminating pneumonia, dissecting aortic aneurysm, pericardial tamponade, a massive
hidden bleed, or septic shock.

PE may also present with nonspecific manifestations such as arrhythmia, fever,

unexplained heart failure, mental confusion, or, rarely, as bronchospasm.

Approach to Diagnosis of Pulmonary Embolism

The most reliable test for diagnosis of PE is pulmonary angiography, because a normal
well-performed pulmonary angiogram excludes the diagnosis of PE, whereas
demonstration of a constant intraluminal filling defect in a pulmonary artery establishes
diagnosis.127128129130131132 However, pulmonary angiography is expensive, invasive,
and not readily available in most hospitals and unavailable in many. Therefore, other
less direct approaches are usually taken. The most useful test is the perfusion lung
scan, because if the test result is normal, diagnosis of PE is excluded.133134 However,
before the scan is performed, the patient should have a thorough clinical evaluation,
because the combination of clinical probability and pulmonary scanning is important in
clinical decision making. Using clinical features, presence or absence of risk factors,
and presence or absence of features that suggest an alternative diagnosis, it is
possible to classify patients into three groups: high, low, and intermediate probability.
In addition, the patient should undergo chest radiography and electrocardiography.
Although the latter tests are often not helpful,135136 they can be useful in ruling out
other disorders that simulate PE. In addition, a chest radiograph is required for proper
interpretation of the perfusion lung scan.137138

A second approach, which is complementary to the first, is to look for a source of PE in

the deep veins of the leg with either venous ultrasound or venography. This approach
can be very helpful, because although <20% of patients with proven PE have clinical
symptoms or signs suggestive of leg vein thrombosis,3 ≈70% have venographic
symptoms or signs suggestive of leg vein thrombosis,3 ≈70% have venographic
evidence of venous thrombosis.3

The perfusion scan remains the pivotal test. If the perfusion scan is normal, the
diagnosis of PE is excluded. If the perfusion scan is abnormal, then the diagnostic
approach depends on the clinical probabilities and the size and V/Q pattern of the
defect. A diagnosis of PE can be made if the lung scan shows a segmental or greater
perfusion defect and normal ventilation and the clinical probability is high or
intermediate. A decision can be made to exclude a diagnosis of PE if clinical probability
is low and the perfusion defect is small, particularly if it is matched (low-probability
defect) (Table 5).

All other combinations of clinical and lung scan probabilities require further
investigation before a diagnosis of PE can be ruled in or out. In such patients, venous
ultrasonography or venography is useful because a positive result allows a diagnosis of
VTE to be made. Unfortunately, a negative test result for venous thrombosis cannot be
used to rule out a diagnosis of PE because tests for venous thrombosis are negative in
≈30% of patients with established PE. The venogram or venous ultrasound may be
negative for venous thrombosis in these patients because the source thrombus has
embolized completely or because it originated in the deep femoral, internal iliac, or
renal veins or the inferior vena cava, which are not usually visualized by venography.
Alternatively, the embolism could have originated in upper limb veins, the right side of
the heart, or the pulmonary arteries.

Electrocardiography and Chest Radiography

With PE, the ECG is often normal or shows nonspecific changes.135136 In patients with
pericarditis or acute myocardial infarction, ECG changes may be diagnostic. In the
appropriate setting, ECG changes of acute right-heart strain strongly suggest PE.

The chest radiograph is rarely, if ever, diagnostic.119135 It may show a pneumothorax,

pulmonary edema, or findings suggestive of primary or secondary malignancy. The
finding of a Hampton hump (a semicircular opacity with the base abutting the pleural
surface) is strongly suggestive of pulmonary infarction, but in the vast majority of
patients chest radiography findings are nonspecific or normal. Other radiographic
features compatible with PE include pleural effusion, subsegmental atelectasis,
pulmonary infiltrate, raised hemidiaphragm, regions of apparent oligemia, or a
prominent pulmonary vascular shadow at the hilum. However, none of these features
are diagnostic of PE because they can be produced by other conditions, including
obstructive lung disease, pulmonary infection, or atelectasis.

Arterial Blood Gases

Measurement of arterial blood gases in patients with PE is rarely useful because arterial
blood gas measurements lack specificity and are only moderately sensitive for
PE.121125135 Hypoxemia and hypocarbia occur in conditions that simulate PE, and
arterial oxygen tensions can be normal in patients with minor PE.

Significant hypoxemia excludes hyperventilation as the cause of the patient’s

symptoms, although this condition is rare.

Lung Scans
Perfusion scanning is performed by injecting isotopically labeled human
macroaggregates of albumin intravenously. The macroaggregates are trapped in the
pulmonary capillary bed and their distribution, which reflects the distribution of lung
blood flow, is recorded with an external photoscanner. The perfusion lung scan is an
important test because it is safe, readily available, essentially noninvasive, and, if
entirely normal, rules out a diagnosis of PE.126133134 Ventilation scanning is performed
with the use of radioactive aerosols that are inhaled and exhaled by the patient while a
gamma camera records the distribution of the radioactivity in the alveolar spaces.

An abnormal perfusion lung scan by itself is nonspecific and seen in a variety of

cardiorespiratory disorders.3120122125137138 By combining perfusion and ventilation
scanning, certain patterns occur that can be used to assign probabilities of
PE.3122123137138139140 In general, the probability of PE is reflected in the size and
pattern of perfusion defects. Thus, large defects are more likely to be caused by PE
than small defects, and mismatched defects (abnormal perfusion and normal
ventilation) are more likely to be caused by PE than are matched
defects.3122123137138139140 However, these distinctions are not absolute. Thus, between
30% and 40% of patients with large perfusion defects with a matching ventilation
defect have PE, and a small mismatched defect may not be diagnostic of PE.3122123

Patients with subsegmental perfusion mismatches have a probability of PE of ≈40%,

and those with subsegmental matches have a probability of ≈25%.3122123 The
probability is lower in patients in whom clinical suspicion of PE is low.3122123

A high clinical probability of PE combined with a high-probability lung scan pattern is

associated with PE in 96% of patients.123 A moderate clinical probability combined
with a high-probability lung scan pattern is positively associated with PE in 80% to
88% of cases.3123 In most circumstances, the presence of these combinations of
clinical probabilities and lung scan findings can be used to make a clinical decision to
diagnose PE and treat the patient accordingly. Unfortunately, these two combinations
of clinical/lung scan patterns (ie, a high-probability lung scan with a high or moderate
clinical probability) occur in only 12% to 32% of patients with abnormal perfusion
scans.3123 In addition, only ≈50% of patients with a high-probability lung scan but a
low clinical probability have PE.123 Although this combination is uncommon, it is
important, because it would be inappropriate to make a diagnosis of PE without further
important, because it would be inappropriate to make a diagnosis of PE without further
investigation in this group.

If both clinical probability and lung scan probability are low, then PE is very unlikely
(occurring in <6% of patients), and for practical purposes a diagnosis of PE can be
excluded.123 This combination of clinical/lung scan pattern occurs in ≈15% of patients
with an abnormal lung scan. Thus, a management decision to either treat or not treat
without further investigation can be made in <50% of patients with clinically suspected
PE with an abnormal lung scan.3123 In the remaining patients with suspected PE and
an abnormal perfusion scan, further investigations for venous thrombosis or PE are
required to either rule in or rule out a diagnosis of PE.3123 An approach to diagnosis of
venous thrombosis is shown in Fig 7.

Approach to Treatment
The objectives of treating venous thrombosis and PE are to prevent local extension of
the thrombus, prevent the thrombus from embolizing, and, in certain clinical
circumstances, accelerate fibrinolysis. Anticoagulants are effective in most patients for
preventing clinically important local extension of thrombosis, but they must be
continued for weeks to months after the acute event and they may not prevent long-
term complications of thrombosis.

Of the two anticoagulants in current use, heparin acts immediately by catalyzing the
inhibition of activated coagulation factors (principally thrombin and factor Xa) by
antithrombin III (AT-III), while coumarins act much more slowly by inhibiting synthesis of
fully gamma-carboxylated vitamin K–dependent coagulation proteins. Both classes of
anticoagulants inhibit the generation of factor Xa and thrombin when administered in
relatively low doses. Oral anticoagulants do not inhibit thrombin activity directly but
modulate further thrombin generation by lowering functional coagulation factors that
participate in positive feedback loops. Heparin can inhibit thrombin activity as well as
further thrombin generation by modulating positive feedback loops.

Low concentrations of heparin can inhibit the early stages of blood coagulation, but
higher concentrations are needed to inhibit the much higher concentrations of thrombin
that are generated if the coagulation process resists modulation. If fibrin is formed,
even higher concentrations of heparin are required to modulate the procoagulant
effects of clot-bound thrombin, which is site-protected from inhibition by heparin/AT-III
and can provide an ongoing procoagulant stimulus in the vicinity of the clot.141 Some
of the new anticoagulants, including hirudin and its fragments, are effective inhibitors of
clot-bound thrombin and may therefore be more effective than heparin in neutralizing
the procoagulant effects of the fibrin-bound thrombin.141

The fibrinolytic enzymes streptokinase, urokinase, and TPA accelerate the rate of
dissolution of thrombi and emboli. Thrombolysis is more expensive than anticoagulant
dissolution of thrombi and emboli. Thrombolysis is more expensive than anticoagulant
therapy and is associated with a higher risk of bleeding, so its use should be restricted
to patients who are likely to benefit from it. Two types of patient groups have the
potential to benefit from thrombolytic therapy: those with major PE and selected
patients with major venous thrombosis. Surgical removal of the thrombus (venous
thrombectomy) or the embolus (pulmonary embolectomy) is rarely indicated. In patients
with venous thrombosis, PE can be prevented very effectively with anticoagulant
therapy. Pulmonary emboli can also be prevented by inserting a filter into the vena
cava, but this approach is used only if anticoagulant therapy is contraindicated
because of bleeding or if PE has recurred despite adequate treatment with
anticoagulants (see below for definition of adequate anticoagulant therapy).

There is good evidence that patients with PE have a high mortality and a high rate of
recurrence if untreated.142 There is also good evidence that patients with symptomatic
proximal143144 or calf vein thrombosis145 have a high recurrence rate without treatment.
Anticoagulation reduces mortality and recurrence in patients with acute PE and
reduces recurrence in patients with DVT.143144145

Use of Anticoagulant Therapy

A working approach to the use of anticoagulants is described below. A more
comprehensive guide, “Guidelines to Anticoagulant Therapy,” (Circulation
1994;89:1449-1489) is available in reprints from the Office of Scientific Affairs,
American Heart Association, 7272 Greenville Ave, Dallas, TX 75231-4596. (Telephone
800-242-8721.)

Heparin
Heparin should be initiated with an intravenous bolus of 5000 U followed either by an
intravenous infusion of 1400 U/h or a subcutaneous injection of ≈17 500 U twice
daily.146147148 A weight-adjusted dose regimen can also be used.149 This regimen
consists of a continuous intravenous infusion in a bolus dose of 80 U/kg followed by an
infusion at 18 U/kg per hour. The aPTT should be performed ≈6 hours after the bolus
and initiation of the continuous infusion and at least daily thereafter to maintain the
aPTT in the therapeutic range equivalent to an anti–factor Xa heparin level of 0.3 to 0.7
U/mL. Warfarin can be started within the first 24 hours. Heparin is continued for 5
days150151 or longer until prothombin time (PT) has been in the therapeutic range for a
minimum of 2 consecutive days. It is essential that the initial dose of heparin be
adequate to achieve a therapeutic aPTT and that the period of overlap of heparin and
warfarin is sufficient to allow the full antithrombotic effects of warfarin to be expressed
(Table 6). The distinction between expression of the anticoagulant and antithrombotic
effects of warfarin is discussed in a subsequent section of this report.

