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reported. In fact, the combination of OCPs with
factor V Leiden heterozygosity increases the risk
of VTE 35-fold [ 50 ]. Heterozygous prothrombin
gene mutation is less affected but still signifi cant
at 16-fold [ 12 ]. Shockingly, the risk of cerebral
venous thrombosis with prothrombin gene mutation and OCP use is increased by a factor of
approximately 150 [ 51 ].
Thrombophilia may present as maternal or
fetal complications during pregnancy. In developed countries, the leading cause of maternal
death is due to pulmonary embolism (PE) and
morbidity caused from PE is as high as 20 % [ 51 ].
Thirty to fi fty percent of pregnancy- associated
VTE have an identifi able inherited hypercoagulable state. Even though factor V Leiden and prothrombin gene mutation are most commonly
found, these patients are at low risk for VTE with
pregnancy. Genetic thrombophilias that are associated with a high risk of venous thrombosis are
protein C or S defi ciency, antithrombin defi ciency,
homozygous states, and compound heterozygosity for prothrombin gene mutation and factor V
Leiden [ 52 ]. Fetal complications that should
increase the suspicion for a possible underlying
thrombophilia are preeclampsia and fetal demise.
Like the antepartum state, the risk of venous
thrombosis continues into the postpartum state
and is higher than that of the antepartum state
[ 53 ]. This risk is present for 6 weeks to 2 months
after delivery. No offi cial guideline for thromboprophylaxis during pregnancy is established to
date. The risk is individualized and unfractionated
heparin, as well as LMWH, has been used for
treatment and prophylaxis in the appropriate clinical situation.
Hormone replacement therapy (HRT) has been
a subject of controversy and debate. It is clear that
oral HRT is risk factor for venous thrombosis.
There is a two- to threefold increased risk of VTE
in the presence of oral HRT. The risk is highest
within the fi rst year of initiation. This risk is not
equivalent when comparing oral estrogens to
transdermal estrogen formulations. Hepatic
metabolism of oral estrogens through the fi rst-pass
effect shifts the hemostatic balance in favor of
thrombosis. There is also a decrease in antithrombin production when oral estrogens are used. Due
Table 22.5 Chronic illnesses with an increased risk for
thromboembolism
Chronic illnesses Infectious diseases
Malignancy HIV
Crohn’s disease CMV
Ulcerative colitis Q fever
Collagen vascular disorders Syphilis
Paroxysmal
nocturiahemoglobinuria (PNH)
Hyperviscosity syndromes Pneumocystis
Myeloproliferative disorders
Nephrotic syndrome
Malaria
to the difference in metabolism, these changes are
not as readily observed with a transdermal preparation. With the addition of an inherited thrombophilia, the risk of VTE increases appreciably [ 10 ].
22.8.5 Chronic Illnesses or Diseases
Many chronic illnesses, controlled or uncontrolled, may increase the incidence of developing
a thrombosis (Table 22.5 ). Some illnesses may
have an underlying genetic susceptibility that
becomes activated later in life which initiates a
reaction that further triggers the onset of the
disease. A patient may have a genetic predisposition for the illness but it is acquired until later in
life. The exact circumstance that induces the
expression of the disease is often not identifi ed.
Infl ammatory bowel disease is a disorder that is
well known to have an association with an
increased risk of venous thromboembolism.
However, other illnesses, such as rheumatoid
arthritis, are reported to have possible associations. A thorough patient history may uncover a
potential hypercoagulable state.
22.9 Genetic Testing for Family
Members
When compared to the vast list of acquired
hypercoagulable risk factors, there are few inherited abnormalities of coagulation that should
be considered for familial testing. Siblings and
children of the affected person are candidates
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S.M. Dentoni
for evaluation. However, genetic testing is not
routine and consequences of a positive test
must be considered prior to evaluation. When
determining who is a candidate for testing, the
underlying familial abnormality impacts who
is tested. Some genetic disorders are regarded
as more powerful based on their VTE risk profi le. Homozygous factor V Leiden, homozygous
prothrombin gene mutation, double heterozygous factor V Leiden and prothrombin gene
mutation, protein C and S defi ciencies, and antithrombin defi ciencies are established as a high
risk group and fi t into this category. An argument
can be made for familial testing depending on
clinical risk factors of the individual such as a
the possible acquisition of a reversible risk factor which may have an impact on long-term
morbidity and mortality (i.e., immobilization,
long travel, medications, or pregnancy). The
presence of heterozygous factor V Leiden or
heterozygous prothrombin gene mutation without other risk factors generally has no impact on
current management [ 54 , 55 ].
