SECTION
SECTION 1 ATHEROSCLEROSIS AND ITS PREVENTION
chapter
14
Venous Disease
Agnes Y. Y. Lee
Definition
n Abnormal conditions of the veins are due to thrombotic
or inflammatory processes that impair the function of the
vessels in returning blood to the heart and may result in
thromboembolic events to the cardiorespiratory vasculature.
Key Features
n The most common venous disease is acute venous
thromboembolism involving deep veins of the legs, with
or without pulmonary embolism.
n Classic clinical features are swelling and pain of the involved
extremity, but significant disease can be clinically silent.
n Diagnosis requires objective investigations because clinical
features are nonspecific.
n Venous thrombosis can be associated with significant short- and
long-term morbidity and, potentially, mortality.
Therapy
n Systemic anticoagulant therapy is highly effective and remains
the mainstay of treatment for acute venous thromboembolism.
n Duration of therapy depends on balancing the risks of
recurrence and anticoagulant-related bleeding.
n Indications for second-line therapy, such as thrombolytic
treatment and vena cava filter insertion, remain poorly
established.
Although venous disease has generally received less attention
than arterial disease, acute and chronic conditions can be
associated with significant morbidity and, potentially, mortal-
ity. Approximately 1 per 1000 persons is affected by venous
thrombosis annually.1 The most common condition is acute
venous thromboembolism involving the deep veins of the
legs, with or without pulmonary embolism. Rarely, thrombus
can form in the venae cavae as well as in the veins of the liver
and the kidneys and in the mesenteric, portal, or central ner-
vous system. A good understanding of the anatomy and path-
ophysiology is helpful in making an accurate diagnosis, but
objective testing is essential because the clinical features of
venous thrombosis are nonspecific. Although highly effective
treatment is available, serious short- and long-term sequelae
can still result from the disease process, underlying comorbid
conditions, and treatment-related complications.
ANATOMY AND PHYSIOLOGY
The veins are vessels that convey blood back to the heart.
The smallest veins are called venules. These arise from capil-
laries, and they unite to form larger veins or tributaries and
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1
CHAPTER
14
ATHEROSCLEROSIS AND ITS PREVENTION: NONCARDIAC VASCULAR DISEASES: Venous Disease
venous plexuses. Large veins from the lower limbs and torso
form the inferior vena cava; veins draining the upper ex-
tremities, head, and neck join to form the superior vena cava.
The venae cavae lead into the right atrium and complete
the circulatory system. Compared with arteries, the veins
are distensible, high-capacitance vessels that can accommo-
date 60% to 75% of the blood volume of the body. Because
the walls of veins contain less elastic tissue and smooth mus-
cle than the arterial walls do, the competency of veins in
directing blood back to the heart is highly dependent on
bicuspid valves, which normally allow only unidirectional
blood flow.2
Veins of the Lower Extremities
The venous system of the lower extremities is composed of
three sets of veins: the deep veins, the superficial veins,
and the communicating veins.
The deep veins, unlike the superficial and communicating
veins, accompany the major arteries. The proximal veins include
the common femoral, deep femoral, superficial femoral, and
popliteal veins (Fig. 14.1). A single vein usually accompanies
the corresponding artery, although duplication of the super-
ficial femoral vein and popliteal vein is not uncommon. The
deep veins of the calf are usually paired when they accompany
the corresponding artery. These include the anterior tibial,
posterior tibial, and peroneal veins.
The superficial venous network includes veins in the thigh,
calf, and foot. These vessels course close to the skin and
are sometimes visible. The most significant superficial veins
are the greater and lesser saphenous veins. The greater
saphenous vein begins at the medial malleolus of the ankle
and courses medially up the entire length of the calf and
thigh to enter into the common femoral vein in the groin.
The lesser saphenous vein arises from the lateral part of the
foot and ascends behind the lateral malleolus. It courses
along the posterolateral aspect of the calf and ends in the
popliteal vein at the lower part of the popliteal fossa.
The communicating veins connect the superficial veins
with the deep veins. The two types are the perforating veins,
which course through the deeper fascial layers outside the
muscles, and the intramuscular sinusoids, which course
through the muscles of the lower extremity.
Veins of the Upper Extremities
The deep veins parallel the corresponding upper extremity
arteries. These are the subclavian, axillary, and brachial
veins in the upper arm and the radial and ulnar veins in the
forearm. The largest superficial veins are the basilic and
187
SECTION
1 VENOUS SYSTEM OF THE LOWER EXTREMITY VENOUS SYSTEM OF THE UPPER EXTREMITY
CHAPTER
14
External jugular vein
ATHEROSCLEROSIS AND ITS PREVENTION

Internal
jugular
vein

Common femoral Axillary vein Subclavian

vein vein Innominate
vein
Deep femoral vein
Superficial femoral Basilic vein
vein Cephalic vein
Greater saphenous
vein

Brachial veins
Median cephalic
vein
Median cubital vein

Lesser saphenous
Popliteal vein vein Cephalic vein
Basilic vein

Radial veins Ulnar veins

Peroneal veins
Deep veins
Anterior tibial veins
Superficial veins

Posterior tibial veins

Figure 14.2 Venous system of the upper extremity.

CENTRAL VENOUS SYSTEM

Left brachiocephalic vein Left internal jugular vein

Figure 14.1 Venous system of the lower extremity.
Right Left subclavian vein
brachiocephalic vein

cephalic veins in the upper arm, which join the deep venous Superior
system in the region of the shoulder (Fig. 14.2). vena cava
The subclavian vein traverses the relatively narrow space
between the first rib and the clavicle to enter the thorax.
The subclavius and scalene muscle tendons and other liga-
ments can encroach on this space, occasionally leading to
venous obstruction. Cervical ribs can also compress the neu- Hepatic veins
rovascular bundle at the junction of the arm with the thorax, Right renal vein
usually leading to nerve, arterial, and venous compression.
Right common Inferior vena cava
Central Veins iliac vein
The major veins emptying into the right atrium are the supe- Right internal
rior vena cava and the inferior vena cava (Fig. 14.3). The iliac vein
superior vena cava is formed on the right side of the medias- Right external
tinum by the joining of the right and left brachiocephalic iliac vein
(innominate) veins, which receive venous tributaries from
the upper torso, including the arms, the head, the neck, and
the overlying soft tissues of the thorax. The subclavian veins Figure 14.3 Central venous system. Only major vessels are
188
and the internal jugular veins, which carry blood from the included.