Therapeutic Range
Therapeutic Range

The concept of a therapeutic range is based on experimental studies in animals152 and

subgroup analysis of the results of two prospective studies in humans.41153 The animal
studies demonstrated that prevention of growth of experimental venous thrombi
required doses of heparin that prolonged the aPTT to approximately twice that of
control subjects. These doses were equivalent to a heparin level of 0.2 U/mL by
protamine titration of the thrombin time. In the clinical studies, comparisons of the
rates of recurrence between patient subgroups demonstrated that risk of recurrence
was increased if the aPTT ratio was less than 1.5 times the mean of the normal range.

The results of these studies have led to the recommendation that the therapeutic range
of heparin should be an aPTT ex vivo (ie, measured on plasma of patients treated with
heparin), which is equivalent to a heparin level by protamine titration of the thrombin
time of 0.2 to 0.4 U/mL or an anti–factor Xa heparin level of 0.3 to 0.7 U/mL. For many
commercial aPTT reagents, the therapeutic range is ≈1.8 to 3.0,98 although for less
sensitive reagents it is 1.5 to 2.0154 (Table 7).

A large between-patient variation in dosage is required to achieve a therapeutic aPTT

response in patients with VTE.146155

With a continuous infusion of heparin started at a dose of 32 000 U per 24 hours after a
bolus of 5000 U, approximately one third of patients are below the therapeutic range at
6 hours, one third are in the therapeutic range, and one third are above the therapeutic
range.146 By adjusting the dose according to a specially developed dose-adjustment
nomogram146 (Table 8) in which the aPTT response is obtained every 6 hours until the
therapeutic range has been achieved, more than 80% of patients are within the
therapeutic range at 24 hours and more than 90% are within this range at 48 hours.146

The anticoagulant effect of heparin is influenced by its nonspecific binding to plasma

proteins that compete with AT-III for heparin binding and by the rate of heparin
clearance.156157 Many of the heparin-binding proteins are acute-phase reactants that
are elevated to a variable degree in sick patients. The elevated levels of these plasma
proteins contribute to heparin resistance seen in sick patients, and the variable
concentrations of these binding proteins contribute to the differences in anticoagulant
response among patients.156157 One of these acute-phase reactant proteins, factor VIII,
also reduces the effect of heparin on the aPTT; thus, in many sick patients the
observed resistance to heparin and variability in dose response is greater when
monitored with an aPTT than with an anti–factor Xa heparin assay or a thrombin
clotting time.158 Differences in the rates of heparin clearance between patients also
contribute to interindividual variability in patients’ responses.

Treatment of patients who fail to achieve an adequate aPTT response despite high
doses of heparin has been clarified by the results of a randomized trial.158 Patients with
venous thrombosis whose aPTT response to high doses of heparin (more than 35 000
venous thrombosis whose aPTT response to high doses of heparin (more than 35 000
U per 24 hours) was subtherapeutic were randomly allocated to monitoring with either
aPTT or a heparin level of 0.3 to 0.7 anti–factor Xa units. These therapeutic ranges (for
both methods of monitoring) correspond to a heparin level by thrombin time protamine
titration of 0.2 to 0.4 U/mL.159 Many patients who had subtherapeutic aPTT values had
heparin levels >0.3 U/mL. In patients randomly assigned to monitoring by aPTT, the
dose of heparin was increased until the test result was in the therapeutic range.
Despite receiving a lower dose of heparin, patients randomly assigned to monitoring by
heparin level had a low rate of recurrence that was no different than the group
randomly assigned to monitoring with aPTT. Heparin assays based on an anti–factor Xa
assay or a thrombin time should be used to monitor heparin therapy in patients who
have a long aPTT due to a “lupus anticoagulant.” The targeted therapeutic range
should be 0.3 to 0.7 anti–factor Xa units or 0.2 to 0.4 U/mL by protamine titration of the
thrombin time.159

Heparin Assays

Heparin assays using a chromogenic substrate are easy to perform in any clinical
laboratory, although they are not often available clinically. Heparin assays are more
expensive than aPTT assays; therefore, it is recommended that their use be limited to
the 10% to 20% of patients whose aPTT response is below the lower limit of the
therapeutic range with heparin doses of 40 000 U per 24 hours.

In patients with an inadequate response to heparin therapy by both the aPTT and
heparin assay, the dosage of heparin is increased, and an assay for AT-III is obtained. If
the AT-III level is <50% of normal, the patient is treated with infusions of plasma or AT-
III concentrate to elevate the AT-III level. However, if the AT-III level is above 60%, the
dose of heparin is increased with the use of a heparin dose-adjustment nomogram.146

Duration of Heparin Therapy

The practice of a 7- to 10-day course of heparin therapy has been changed because of
the findings of two randomized studies performed in patients with DVT. The studies
reported that a 4- to 5-day course of heparin was as effective as a 9- to 10-day course
of heparin.150151 The results of these two studies have important practical implications
because the shorter course of heparin facilitates early discharge of patients from the
hospital.

Although the findings of these studies can likely be generalized to most patients, they
may not be applicable to patients with large iliofemoral vein thrombosis or major PE,
because these two classes of patients were excluded from one study150 and formed
only a small proportion of patients in the second.151 It is our practice to treat patients
with large iliofemoral vein thrombi and those with major PE with a 7- to 10-day course
of heparin and to delay starting warfarin therapy until the aPTT has been in the
therapeutic range for 3 days. The delay in starting warfarin is used to ensure that
patients receive an adequate dose of heparin for at least 5 days.

Subcutaneous Heparin

The relative efficacy and safety of heparin administered by subcutaneous and

continuous intravenous infusion have been compared in randomized trials. These
studies demonstrate that the two methods are equally safe and effective, provided that
heparin is given in an adequate starting dose and that the dose is adjusted according
to the aPTT (Table 9).148160161162163

However, there is a clinically important reduction in the bioavailability of heparin when

administered subcutaneously in doses up to 15 000 U twice daily that results in
subtherapeutic anticoagulant and antithrombotic effects in a large percentage of
patients.153 On the other hand, there is good evidence from one large study that
heparin administered subcutaneously is both safe and effective when started at a dose
of 17 500 U twice daily after an intravenous bolus of 5000 U. The dose is then adjusted
according to the aPTT.148 The aPTT is performed 6 hours after the morning injection
and the dose is then adjusted to maintain the midinterval aPTT at 1.5 to 3.0 times the
control value.148 Dose estimation is a little more difficult than with continuous infusion,
but the feasibility of this approach has been demonstrated in a number of clinical
trials.148160 Subcutaneous administration is difficult in patients in shock or heart failure
because of poor and variable subcutaneous tissue blood flow.

Low-Molecular-Weight Heparins

Administration of LMWHs in a fixed dose by subcutaneous injection has been

compared with administration of dose-adjusted heparin by continuous infusion for
treatment of venous thrombosis. The results, which have been summarized in a meta-
analysis,164 indicate that LMWHs are at least as effective and safe as standard heparin.
These findings raise the possibility that selected patients with venous thrombosis might
be suitable candidates for treatment at home, an advance that would reduce cost and
improve patient convenience.

Like heparin,165 LMWHs do not cross the placental barrier,166167168 and descriptive
studies suggest they might be safe and effective171 in pregnancy. In a randomized trial
LMWHs were associated with a much lower incidence of heparin-induced
thrombocytopenia than heparin170 and a lower incidence of osteoporosis.164

Oral Anticoagulants
The need for oral anticoagulants after an initial course of heparin is based on the
results of two randomized studies that demonstrated that the incidence of out-of-
hospital recurrences could be markedly reduced if heparin therapy was followed by a
3-month course of warfarin.143145 In one study in which the dose of warfarin was
3-month course of warfarin. In one study in which the dose of warfarin was
adjusted to obtain an INR of 3.0 to 4.5, the incidence of bleeding was very high.
Another study was then conducted in which patients with proximal vein thrombosis
were randomly assigned to treatment with either high- (INR, 3.0 to 4.5) or moderate-
intensity (INR, 2.0 to 3.0) warfarin after an initial course of heparin therapy.37 The
incidence of recurrence was equally low in both groups, but bleeding was
approximately four times higher in the high-intensity group. Based on the results of this
study, and subsequent experience with other prospective clinical studies, the
recommended therapeutic range is an INR of 2.0 to 3.0.

An INR of 3.0 to 4.0 has been recommended for patients with antiphospholipid
antibodies,171172173 although there is some disagreement on this issue.174

Antithrombotic Effect of Warfarin

Warfarin therapy is usually monitored by prothrombin time (PT), a test that is
responsive to reduction of 3 of the 4 vitamin K–dependent procoagulant clotting
factors (factors II, VII, and X). The conventional view is that the antithrombotic effect of
warfarin is reflected by its anticoagulant effect as measured by PT. However, this view
may not be correct during the induction phase of warfarin therapy. During the first few
days of warfarin therapy, PT primarily reflects the reduction of factor VII activity, which
has a half-life of only ≈6 hours, which is similar to the half-life of the natural
anticoagulant protein C. Subsequently PT is prolonged by depression of factors X and
II (prothrombin). Therefore, for the first 24 hours of warfarin therapy there is potential for
a transient hypercoagulable state, resulting from a reduction of levels of protein C
before the effects of warfarin on the activities of factors X and II are fully expressed.
There is evidence that reductions of factor II and, possibly, factor X are more important
than reduction of factors VII and IX for the antithrombotic effect of warfarin. The
evidence supporting this view comes from the following observations. First, the
experiments of Wessler and Gitel,175 performed more than 40 years ago with a stasis
model of thrombosis in rabbits, showed that the antithrombotic effects of warfarin
require 6 days of treatment, whereas the anticoagulant effect of warfarin as reflected by
prolongation of PT is seen within 2 days. These findings are consistent with an
explanation that the antithrombotic effect of warfarin requires a reduction in activity of
factor II, which has a half-life of ≈60 hours. Second, in more recent experiments in a
rabbit model of tissue factor–induced intravascular coagulation, Zivelin et al176
demonstrated that the protective effect of warfarin primarily reflects its ability to lower
factor II levels. Thus, selective infusion of factor II, and to a lesser extent factor X,
abolished the protective effects of warfarin in this model. In contrast, infusion of factor
VII or IX had no effect.

The concept that the antithrombotic effect of warfarin reflects its ability to lower factor
II levels provides a rationale for overlapping heparin with warfarin in treatment of
patients with thrombotic disease until the factor II level is lowered into the therapeutic
patients with thrombotic disease until the factor II level is lowered into the therapeutic
range. Given that factor II has a half-life of ≈60 hours, an overlap of at least 4 days is
necessary.