22.10 Anticoagulation Prophylaxis
During Lower Extremity
Venous Procedures in
Thrombophilic Patients
Currently, there are no guidelines available for
the indication of prophylactic intensity anticoagulation during lower extremity venous procedures. To make matters more confusing, there
is no consensus among phlebologists for the
use of prophylactic anticoagulation during these
procedures.
Understanding thrombophilia, identifying
potential hypercoagulable patients, and evaluating
situational risk factors will help guide decision in
the use prophylactic intensity anticoagulation.
The risk/benefi t profi le of low- dose anticoagulation is favorable in most situations and should be
considered in any patient who may be predisposed to having a periprocedural venous thromboembolism. In fact, at the time of a minimally
invasive venous procedure, if a patient is on anticoagulation for reasons other than a venous
thromboembolic event, some phlebologists feel
that it is not necessary to interrupt anticoagulation and the procedure can be accomplished on
full anticoagulation. This author believes that in
most circumstances, a patient with a congenital,
acquired, or situational hypercoagulable state
should be on prophylactic intensity anticoagulation (if not already on therapeutic intensity anticoagulation) starting the morning of the procedure
and continued for 7–10 days. At the completion
of anticoagulation, the absence of thrombus
extension at or near the junction of the deep
venous system should be documented by ultrasound evaluation. It is my practice to again evaluate the treated lower extremity by ultrasound 1
week after discontinuation of anticoagulation to
ensure the absence of thrombus in the deep
venous system and document the stability of any
superfi cial thrombus previously identifi ed. It is
important to realize that recommendations
regarding anticoagulation prophylaxis for venous
procedures are variable within the phlebologic
community. All risks and benefi ts of the proposed
procedures and the patient’s thrombophilic profi le must be well thought-out prior to determining
the most appropriate treatment course. Patients
must have a clear understanding of all the options
and possible outcomes. If uncomfortable with the
clinical situation, reevaluate the treatment plan.
Not every patient with varicose vein disease is an
appropriate candidate for invasive or minimally
invasive treatment. Conservative treatment with
the daily use of medical strength compression
stockings may be the best option.
Conclusion
With the advances in vein treatment and the
evolving area of thrombophilia, a clear understanding of lurking hypercoagulable states is
imperative when providing the best possible
care and treatment for a patient. Both inherited and acquired thrombophilic states are
identifi ed when the appropriate level of clinical suspicion is used. Disease states and illnesses not often recognized as risk factors for
VTE are defi ned. The appropriate diagnosis,
prophylaxis, and treatment will improve
the patient’s outcome and prevent long- term
22 Thrombophilias
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323
consequences that carry high morbidity. Genetic
testing is controversial in many instances and
may be recommended if the result will have a
signifi cant impact on the patient.
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Part VI
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Special Topics
Lymphedema
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James Laredo and Byung Boong Lee
2 3
Contents
23.1 Introduction ................................................ 327
23.2 Anatomy and Physiology ........................... 328
23.3 Pathophysiology ......................................... 329
23.4 Stages of Lymphedema .............................. 330
23.5 Primary Lymphedema ............................... 331
23.6 Secondary Lymphedema ........................... 332
23.7 Diagnosis ..................................................... 332
23.7.1 Clinical Evaluation....................................... 332
23.7.2 Noninvasive Radiologic Studies .................. 334
23.7.3 Minimally Invasive Radiologic Studies ....... 334
23.8 Treatment of Lymphedema ....................... 335
23.8.1 General Considerations ................................ 335
23.8.2 Physical Treatments ..................................... 335
23.8.3 Prevention of Infection ................................ 338
23.8.4 Pharmacologic Treatment ............................ 338
23.8.5 Surgical Therapy .......................................... 338
References ................................................................. 339
Abstract
Lymphedema is the result of impaired lymphatic function. Lymphedema is characterized
by swelling of tissues, most commonly involving the lower extremities in 80 % of cases. It
can also occur in the arms, face, trunk, and
external genitalia. Leg edema is a common
condition that is seen by all practicing clinicians. The differential diagnosis of lower
extremity edema is extensive and includes
systemic causes such as congestive heart failure, renal insuffi ciency, hepatic insuffi ciency,
hypoalbuminemia, and medications and local
causes such as deep vein thrombosis, venous
insuffi ciency, lymphedema, lipedema, and
cellulitis. A detailed understanding of the
anatomy and physiology of the lymphatic system and the pathophysiology of lymphedema
will contribute to the proper diagnosis and
treatment of this complex and important clinical condition.
