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84 Chapter 8 Molecular mechanisms of CVD and its progression to VLU
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irreparable damage to the mitochondria, DNA, lipid peroxidation, and protein oxidation and nitration, leading to
modication of many proteins and inactivation of multiple
enzymes, and ultimately disruption of cellular functions.
7
ONOO– affects DNA and causes single-strand breaks,
which activates poly-ADP ribose polymerase (PARP) and
builds at the DNA nicks a branched poly-ADP-ribose
(PAR) polymer to initiate the repair process.
50
In a study to
evaluate ONOO– and PARP activity, the researchers evaluated tissue biopsies of VLU versus normal tissue as control
and found both elevated PAR (PARP, DNA damage/repair)
and elevated nitrotyrosine (an ONOO– metabolite).
50
This
indicated that the pathophysiology of VLU in part involves
the generation of ONOO– with its many destructive properties, including DNA damage. Of note, ONOO– and its
damage of DNA could lead to gene mutations and carcinogenic transformation of VLU, as is seen with squamous cell
carcinoma.
7
Future work should examine if inhibition of
ONOO– formation can alter the progression of VLU and
improve healing.
Accumulating research evidence has demonstrated
other potential biomarkers, including cytokines,
chemokines, growth factors, and proteolytic enzymes
(MMP, EMMPRIN, TIMP), in tissue specimens, serum,
and wound uid from patients with VLU.
20
In addition, changes in the levels of membrane type MMPs
(MT-MMPs) and a disintegrin and metalloproteinase
with thrombospondin motif (ADAMTS) have been associated with various stages of CVD and VLU.
7,21
While
the presence of these inammatory biomarkers might
be an epiphenomenon, they could have an integral function in the pathophysiology of CVD and VLU, providing
important areas for further research studies and future
clinical treatments.
8.9 CONCLUSION
The pathophysiology of CVD and VLU is complex and
multifactorial, involving predisposing genetic and environmental factors, alterations of key functional proteins and
enzymes, endothelial dysfunction, changes in shear stress,
injury to the glycocalyx, and activation of several adhesion molecules. These events lead to leukocyte activation
and transmigration into the vein wall, valves, and interstitium, with the release of different cytokines, chemokines,
growth factors, and proteolytic enzymes. Various metabolites have been identied and may represent signatures
of metabolic cellular dysfunction. Venous dysfunction and
inammation of the lower limb tissue ensue, leading to the
manifestations observed clinically as CVD and VLU. Further escalating the inammatory process is oxidative stress
driven by iron deposition from erythrodiapedesis and red
blood cell degradation, resulting in toxic levels of iron and
generation of reactive oxygen and nitrogen species. These
oxidative and nitrating compounds disrupt multiple cellular functions and cause tissue damage. Ultimately, progressive inammation leads to advanced forms of CVD, skin
changes, and VLU. Further research of the pathophysiology and mechanistic pathways will provide a better understanding of the complex disease process and help develop
new and targeted therapies of CVD and VLU.
ACKNOWLEDGMENTS
Dr. R.A. Khalil was supported by the BRI Fund to Sustain
Research Excellence from Brigham Research Institute and
grants from the National Heart, Lung, and Blood Institute
(HL111775, R56HL147889, and R01HL147889-A1).
Consensus Statements 8.0 of the American Venous Forum on the molecular mechanisms of chronic venous disease
and its progression to venous leg ulcer
No. Consensus Statements
8.1 Genetic predisposition, gene polymorphisms, and environmental factors participate in the development of CVD.
8.2 Venous reux, valve incompetence, and venous obstruction cause venous hypertension.
8.3 Endothelial dysfunction, changes in shear stress, glycocalyx injury, and expression of adhesion molecules promote leukocyte
adhesion and initiate an inammatory response.
8.4 Changes in structural proteins such as collagen and elastin are key features in varicose veins likely due to post-translational
modications by matrix metalloproteinases (MMPs), resulting in vein wall weakness and decreased elasticity.
8.5 Inammatory cell inltration and cytokine accumulation are accentuated with the progress of CVD, particularly in ulcers, as
they attempt wound closure, but could also be responsible for persistently impaired wound healing.
8.6 Changes in connexins and other junctional proteins, erythrocyte inltration, hemosiderin release, iron deposition, accumulation of tissue metabolites, and the generation of reactive oxygen and nitrogen species cause signicant cellular damage and
aggravate ulcers, while the physiological enzyme activities to restore cellular function and promote healing are compromised.