Optimal Duration
Patients with VTE are usually treated with oral anticoagulants for 3 to 6 months. Shorter
courses of oral anticoagulant therapy have been investigated in randomized trials, but
the results have been inconclusive.177178179 It is now clear that risk of recurrence varies
in different subgroups. The risk of PE in patients with isolated calf DVT is very low.85
There also is evidence46180 that risk of recurrence is less in patients with a temporary or
reversible risk factor (eg, thrombosis secondary to surgery or trauma) than it is in those
with a continuing risk factor (such as associated malignancy) or with idiopathic DVT
(thrombosis in the absence of a recognized risk factor). Prandoni and associates180
reported that in patients with proximal vein thrombosis treated with oral anticoagulants
for 3 months, the rate of recurrent VTE was 24% over 80 weeks in patients with
idiopathic venous thrombosis compared with 4.8% in those with a reversible risk
factor. A similar observation was made by Levine and associates.46 In 301 patients with
proximal DVT given 3 months of warfarin and then followed for an additional 9 months,
there were 26 recurrent thromboembolic events in 212 patients (12.3%) with either
continuing risk factors or idiopathic DVT, compared with 0 in 89 patients with a
transient reversible risk factor (P=.0007). None of the recurrences were fatal. Thus,
patients with an identifiable reversible risk factor (such as surgery) appear to respond
well to a 6-week to 3-month course of therapy, whereas patients without a reversible
risk factor have a high incidence of recurrence despite 3 months of oral
anticoagulation.

Similar findings have been reported in two randomized studies. In the first report, 712
patients with DVT and PE were randomly assigned to either 4 or 12 weeks of
anticoagulant therapy.47 The rate of recurrent VTE was 7.8% in patients treated for 4
weeks and 4.0% in those treated for 12 weeks. Only 1 of 116 patients (0.86%) with
postoperative VTE had a recurrent event; whereas among the 506 “medical” patients,
4.0% of patients treated for 12 weeks and 9.1% of patients treated for 4 weeks
experienced a recurrence. Only 1% of all patients had fatal PE. These results suggest
that a short course of anticoagulation might be adequate for patients with
postoperative thrombosis, but a longer course of treatment is necessary for patients
without a reversible risk factor. In a more recent study,181 897 patients with a first
episode of DVT or PE were treated with at least 5 days of heparin or LMWH and
randomly allocated to receive 6 weeks or 6 months of warfarin, with the goal of
reaching an INR of 2.0 to 2.85. The incidence of recurrence over 2 years of follow-up
was 18.1% in the 443 patients who received 6 weeks of oral anticoagulation compared
with 9.5% in the 454 patients who received 6 months of therapy (P<.001). However, as
in the other studies, the incidence of recurrent thromboembolism was much lower in
in the other studies, the incidence of recurrent thromboembolism was much lower in
both groups in patients with reversible risk factors.

The observed difference in recurrence rates between patients with and without
reversible risk factors is relevant to the issue of optimal duration of oral anticoagulant
therapy. Thus, the low absolute incidence of thrombosis in patients with temporary risk
factors suggests that a short course of treatment might be appropriate for the
subgroup of patients with reversible risk factors, whereas long-term anticoagulant
therapy should be considered for patients without a reversible predisposing factor. At
present, however, there is insufficient evidence to support lifelong treatment for all
patients with idiopathic thrombosis. Instead, it would be reasonable to use
anticoagulant therapy for 6 weeks in patients with a reversible risk factor and to
continue anticoagulation for up to 6 months in patients with idiopathic venous
thrombosis. An indefinite duration of anticoagulation should be considered in patients
with venous thrombosis associated with active malignant disease who are often
bedridden and receiving chemotherapy, which contributes to their hypercoagulable
state.182 Long-term anticoagulant therapy should also be considered for patients who
have multiple recurrent episodes of idiopathic VTE and those with inherited
thrombophilia who have suffered one or more unprovoked episodes of major VTE.45

Recommendations for Duration of Warfarin Therapy

Patients with a first episode of VTE should be treated for 6 weeks to 3 months if they
have a reversible risk factor and for 3 to 6 months if they have idiopathic venous
thrombosis. Warfarin therapy should be continued for longer periods, possibly for life,
in patients with documented idiopathic thrombosis who have 1 of the 4 inherited
molecular abnormalities (deficiencies of AT-III, protein C, protein S, or activated protein
C resistance) and in those who have a lupus anticoagulant or anticardiolipin antibody,
because these laboratory abnormalities predispose them to recurrent venous
thrombosis. Treatment of patients with these blood abnormalities who develop venous
thrombosis after a well-recognized provocation (eg, surgery) is uncertain. Indefinite
anticoagulation might not be warranted, although some authorities believe so. The AHA
also recommends that patients who have more than two documented episodes of
recurrent venous thrombosis and patients with at least one episode of thrombosis and
active cancer should be treated with anticoagulants indefinitely. Finally, patients with
ongoing risk factors (eg, immobilization in a plaster cast) should be treated until the
period of risk is over.

Most patients requiring long-term anticoagulant therapy respond well to warfarin

targeted to an INR of 2.0 to 3.0. However, some patients with cancer have a resistance
to warfarin and require long-term treatment with heparin, administered in full doses by
subcutaneous injection. The optimal intensity of anticoagulation therapy is uncertain for
patients with a lupus anticoagulant or cardiolipin antibody who require long-term
anticoagulation. There are reports, based on retrospective analyses of observational
anticoagulation. There are reports, based on retrospective analyses of observational
studies, that patients with the antiphospholipid antibody syndrome and thrombosis are
inadequately protected from recurrent episodes of VTE if treated at a targeted INR of
2.0 to 3.0.171172173 In contrast, a recent smaller prospective study in lupus
anticoagulant–positive patients with venous thrombosis174 but without other
manifestations of the antiphospholipid antibody syndrome reported that these patients
with fewer complications respond well to warfarin at an INR intensity of 2.0 to 3.0. It is
uncertain whether the discrepant findings reported in these studies result from
differences in patient populations or differences in the responsiveness of PT reagents
to the lupus anticoagulant in patients who receive anticoagulation with warfarin. Thus,
it is possible that with some PT reagents the INR result is artifactually prolonged by the
lupus anticoagulant and therefore does not reflect the true anticoagulant effects of
warfarin.

Thrombolytic Therapy
Thrombolytic therapy is more effective than heparin in producing rapid lysis of
thromboemboli. However, it is more expensive than heparin, it is associated with a
higher risk of bleeding,55183 and it is not indicated in most patients with PE because
they do well clinically with anticoagulant therapy. It is contraindicated in the
postoperative period and in other situations in which there is a high risk of bleeding.
Thrombolytic therapy has lifesaving potential for patients with massive PE184185 and
should be considered in patients with major PE who have syncope, hypotension,
severe hypoxemia, or heart failure.184185186 Thrombolytic therapy should also be
considered for patients with a submassive embolism and underlying cardiac or
respiratory disease. Limited evidence suggests that thrombolytic therapy prevents
postthrombotic syndrome in some patients with acute venous thrombosis of recent
onset.183187 Thrombolytic therapy may also be indicated in selected patients (both
young and old without risk factors for bleeding) with extensive proximal vein
thrombosis.187188

Caval Interruption
Although anticoagulation is the standard treatment for acute venous thrombosis and
PE, venous interruption procedures may be indicated for VTE when anticoagulation is
ineffective or unsafe. The most common indication for venous interruption in patients
with DVT or PE is anticoagulant-induced bleeding or anticipation of hemorrhagic
complications in a patient with a predisposing lesion, such as a bleeding peptic ulcer,
gastrointestinal malignancy, recent intracranial operation, or an underlying hemorrhagic
state (eg, liver failure or thrombocytopenia). The second indication for venous
interruption is failure of anticoagulation, provided that the anticoagulant effect has been
within the prescribed therapeutic range (an aPTT corresponding to an anti–factor Xa
heparin level >0.3 U/mL or an INR >2.0). Development of new PE or substantial
extension of venous thrombosis should be documented by objective tests before
extension of venous thrombosis should be documented by objective tests before
recurrent thromboembolism is accepted as a diagnosis, because new symptoms in a
patient with an established venous thrombosis of PE are often misinterpreted as
evidence for recurrence in a patient receiving anticoagulation.

Other indications for venous interruption are more controversial. These include

• Major PE with severe cardiovascular instability

• As an adjunctive procedure in patients who undergo pulmonary embolectomy

• Prophylactic interruption of the inferior vena cava in patients at exceptionally high risk
of VTE, particularly if there is a relative contraindication to anticoagulation

Intracaval Devices
The first intracaval device to be widely used was the inferior vena caval umbrella
devised by Mobin-Uddin et al.189 The umbrella filter is inserted through a cutdown in
the internal jugular vein and passed under fluoroscopic control through the superior
vena cava and right atrium into the inferior vena cava, where its position below the
renal veins is confirmed by phlebography. When it is expelled from its capsule
applicator, the pointed struts engage the wall of the cava and hold the filter in place.
The device contains fenestrations to maintain venous blood flow.

The results following implantation of 4699 filters during the first 6 years after the
umbrella filter became available were summarized by Mobin-Uddin.190 The initial
design had a diameter of 23 mm and was associated with proximal migration in 27 of
2848 applications (0.9%). The frequency of proximal migration was reduced to 0.4% by
increasing the diameter to 28 mm. Complete occlusion of the filter occurred in 30% to
45% of patients due to thrombosis around the device or trapping of an embolus.190191
The reported rate of recurrent PE was 12%.192 Less common complications included
perforation of adjacent organs (eg, duodenum or ureter) and breakage.

The Greenfield filter has essentially replaced the Mobin-Uddin umbrella. The filter,
which resembles an umbrella consisting only of struts, is placed with its apex directed
proximally. With this design, emboli are retained in the center of the cone, where the
spokes are closer together and the trapping efficiency greater.193 The central
positioning of entrapped emboli facilitates blood flow past the trapped embolus and
may encourage fibrinolysis, thereby accounting for the high rate of patency with this
device (95%).191 Magnant and coworkers194 reviewed the experience with placement
of the Greenfield filter. They concluded that percutaneous placement of inferior vena
caval filters had supplanted operative placement and that no major morbidity had been
associated with use of the Greenfield filter. The bird’s nest filter was invented by Roehm
and described in 1984.195 When compared directly with the Greenfield device, the
bird’s nest filter appeared to be more readily dislodged and more easily subjected to
bird’s nest filter appeared to be more readily dislodged and more easily subjected to
local thrombosis.195

Occlusion of the cava by a balloon has been proposed by Hunter et al196 and Moser et
al.197 The balloon is inserted as a percutaneous procedure. A potential advantage of
balloon occlusion is that caval obstruction can be temporary; once the threat of
embolization has subsided, the balloon can be deflated and removed. However,
thrombosis can occur around the balloon. In a report of up to 18 years of experience
involving 191 cases, Hunter and associates198 reported no malfunction of the inflation
mechanism and no migration from the site of inflation. No patients had recurrent PE
after balloon inflation. In 39% of patients, the legs appeared normal and free of edema.

Surgical Removal
Thrombectomy for acute venous thrombosis and pulmonary embolectomy for acute PE
to relieve acute obstruction are rarely used. Thrombectomy is of limited benefit
because it is usually complicated by acute recurrence despite postoperative
anticoagulant therapy; it leaves a de-endothelialized venous surface that is highly
thrombogenic.199 However, it is indicated to rapidly reduce venous obstruction in
patients with phlegmasia cerulea dolens with impending venous gangrene. Although
pulmonary embolectomy can be a lifesaving procedure in a patient with massive
embolism,200 most hospitals do not have the resources, personnel, or facilities for this
type of surgery. Furthermore, most patients who are likely to benefit from pulmonary
embolectomy die before they can be diagnosed and treated,201 and some candidates
for emergency pulmonary embolectomy survive and do well with medical therapy. On
the other hand, elective pulmonary thromboendarterectomy can be very effective and
lifesaving in selected patients with chronic large-vessel thromboembolic pulmonary
hypertension.202203 This operation, which has been available for years but abandoned
by many centers because of a high postoperative mortality, has been revived by the
work of the San Diego group.202203 The success of the procedure is highly dependent
on the availability of a skilled and experienced team of surgeons and internists.