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head and neck, join to form the right and left brachiocephalic pathways (Fig. 14.4). The interruption of normal blood flow SECTION
veins. by the thrombus produces venous hypertension, which 1
The inferior vena cava is formed by the right and left results in the clinical manifestations of deep venous throm- CHAPTER

common iliac veins in the pelvis and receives tributaries from bosis. Damage to the venous valves, either secondary to 14
the pelvic and abdominal viscera as well as from the overlying previous thrombosis or from inherent structural defects,

ATHEROSCLEROSIS AND ITS PREVENTION: NONCARDIAC VASCULAR DISEASES: Venous Disease

soft tissues of the lower torso. The common iliac veins
are formed by the external iliac veins, which carry blood pre-
dominantly from the legs, and the internal iliac veins, which
carry blood from the pelvic viscera. The inferior vena cava also
receives venous tributaries from the abdominal viscera, most
notably the liver and the kidneys. The hepatic veins and renal
veins empty directly into the inferior vena cava; the venous
drainage from most of the gut, the pancreas, and the spleen
passes through the portal vein into the hepatic sinusoids and
then through the hepatic veins into the inferior vena cava.
PATHOPHYSIOLOGY
Venous disease primarily arises from pathologic processes
that lead to thrombosis of the circulating blood. This is often
accompanied by an inflammatory response of the vessel
walls, which can further propagate the thrombotic process.
Thrombus formation is dependent on thrombin generation,
which is promoted through the activation of the coagulation
leads to chronic venous reflux, formation of varicose veins,
and skin changes.
Mechanisms
Virchow’s triad describes the three basic mechanisms that
can lead to thrombus formation: venous stasis, vessel wall
damage, and hypercoagulability.3 In many clinical situations,
all three mechanisms may play a role. Venous stasis is usu-
ally caused by extrinsic compression of the vessel by tumor
masses, adenopathy, fibrosis, or anatomic strictures. Condi-
tions resulting in prolonged immobility, such as paralysis or
casting of a lower limb, can also predispose to venous stasis
and thrombosis. Thrombi within the deep veins are thought
to arise most commonly at the valves within the soleal sinu-
soids in the calf and to propagate into the deep calf veins
(Fig. 14.5).4 Vessel wall or endothelial damage leads to
exposure of the subendothelium, whereby exposure of
membrane-bound tissue factor results in activation of the
extrinsic coagulation pathway.

Figure 14.4 Coagulation

pathways. A simplified schematic COAGULATION PATHWAYS
of the extrinsic, intrinsic, and
common pathways of the
coagulation cascade. TF, tissue
factor. Extrinsic pathway

TF + VII

TF-VIIa

Common pathway
XI IX X

Contact factors

Xla

IXa

Intrinsic
VIII VIIIa Prothrombin
pathway
Xa

V Va
Platelet
Thrombin
activation

XIII

XIIIa

Fibrinogen Fibrin CLOT

189

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SECTION
CLINICAL RISK FACTORS ASSOCIATED WITH VENOUS
1 PROPAGATION OF A THROMBUS
THROMBOEMBOLISM
CHAPTER
14 Physiologic conditions Advanced age
Obesity
ATHEROSCLEROSIS AND ITS PREVENTION

Postpartum
Blood Pregnancy
flow Surgery or trauma Major trauma
A Major surgery
Pelvic or hip fracture
Paralysis or stroke
Spinal cord injury
Prolonged immobilization
Medical conditions Cancer
Acute myocardial infarction
Congestive heart failure
B Chronic respiratory failure
Inflammatory bowel disease
Hematologic disorders
Nephrotic syndrome
Inherited thrombophilia
Medications Anticancer therapy
Oral contraceptives
Hormone replacement therapy
C
Other History of venous thromboembolism
Central venous catheter

Table 14.1 Clinical risk factors associated with venous

thromboembolism.

Thrombus INHERITED THROMBOPHILIA

Common G1691A mutation in the factor V gene

Figure 14.5 Propagation of a thrombus. Thrombus typically disorders (factor V Leiden)
begins at the valve and can extend either distally (away from the G20210A mutation in the prothrombin
heart) or proximally (toward the heart).
(factor II) gene
Homozygous C677T mutation in the
Any surgical procedure, particularly major orthopedic sur- methylenetetrahydrofolate reductase gene
gery, or extensive soft tissue trauma will increase the risk of Rare disorders Antithrombin deficiency
thrombosis. Hypercoagulability occurs when there is excessive Protein C deficiency
activation of the coagulation pathways due to genetic or Protein S deficiency
acquired conditions that increase the plasma levels of coagu- Very rare Dysfibrinogenemia
lant proteins (e.g., elevated factor VIII levels), decrease the disorders Homozygous homocystinuria
concentration of natural anticoagulants (deficiencies of anti- Probably Increased levels of factor VIII, factor IX,
thrombin, protein C, or protein S), inhibit the inactivation of inherited factor XI, or fibrinogen*
coagulation cofactors (factor V Leiden), or suppress the fibrino-
*Levels of factor VIII and fibrinogen may also increase as part of the acute-
lytic system (dysplasminogenemia). Many clinical conditions phase response.
(e.g., chemotherapy, estrogens) can impair several of these
pathways. The mechanisms behind other hypercoagulable Table 14.2 Inherited thrombophilia.
conditions, such as antiphospholipid antibody syndrome and
hyperhomocysteinemia, are still not well understood.

Risk Factors
A number of clinical risk factors have been associated with
thromboembolism (Table 14.1).5 In addition, patients may
have underlying biochemical or genetic conditions that
inherently increase their risk of thrombosis in any clinical
situation (Table 14.2).6 Providing adequate prophylaxis in
patients with identifiable risk factors can help reduce the risk
190
of thrombosis.
CLINICAL PRESENTATIONS
Acute venous disease may be manifested as deep venous
thrombosis or superficial phlebitis. Chronic venous disease is
a result of venous insufficiency and includes varicose veins
and postphlebitic syndrome. The clinical features in these con-
ditions are largely reflective of the resultant venous congestion
and any associated inflammation of the involved vessel walls.