8.7 Genome-wide association studies have conrmed a genetic predisposition with characteristic phenotypes and CVD. Additional cytokines, growth factors, proteolytic enzymes (ADAMTS, MT-MMP), degradomic molecules, and metabolic signatures
have been detected in ulcers and could affect ulcer progression and the healing process.
8.8 Understanding the genetic, cellular, and molecular pathways could help to design new approaches to halt CVD progression
to ulcer. Identifying the sequence of molecules involved in pathology and the healing process will provide new biomarkers for
disease progression, the stage of wound healing, and identify potential targets for therapy.
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CHAPTER
9
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Classification of chronic venous
disorders of the lower limbs
Fedor Lurie and Patrick Sullivan
9.1 INTRODUCTION
The need for standard terminology and uniform nosology is
fundamental to advancing the science and clinical communication about chronic venous disorders (CVDs). Semantic
ambiguities that until the 1990s persisted in the literature
and clinical records impeded progress in understanding
venous pathology and created communication gaps among
practitioners, researchers, and payers. Introduction of
duplex ultrasound scans in the 1980s made it possible to
localize pathological and pathophysiological abnormalities
of individual segments of the lower extremity veins. Availability of such diagnostic information crystalized the need
for a unifying classication of CVD that includes a standard description of the clinical presentation of the lower
limbs, anatomical location of different types of pathological changes in the venous system, and the etiological nature
of these pathologies. After the fth annual meeting of the
American Venous Forum (AVF), Drs. Kistner and Eklof
formed a working group that included Drs. Comerota,
Nicolaides, Raju, Richardson, and Strandness. They convened the First Pacic Vascular Symposium in June 1993
and proposed an additional pathophysiologic component
into the classication of CVD. In the following year, the
AVF held a consensus conference at its sixth annual meeting, at which an international subcommittee developed the
rst Clinical-Etiological-Anatomical-Pathological (CEAP)
document and a reporting standard for CVD.[1, 2]
9.2 DEVELOPMENT AND EVOLUTION
OF THE CEAP CLASSIFICATION
As a nosologically constructed group, CVD includes a wide
variety of conditions that differ in etiology, pathological
processes, hemodynamic abnormalities, and anatomical
location of the pathological changes. Yet, clinical manifestations of these disorders are very similar or identical.
Etiological factors and specic pathological processes in
their interaction with the physiological and psychological
background of a specic patient dene the severity of CVD,
making the relationship between clinical manifestations
and severity of CVD quite illusionary. Realizing this complexity, the CEAP subcommittee decided to clearly separate
the descriptive classication of CVD from an instrument
that can assess the severity of CVD. The latter has evolved
into the Venous Clinical Severity Score (VCSS), which is
described in another chapter.[3]
With the understanding that a classication system
reects the state of knowledge at the time of its creation,
the CEAP was intended to be a dynamic document, requiring revisions and clarications as new evidence and science
emerge. However, the four main components of this classication are thought to remain stable over time, reecting
the four major relatively independent dimensions of CVD:
the clinical signs (clinical class) “C,” etiology “E,” anatomical location of a pathology “A,” and the description of the
pathology “P.” Separation of the four components allows
correlating clinical signs of CVD with underlying pathology. Although CEAP describes a lower limb at a point of
time, serial investigations of the same limb provide vital
information for studies of natural history and the impact
of different treatment modalities.
After endorsement by the joint councils of the Society
for Vascular Surgery and the North American Chapter
of the International Society for Cardiovascular Surgery,
CEAP classication was disseminated through a variety
of journals and books worldwide and became universally
accepted as a standard for describing a limb affected by
CVD. Increasing use of CEAP classication in clinical practice highlighted some deciencies of this instrument. Following results of the European Venous Registry, rening
the “C” of CEAP was suggested at the International Union
of Phlebology congress in Rome in 2001.[4] In April2002,
the AVF established an ad hoc committee on CEAP, which
completed its work in 2004 by publication of the revision
of the CEAP classication.[5] The revisions included the
division of class C4 into two subgroups that reect a different risk for ulceration; a new descriptor, n, for “E,” “A,”
and “P” when no venous abnormality is identied; and two
options for writing the CEA—the “advanced CEAP” and
the simplied “basic CEAP.” In addition, the 2004 revision
included denitions of the terms atrophie blanche, corona
phlebectatica, eczema, edema, lipodermatosclerosis, pigmentation, reticular vein, telangiectasia, varicose vein, and
venous ulcer. These denitions served as a starting point
for the development of standard venous terminology,
published in two international consensus documents—
VEIN-TERM and Vein Glossary.[6, 7]
DOI: 10.1201/9781003328971-10
8787
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In the years since publication of the 2004 revision of
CEAP, it became apparent that the classication needs
more precise nomenclature, better description of the
properties of diagnostic tests, and better denitions of the
underlying pathology.[8, 9] In May2017, the AVF created
a CEAP task force charged with revision of CEAP. The
task force followed a modied Delphi consensus process
guided by four principles: preservation of reproducibility,
compatibility with prior versions, evidence based, and
practicality.