Upper-Extremity DVT
The frequency of upper-extremity venous thrombosis involving the axillary and/or
subclavian veins has increased in the last decade with the increasing use of long-term
indwelling catheters. Upper-extremity venous thrombosis is classified as primary and
secondary. Primary upper extremity thrombosis can be caused by local venous
compression produced by unusual movements or positions of the arm (“effort
thrombosis”), whereas secondary thrombosis is usually caused by indwelling
intravenous devices.204205 Effort thrombosis has been described following weight-
lifting, pole-vaulting, racquet sports, or direct and prolonged pressure to the axilla.
Axillary vein thrombosis can also be a manifestation of the thoracic inlet syndrome or
can be caused by direct trauma or compression by tumor.206 Axillary or subclavian vein
can be caused by direct trauma or compression by tumor.206 Axillary or subclavian vein
thrombosis has been described in AT-III deficiency, protein S deficiency,
hypoplasminogenemia, and antiphospholipid syndrome.207208209210 Thrombosis
secondary to the use of long-term indwelling catheters, often used in administration of
chemotherapy, is now a much more common cause of upper-extremity thrombosis
than effort thrombosis.

Upper-extremity venous thrombosis can be complicated by PE211 and rarely by

massive PE.212213 The most important complications are long-term disability caused by
venous hypertension and loss of venous access in patients requiring long-term
chemotherapy. Venous hypertension can produce swelling, fatigability, aching, and
weakness of the affected arm, particularly following activity. The symptoms can be
disabling in athletes or manual laborers during and after activity involving the affected
arm. The reported frequency of disabling upper-extremity venous hypertension after
spontaneous axillary/subclavian vein thrombosis varies from 25% to 47%.214215216
Lower rates (12%) have been reported in a series of patients treated with
thrombolysis,217 but no randomized trials have been reported comparing
anticoagulants with thrombolysis.

The diagnosis of upper-extremity vein thrombosis is usually suspected on clinical

grounds and confirmed by venography. Optimal visualization of the thrombosed
axillary/subclavian veins is best achieved by injecting the radiographic contrast into the
median basilic vein. Injection of contrast material into a distal vein in the hand or wrist
will demonstrate an obstruction and the presence of collateral vessels but does not
usually outline the thrombus. Imaging studies in which color flow duplex ultrasound
was used lack the sensitivity of venography for upper-extremity thrombosis.218

Various treatments have been advocated for primary upper-extremity thrombosis.

Resolution of acute symptoms can usually be obtained with either anticoagulant or lytic
agents.145146147 Anticoagulant therapy is not usually associated with anatomic
resolution of the thrombus and clinical improvement because collaterals develop and
bypass the obstruction. Thrombolytic therapy appears to be more effective than
anticoagulants in producing early resolution.219220 Local therapy administered through
a small catheter introduced through the basilic vein and advanced into the clot has
been advocated. A loading dose of 250 000 IU urokinase infused into the clot over 1
hour and then continued at a lower dose of 1000 IU/min for up to 24 hours has been
used successfully.221 The patient is then treated with heparin for 5 days, followed by
warfarin for 3 months. Surgical removal of the first rib has been advocated by some if
symptoms of venous obstruction persist after a course of conservative treatment.
However, the effectiveness of this invasive approach has never been evaluated in an
appropriately designed clinical trial.

Long-term venous access through a central venous catheter is required for treatment
Long-term venous access through a central venous catheter is required for treatment
of long-term disorders requiring chemotherapy, antibiotics, or hyperalimentation.
Thrombosis of the subclavian/axillary vein is a common complication of central venous
catheterization. These thrombi may be asymptomatic,222223 although spontaneous
resolution is uncommon when long-term venographic follow-up studies are
performed.224

The standard treatment of secondary axillary/subclavian vein thrombosis has been

removal of the catheter, limb elevation, and anticoagulation. This approach usually
results in rapid improvement of symptoms, but on follow-up 70% of patients have been
reported to have some pain and/or swelling in the affected arm.225 Of greater
importance, the venous lumen is obliterated and cannot be used again for venous
access. Thrombolytic therapy has been used successfully to treat secondary upper-
extremity thrombosis.226227228 Initial reports used high-dose systemic therapy. More
recently local catheter-directed thrombolytic therapy has been used with apparent
success.229

A dosage regimen of urokinase has been established, empirically consisting of 250 000
IU/h for 2 hours followed by 60 000 IU/h until clot lysis has been achieved. Heparin can
be given in full doses either during or after completion of thrombolytic therapy and
anticoagulation with heparin, followed by warfarin for ≈3 months. With this approach, a
78% lysis rate has been reported in a small study of 31 patients.229 Successful lysis is
more common with fresh thrombi.230

Diagnosis of Venous Thromboembolism in the Pregnant Patient

The diagnosis of VTE during pregnancy is difficult because leg pain and swelling are
frequent and usually not due to DVT,231 and performance of radiological procedures is
a problem because of the fear of exposing the fetus to radiation.

Deep Vein Thrombosis

As in the nonpregnant patient, venous ultrasonography is used as the initial diagnostic
test. If venographic confirmation of an equivocal test result is required, a limited
venogram can be performed without risk to the fetus by covering the patient’s
abdomen with a lead-lined apron. A limited venogram allows visualization of the calf
veins, popliteal vein, and most of the superficial femoral vein but not the iliac vein.
Therefore, a normal limited venogram does not exclude iliac vein thrombosis.

Pulmonary Embolism
The diagnosis of PE in pregnancy is essentially the same as in the nonpregnant patient,
with three exceptions designed to avoid exposure of the fetus to ionizing radiation: (1)
Ventilation and perfusion scanning are performed at 50% of the usual dose; (2)
pulmonary angiography, if indicated, should be performed via the brachial route rather
than the femoral route; and (3) venography, if indicated, should be limited, with
than the femoral route; and (3) venography, if indicated, should be limited, with
shielding of the abdomen.

Chest radiography, perfusion, and ventilation lung scanning are performed with a
reduced dose of radioisotope for the perfusion scan (1 to 2 MCi). If the perfusion scan
is normal, PE is excluded; if the lung scan indicates a high probability of PE, the
diagnosis is made and the patient is treated with anticoagulants. If the scan is
nondiagnostic, the patient is investigated for DVT by IPG or duplex ultrasound; if the
test results are abnormal, the patient should be treated with anticoagulants. If the
results are normal, a pulmonary angiogram should be considered.

Management of Venous Thromboembolism During Pregnancy

An excellent review of this subject has been published,232 and the recommendations
outlined below follow this report, which should be read for additional details.

Heparin
A recent critical review of the literature of heparin therapy during pregnancy233 reported
that, contrary to a previous report,234 heparin therapy during pregnancy is safe for the
fetus. The conclusion is corroborated by a cohort study in which the rates of premature
birth, spontaneous abortion, stillbirth, neonatal death, and congenital malformation
were not significantly higher in 100 pregnant women treated with heparin than in the
normal population.235 Because heparin does not cross the placenta, there is no
increased risk of bleeding for the fetus.

Warfarin
In the review cited previously, the pooled rate of adverse effects associated with
warfarin therapy was high (26.1%).233 Warfarin exposure between 6 and 12 weeks of
gestation can be associated with warfarin embryopathy, which is characterized by
stippled epiphyses and nasal hypoplasia. In a study by Iturbe-Alessio et al,236 10 of 35
term pregnancies in which warfarin was administered between 6 and 12 weeks were
associated with warfarin embryopathy. This is likely to be an overestimate, and the true
incidence of warfarin embryopathy is likely to be ≈5% of infants if maternal exposure
occurs between 6 and 12 weeks of gestation. Warfarin embryopathy has not been
reported with warfarin exposure outside this time period. Central nervous system
abnormalities, both hemorrhage and malformations, have been reported after warfarin
exposure at any time during pregnancy, but the incidence is very low.233236 Therefore,
heparin is the anticoagulant of choice for treatment of VTE during pregnancy. If warfarin
is used, it should be restricted to the second and early third trimesters and avoided
between 6 and 12 weeks of gestation and near term to avoid delivery of an
anticoagulated fetus.

Treatment of Acute Deep Venous Thrombosis and Pulmonary Embolism

Treatment of Acute Deep Venous Thrombosis and Pulmonary Embolism
Heparin is usually initiated with an intravenous bolus of 5000 U followed by a
maintenance dose administered as a continuous intravenous infusion of 32 000 U per
24 hours to prolong the aPTT into the therapeutic range (≈1.8 to 2.5 times control for
most reagents) for 5 to 7 days. After the initial intravenous dose of heparin,
subcutaneous heparin should be administered every 12 hours in doses adjusted to
prolong a 6-hour postinjection aPTT into the therapeutic range. The aPTT should be
checked regularly, because heparin requirements may vary as pregnancy progresses.
The patient should be monitored three times in the first week and then at least weekly
thereafter. Anticoagulant therapy should be continued throughout pregnancy and for 4
to 6 weeks after delivery. If the episode of VTE occurs late in pregnancy,
anticoagulation should be continued for a total of 3 months after the episode.

Long-term Anticoagulant Therapy Before Pregnancy

Patients who receive long-term warfarin therapy before pregnancy for DVT/PE or
prevention of systemic embolism should be treated with subcutaneous heparin every
12 hours throughout pregnancy in doses adjusted to prolong the 6-hour postinjection
aPTT to ≈1.5 to 2.5 times control. Two options are available when patients receiving
long-term anticoagulant therapy decide to conceive. The first is to switch the patient to
heparin before conception. This has the advantage of avoiding any exposure of the
fetus to warfarin but increases the duration of heparin exposure if conception is
delayed. The second option is to continue warfarin and perform regular pregnancy
tests when conception is attempted. As soon as the pregnancy test result is positive,
warfarin should be stopped and heparin started. This is probably safe for the fetus,
provided warfarin is discontinued before 6 weeks of gestation. As mentioned above, no
cases of fetal embryopathy have been described with warfarin exposure before 6
weeks of gestation. Warfarin therapy can be resumed after delivery.

Previous Deep Venous Thrombosis and Pulmonary Embolism

The optimal treatment of pregnant patients with previous DVT/PE is unknown because
there are no large prospective trials to provide reliable estimates of the incidence of
recurrence during pregnancy. Prophylaxis with standard heparin, 5000 U every 12
hours, is a reasonable approach and is associated with a very low recurrence rate.235
Surveillance with weekly IPG or duplex ultrasonography may be a reasonable
alternative to heparin during pregnancy.

Delivery and Postpartum

If the patient is receiving 5000 U of heparin every 12 hours at term, heparin can be
discontinued at onset of labor. No increase in bleeding is anticipated with this
approach. If adjusted-dose heparin is being administered at term, some pregnant
patients can have a prolonged aPTT for as long as 20 hours after their last dose of
237
subcutaneous heparin.237 To overcome the potential risk of a long aPTT at delivery,
elective induction can be planned and heparin therapy discontinued 24 hours before
induction. In patients considered to be at high risk for thrombotic complications, an
intravenous heparin infusion can be started after discontinuation of subcutaneous
heparin. Because the half-life of intravenous heparin is short,238 heparin can be
discontinued 4 to 6 hours before delivery with the expectation that the aPTT will be
normal at time of delivery.