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Veins of the Lower Extremities
Deep Venous Thrombosis
The majority of patients presenting with deep venous thrombosis
complain of pain or swelling of the involved leg. The pain is often
nonspecific, and it is usually described as a dull, aching sensation
in the calf or entire leg. With more extensive thrombosis, some
patients experience a heavy or “charley horse” sensation of the
leg. Pain that is described as sharp, pinpointed in a specific loca-
tion, or isolated to the anterior aspect of the lower leg is almost
never associated with deep venous thrombosis. Swelling is also a
frequent symptom that prompts the patient to seek medical atten-
tion. The swelling is usually unilateral, beginning in the lower leg
or ankle, and it gradually advances proximally. Because bilateral
deep venous thrombosis is uncommon, patients presenting with
bilateral leg edema are less likely to have deep venous thrombosis
than are those with swelling in one leg. On occasion, the patient
will notice erythema and may describe having a bluish hue of
the involved leg after prolonged standing or sitting.
Physical examination may demonstrate pitting edema,
discoloration, and tenderness to palpation along the deep
venous distribution of the leg (calf, popliteal fossa, and medial
thigh). The involved calf may feel heavier, and its circum-
ference at 10 cm below the tibial tuberosity will often show
enlargement compared with the unaffected calf. The classic
Homans sign of pain elicited on dorsiflexion of the foot is uncom-
mon and nonspecific for deep venous thrombosis. A palpable
cord underneath the skin is not characteristic of deep venous
thrombosis unless there is accompanying superficial thrombo-
phlebitis. When there is extensive thrombosis with complete
obstruction of the deep venous system, severe venous congestion
can result in tissue ischemia. This condition (phlegmasia cerulea
dolens) is relatively rare and is manifested as severe pain of the
lower extremity accompanied by cyanosis and swelling.
Many other leg pathologic processes (e.g., ruptured Baker’s
cyst, cellulitis, musculoskeletal conditions) can mimic the
presentation of deep venous thrombosis. Patients may occa-
sionally present with signs and symptoms from pulmonary
emboli as the first manifestation of clinically silent lower
extremity deep venous thrombosis (see Chapter 85).
Superficial Thrombophlebitis
Superficial thrombophlebitis is common in the elderly and is
usually a benign condition. It usually is manifested as redness
and pain in the thrombosed vein and is more common in the
lower extremities. Physical examination will reveal a tender,
red, warm cord beneath the skin that follows the course of
a superficial vein. Swelling of the involved leg is not a
typical feature of isolated superficial thrombophlebitis, and
its presence suggests that there may be underlying deep
venous thrombosis. Approximately 10% to 20% of cases
are associated with deep venous thrombosis.
Chronic Venous Insufficiency
Chronic venous insufficiency is a common clinical problem.
Varicose veins are dilatations of the superficial veins second-
ary to venous reflux and are considered the hallmark of
venous insufficiency. However, patients with venous insuffi-
ciency do not always have varicosities and may be asymptom-
atic. Some will present with patches of reticular superficial
venules or chronic skin changes, including hyperpigmentation
(stasis dermatitis) and ulcerations. Up to half of patients with
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CLASSIFICATION OF CHRONIC VENOUS INSUFFICIENCY
SECTION
1
CHAPTER
Class Description
14
0 No signs of venous disease
ATHEROSCLEROSIS AND ITS PREVENTION: NONCARDIAC VASCULAR DISEASES: Venous Disease
1 Telangiectases or reticular veins
2 Varicose veins
3 Edema
4 Skin changes ascribed to venous disease
5 Skin changes with healed ulceration
6 Skin changes with active ulceration
Table 14.3 Classification of chronic venous insufficiency.
deep venous thrombosis of the legs may go on to develop
postphlebitic syndrome.7 This is characterized by fluctuating
but chronic discomfort and swelling of the involved leg.
These symptoms are exacerbated by prolonged sitting or
standing and vigorous exercise. Severe cases may develop
venous ulcerations of the skin, which typically occur over
the medial aspect of the lower leg near the ankle. The sever-
ity of chronic venous disease can be classified according to
the grading system recommended by the American Venous
Forum (Table 14.3).8
Veins of the Upper Extremities
Deep Venous Thrombosis
Upper extremity deep venous thrombosis may occur sponta-
neously or secondary to vessel trauma from instrumenta-
tion or catheterization. Spontaneous or primary thrombosis
of the subclavian or axillary vein is known as the Paget-
Schroetter syndrome.9 This is also referred to as effort-related
thrombosis because repetitive or strenuous upper extremity
exercise is occasionally reported in association with the throm-
botic event. This typically occurs in young patients in the second
or third decade, with a slightly higher prevalence in men. About
60% of cases occur in the dominant arm. Patients usually com-
plain of dull, aching pain in the shoulder or axilla and swelling of
the arm. Symptoms worsen with vigorous use of the arm and
improve with rest and elevation. Physical examination usually
reveals a mild to moderate amount of arm edema. On occasion,
mild cyanosis of the hand and fingers as well as dilated collateral
veins over the arm and chest is observed.
More commonly, deep venous thrombosis of the upper
extremity occurs in patients who have or have had indwell-
ing central venous catheters or pacemakers.10 The majority
of cases are asymptomatic and are diagnosed when patients
present with catheter malfunction. Alternatively, the cathe-
ter may function normally and the patient develops arm pain
and swelling. Shoulder pain is not uncommon, and this may
be due to local inflammatory reaction. With long-standing
thrombosis, collateral veins will develop and are visualized
as dilated veins on the involved side of the chest wall.
As with deep venous thrombosis of the lower extremities,
clinical presentation of upper extremity thrombosis is non-
specific. Identical signs and symptoms may occur in patients
with thoracic outlet venous obstruction from tumor mass or
adenopathy, without associated deep venous thrombosis.
Clinically significant pulmonary emboli have been reported
with upper limb deep venous thrombosis in patients who
191
do not have local symptoms.
SECTION Superficial Thrombophlebitis
1 Superficial thrombophlebitis is uncommon in the upper
CHAPTER extremities. It usually occurs in association with local inflam-
14 mation or infection secondary to venipuncture, catheter inser-
tion, or chemical phlebitis. It is manifested as a tender, red,
ATHEROSCLEROSIS AND ITS PREVENTION
warm cord beneath the skin that follows the course of the
superficial vein. Swelling of the involved arm is not a typical
feature of isolated superficial thrombophlebitis; its presence
suggests that there may be underlying deep venous
thrombosis.
Chronic Venous Insufficiency
Chronic venous insufficiency that follows an episode of
thrombosis is less frequent in the upper extremities than in
the legs, and it is a more common complication in patients
who have had primary thrombosis than in those with cathe-
ter-related thrombosis.11 The typical features are heaviness
and swelling of the involved arm that are exacerbated with
exercise. Dilated superficial veins are often observed in the
arms or chest wall. The clinical findings are indistinguishable
from those of patients with chronic lymphedema, which can
occur after nodal dissection of the axilla in breast cancer
surgery.
Central Veins
Inferior Vena Cava Thrombosis
Patients with thrombosis affecting the inferior vena cava
may present with bilateral leg swelling, vague abdominal
pain, and increasing girth from ascites. Men may also com-
plain of scrotal edema. Over time, dilated superficial veins
will develop on the abdominal wall, representing venous
flow in collaterals. All of these symptoms result from the
increased venous pressure and venous congestion of the leg
veins and mesenteric vessels. Depending on the degree of
obstruction of the inferior vena cava, symptoms may be mild
or severe. Depending on the location of the thrombus, organ
damage of the kidneys or liver may result secondary to
ischemia from venous congestion. Like thrombi in the leg
and pelvic veins, thrombi in the inferior vena cava are
sources of clinically significant pulmonary emboli. These
emboli can be life-threatening because of their large size.
Superior Vena Cava Syndrome
As with the inferior vena cava, thrombosis of the superior
vena cava may be manifested with fulminant symptoms.
Patients may develop a sudden or gradual onset of periorbi-
tal edema, facial swelling, and plethora, with or without
swelling of the neck and arms. Dilated superficial veins on
the chest wall are usually prominent. Many cases are asso-
ciated with thoracic malignant disease and occasionally
develop as a complication of an indwelling central venous
catheter.12 Thrombus in the superior vena cava may extend
directly into the right atrium and can serve as a source of
potentially fatal pulmonary emboli.
DIAGNOSTIC TECHNIQUES