23.1 Introduction
J. Laredo , MD, PhD, FACS, RVT, RPVI (*)
Department of Surgery, Division of Vascular Surgery ,
George Washington University Medical Center ,
22nd and I Street, NW, 6th Floor ,
Washington , DC , USA
e-mail: jlaredo@mfa.gwu.edu
B. B. Lee , MD, PhD, FACS
George Washington University Medical Center ,
Washington , DC , USA
e-mail: bblee38@comcast.net
E. Mowatt-Larssen et al. (eds.), Phlebology, Vein Surgery and Ultrasonography,
DOI 10.1007/978-3-319-01812-6_23, © Springer International Publishing Switzerland 2014
Lymphedema is the result of impaired lymphatic
function. The lymphatic system is an essential
component of the human circulatory system. It is
comprised of a complex network of vessels. The
major function of the lymphatic system is the
maintenance of interstitial fl uid homeostasis and
prevention of edema [ 1 , 2 ]. Other important func-
tions include transportation of white blood cells
and antigen-presenting cells to the lymphoid
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J. Laredo and B.B. Lee
organs and lipid absorption from the gastrointestinal tract [ 1 , 2 ].
Lymphedema is characterized by swelling of
tissues, most commonly involving the lower
extremities in 80 % of cases [ 3 , 4 ]. It can also occur
in the arms, face, trunk, and external genitalia. Leg
edema is a common condition that is seen by all
practicing clinicians. The differential diagnosis of
lower extremity edema is extensive and includes
systemic causes such as congestive heart failure,
renal insuffi ciency, hepatic insuffi ciency, hypoalbuminemia, and medications and local causes such
as deep vein thrombosis, venous insuffi ciency,
lymphedema, lipedema, and cellulitis [ 2 – 5 ].
A detailed understanding of the anatomy and
physiology of the lymphatic system and the
pathophysiology of lymphedema will contribute
to the proper diagnosis and treatment of this complex and important clinical condition.
23.2 Anatomy and Physiology
The lymphatic system is found throughout the
body and is composed of four components: lymphatic vessels, lymph fl uid, lymph nodes, and
lymphocytes [ 1 , 2 ]. Lymphatic vessels generally
accompany the venous system throughout the
body except in the central nervous system,
hepatic sinusoids, and cortical bony skeleton,
where these perivascular spaces serve the function of the lymphatic vessels [ 1 – 3 ]. Lymphatic
fl uid from the lower extremities, pelvis, abdominal viscera, thorax, left arm, and left head and
neck drains into the central venous system via the
thoracic duct. Lymphatic fl uid from the right
arm, right head and neck, and parts of the thorax
drains into the central venous system via the right
lymphatic duct [ 1 – 3 ]. Numerous interconnec-
tions exist as well as signifi cant variants [ 1 ]. In
addition, an extensive system of superfi cial lymphatic vessels extends over the surface of the
entire body draining into communication watersheds, regional lymph nodes, and ultimately the
deep lymphatic system.
Analogous to the venous system, the lymphatic
system has both a superfi cial and deep system in
the extremities that is separated by the muscle
fascia (Fig. 23.1 ). The superfi cial lymphatic sys-
tem collects lymph from the skin and subcutaneous tissue, and the deep lymphatic system collects
lymph from subfascial structures, such as the
muscle, bone, and deep blood vessels. The superfi cial and deep systems of the lower extremities
merge within the pelvis and those of the upper
extremity merge in the axilla. The two drainage
systems function in an interdependent fashion
such that the deep lymphatic system participates
in lymph transport for the skin during lymphatic
obstruction [ 1 – 3 ].
The lymphatic vasculature is composed of a
hierarchal network of initial and collecting lymphatic vessels that exhibit molecular, cellular,
and functional differences. Initial lymphatic vessels consist of a single layer of endothelial cells
with end-to-end or overlapping junctions
[ 1 , 2 , 6 ]. The basement membrane is scant or
absent around the initial lymphatic vessels, which
are connected to the extracellular matrix by
fi brillin- containing anchoring fi laments. These
anchoring fi laments may modulate the uptake of
interstitial fl uid through molecular signaling in
addition to pulling apart endothelial cells. The
initial lymphatic vessels drain into the collecting
lymphatics (Fig. 23.2 ) [ 1 , 6 ].