After delivery, heparin and warfarin should be restarted as soon as hemostasis is

obtained, and heparin can be discontinued after an appropriate period of overlap.
When administered to the nursing mother, warfarin is safe for the breastfed infant.239240

Other Therapeutic Modalities

There are very few reports on the use of thrombolysis during pregnancy. As a general
rule, pregnancy is a relative contraindication to thrombolytic therapy, and its use should
be restricted to patients with massive PE.241242 LMWHs do not cross the placenta and
have been used successfully during pregnancy.169243244 Their advantage over standard
heparin is a more predictable dose response and a longer half-life after subcutaneous
injection, which allows administration once daily without frequent monitoring.244

Management of Venous Thromboembolism in Children

Venous thromboembolism in children is much less common than in adults. In general,
recommendations for antithrombotic therapy have been extrapolated from those used
for adults. However, optimal dosing for antithrombotic therapy in children is likely to
differ from adults because the anticoagulant response to antithrombotic agents is
different.

Incidence
Incidence of DVT/PE in the adult population is ≈2.5% to 5.0%.254245 In comparison,
incidence of DVT/PE in the general pediatric population is reported to be 0.07 per 10
000 and 5.3 per 10 000 hospital admissions.246247248 Other comparisons illustrating the
lower risk of DVT/PE during childhood are the <1% incidence of clinically apparent
DVT/PE after lower limb or scoliosis surgery249 and the relative absence of DVT/PE in
children with congenital thrombophilias.250251

Clinical Features
Ninety-five percent of DVT/PE in pediatric patients occurs as a complication of serious
diseases such as prematurity, cancer, trauma/surgery, and congenital heart
disease.250251252253 Congenital prethrombotic disorders account for <10% of DVT/PE
in children.250251 Children at greatest risk for DVT/PE are younger than 1 year or
teenaged.250251252253 DVT in the lower extremities is the most frequent noncentral
venous line thrombotic complication in children.251 The clinical presentations of DVT
venous line thrombotic complication in children.251 The clinical presentations of DVT
and PE are similar to those in adults.248250251253

Central Venous Lines

Forty percent of DVT in children and more than 80% in newborns occurs in the upper
venous system secondary to use of central venous lines,250251252 which are employed
for short-term intensive care or long-term supportive care in children requiring total
parenteral nutrition or therapy for cancer. Central venous line–related DVT requires
repeat anesthesia for replacement and can be complicated by PE254255256257 ; it can
cause superior vena cava syndrome257258259260261 and chylothorax257258262263 and can
obliterate the upper venous system264265 and so lead to postthrombotic syndrome in
the upper extremities.

Treatment of Children
Children older than 2 months who have DVT or PE should be treated with intravenous
heparin (bolus 75 U/kg; initial maintenance of 20 U/kg per hour) sufficient to prolong
the aPTT to a range that corresponds to an anti–factor Xa level of 0.3 to 0.7 U/mL.

Treatment with heparin should be continued for 5 to 10 days and oral anticoagulation
overlapped with heparin for 4 to 5 days. For many patients heparin and warfarin can be
started together and heparin discontinued on day 6 if the INR is therapeutic. Heparin
therapy should be used for a longer period for massive PE or iliofemoral thrombosis.

Long-term anticoagulant therapy should be continued for at least 3 months, with oral
agents (initial dose 0.2 mg/kg per day) to prolong PT to an INR of 2.0 to 3.0.

Either indefinite warfarin therapy with an INR of 2.0 to 3.0, low-dose anticoagulant
therapy (INR, <2.0), or close monitoring should be considered for children with a
second recurrence of venous thrombosis or a continuing risk factor such as central
venous line, antithrombin deficiency, or protein C or S deficiency.

Newborns with a central venous line in place should be treated with intravenous
heparin in doses of 1 to 5 U/h through the catheter.266267268269270

Treatment of Newborns
The optimal regimen for anticoagulation therapy in treatment of newborns with DVT,
PE, or arterial thrombosis is uncertain. If anticoagulation is indicated, a short course (10
to 14 days) of intravenous heparin (75 U/kg bolus; maintenance 28 U/kg per hour),
sufficient to prolong the aPTT to an anti–factor Xa level of 0.3 U/mL, should be used.

The role of thrombolytic agents in treatment of VTE is uncertain. Further clinical

investigation is needed before more definitive recommendations can be made. If
thrombolytic therapy is used, either urokinase or TPA is preferable to streptokinase,
thrombolytic therapy is used, either urokinase or TPA is preferable to streptokinase,
and supplementation with plasminogen may be helpful.

Complications of Anticoagulation
Treatment of patients who develop complications during anticoagulant therapy involves
management of the actual complication and subsequent management of the
thromboembolic event for which the patient is being treated.

Bleeding is by far the most important complication of anticoagulant therapy. The

approach to bleeding depends on the severity of bleeding, the anticoagulant and dose
used, results of laboratory tests at the time of bleeding, the length of time the patient
has been treated with anticoagulants, and the seriousness of the thromboembolic
event for which the patient is being treated.

Heparin
The frequency of clinically important bleeding during a 5- to 10-day course of heparin
therapy varies between 3% and 10%, depending on whether the patient is at high or
low risk.148151153160162271272 In many cases bleeding is not life-threatening and does
not require discontinuation of heparin. Because heparin has a relatively short
circulating half-life (60 minutes),273274275276 the anticoagulant effect is reversed fairly
rapidly after treatment is discontinued. In most cases bleeding is treated by
discontinuing heparin, applying local pressure as appropriate, and replacing blood if
necessary.

If bleeding is potentially life-threatening (eg, intracerebral, intraspinal, retroperitoneal, or

severe gastrointestinal), heparin should be stopped and the anticoagulant effect
reversed with protamine sulfate. Protamine sulfate is a strong basic substance that
rapidly neutralizes the effect of heparin. The appropriate neutralizing dose depends on
the dose of heparin and route and time of administration. If protamine sulfate is used
within minutes of intravenous heparin injection, then a full neutralizing dose, 1 mg
protamine per 100 U heparin, should be given. Since the half-life of heparin is ≈60
minutes, only 50% of a full neutralizing dose is required 1 hour after the last heparin
injection, and only 25% of the full neutralizing dose is required after 2 hours.147

Protamine sulfate can produce a hypotensive response if given rapidly, so the dose
should be injected slowly over a 20-minute period.277278279 Some patients may also
develop a hypersensitivity reaction to protamine sulfate.

Heparin rebound may occur if very large doses of heparin are given.280281282283
Therefore, it may be necessary to repeat administration of protamine if laboratory tests
demonstrate a residual heparin effect.169 A direct assay of heparin activity, thrombin
time, or aPTT should be performed both before and immediately after protamine is
infused, and the test should be repeated 2 hours later to determine whether the
infused, and the test should be repeated 2 hours later to determine whether the
neutralizing effect of protamine on heparin is permanent or transient.

If bleeding occurs when the aPTT response is in the therapeutic range or just beyond
the therapeutic range, or if the anticoagulant-associated bleeding is potentially life-
threatening, treatment with anticoagulant therapy should be stopped, and an
alternative form of treatment should be used to manage the thromboembolic event. If
the patient has proximal vein thrombosis or major PE, a caval interruption procedure
should be considered.284 If the patient has calf vein thrombosis, the course of the
thrombus can be monitored with serial venous ultrasound imaging99111 and a caval
interruption procedure used if thrombosis is extended.

The risk of bleeding is influenced by five variables: the patient’s clinical condition,151
the dose of heparin,285286 the anticoagulant response,286287 method of
administration,151288 and concomitant use of aspirin or thrombolytic agents.289290291292

The most important risk factor for bleeding is recent surgery or trauma. Other risk
factors are renal failure, old age, and peptic ulcer disease. There is a relation between
bleeding and both heparin dose and anticoagulant effect.285286287293294 Bleeding is
greater when heparin is administered by intermittent intravenous injection.162288

Other Complications of Heparin Therapy

Other complications of heparin are thrombocytopenia,295296 with or without
thrombosis296 ; osteoporosis,297298299300301302 which occurs only with long-term
treatment; and local skin hypersensitivity and skin necrosis confined to subcutaneous
injection sites.303 Other complications are very rare and include anaphylaxis,
hypoaldosteronism,304305306 and alopecia. In addition, patients treated with heparin
can develop hyperkalemia307 and often develop an asymptomatic increase in plasma
levels of hepatic transaminases.308

If a patient develops local skin reactions at the site of injection, the source of heparin
should be changed because local reactions may not occur with a different preparation
of heparin, including LMWHs.

Thrombocytopenia

Thrombocytopenia is a well-recognized complication of heparin therapy. Two forms of

thrombocytopenia are described: an early benign, reversible nonimmune
thrombocytopenia and a late, more serious IgG-mediated immune thrombocytopenia.
The mechanism of the early form, which is not associated with adverse clinical
sequelae, is uncertain but could be the result of direct weak activation of platelets by
heparin.309310311312 The immune form of heparin-induced thrombocytopenia is
characterized by strong IgG-mediated platelet activation170296313 and is associated
with a substantial risk of thrombotic complications.
with a substantial risk of thrombotic complications.

The incidence of serologically confirmed heparin-induced thrombocytopenia was

investigated in a large clinical trial that compared unfractionated heparin (7500 U twice
daily) with LMWH (30 mg enoxaparin twice daily) for prophylaxis after elective hip
surgery.170 The incidence of heparin-induced thrombocytopenia was ≈1% at 7 days
and ≈3% at 14 days in patients receiving unfractionated heparin and 0% in those
receiving LMWH. Other prospective studies with higher (therapeutic) doses of heparin
have reported a similar incidence of thrombocytopenia.314315316317318319320321322323324

Heparin-induced thrombocytopenia usually begins between 5 and 15 days after the

start of heparin therapy (median, 10 days),170295325 but it has been reported within
hours of starting heparin in patients who have received heparin within the previous 3
months.295303326 Thrombosis associated with heparin-induced thrombocytopenia can
be heralded by a fall in platelet count without overt thrombocytopenia (eg, from 350
000 to 150 000). For this reason, patients who receive heparin should undergo a
platelet count daily, and if the platelet count falls by 50% or more, heparin should be
stopped and an alternative management strategy instituted.

Thrombocytopenia and Paradoxical Thrombosis

Heparin-induced thrombocytopenia is a highly prothrombotic disorder. In a large

prospective study of heparin therapy after elective hip surgery, risk for thrombosis was
dramatically increased (odds ratio, 37) in patients with heparin-induced
thrombocytopenia, compared with those who did not develop it.173 Although many
case series have emphasized the association of heparin-induced thrombocytopenia
with arterial thrombosis (“white clot syndrome”), it is now clear that venous thrombosis
is much more common with heparin-induced thrombocytopenia than arterial
thrombosis.170327 Overall, prospective studies suggest that thrombosis associated with
heparin-induced thrombocytopenia occurs in ≈1% of patients who receive
unfractionated heparin for more than 5 days.170324

Bleeding complications have been described in patients with heparin-induced

thrombocytopenia, but they are less frequent and much less important than thrombotic
complications.325

Laboratory Manifestations and Pathogenesis

Typically, the platelet count nadir in heparin-induced thrombocytopenia is between 20

and 150 000 per milliliter (median nadir, 50 000).325 Approximately 5% of patients have
concomitant hypofibrinogenemia associated with disseminated intravascular
coagulation.325 The platelet count usually returns to baseline levels within 1 week of
discontinuing heparin.