Veins of the Lower Extremities
Deep Venous Thrombosis
Patients with deep venous thrombosis may have minimal
or atypical symptoms, and clinical features that are gener-
192
ally considered diagnostic can be found in nonthrombotic
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disorders.13 Only about 25% of patients who present with
compatible symptoms have deep venous thrombosis confirmed
on objective testing. On the other hand, imaging techniques
can produce false-positive or false-negative results. Therefore,
both clinical assessment and diagnostic imaging are essential to
make an accurate diagnosis and to avoid the risks of either
untreated thrombosis or unnecessary anticoagulation.
A proper clinical assessment includes a careful evaluation
of the patient’s signs, symptoms, and risk factors for venous
thromboembolism. Alternative diagnoses should be consid-
ered, especially if the patient has atypical symptoms or no
risk factors. To improve the consistency and accuracy of
the clinical examination, a clinical prediction rule for deter-
mining the pretest likelihood of deep venous thrombosis
has been developed and validated (Table 14.4).14 On the
basis of the total score given for the presenting clinical fea-
tures, patients are stratified into low-, intermediate-, or
high-probability categories for having deep venous thrombo-
sis. The most subjective and problematic item in this 9-point
clinical model is the identification of an alternative diagnosis.
Nonetheless, the model has been proved to be robust and
helpful in multiple medical settings, including outpatient
clinics, emergency departments, and in-hospital services.
The currently available imaging technologies available for
diagnosis of acute deep venous thrombosis include venous
ultrasonography, contrast venography, computed tomographic
scanning, and magnetic resonance imaging. Impedance
plethysmography and scanning with fibrinogen labeled with
iodine 125 are outdated methods and are considerably less
accurate. Magnetic resonance imaging is not widely used,
and evidence of its accuracy remains limited. In addition to
WELLS’ CLINICAL ASSESSMENT MODEL FOR THE PRETEST
PROBABILITY OF LOWER EXTREMITY DEEP VENOUS
THROMBOSIS
Score*
Active cancer (treatment ongoing or within previous 1
6 months or palliative)
Paralysis, paresis, or recent plaster immobilization of 1
the lower extremities
Recently bedridden >3 days or major surgery within 1
4 weeks
Localized tenderness along the distribution of the 1
deep venous system
Entire leg swollen 1
Calf swelling >3 cm asymptomatic side (measured 1
10 cm below tibial tuberosity)
Pitting edema confined to the symptomatic leg 1
Collateral superficial veins (nonvaricose) 1
Previously documented deep venous thrombosis 1
Alternative diagnosis as likely as or greater than 2
that of deep venous thrombosis
*In patients with symptoms in both legs, the more symptomatic leg is used.
Pretest probability is calculated as the total score: high  3; moderate, 1 or
2; low  0.
Table 14.4 Wells’ clinical assessment model for the pretest proba-
bility of lower extremity deep venous thrombosis.
these imaging techniques, testing of D-dimer levels in the
blood has been established as a reliable test for exclusion
of acute deep venous thrombosis in symptomatic patients.
Although contrast venography remains the reference stan-
dard technique for diagnosis of deep venous thrombosis, the
most popular test is venous ultrasonography. The compres-
sion technique in combination with real-time B-mode imag-
ing has proved to be sensitive (95%) and highly specific
(96%) for diagnosis of symptomatic, proximal deep venous
thrombosis.15 This involves the application of direct pressure
on the transverse diameter of the vein with the ultrasound
transducer. Inability to fully compress the vessel is consid-
ered diagnostic for deep venous thrombosis. In many centers,
three-point compression at the inguinal region, mid thigh,
and popliteal fossa is the standard approach to detect deep
venous thrombosis in the leg. Other strategies involve com-
pression along the length of the femoral vein and the pop-
liteal vein, below the calf trifurcation, and into the calf
veins. The addition of Doppler or color imaging does not
substantially add to the accuracy of compression ultrasonog-
raphy but is sometimes helpful for identifying the vessel
and assessing the amount of residual blood flow (Fig. 14.6).
In addition to imaging of the veins, the ultrasound examina-
tion is useful for detecting conditions that can mimic deep
venous thrombosis, such as ruptured Baker’s cyst or an
abscess. The entire examination usually takes no longer than
10 to 15 minutes.
The major advantages of ultrasonography are that it
does not use ionizing radiation and is noninvasive, readily
available, and relatively inexpensive. Portable ultrasound
machines are also available for examination in the hospital
of patients who are too ill to be transported to the radiology
Figure 14.6 Doppler ultrasound appearance of deep venous
thrombosis. The superficial femoral vein is filled with echogenic
material representing thrombus, and no flow can be identified in
the vein on Doppler evaluation. Flow can be identified in the
adjacent artery on color Doppler evaluation (arrows).
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department. The clinical limitations of ultrasonography are SECTION
its poor ability to diagnose isolated calf vein thrombosis 1
and its reduced sensitivity in patients with asymptomatic CHAPTER
disease. The variability in the diagnostic accuracy of ultra- 14
sonography in detecting calf vein thrombosis may be related
ATHEROSCLEROSIS AND ITS PREVENTION: NONCARDIAC VASCULAR DISEASES: Venous Disease
to the small size of the thrombus, the experience of the
sonographers, and the differences in populations of patients.
The usefulness of ultrasonography is also somewhat reduced
in patients with significant leg edema or morbid obesity
because of the inability of the ultrasound beam to adequately
penetrate the tissues and to visualize the veins. Any equivo-
cal findings on ultrasonography should be confirmed with
contrast venography. When venography is not available or
is contraindicated because of medical reasons (e.g., allergy
to the contrast material, renal failure), serial ultrasono-
graphy is recommended. This requires the patient to return
to the ultrasound department for one or two repeated ultra-
sound examinations during the next 5 to 10 days. Serial
ultrasonography will help detect potential proximal exten-
sion of a calf thrombus if one is missed on initial presenta-
tion. Proximal extension into the larger veins of the leg
may occur in 20% to 30% of patients who present with
isolated calf vein thrombosis. Untreated calf vein thrombosis
may spontaneously resolve in 20% of cases and is consid-
ered to be less significant in terms of the risk of clinically
important sequelae.16
Venography is more reliable than ultrasonography in
detecting smaller thrombi in the calf veins, but it is an invasive
study that requires the injection of iodinated contrast material
into a small vein in the foot and visualization of the venous
flow by fluoroscopy. An intraluminal filling defect on two or
more views is considered diagnostic of acute deep venous
thrombosis. Other findings, such as nonfilling of veins and
abrupt cutoff of contrast dye, are less reliable as diagnostic
criteria. Phlebitis or allergic reactions to the contrast material
occur in up to 2% of patients. The examination is uncomfort-
able for patients and is technically demanding. Many centers
do not have the expertise to perform adequate venography.
The contrast load is also contraindicated in patients with renal
insufficiency or severe congestive heart failure.
Magnetic resonance imaging has a limited role for diagno-
sis of acute deep venous thrombosis but is a valuable tool
in detecting cerebral venous thrombosis.17,18 Its ability to
differentiate old versus new thrombus on the basis of signal
characteristics of the thrombus is also an advantage over
ultrasonography. This feature is particularly important for
diagnosis of recurrent deep venous thrombosis, which
remains difficult to diagnose by ultrasonography and venog-
raphy. Acute thrombi are usually hypoechoic and expand
the caliber of the vessel on ultrasonography. As the thrombus
matures, it usually contracts and becomes more echogenic.
However, these criteria are difficult to apply in individual
patients and are unreliable in diagnosis of recurrent thrombo-
sis, especially in patients without previous studies for compar-
ison. Contrast-enhanced computed tomographic scanning of
the lower extremities has been used to detect deep venous
thrombosis in combination with scanning of the chest for
pulmonary emboli. There are reports exhibiting the high
accuracy of this double imaging technique used in patients
thought to have acute pulmonary embolism.19,20 However,
193
critics have pointed to the large dose of radiation from this
SECTION approach and the limited accuracy of the venous imaging
DIAGNOSTIC STRATEGY FOR DEEP
1 portion. Venography is considered the current standard for
VENOUS THROMBOSIS OF THE LOWER EXTREMITIES
CHAPTER diagnosis of recurrent deep venous thrombosis, but it is lim-
14 ited by availability and the expertise required to perform
the test and to interpret the findings.
ATHEROSCLEROSIS AND ITS PREVENTION