Collecting lymphatic vessels are composed of
endothelial cells that are surrounded by a welldefi ned basement membrane. Intraluminal bicuspid valves are present within the collecting
lymphatic vessels. Valves partition collecting
lymphatic vessels into discrete contractile segments, termed “lymphangions,” which are surrounded by the smooth muscle and contract to
actively transport lymphatic fl uid through lymph
nodes and throughout the lymphatic system
(Fig. 23.2 ) [ 1 , 2 , 6 ].
Since the lymphatics lack a central pump, lymphatic fl uid is propelled through the lymphatics
through the concerted effects of respiratory
motions, skeletal muscle contractions, and the
autocontractility of the mural smooth muscle of
the vasculature itself. In the skeletal muscle, lymphatics are usually paired with arterioles, so that
arterial pulsations can also contribute to the periodic expansion and compression of the initial lymphatic vessels to enhance fl uid uptake [ 1 – 3 , 7 ].
23 Lymphedema
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Fig. 23.1 Schematic
diagram of the lymphatic
system demonstrating the
superfi cial and deep
lymphatics and lymph nodes
329
23.3 Pathophysiology
Lymphedema is an imbalance between lymphatic
fl uid formation and lymphatic fl uid absorption,
representing a high-output or low-output failure
of the lymphatic system or a combination of both.
The increase of interstitial fl uid leads to a cascade
of remodeling that leads to permanent changes in
the tissues of the affected limb [ 1 – 3 , 7 ].
High-output failure (also known as dynamic
insuffi ciency) occurs when excessive lymphatic
fl uid formation exceeds the transport capacity of the intact lymphatic system. Increases
in lymphatic fl uid production may arise when
Starling forces shift net pressure to favor the
fl ow of fl uid into the interstitium. Increases
in venous pressure result in increased hydrostatic pressure within the venules, and capillaries increase the driving force for ultrafi ltration
[ 1 – 3 ]. The loss of oncotic pressure, as seen in
hypoproteinemic states such as malnutrition,
has a similar effect. Elevated venous pressure
occurs in patients with right heart failure, deep
vein thrombosis, and venous insuffi ciency.
Local infl ammation increases capillary permeability, accelerating the loss of fl uid and plasma
proteins into the interstitium [ 1 – 3 ].
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J. Laredo and B.B. Lee
Afferent
lymph vessels
10×
Cortical
sinus
Medulla
Capsule
Fig. 23.2 Schematic diagram of the lymphatic vessels.
Note the initial lymphatic vessels that are represented as
solid green, smaller-diameter vessels that drain into the
larger-diameter collecting lymphatic vessels. Note the
In contrast, low-output failure (also known as
mechanical insuffi ciency) occurs when there is
injury or impairment of the lymphatic system due
to paralysis, obstruction, or inadequacy of the lymphatics (e.g., lymphedema from fi larial lymphatic
obstruction or congenital hypoplasia) [ 1 – 3 ]. As
lymphatic obstruction progresses, tortuosity, dilatation, and pooling of lymphatic fl uid give way to
massive ectasia, valvular destruction, retrograde
lymph fl ow, and lymph coagulation. Intrinsic
truncal contractions fail; intraluminal valves
give way, and hydrostatic pressure increases in
the superfi cial valveless lymphatic watersheds.
Chronic infl ammation results in mast cell infi ltration, disruption of the interstitial elastin fi ber
network, intense lymphangiogenesis and hemangiogenesis, fi brosis, progressive fat deposits, and
skin thickening [ 1 – 3 ].
Dermal edema is the hallmark of lymphedema
and represents the earliest clinical manifestation
of lymphatic impairment [ 1 , 2 ]. The presence of
dilated lymphatic vessels may also be evident.
With prolonged lymphatic impairment, tissue
changes include fi broplasia, hyperkeratosis, and
increases in stromal cells. In addition, elastic tissue fragmentation, clumping, and loss of mature
elastic fi bers also occur. Abundant subcutaneous
fat becomes a predominant component of the
swelling seen in the affected limb [ 3 , 7 ].