Heparin-induced thrombocytopenia is caused by an IgG that activates platelets via

328329
their FcκII receptors.328329 The major target antigen is a heparin sulphate/platelet factor
IV complex that localizes the IgG on the platelet surface.330331332333 The thrombogenic
diathesis results from in vivo platelet activation334 as well as generation of
procoagulant platelet-derived microparticles.335 In addition, heparin-induced
thrombocytopenia IgG has been shown to activate endothelium in vitro via recognition
of a heparin sulfate/platelet factor IV complex.332333336

Laboratory Testing

Platelet activation assays that use washed target platelets337338 have a sensitivity and
specificity for heparin-induced thrombocytopenia of at least 95%.170 Typically, heparin-
induced thrombocytopenia IgG activates platelets at low (0.5 to 1.0 U/mL) but not high
(10 to 100 U/mL) concentrations of heparin.337339340 Aggregation studies in which
citrated plasma is used are much less sensitive to heparin-induced thrombocytopenia
IgG than assays in which washed platelets are used.340341342 An ELISA assay with the
platelet factor IV/heparin target antigen has been developed330 that shows good
concordance with the platelet activation assay.342

Although heparin-induced thrombocytopenia is much less common with LMWH

preparations than standard heparin, in vitro studies indicate that LMWHs show immune
cross-reactivity in ≈70% of instances.170343 In contrast, in vitro cross-reactivity is much
less common (≈10%) with the heparinoid Orgaran,344 which has been used
successfully as a substitute for heparin in patients with heparin-induced
thrombocytopenia.345

Treatment

Two different antithrombotic agents have been evaluated in descriptive studies. These
are Orgaran344345 and the defibrinogenating snake venom ancrod (Arvin).346347
Intravenous administration of Orgaran produces immediate onset of anticoagulation
after bolus administration. Ancrod has the advantage of exhibiting no cross-reactivity
with heparin, but there is a delay of ≈12 hours before effective defibrinogenation can be
achieved. In addition, neither thrombin generation nor platelet activation are inhibited
by ancrod348 and the magnitude of the anticoagulant effect is less predictable than
with Orgaran. Ancrod is also contraindicated in patients with disseminated
intravascular coagulation or septicemia.349 Long-term (ie, >3 weeks) anticoagulation
with ancrod is limited by development of antibodies that render patients resistant to its
effects.346350 Unfortunately, neither of these agents is approved for use in the United
States, but they can be obtained for compassionate use. Initial experience with hirudin
from Europe is very promising, but it is not approved for use in North America.

Complications of Oral Anticoagulants

Bleeding is by far the most common complication of oral anticoagulant therapy.351
Randomized studies have shown that the risk of bleeding is influenced by the intensity
Randomized studies have shown that the risk of bleeding is influenced by the intensity
of anticoagulation,37352353354 and several studies have shown that the risk of clinically
important bleeding is reduced by lowering the therapeutic range for the INR from 3.0 to
4.5 to 2.0 to 3.0. Although this difference in anticoagulant intensity is produced by a
mean reduction in the dose of warfarin of only ≈1 mg, the effect on bleeding is
profound. Randomized studies have also shown that the rate of oral anticoagulant–
induced bleeding is increased by concomitant use of high doses of aspirin that both
impair platelet function and produce gastric erosions.351355356 Multivariate analysis of
cohort studies also suggests that risk of bleeding is influenced by the underlying
clinical disorder.354357 These studies reported that the risk of major bleeding is
increased by age >65 years, a history of stroke or gastrointestinal bleeding, and the
presence of serious comorbid conditions such as renal insufficiency or anemia.358359360
Bleeding that occurs when the INR is <3.0 is frequently associated with an obvious
underlying cause37 or an occult gastrointestinal or renal lesion.353

Drugs that are known to interact with coumarins should be avoided if possible.361
However, if concomitant use of drugs that interact with warfarin is necessary, PT
should be monitored more frequently in the first few days to weeks of combined use to
anticipate a change in dosage. Furthermore, all new drugs should be viewed as having
the potential to interact with coumarins, and the frequency of PT monitoring should be
increased in the initial period after introduction. Drugs known to inhibit platelet function
should be avoided unless prescribed to augment the antithrombotic effects of warfarin.
For example, low-dose aspirin (100 mg/d) augments the antithrombotic effects of
coumarins in patients with prosthetic heart valves but at an increased risk of minor
bleeding.362

The frequency of bleeding depends very much on intensity of the anticoagulant effect
and patient-related risk factors.352358363 If moderate-dose anticoagulant therapy is
used to prolong the INR to between 2.0 and 3.0, bleeding is relatively
uncommon.352358363364365366367 Most episodes occur in patients with a potential
bleeding source such as a peptic ulcer, gastritis, renal calculus, or malignancy.
Bleeding complications in patients on long-term anticoagulant therapy tend to occur
early and may unmask an underlying local source. In randomized trials of moderate-
intensity warfarin (INR, 2.0 to 3.0) in patients with nonvalvular atrial fibrillation versus
untreated control subjects, the typical annual incidence of major bleeding was between
1.0% and 1.5% in the warfarin groups and 0.5% to 1.0% in the control groups.
However, patients selected for these trials were at low risk for bleeding, so in practice,
bleeding on warfarin is higher than reported by these studies.

Management of Bleeding

If bleeding occurs during oral anticoagulant treatment in a patient with VTE,

management depends on severity of bleeding, INR at the time of bleeding, and
whether or not the patient has completed most of the prescribed course of
whether or not the patient has completed most of the prescribed course of
anticoagulant therapy.

If the INR is above the therapeutic range, treatment can be discontinued until bleeding
has stopped and then reintroduced cautiously at a lower intensity. If the INR is within
the therapeutic range, a local source of bleeding should be sought, particularly if
bleeding is gastrointestinal or from the urinary tract. However, if the INR is markedly
prolonged, it is not usually necessary to look for a source of bleeding.

If bleeding is life-threatening and the INR prolonged, the coagulation defect should be
reversed immediately by infusion of plasma, and vitamin K1 should be administered in
a dose of 10 mg to 25 mg either intravenously by slow infusion or by subcutaneous
injection.

If bleeding is not life-threatening and the INR is markedly prolonged, then the
anticoagulant effect can be reversed by administering 5 mg vitamin K1 by
subcutaneous injection.

Vitamin K1 can interfere with subsequent warfarin therapy when doses of 10 mg or

more are used, and it can cause refractoriness to further warfarin therapy for up to 2
weeks.

Skin Necrosis

The most important nonhemorrhagic side effect of warfarin is skin necrosis. This
uncommon complication is usually observed on the third to eighth day of
therapy353354357360365366368369370371372373 and is caused by extensive thrombosis of the
venules and capillaries within the subcutaneous fat. An association has been reported
between warfarin-induced skin necrosis and protein C deficiency,368372373 and less
commonly, protein S deficiency,374 but this complication can also occur in persons
without a deficiency. A role for protein C deficiency seems probable and is supported
by the similarity of the lesions to those seen in neonatal purpura fulminans, which
complicates homozygous protein C deficiency. The reason for the unusual localization
of the lesions to subcutaneous fat deposits remains a mystery. The optimal technique
for initiating anticoagulant therapy in patients with known protein C or protein S
deficiency is uncertain. A reasonable empirical approach is to start with an initial
course of heparin, begin warfarin at a maintenance dose of 5 mg, and give both
anticoagulants in combination for ≈7 days.

In patients who develop warfarin-induced skin necrosis, warfarin should be

discontinued, vitamin K1 should be given to increase levels of protein C, and full doses
of heparin should be administered to achieve a rapid anticoagulant effect. Treatment of
patients with warfarin-induced skin necrosis who require anticoagulant therapy for an
indefinite period is difficult. These patients can be treated with subcutaneous heparin
long term, but this is inconvenient and carries a risk of osteoporosis. It might be safe to
reintroduce warfarin in low doses initially in combination with heparin and to use
combined treatment for 10 to 14 days, during which time the warfarin dose is gradually
increased.373 It should be noted, however, that heparin may not terminate coumarin
necrosis,375376 and some have reported that heparin failed to prevent continuing skin
necrosis in homozygous protein C deficiency with very low protein C levels.377378379380

Management When Anticoagulants Are Stopped

Management of thromboembolism is influenced by the nature of the thromboembolic
event, the time during the course of anticoagulant therapy that bleeding occurred, and
the INR level during bleeding.

If bleeding occurs in a patient with calf vein thrombosis who has received an adequate
course of heparin therapy, then oral anticoagulant therapy can be stopped and
replaced with low-dose heparin 5000 U twice daily SC. If bleeding occurs toward the
end of a course of anticoagulant therapy (eg, >2 months after starting treatment) in a
patient with proximal vein thrombosis, a decision can be made to terminate the course
of anticoagulants.

Long-term Warfarin Therapy and Elective Surgery

Long-term anticoagulation is indicated in patients with a sustained high risk of arterial
or venous thromboembolism. Elective surgery in such patients can be difficult. A
number of approaches are available, but none have been evaluated in appropriately
designed clinical studies. In general, the management choice should take into account
the risk of thromboembolism if the patient is left untreated and the risk of bleeding if
aggressive perioperative-operative anticoagulation is used.

The least complicated approach is to stop oral anticoagulants and perform elective
surgery when the INR has returned to the normal range. Oral anticoagulants can then
be started postoperatively in combination with low-dose or full-dose heparin, the
choice of heparin regimens depending on the anticipated risk of postoperative
bleeding. White and associates381 have reported that it takes ≈4 to 5 days for an INR
between 2.0 and 3.0 to return to the normal range after warfarin is discontinued.
Stopping anticoagulants 4 to 5 days preoperatively is appropriate in patients with atrial
fibrillation or mechanical prosthetic valves because the risk of thrombosis in untreated
patients is <10% per year.382383 This annual incidence translates to a risk of
thromboembolism of <0.1% over the 2 or 3 days that patients are without protection. A
modification of this approach, which would further decrease risk, is to delay stopping
warfarin until 2 days before surgery and reverse the anticoagulant effect with a 1- or 2-
mg dose of vitamin K by subcutaneous injection, repeated if the INR is still prolonged
24 hours after injection. Low doses of vitamin K1 (1 to 2 mg) have been reported to
lower the INR within 24 hours without producing warfarin resistance when
lower the INR within 24 hours without producing warfarin resistance when
anticoagulant treatment is reintroduced postoperatively.384

A more aggressive approach should be considered for patients who are at high risk of
developing postoperative venous thrombosis. These include patients with a past
history of venous thrombosis or recurrent venous thrombosis, particularly if they have a
persistent risk factor for venous thrombosis. Two treatment options are available for
these high-risk patients. The first is to lower the dose of warfarin and perform the
operation at an INR of ≈1.5; this approach has been shown to be safe and effective in
preventing postoperative venous thrombosis in high-risk orthopedic surgical
patients.385 The second option is to stop warfarin and replace the oral anticoagulant
with full-dose heparin by continuous intravenous infusion preoperatively, stop heparin 6
hours before surgery, and restart anticoagulant therapy with heparin and warfarin
postoperatively. Postoperative heparin should be delayed for at least 12 hours or
longer if there is evidence of excessive bleeding or risk of serious postoperative
bleeding.