Signs or symptoms of suspected DVT

D-dimer testing is a useful tool to exclude acute deep
venous thrombosis.21 D-dimer assays were developed about
2 decades ago to measure this degradation product of cross- Clinical probability
linked fibrin. D-dimers are generated when a thrombus
undergoes physiologic breakdown through the process of
fibrinolysis. To date, many different assays have been evalu- Low clinical Intermediate or high
ated for their accuracy in diagnosis of deep venous throm- probability clinical probability
bosis, but not all are clinically useful.21,22 Currently, all
D-dimer assays are based on enzyme-linked immunosorbent
D-dimer Venous
assay, latex agglutination, or whole blood red cell agglutina- test ultrasonography
tion techniques. The enzyme-linked immunosorbent assays
provide quantitative results and have a sensitivity of more
than 95% but a specificity of 30% or less. New-generation
quantitative latex agglutination assays have comparable sen- Negative Positive Positive Negative
sitivities and marginally higher specificities. The whole blood
red cell agglutination assay has a sensitivity of about 85%
Exclude Venous Diagnose D-dimer
and specificity ranging from 30% to 60%.22 Older latex DVT ultrasonography DVT test
agglutination tests are not useful for diagnosis of deep
venous thrombosis because of poor sensitivity and low spec-
ificity, but they are reasonable for crude measurements of
D-dimer, as in cases of disseminated intravascular coagulo- Positive* Negative Positive Negative
pathy. The lack of specificity of D-dimer testing is due to
the elevation of D-dimer levels in nonthrombotic situations, Diagnose Exclude Serial venous Exclude
such as infection, inflammation, pregnancy, and malignant DVT DVT ultrasonography† DVT
disease. In general, a positive D-dimer test result is not useful
because the test lacks specificity, whereas a negative result
helps exclude acute deep venous thrombosis in selected clin-
Positive Negative
ical situations. However, the results of D-dimer assays
should not be used alone in the assessment of suspected deep
venous thrombosis. Diagnose Exclude
Because of the lack of specificity of the D-dimer testing, DVT DVT
it should be used only in conjunction with another diagnos-
tic test or a validated clinical prediction rule. Management * Re-evaluate history and review ultrasound examination for features suggestive
of old rather than new thrombosis. If ultrasound findings are inconclusive,
studies have shown that it is safe to withhold anticoagulant venography should be considered.
therapy in patients with a negative D-dimer assay result in
† In patients with a high clinical probability or who cannot return for serial
combination with either a normal finding on ultrasound
ultrasonography, venography is recommended. Venography can also be
examination or a low probability of deep venous thrombosis.23 considered in patients with cardiorespiratory compromise.
The likelihood for development of deep venous thrombosis in
such patients during the next 3 months is less than 2%. There- Figure 14.7 Diagnostic strategy for deep venous thrombosis
fore, the appropriate use of D-dimer testing can reduce the (DVT) of the lower extremities.
need for ultrasound examinations to investigate patients with
a suspected first episode of deep venous thrombosis.
By the combination of clinical assessment with the avail- Confirmation can be obtained with venous ultrasonography.
able technologies, deep venous thrombosis can be reliably Thrombosis is detected with the same ultrasound criteria as
diagnosed in almost all patients on initial presentation.24,25 are used for deep venous thrombosis.
A reasonable diagnostic strategy for suspected lower extrem-
ity deep venous thrombosis is shown in Figure 14.7. Venous Insufficiency
Although this strategy simplifies the diagnostic process and The sine qua non of venous insufficiency is incompetent
reduces the cost associated with investigations, it does not venous valves. In patients with varicose veins, the incompe-
replace the physician’s clinical judgment, which should be tent valves are in the superficial veins, resulting in reflux
appropriately exercised in all cases. and venous stasis of these small vessels. In patients with deep
venous thrombosis, damage to the valves may result in the
Superficial Thrombophlebitis development of postphlebitic syndrome.
Superficial thrombophlebitis is mainly diagnosed on the Doppler ultrasonography is the test of choice to identify
basis of the clinical examination. A palpable red and tender the presence and location of refluxing venous segments.
194
cord representing the thrombosed vessel is characteristic. Retrograde flow of blood in superficial, communicating,

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and deep veins can readily be identified, particularly with
color Doppler study. Venous reflux of more than 0.5 second
is considered abnormal.26
Other studies that aid in the diagnosis of venous insuffi-
ciency include photoplethysmography and direct measure-
ments of venous pressure, which is typically elevated in this
condition. Photoplethysmography relies on color changes
to assess refilling rates of small skin veins after exercise.
These rates are substantially reduced in patients who have
significant venous insufficiency. Direct venous pressure mea-
surements require the placement of a small needle with a
pressure transducer in a vein in the foot.
Veins of the Upper Extremities
As it is for lower extremity deep venous thrombosis, venous
ultrasonography is the favored initial screening test; contrast
venography remains the reference standard for diagnosis
of deep venous thrombosis of the upper limbs. However,
because the proximal sections of the subclavian and innomi-
nate veins are poorly visualized and cannot be compressed
under the clavicle, ultrasonography is not as accurate in this
setting compared with detection of deep venous thrombo-
sis of the legs.27 In patients with central venous catheters
or pacemaker wires, visualization of the entire vein may also
be obscured. Large thrombi are usually identified, but small
thrombi can be missed (Fig. 14.8). Use of dampening or
absence of Doppler signals alone as the criterion for diagno-
sis of deep venous thrombosis is unreliable because extrinsic
A bosis in the central vasculature and may also provide an
B
Figure 14.8 Thrombus surrounding a central venous
catheter. This 29-year-old man with Crohn’s disease presented
with arm swelling. A, Echogenic thrombus (arrows) surrounding the
catheter in the basilic vein. B, The catheter can be seen to extend
more proximally through the subclavian vein into the superior vena
cava. No thrombus surrounds the more proximal portion of the
catheter (arrows) in the subclavian vein.
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venous compression from central masses or strictures can SECTION
produce the same results. Therefore, contrast venography 1
should be used if the ultrasound findings are equivocal and CHAPTER
the clinical features are compatible with upper extremity 14
thrombosis.
ATHEROSCLEROSIS AND ITS PREVENTION: NONCARDIAC VASCULAR DISEASES: Venous Disease
Central Veins
Inferior Vena Cava Thrombosis
Doppler ultrasonography can diagnose venous thrombosis
in the inferior vena cava or the iliac veins in the pelvis
either directly by visualizing the thrombus or indirectly by
detecting dampening of the Doppler spectrum in the com-
mon femoral veins in the legs. Visualization of the inferior
vena cava and iliac veins is sometimes difficult because
of their greater depth and overlying bowel gas, which
frequently blocks the ultrasound beam. Obstruction of the
hepatic veins or the adjacent inferior vena cava (Budd-Chiari
syndrome) can be easily identified by ultrasound examina-
tion because the liver frequently serves as a good acoustic
window in transmitting the ultrasound beam.
Computed tomography and magnetic resonance imaging are
other alternative studies that can demonstrate masses and
thrombosis that obstruct either the pelvic veins or the inferior
vena cava. Contrast agents are required in these tests to help
delineate thrombus from surrounding soft tissue structures.
Superior Vena Cava Thrombosis
Doppler ultrasonography can be used initially to diagnose
superior vena cava obstruction. Central thrombus extending
into the subclavian or more distal vessels can be readily
detected. However, isolated central thrombi in the superior
vena cava and other conditions obstructing central venous
return (e.g., masses or fibrosis) are not well visualized by
ultrasonography because the bony thorax blocks the ultra-
sound beam.
The normal variations that occur from transmitted pres-
sure changes related to respiration and atrial contractions
may be reduced or completely eliminated. In most instances,
contrast-enhanced computed tomography is the test of
choice in investigating a patient with symptoms of superior
vena cava syndrome (Fig. 14.9). This study can detect throm-
Figure 14.9 Obstruction of the superior vena cava caused by
mediastinal adenopathy. In this 55-year-old man with lung
carcinoma, a lymph node mass (arrows) is obstructing the superior
vena cava. Multiple collateral vessels are demonstrated 195
(arrowheads).
SECTION alternative diagnosis for the symptoms of venous congestion MANAGEMENT
1 (e.g., bronchogenic carcinoma).
CHAPTER Magnetic resonance imaging is also being used to evaluate Veins of the Lower Extremities
14 conditions that obstruct the central veins within the thorax. Deep Venous Thrombosis
It can demonstrate venous patency as well as identify The most effective way of reducing the frequency of venous
ATHEROSCLEROSIS AND ITS PREVENTION