Trabeculae
Medullary
sinus
Subcapsular
Blood vessel
entering the
hilum
Lymphocytes in
outflowing lymph
Efferent
lymph vessel
smooth muscle cells around the collecting lymphatics and
the presence of valves. Segments of collecting lymphatic
vessels located between two valves are known as
“lymphangions”
sinus
Slow flowing
lymph
Lymphocyte
Reticular fiber
The infl ammatory cells present in the edematous tissue contribute to the ongoing fi brosis. It is
believed that the infl ammatory cells fail to
migrate to the lymph nodes due to impaired lymphatic transport and dysfunctional lymphangiogenesis, leading to worsening edema and further
infl ammation. This ultimately results in impaired
immune traffi cking and decreased clearance of
pathogens [ 1 , 2 ].
Lymphedema is a progressive and usually
painless swelling of the limbs or genitals that is
the result of decreased transport capacity of the
lymphatic system. Lymphedema can be primary
or secondary. Primary lymphedema is due to a
defect in the lymph conducting pathways.
Secondary lymphedema is due to an acquired
cause (such as fi lariasis, previous surgery, radiation therapy, malignancy, infection, and infl ammation) that results in injury and impairment of
the lymphatic system (Fig. 23.3 ) [ 2 – 4 , 7 , 8 ].
23.4 Stages of Lymphedema
Regardless of the etiology, lymphedema is clinically staged by the extent of visible tissue degradation (Table 23.1 ) [ 9 – 12 ]. In the early stages of
lymphedema (stage I), the associated limb swelling resembles other types of edema such as that
23 Lymphedema
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Primary
(inherent defect)
Cogenitial (Age<1 year)
Aplastic lymphatics
Typically bilateral lower extremities
Lymphedema
praecox (Age 1–35years)
Hypoplastic lymphatics
Typically unilateral (foot and calf),
often adolescent
Lymphedema tarda (Age >35 years)
Fig. 23.3 Primary and secondary lymphedema.
Lymphedema is the result of decreased transport capacity
of the lymphatic system. Lymphedema can be primary or
Lymphedema
Secondary
(extrinsic damage)
Chronic venous insufficiency
Filariasis
Recurrent infection
Surgery involving lymphatics
Radiation therapy
Malignancy/tumour (advanced)
Trauma
secondary. Primary lymphedema is due to a defect in the
lymph conducting pathways. Secondary lymphedema is
due to an acquired cause
Table 23.1 Stages of lymphedema
Latency Risk for lymphedema present. No clinical
change evident
Stage I Pitting, reduces overnight with simple
measures (elevation). No fi brosis
Stage II No longer pitting, no full reduction with
elevation, evident fi brosis
Stage III Nonreversible, hardened fi brosis and
sclerosis of cutaneous and subcutaneous
tissues
seen with congestive heart failure, renal insuffi ciency, and venous disease. At this stage, the
swelling is completely relieved with elevation
usually pitting with no evidence of fi brosis. As
the condition progresses (stage II), the edema is
no longer relieved with elevation or rest, and skin
changes begin to appear such as induration of the
skin and progressive hardening. The edema also
becomes nonpitting. In the late, chronic stage of
lymphedema (stage III), the edema is severe, and
the skin is fi brotic with numerous skin changes
that include hyperkeratosis, warty projections,
cobblestoning, and lichenifi cation (Fig. 23.4 ).
Stage III lymphedema is also known as “elephantiasis” because the affected limb begins to resemble the leg of an elephant [ 9 , 10 , 13 ].
23.5 Primary Lymphedema
In patients with primary lymphedema, the cause of
decreased lymphatic transport can be an intrinsic
“defect” or a malfunction of the lymph conducting
elements, which is believed to be a genetically
determined abnormality of lymph drainage [ 2 ].
The majority of lymphedemas classifi ed as primary lymphedema have inborn abnormalities of
the lymphatic system that manifest mostly with
irregular or abnormal structural development
caused by abnormal (mutant) genes [ 2 , 11 ]. These
abnormalities result in lymphatic hypoplasia, aplasia, numerical hyperplasia, or dilation (lymphangiectasia) with valvular incompetence [ 2 , 11 ].
Primary lymphedemas have been classifi ed into
three groups, depending on the age of onset: congenital (before age 2), praecox (onset between ages
2 and 35), and tarda (after age 35). Lymphedema
praecox is the most common form of primary
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