Approach to Thrombophilia
Thrombophilia is defined as an increased tendency to thrombosis. It can be inherited or
acquired.386 The term implies that there is an ongoing stimulus to thrombogenesis or a
defect of the natural anticoagulant or fibrinolytic mechanism that predisposes the
patient to thrombosis or recurrent thrombosis. Thrombophilia is often suspected on
clinical grounds because a patient presents with clinical features listed in Table 10. The
most important of these clinical features are idiopathic thrombosis, a family history of
thrombosis, recurrent thrombosis, thrombosis at a young age, thrombosis after trivial
provocation, and thrombosis in an unusual site. The spectrum of thrombophilia can
range from an increased tendency to thrombosis, which is easily controlled by
anticoagulant therapy, to progressive and intractable thrombosis, which is resistant to
all forms of therapy. The former manifestations of thrombophilia are much more
common than the latter, which is sometimes seen in malignant disease.

Patients are considered thrombophilic if they have laboratory or clinical disorders that
are known to be associated with an increased risk of thrombosis. Thrombophilic
conditions can be inherited or acquired (Table 11). The inherited molecular
abnormalities associated with an increased risk of venous thromboembolism are AT-III
deficiency, protein C and protein S deficiencies, dysfibrinogenemia, and activated
protein C resistance.387388389390391392393394395396 Of these, AT-III deficiency and protein
C and protein S deficiency are seen in ≈10% of patients with idiopathic venous
thrombosis and dysfibrinogenemia in <0.5%. Thus, until recently only ≈10% of patients
with clinically suspected thrombophilia had an associated observable genetic defect.
This state of affairs changed dramatically with the discovery of activated protein C
(APC) resistance by Dahlback and colleagues in 1993.397 These investigators found
(APC) resistance by Dahlback and colleagues in 1993. These investigators found
that adding APC to plasma obtained from a patient with recurrent thrombosis failed to
prolong aPTT, and the term “APC resistance” was introduced to describe the
abnormality. This laboratory finding was confirmed by other investigators, who reported
that between 20% and 60% of patients with recurrent thrombosis had APC
resistance.398399400

APC resistance is transmitted in an autosomal dominant manner.399 The genetic defect

underlying many cases of APC resistance was described in 1994. Most patients with
APC resistance have a mutant factor V molecule (factor V Leiden), which resists
proteolysis by APC when activated to factor Va.401 The genetic defect causing APC
resistance is common; it occurs in ≈5% of normal populations.398399 Sixty percent of
women in whom thrombosis occurred while they were taking oral contraceptives have
been reported to have APC resistance.402

Thus, 1 of the 4 inherited disorders (APC resistance, protein C deficiency, protein S

deficiency, and AT-III deficiency) is found in at least half of all patients with idiopathic
venous thrombosis.

The main acquired factors that predispose a patient to thrombosis are the presence of
an anticardiolipin antibody (lupus anticoagulant), malignancy,182403 and chemotherapy
for cancer.182 Less common are paroxysmal nocturnal hemoglobinuria,
myeloproliferative disorders, nephrotic syndrome, and hormonal treatment for
infertility.404405 Other inherited laboratory abnormalities for which an association has
not been proved are plasminogen deficiency, heparin cofactor II deficiency, increase in
histidine-rich acid glycoprotein, and reduced plasminogen activator activity due to
either increased levels of plasminogen activator inhibitor or reduced levels of TPA.

In addition, preoperative and postoperative reductions in fibrinolytic activity associated

with increased plasminogen activator inhibitor and reduced activity of plasminogen
activator have been shown to be associated with an increased risk of postoperative
thrombosis.406

Investigation of Thrombophilia
Laboratory testing for inherited AT-III, protein C or protein S deficiency, and resistance
to activated protein C should be performed when the patient is not being treated with
anticoagulants, at a time remote from the acute thrombotic event, and after excluding
the various acquired disorders known to perturb the levels of some of these naturally
occurring anticoagulants. Whenever possible, the diagnosis of inherited deficiency
should be confirmed by family studies. If anticoagulant therapy is indicated because of
the underlying thrombotic process, then testing for AT-III deficiency can be done while
the patient is being treated with oral anticoagulants (a low result would be diagnostic,
although an AT-III level in the normal range would not exclude AT-III deficiency). Assays
for protein C and protein S can be performed while the patient is on high-dose
for protein C and protein S can be performed while the patient is on high-dose
subcutaneous heparin. Testing for APC resistance with coagulation-based assays
during anticoagulant therapy has been difficult in the past. The problem can be
overcome by using genetic testing for factor V Leiden or a tissue factor–dependent
factor V assay that permits reliable diagnosis of APC-resistant factor Va in patients
receiving anticoagulant therapy.407

Before labeling the patient as having a deficiency, it is important to repeat the test on
several occasions, exclude an underlying acquired abnormality that could produce a
falsely low test result, and, if possible, perform studies in family members to confirm
the inherited nature of the deficiency. If a laboratory marker of thrombophilia is found,
comprehensive family studies should be performed to determine whether other family
members have the defect, since asymptomatic carriers should be counseled about the
need for prophylaxis when they are exposed to high-risk situations. In addition, female
patients with thrombophilia or asymptomatic carriers of AT-III, protein C or protein S
deficiency, and those with factor V Leiden require counseling with regard to future
pregnancies, oral contraceptives, and postmenopausal estrogen replacement therapy.

Many investigations for an acquired thrombophilic state can be performed at the same
time as assays for inherited thrombophilia. The antiphospholipid antibody syndrome
should be investigated by both an antiphospholipid antibody test and tests for
circulating anticoagulants. Malignancy should be suspected in patients without other
detectable causes for venous thrombosis who present with idiopathic venous
thrombosis, recurrent venous thrombosis, including recurrent superficial venous
thrombosis, and thrombosis in an unusual site such as the portal vein, mesenteric vein,
or vena cava. Malignancy should also be suspected in patients who develop recurrent
thrombosis despite adequate oral anticoagulant or heparin therapy and in patients with
the syndrome of thrombophlebitis migrans. Malignancy is usually suspected on the
basis of compatible clinical manifestations, although patients with occult malignancy
can present with thrombosis. However, in patients with first-episode typical DVT,
without special features of a thrombophilic state, expensive or uncomfortable
investigations for malignant disease should not be performed if simple investigations
(complete blood count, chest radiograph, and fecal occult blood testing) are negative.
If malignancy is suspected, a computed tomography scan of the abdomen and/or an
ultrasound of the abdomen and pelvis should be performed. If there is evidence of an
iron deficiency anemia or if testing for fecal occult blood is positive, then endoscopy
and/or barium studies should be performed to investigate the lower and upper
gastrointestinal tract.

Screening for a myeloproliferative disorder is performed by a complete blood count,

including a platelet count. Paroxysmal nocturnal hemoglobinuria is suspected from the
results of a complete blood count that usually show anemia with evidence of either
hemolysis or bone marrow hypoplasia and the diagnosis is confirmed by
hemolysis or bone marrow hypoplasia and the diagnosis is confirmed by
demonstrating hemoglobinemia, hemoglobinuria, and hemosiderinuria and by
performing Ham’s test or Hartman’s sugar/water test. The nephrotic syndrome is
suspected if there is generalized edema, hypoalbuminemia, and proteinuria.

Antiphospholipid Syndrome
Antiphospholipid syndrome can present in a number of ways.403 Acquired circulating
anticoagulants were first identified in patients with systemic lupus erythematosus in
1948,408 and an association with thrombosis was noted 15 years later.409 The
phenomenon was called the lupus anticoagulant, but this anticoagulant is not
restricted to patients with systemic lupus erythematosus.

Antiphospholipid syndrome is diagnosed when patients with a positive assay for

antibody against phospholipids have one or more of the following manifestations:
venous or arterial thrombosis, thrombocytopenia, or recurrent fetal
wastage.403410411412413 The laboratory tests developed to detect lupus anticoagulants
include aPTT,414 kaolin clotting time, dilute phospholipid test, platelet neutralization
tests, and tissue thromboplastin inhibition tests415 ; the coexistence of antibodies to
cardiolipin has been noted.416 IgG and IgM antibodies to phosphatidylserine,
phosphatidylinositol, phosphatidic acid, and cardiolipin were found in subjects with the
lupus anticoagulant.417

Both arterial and venous thromboses occur in patients with antiphospholipid

syndrome. Thrombosis in unusual sites has been described, including the Budd-Chiari
syndrome, portal vein thrombosis, and inferior vena caval thrombosis. Antiphospholipid
syndrome has been reported in patients with transient ischemic attacks, multi-infarct
dementia, and myocardial infarction410 ; thrombosis of the cerebral, splenic, portal,
hepatic, renal, subclavian, and retinal veins and of the inferior vena cava; and coumarin
skin necrosis, adrenal gland hemorrhage, and
infarction.210410411412413414415416417418419420421422423424425426427428429430431432
Antiphospholipid syndrome may be the cause of cerebral ischemic events in
patients.433

Myeloproliferative Syndromes
Myeloproliferative syndromes have been associated with cerebral or mesenteric
venous thrombosis; thrombosis of the splenic vein, portal vein, and hepatic vein; and a
variety of arterial events, including strokes, myocardial infarction, vague neurological
symptoms, and ischemia of the fingers and toes.434435436437438439440441442 In
polycythemia vera, hypercoagulability is caused by increased viscosity of blood
resulting from the increased hematocrit.443 Treatment with phlebotomy should be
aimed at maintaining the hematocrit in the low-normal range (40% to 45%).443
However, other agents may be needed to lower the platelet count.
However, other agents may be needed to lower the platelet count.

Anagrelide, a quinazolin compound, is a new drug available for the management of

thrombocythemia. Silverstein et al444 have accumulated data on more than 500
patients with essential thrombocythemia treated with anagrelide, with a 93% success
rate in reducing platelet count to less than 650×109/L. This reduction is associated with
parallel relief of symptoms (transient ishemic attacks, venous thrombosis,
erythromelalgia) without a significant number of side effects. Fluid retention may be a
side effect of its use in some patients, including those with congestive heart failure.
Anagrelide may become front-line therapy for thrombocythemic states not only
because of its selective efficacy in inhibiting megakaryocyte maturation but because no
documented leukemogenic effect has been found after 8 years of use.

Anagrelide will not likely displace two other agents, hydroxyurea and ∝-interferon, that
are effective in treatment of thrombocythemia. Even though rare cases of leukemia
have followed the use of hydroxyurea in myeloproliferative disorders, the ease and
effectiveness of its low-cost administration continue to make it a valuable agent for
these patients. The cytokine ∝-interferon requires frequent subcutaneous injection of an
expensive agent whose use may be accompanied by significant side effects. Because
the side effects of interferon are usually manageable and transitory, and because
injections may be decreased from three times weekly to once weekly, this cytokine
should be considered for some patients.

No absolute relation between platelet number and frequency of thrombotic

complications has been established in thrombocythemia, but it has been demonstrated
that the longer the platelet count is less than 600×109/L, the lower the incidence of
thrombotic complications.445 High vascular complication rates in patients >60 years
and in patients with a history of a thrombotic event make both of these patient groups
candidates for therapeutic intervention. A randomized trial of hydroxyurea has
demonstrated a significant reduction in thrombotic events (3.6% versus 24%) in favor
of those treated with drug therapy.446 In younger patients with asymptomatic
thrombocythemia, therapeutic recommendations should remain conservative.447 Low-
dose aspirin appears adequate for most patients.

Trousseau’s Syndrome
Most patients with malignancy and thrombosis do not have Trousseau’s syndrome,
which refers to a thrombus that is characteristically migratory and recurrent.
Thrombosis occurs in leg veins, neck veins, superficial veins of the thorax and
abdomen, the dorsal vein of the penis, subclavian and axillary veins, cerebral veins,
and visceral veins.444445446 Arterial thromboses can also occur.447 Thrombosis tends to
be associated with mucinogenic adenocarcinoma.