thrombi, masses, strictures, or fibrosis, which can obstruct
the veins. Intravascular contrast agents are useful in differen-
tiating thrombus from other pathologic processes. Magnetic
resonance imaging can also be useful in patients who are
not able to receive iodinated contrast media because of
severe allergic-type reactions or renal insufficiency. How-
ever, patients who receive gadolinium-based contrast agents
can also have allergic-type reactions, particularly if they
have been demonstrated to have a previous allergic reaction
to iodinated contrast material. Pacemakers and many types
of cerebral aneurysm clips preclude patients from under-
going this test.
A reasonable diagnostic imaging strategy for suspected
deep venous thrombosis in the upper extremity, neck, or
superior vena cava is shown in Figure 14.10.
DIAGNOSTIC STRATEGY FOR DEEP VENOUS THROMBOSIS
OF THE UPPER EXTREMITIES OR SUPERIOR VENA CAVA
Signs or symptoms of suspected central venous
thrombosis of upper limbs, neck, or chest:
New arm swelling
New asymmetric facial swelling
Upper arm or shoulder pain
Pitting edema of the arm
Cyanosis of the arm
Dilated superficial veins of the chest wall
thrombosis is to use prophylaxis in appropriate clinical situa-
tions. Low-, moderate-, and high-risk situations can be iden-
tified on the basis of the patient’s inherent risk of venous
thromboembolism and the external factors that can heighten
the risk of thrombosis (see Tables 14.1 and 14.2). In high-risk
situations, up to 50% to 60% of the patients may develop
venous thromboembolism, and approximately 2% to 4% of
them will experience fatal pulmonary embolism.28 Although
prophylaxis is effective in reducing the risk by 50% to 80%,
a substantial number of patients with high risk will still
develop deep venous thrombosis. The options for prophy-
laxis are mechanical (e.g., compression stockings, pneumatic
compression devices) and pharmacologic (e.g., subcutaneous
unfractionated or low-molecular-weight heparin). The deci-
sion to use either or both mechanical and chemical prophy-
laxis should take into consideration the patient’s risk
factors for bleeding and the ability of the patient to tolerate
lower extremity compression. Table 14.5 outlines the gen-
eral recommendations for prophylaxis in various medical
and surgical settings.28 Prophylaxis should be continued as
GENERAL RECOMMENDATIONS FOR PROPHYLAXIS OF DEEP
VENOUS THROMBOSIS
General medical disorders
Low-dose unfractionated heparin or low-molecular-weight heparin
Elastic compression stockings may be added to pharmacologic
agents

Ultrasonography Acute spinal cord injury

Low-molecular-weight heparin
If anticoagulation is contraindicated, intermittent pneumatic
Presence of echogenic Equivocal Absence of echogenic compression with elastic compression stockings
material compatible results material*
with thrombus General surgery
Early ambulation
Diagnose upper Serial ultrasonography For low- or moderate-risk surgery, low-dose unfractionated heparin
limb thrombosis in five or more days or low-molecular-weight heparin
Contrast For high-risk surgery (e.g., cancer), low-molecular-weight heparin
venography or For patients with active or a high risk of bleeding, intermittent
computed pneumatic compression
tomography
Orthopedic surgery
For total hip replacement: warfarin, low-molecular-weight heparin,
Intraluminal No intraluminal fondaparinux, or adjusted-dose unfractionated heparin
filling defect filling defect
For total knee replacement: warfarin, low-molecular-weight
heparin, fondaparinux, or intermittent pneumatic compression
Diagnose upper Exclude upper For hip fracture: warfarin, low-molecular-weight heparin, or
limb thrombosis limb thrombosis fondaparinux

Neurosurgery
* In patients with no echogenic material visualized on ultrasound examination,
venography should be performed if the clinical suspicion is high. Otherwise, serial Intermittent pneumatic compression or low-molecular-weight
ultrasonography is a reasonable alternative.
heparin with elastic stockings

196 Figure 14.10 Diagnostic strategy for deep venous thrombosis Table 14.5 General recommendations for prophylaxis of deep
of the upper extremities or superior vena cava. venous thrombosis.

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long as the patient remains at risk for thrombosis, and studies
suggest that prophylaxis should be extended beyond hospital
discharge in certain populations of patients, such as those
having hip replacement or cancer surgery.
The standard treatment of symptomatic deep venous
thrombosis is systemic anticoagulant therapy with a heparin
followed by a coumarin derivative.29,30 Many new antico-
agulants are being developed, and some have the potential
to replace traditional agents.31 In the past decade, the use
of low-molecular-weight heparins has largely replaced the
traditional standard of unfractionated heparin for the initial
treatment of venous thromboembolism, and more recently,
a synthetic, indirect activated factor X inhibitor, fonda-
parinux, was shown to be comparable to heparins for initial
treatment.32,33 In comparison with unfractionated heparin,
low-molecular-weight heparins and fondaparinux have
more predictable anticoagulant effects, require no laboratory
monitoring, can be given subcutaneously, and are associated
with a lower risk of heparin-induced thrombocytopenia. Large
meta-analyses have also shown that unmonitored, weight-
adjusted subcutaneous low-molecular-weight heparin is safer
and more effective than unfractionated heparin administered
by continuous infusion guided by laboratory monitoring of
the activated partial thromboplastin time.34 Low-molecular-
weight heparins and fondaparinux also have the advantage of
being available on an outpatient basis, thereby improving the
patient’s general quality of life and leading to substantial cost
savings by reducing hospitalization.
Once a diagnosis of deep venous thrombosis has been con-
firmed, a low-molecular-weight heparin can be started with
weight-based dosing. Laboratory monitoring is not required
routinely, but it is recommended in patients with renal insuf-
ficiency, with morbid obesity, or who are pregnant. The
peak anti-Xa levels at 3 to 4 hours after an injection should
be measured in these patients because the pharmacokinetics
and pharmacodynamics of these drugs have not been well
studied in these special populations of patients. Similarly,
the distribution and clearance of these drugs may be differ-
ent in patients who have extensive iliofemoral deep venous
thrombosis or who are hemodynamically unstable because
of accompanying pulmonary emboli. These patients require
hospitalization and are usually treated with unfractionated
heparin. Unfractionated heparin should be given as an
initial bolus followed by a continuous intravenous infusion.
A weight-based or standard nomogram should be used to
adjust the dose of unfractionated heparin according to the
activated partial thromboplastin time to ensure that thera-
peutic levels are reached as soon as possible and are main-
tained.35 Like low-molecular-weight heparins, fondaparinux
is given subcutaneously once daily in doses adjusted for
the patient’s weight, and it is cleared by the renal route.
Unlike the heparins, fondaparinux can cross the placental
barrier; it has been used in pregnant women with heparin
hypersensitivity, but the safety data are very limited. These
parenteral agents should be given for a minimum of 5 days
in patients with uncomplicated thrombosis and for 7 days
or longer in those who have extensive disease. These agents
must also be continued until the anticoagulant level achieved
by the coumarin derivative is therapeutic for at least 2 days.
Oral anticoagulant therapy with use of a coumarin deriva-
tive or vitamin K antagonist is usually given within 24 to
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48 hours of starting a heparin or fondaparinux. In North SECTION
America, the most common agent used is warfarin. Because 1
of the narrow therapeutic window, the anticoagulant CHAPTER
response must be measured and monitored on a regular basis 14
to adjust the warfarin dose to maintain therapeutic levels.36
ATHEROSCLEROSIS AND ITS PREVENTION: NONCARDIAC VASCULAR DISEASES: Venous Disease
An international normalized ratio of 2.0 to 3.0 is considered
the acceptable therapeutic range for oral anticoagulation in
deep venous thrombosis. The ratio is calculated on the basis
of the measured prothrombin time and the sensitivity of the
specific reagent used to measure the prolonged clotting
time. This standardization of the prothrombin time measure-
ment allows direct comparisons of results from different
laboratories.
Low-molecular-weight heparin is now the preferred ther-
apy for initial and long-term treatment of deep venous
thrombosis and pulmonary embolism in patients with can-
cer.37,38 It is more efficacious than the traditional regimen
with heparin followed by a coumarin derivative and does
not require laboratory monitoring.
The optimal duration of anticoagulation after an episode of
deep venous thrombosis is dependent on a number of fac-
tors. Clinical trials have shown that a minimum of 3 months
is required, but longer periods of anticoagulation are recom-
mended for patients with ongoing risk factors, such as active
cancer, or who have had previous episodes of thrombo-
sis.39,40 Continuing vitamin K antagonist therapy is highly
effective and will reduce the risk of recurrent thrombosis
by more than 80%, but this is accompanied by a risk of
major bleeding of 1% to 12% per year. Therefore, the deci-
sion to continue or to stop anticoagulant therapy should
be based on the risk of recurrent thrombosis versus the
risk of major, serious bleeding in each individual patient.
Preliminary data have suggested that D-dimer levels may
be useful in stratifying patients into different risk groups
for recurrent thrombosis.41 Some general recommendations
for the duration of therapy are outlined in Table 14.6.
Second-line therapies for acute treatment of deep venous
thrombosis include thrombolytic therapy and inferior vena
cava filter placement. Unfortunately, the efficacy and safety
of these modalities have not been sufficiently investigated in
clinical trials. Catheter-directed or systemic thrombolysis to
treat extensive proximal lower extremity deep venous
thrombosis has been advocated by some, particularly if
the thrombus extends into the iliac veins in the pelvis.
Although there is evidence that radiographic thrombus reso-
lution is accelerated by thrombolytic therapy, significant
improvement in clinical recovery or a reduction in the risk
of postphlebitic syndrome has not been demonstrated.42
Furthermore, the risk of major bleeding, especially intracra-
nial bleeding, is approximately 2% in patients who receive
thrombolysis.43 A recent randomized trial comparing unfrac-
tionated heparin alone with different thrombolysis regimens
showed venographic improvement with thrombolysis but a
substantially higher rate of major bleeding and pulmonary
embolism.44 Clearly, risk assessment tools are necessary to
identify those patients who may benefit from thrombolysis.
Limited evidence is available for the use of inferior vena
cava filters. A multicenter, randomized clinical trial demon-
strated that inferior vena cava filters can reduce the risk of
early pulmonary embolism in patients with proximal deep
197
venous thrombosis who were also treated with anticoagulant
SECTION therapy; but after 2 years, this benefit was lost, and the
1 patients who received a filter were more likely to develop
CHAPTER recurrent deep venous thrombosis.45 Furthermore, there
14 was no difference in the long-term mortality between
patients with a filter and those without. On the basis of cur-
ATHEROSCLEROSIS AND ITS PREVENTION
rent evidence, the insertion of an inferior vena cava filter
should be reserved for settings in which anticoagulation is
contraindicated.46,47 One possible approach to provide early
protection against pulmonary embolism without increasing
the risk of recurrent deep venous thrombosis is to use a tem-
porary or retrievable filter. Further studies are required to
evaluate this potential option.
Venous Insufficiency
Graduated compression stockings remain the first line of treat-
ment for venous insufficiency. Although frequently useful for
reducing swelling and providing pain relief, stockings do not
address the underlying problem of valvular insufficiency.
Compliance also tends to be poor because of cost, unattrac-
tiveness, and difficulty with putting the stockings on. In
patients who are not responsive to conservative measures,
more invasive treatment methods are available. In patients
who have venous insufficiency that is isolated to the superfi-
cial system, the injection of sclerosing agents into the involved
veins may be beneficial in mild cases. More extensive reflux
can be dealt with by stripping, if possible, all of the incompe-
tent veins. Laparoscopic techniques have now been developed
as an alternative to open surgical methods in suitable
patients.48 These measures to deal with reflux of the superfi-
cial veins are not successful if there is also reflux of the deep
veins. Simply stripping or sclerosing the refluxing superficial
venous segments can exacerbate limb swelling by eliminating
collateral pathways. Several surgical techniques are available
for reflux of the deep veins, including direct repair of the
valves and transposition of venous segments with competent
valves. Success rates are disappointing. Patients with skin