Treatment of Trousseau’s syndrome can be difficult. Coumarin is usually not

448449
effective.448449 Heparin often controls the thromboembolic manifestations and can be
given long term on an outpatient basis in full therapeutic doses.448

Management of Thrombophilia
All thrombophilic patients should receive prophylaxis in high-risk situations, and some
require long-term anticoagulant therapy. Lifelong anticoagulant treatment should be
considered for thrombophilic patients with a documented episode of thrombosis, with
or without a laboratory abnormality, while thrombophilic patients without documented
evidence of thrombosis should receive prophylaxis when exposed to high-risk
situations (eg, surgery, prolonged immobilization, pregnancy). In patients with
polycythemia vera, the hematocrit and platelet count should be controlled with
appropriate therapy. In addition, female patients with thrombophilia and asymptomatic
carriers of AT-III, protein C or protein S deficiency, and the factor V gene mutation
require counseling about future pregnancy, use of oral contraceptives, and
postmenopausal estrogen replacement therapy.

Descriptive studies in AT-III deficiency suggest that risk of thrombosis in the

unprotected pregnant patient is very high.450451 While the risk of thrombosis for protein
C and protein S deficiencies during pregnancy is lower than for AT-III deficiency, risk of
postpartum thrombosis is high in all three groups.451

Three approaches can be used to treat a thrombophilic patient during pregnancy:

1. Full-dose heparin by subcutaneous injection every 12 hours for the duration of

pregnancy. The dose should be adjusted to maintain the aPTT in a range
equivalent to a heparin level of 0.2 to 0.4 U/mL by protamine titration.

2. Low-dose heparin 5000 U SC every 12 hours for the duration of pregnancy.

3. Frequent surveillance with IPG or duplex ultrasound imaging for the duration of
pregnancy.

The first option should be considered for patients who must take oral anticoagulants as
long as they live, including those at risk of cardiac embolism; patients with previous
venous thrombosis associated with deficiencies of AT-III, protein C, and protein S or
with lupus anticoagulant; and any patient with two or more previous episodes of
venous thrombosis. The second option should be considered in asymptomatic carriers
of AT-III deficiency and patients with previous idiopathic venous thrombosis or
thrombosis during an uncomplicated pregnancy. It would be reasonable to consider
either the second or third option in asymptomatic carriers of protein C or protein S
deficiency and the third option in patients with only one episode of previous venous
thrombosis after provocation.
“Management of Deep Vein Thrombosis and Pulmonary Embolism” was approved by
the American Heart Association Science Advisory and Coordinating Committee on
February 15, 1996.

Requests for reprints should be sent to the Office of Science and Medicine, American
Heart Association, 7272 Greenville Ave, Dallas, TX 75231-4596.

Download figure | Download PowerPoint

Figure 1. Valve cusp thrombus (autopsy specimen).

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Figure 2. Cumulative incidence of recurrent venous thromboembolism after the
first episode of symptomatic deep vein thrombosis.

Download figure | Download PowerPoint

Figure 3. Location of venous thrombi in symptomatic outpatients. Reprinted from
Cogo et al78 with permission.

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Figure 4. Diagnostic approach to deep vein thrombosis.
Download figure | Download PowerPoint
Figure 5. Management of clinically suspected deep vein thrombosis with venous
ultrasonography at presentation and on day 7. Reprinted from Prandoni et al.112

Download figure | Download PowerPoint

Figure 6. Diagnosis of recurrent venous thrombosis. *On venous
ultrasonography; if positive in a venous segment that had been compressible on
previous assessment.

Download figure | Download PowerPoint

Figure 7. Diagnostic approach when pulmonary embolism is suspected. *Can be
followed with serial venous ultrasound. +Pulmonary angiography may be
preferable in a patient whose condition is unstable. xBilateral venograms could
be performed initially and proceed only if results are negative. †Other
combinations include low clinical probability and intermediate or indeterminant
lung scans and intermediate clinical probability and low-probability lung scans.

Table 6. Guidelines for Use of Anticoagulants

Bolus dose of heparin: 5000 U IV

Initial maintenance 32 000 U IV per 24 h by continuous infusion or 17 000 U subcutaneously

dose of heparin: to be repeated after adjustment at 12 h

Adjust dose of heparin at 6 h according to nomogram. Maintain aPTT in therapeutic range.

Adjust dose of heparin at 6 h according to nomogram. Maintain aPTT in therapeutic range.

Repeat aPTT 6 times every hour until in therapeutic range and then daily (see nomogram).

Start warfarin 10 mg at 24 h and 10 mg next day.

Overlap heparin and warfarin for at least 4 d.

Perform PT daily and adjust warfarin dose to maintain INR at 2.0 to 3.0.

Continue heparin for a minimum of 5 d, then stop if INR has been in therapeutic range for at least 2
consecutive days.

Continue warfarin for 3 mo and monitor PT daily until in therapeutic range, then 3 times during first
week, twice weekly for 2 wk, or until dose response is stable, and then every 2 wk.

Obtain a pretreatment hemoglobin level, platelet count, PT, and aPTT and repeat platelet count daily
until heparin stopped.

1
See text for modified recommendations for iliofemoral thrombosis and major
pulmonary embolism.

aPTT indicates activated partial thromboplastin time; PT, prothrombin time; INR,
International Normalized Ratio.

Table 1. Risk Factors for Venous Thromboembolism

Age >60 y

Extensive surgery1

Previous venous thromboembolism

Marked immobility, preoperative or postoperative

Major orthopedic surgery

Hip surgery

Major knee surgery

Major knee surgery

Fracture of pelvis, femur, or tibia

Surgery for malignant disease

Postoperative sepsis

Major medical illness

Heart failure

Inflammatory bowel disease

Sepsis

Myocardial infarction

1Risk of postoperative thrombosis is increased by patient’s age, presence of

varicose veins, obesity, and length of surgery.

Table 2. Risk Categories for Venous Thromboembolism

Thrombolic Category 1, Low Risk Category 2, Moderate Category 3, High Risk

Event Risk1

Patient younger than 40 General surgery in Hip and major knee

y patient older than 40 y surgery

Uncomplicated surgery Acute myocardial Previous venous

(eg, hysterectomy) infarction thrombosis

Minimal immobility Chronic illness Surgery for extensive

malignant disease

Leg fracture in a patient

younger than 40 y

Calf vein ≈2% 10-20% 40-70%

thrombosis
Proximal vein ≈0.4% 2-4% 10-20%
thrombosis

Fatal <0.02% 0.2-0.5% 1-5%

pulmonary
embolism

1
Risk increased by patient’s age, length of surgery, obesity, varicose veins, chronic
illness, and postoperative sepsis.

Table 3. Recommended Prophylaxis

Low Risk Moderate Risk1 High Risk

Early Low-dose heparin (5000 U bid) or LMWH or moderate-dose warfarin or

ambulation intermittent pneumatic compression2 adjusted-dose heparin

1
Low-molecular-weight heparin is a reasonable but more expensive option.
2
Method of choice for neurosurgery, urogenital surgery, or if unusually high risk of
hemorrhage (eg, spinal or eye surgery).

LMWH indicates low-molecular-weight heparin.

Table 4. Criteria for Clinical Pretest Probabilities

Category Proportion of Patients in Venous Thrombosis on

Category (%) Venography (%)

High probability:

Classic clinical features 15 78

and at least one risk factor

Low probability:

Atypical clinical features and no 60 5

risk factors
 Intermediate probability:

Features do not correspond 25 23

to low or high probability

Table 5. Probabilities of Pulmonary Embolism Based on a Combination of Clinical

Impression and Lung Scan Findings

Clinical High Inter- Low Low High Other Combi-

Suspicion mediate nations

Lung scan High High Low High Intermediate1 —

or low

Likelihood of PE 96 80-88 2-6 50 10-50

(%)

1Hull RD 1983,3 PIOPED 1990.128

Table 7. Therapeutic Range for Heparin

Test Therapeutic Range

aPTT ≈1.5-3.0 times1 mean of laboratory normal range

Heparin level: thrombin/protamine titration 0.2-0.4 U/mL

Heparin level: Antifactor Xa 0.3-0.7 U/mL

1
Depends on sensitivity of aPTT reagents to heparin.

aPTT indicates activated partial thromboplastin time.

Table 8. An Intravenous Heparin-Dose Nomogram Based on aPTT Drawn 6 Hours

After Starting Heparin1

aPTT Bolus Stop Infusion Rate Change Rate Change Repeat

aPTT Bolus Stop Infusion Rate Change Rate Change Repeat
(s) Dose (min) (mL/h)2 (U/24 h) aPTT

<50 5000 U 0 +3 2880 6h

50-59 0 0 +3 2880 6h

60- 0 0 −2 1920 Next AM

853

86-95 0 0 −2 1920 Next AM

96- 0 30 −4 3840 6h
120

>120 0 60 −4 3840 6h

1
As recommended in Table 6.
2
When infusion fluid 1 mL/h=40 U/h (ie, 20 000 U heparin in 500 s).
3
aPTT equivalent to heparin level of 0.3-0.7 U/mL by antifactor Xa assay.

aPTT indicates activated partial thromboplastin time.

Table 9. Pooled Analysis Randomized Trials of Continuous Intravenous Versus

Subcutaneous Heparin

Trial No. of Patients PE Fatal PE Major Bleeding

Continuous intravenous 437 8 (1.8%) 1 (0.23%) 21 (4.8%)

(0.57-3.1) (2.8-6.8)

Subcutaneous 441 12 (2.7%) 1 (0.23%) 17 (3.9%)

(1.2-4.2) (2.1-5.6)

PE indicates pulmonary embolism.

 Table 10. Clinical Manifestations of Thrombophilia

Family history of venous thrombosis

Thrombosis at a young age

Recurrent venous thrombosis

Idiopathic venous thrombosis

Venous thrombosis following minimal provocation (eg, antepartum thrombosis, thrombosis after a long
car ride or airplane flight while taking oral contraceptives)

Venous and arterial thrombosis in combination

Thrombosis in an unusual site

Inferior vena cava

Mesenteric vein thrombosis

Cerebral vein thrombosis

Renal vein thrombosis

Hepatic vein thrombosis

Axillary vein thrombosis

Recurrent thrombosis despite adequate anticoagulant therapy (malignant disease)

Some clinical manifestations of thrombophilia are particularly characteristic of

special thrombophilic disorders. These deficiencies are shown in parentheses.

Table 11. Causes of Thrombophilia

Familial Thrombophilic (Inherited) Disorders Acquired Thromboembolic Disorders

Established association Malignancy

 Established association Malignancy

APC resistance Antiphospholipid antibody

AT-III deficiency Paroxysmal nocturnal hemoglobinuria

Protein C deficiency (heterozygous autosomal Myeloproliferative syndrome

dominant)

Protein C deficiency (homozygous autosomal Nephrotic syndrome

recessive)

Protein S deficiency Estrogen therapy for infertility

Dysfibrinogenemia1 Chemotherapy for cancer

Reduction in postoperative fibrinolytic

activity

Unestablished association

Plasminogen deficiency

Heparin cofactor II deficiency

Increased histidine-rich glycoprotein

Decreased plasminogen activator activity

1Rare.

APC indicates activated protein C; AT-III, antithrombin III.

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