ulcerations are treated with local wound care. Skin grafting
and plastic surgery may be required in severe cases.
Superficial Thrombophlebitis
Superficial thrombophlebitis, without accompanying deep
venous thrombosis, usually does not require treatment with
GENERAL RECOMMENDATIONS FOR THE DURATION OF ANTICOAGULATION FOR DEEP VENOUS THROMBOSIS
Patient Characteristics Associated with Thrombotic Event
Reversible major risk factor (major surgery, pelvic or leg trauma, major medical illness)
Weak risk factor (estrogen use, long-distance travel, minor trauma) and no inherited or
acquired thrombophilia identified
Unprovoked thrombotic event with no inherited or acquired thrombophilia identified
Unprovoked thrombotic event with heterozygous factor V
Leiden or prothrombin G20210A mutation
Recurrent unprovoked events with or without thrombophilic state identified
Unprovoked thrombotic event with antithrombin, protein C, or protein S deficiency;
homozygous factor V Leiden; double heterozygosity; antiphospholipid antibody
syndrome; advanced malignant disease
198 *May consider longer duration of therapy on the basis of the patient’s preference and risk of bleeding.
Table 14.6 General recommendations for the duration of anticoagulation for deep venous thrombosis.
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systemic anticoagulation. Warm compresses, nonsteroidal
anti-inflammatory agents, and leg elevation are usually
effective methods of providing symptomatic relief. Patients
who do not respond to these conservative measures will
usually respond rapidly to a short course of subcutaneous
unfractionated or low-molecular-weight heparin therapy.49
Recurrent or refractory cases should prompt the physician
to look for an underlying cause, such as malignant disease
or inherited thrombophilia.
Veins of the Upper Extremities
Deep Venous Thrombosis
Very little research has been done to study the optimal treat-
ment for deep venous thrombosis of the upper extremities.
For patients with either primary (or effort-related) thrombosis
or catheter-related thrombosis of the subclavian or axillary
vein, conventional treatment consists of initial therapy with
either low-molecular-weight or unfractionated heparin, fol-
lowed by long-term oral anticoagulant therapy.50 Anticoagu-
lation should be continued for a minimum of 3 months, longer
if a catheter remains in place. As it is for lower extremity deep
venous thrombosis, the use of thrombolysis or other more
aggressive interventions is controversial.
Many vascular surgeons consider catheter-directed throm-
bolysis to be the preferred initial treatment of selected
patients with primary upper extremity deep venous thrombo-
sis. The risk of recurrent thrombosis and postphlebitic
syndrome may be reduced, but long-term evidence to support
this is lacking. Post-lysis venography may allow better visual-
ization of the involved anatomy to test for positional, extrinsic
venous compression at the thoracic outlet, thereby facilitating
plans for more aggressive intervention, if indicated. Venous
angioplasty and subsequent stenting can correct underlying
strictures, although surgical decompression has been found
to be necessary to maintain long-term venous patency in
patients with significant thoracic outlet obstruction.
Catheter-related thrombosis should be treated conserva-
tively with anticoagulant therapy. Removal of the catheter
is not necessary and has not been shown to improve out-
comes. If the catheter is functioning, routine use should con-
tinue. If the catheter is blocked, patency sometimes returns
after a few days of anticoagulation, and the catheter can
Risk of Duration of
Recurrence Anticoagulant Therapy
<5% per year 3 months
5%-10% per year 3-6 months
10% per year 3-6 months*
>10% per year Extended or indefinite
therapy*
be salvaged for use. Previously, prophylaxis with low-dose
warfarin was recommended, but more studies have shown
that low-dose anticoagulant prophylaxis with either warfarin
or low-molecular-weight heparin is not effective.
Central Veins
Thrombosis of the inferior or superior vena cava requires
systemic anticoagulation to prevent clinically significant
pulmonary emboli and to relieve venous obstruction. Inter-
ventional radiologic techniques can be used to instill throm-
bolytic agents directly into the thrombi in certain patient
subsets. This may result in faster lysis of thrombi and control
of local symptoms. In patients who cannot tolerate anticoag-
ulant therapy, placement of a vena caval filter is indicated
because of the high incidence of pulmonary embolism.
PROGNOSIS
Prognosis depends on the etiology of the venous disease.
Overall, anticoagulant therapy is effective in treating un-
complicated deep venous thrombosis of the upper or lower
extremities. The most common complications are pulmonary
embolism, recurrent deep venous thrombosis, and postphle-
bitic syndrome. Pulmonary embolism occurs in 40% of
patients who present with deep venous thrombosis, but most
of these cases are asymptomatic, and treatment does not
differ. The risk of recurrent thrombosis after a 3-month
course of anticoagulant therapy is approximately 2% to
5% per year in patients with provoked or secondary deep
venous thrombosis and 10% to 15% per year in those with
idiopathic thrombosis. About 5% of the recurrent thrombotic
events are fatal. Postphlebitic syndrome occurs in up to 50%
of patients, but the majority of the cases are mild and
manageable with conservative treatment. Anticoagulant-
related bleeding must also be considered in patients receiving
long-term anticoagulation. The risk of major bleeding is
approximately 1% to 3% per year, but it varies consider-
ably, depending on a number of patient-related factors.
Approximately 20% of all major bleeding events are fatal.
Patients with poor prognosis after an episode of deep
venous thrombosis are those with underlying malignant
disease or aggressive thrombophilia (e.g., antiphospholipid
antibody syndrome). Cancer patients have a substantial risk
of recurrent thrombosis despite conventional anticoagulation
with heparin and vitamin K antagonist therapy. These patients
also have a higher risk of bleeding due to thrombocytopenia,
invasive procedures, and other comorbid conditions. Low-
molecular-weight heparins are more effective and probably
safer than vitamin K antagonist therapy in patients with can-
cer. Although extended or indefinite anticoagulant therapy is
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generally recommended in patients with metastatic disease, SECTION
quality of life and life expectancy are important issues to con- 1
sider in deciding on how long to treat these patients with anti- CHAPTER
coagulant therapy. Indefinite anticoagulant therapy may also 14
be indicated in some patients with symptomatic antiphospho-
ATHEROSCLEROSIS AND ITS PREVENTION: NONCARDIAC VASCULAR DISEASES: Venous Disease
lipid antibody syndrome. Some of these patients are also resis-
tant to conventional anticoagulant therapy, and a combination
of antithrombotic and antiplatelet agents may be necessary to
prevent recurrent thrombotic events.
SUMMARY
Venous thromboembolism is the most common disease
affecting the veins. It affects approximately 0.1% of persons
per year, and the incidence rises dramatically with increasing
age. The basic pathophysiologic process involves perturba-
tion of the hemostatic balance to favor thrombosis. This
can result from venous stasis, vessel wall damage or endothe-
lial dysfunction, or hypercoagulability from excessive activa-
tion of the coagulation pathway. Although many patients
develop deep venous thrombosis in the presence of risk fac-
tors, deep venous thrombosis can also occur without obvious
provocation. Some of the patients with idiopathic thrombosis
have an inherited or acquired thrombophilic condition,
whereas the remainder have no identifiable biochemical or
genetic abnormality. Many noninvasive methods are now
available to diagnose deep venous thrombosis, but contrast
venography remains the reference standard. Compression
ultrasonography is the initial test of choice in evaluating a
patient with suspected deep venous thrombosis of the ex-
tremities, but equivocal or conflicting results require further
confirmatory testing. The cornerstone of deep venous throm-
bosis prevention and treatment is systemic anticoagulant
therapy, which is highly effective but somewhat burden-
some. To reduce the incidence of thrombosis, prophylaxis
should be used in appropriate medical and surgical settings.
In patients with confirmed deep venous thrombosis, outpa-
tient low-molecular-weight heparin therapy is the initial
treatment of choice, but these agents must be given as sub-
cutaneous injections. Long-term therapy with a vitamin K
antagonist is needed to prevent recurrent thrombosis, but
laboratory monitoring is necessary to ensure adequate
anticoagulant levels and to minimize the risk of bleeding.
Monotherapy with low-molecular-weight heparin is pre-
ferred to vitamin K antagonists in patients with cancer. The
long-term prognosis of most patients with venous thrombosis
is favorable, provided the diagnosis is accurate and adequate
treatment is instituted without significant delay. Serious
morbidity and mortality can result from misdiagnosis,
delayed treatment, or treatment-related complications.
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