The sole purpose of CEAP is to describe a lower limb of
a patient with CVD at a single point in time. Reproducibility, meaning that two different clinicians assessing the same
patient at the same time point should agree on the patient’s
CEAP classication, is the most important property of
CEAP. However, repeatability (assessing the same patient
at a different time point when the disease may have progressed or regressed) and responsiveness (assessing change
in CEAP after treatment) are not the focus of CEAP. Therefore, only studies that address the reproducibility were
considered in the analysis of evidence and revision process.
Extensive revisions may limit opportunities for meta-analyses and comparative evidence synthesis. Therefore, only
revisions that allowed comparisons between the newest
and previous versions of CEAP were considered if they
were supported by an appropriate level of evidence. In
addition, a balance was considered between a highly specic description of a lower limb and a classication that is
sufciently simple for use in routine clinical settings. The
revisions suggested by the task force were approved by the
AVF at the 31st annual meeting in February2019 and published in 2020 [10] (Table9.1).
9.3 TERMINOLOGY
AND DEFINITIONS
The terminology used in the CEAP classication is dened
in VEIN-TERM and Vein Glossary documents [6, 7] with
a few clarications included in the 2020 update.[10] As a
clinical descriptive classication of CVDs, CEAP should be
applied only to limbs that are affected by such, dened as
“the full spectrum of morphological and functional abnormalities of the venous system.”[6]
9.3.1 Key terms used in CEAP 2020
9.3.1.1 Atrophie blanche (white atrophy)
Localized, often circular, whitish and atrophic skin areas
surrounded by dilated capillaries and sometimes hyperpigmentation. Atrophie blanche is not to be confused with
healed ulcer scars, which may also exhibit atrophic skin
with pigment changes, but are distinguishable from atrophie blanche by appearance and by a history of ulceration
and are excluded from this denition.
9.3.1.2 Axial reflux
Uninterrupted retrograde venous ow from the groin to the
calf. Supercial reux is conned to the supercial venous
TABLE 9.1 The updated 2020 CEAP classication of
chronic venous disorders. [10] A. Summary of the
clinical (C) classication. B. Summary of the etiology
(E) classication C. Summary of the anatomic (A)
classication. D. Summary of the pathologic (P)
classication
A. Clinical class “C” Each clinical class subcharacterized by a
subscript indicating the presence (symptomatic, S) or absence
(asymptomatic, A) of symptoms attributable
Clinical
class
C0 No visible or palpable signs of venous disease
C1 Telangiectasias or reticular veins
C2 Varicose veins
C2r Recurrent varicose veins
C3 Edema
C4 Changes in skin and subcutaneous tissue secondary
C4a Pigmentation or eczema
C4b Lipodermatosclerosis or atrophie blanche
C4c Corona phlebectatica
C5 Healed venous ulcer
C6 Active venous ulcer
C6r Recurrent active venous ulcer
B. Summary of the etiology (E) classication
E class Description
Ep Primary
Es Secondary
Esi Secondary e intravenous
Ese Secondary e extravenous
Ec Congenital
En No cause identied
C. Summary of the anatomic (A) classication. In advanced
CEAP use common anatomical abbreviations for venous segments.
A class Description
As Supercial
Ad Deep
Ap Perforator
An No venous anatomic location identied
D. Summary of the pathologic (P) classication
P class Description
Pr Reux
Po Obstruction
Pr,o Reux and obstruction
Pn No pathophysiology identied
Description
to CVD
system, deep reux is conned to the deep venous system,
perforator reux to the perforating system, and combined
reux involves any combination of the three venous systems (supercial, deep, perforating).
9.4 CEAP 2020 89
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9.3.1.3 Chronic venous insufficiency
A term reserved for advanced CVD (C3–C6 classes of the
CEAP classication) that is applied to functional abnormalities of the venous system producing edema, skin
changes, or venous ulcers.
9.3.1.4 Corona phlebectatica (corona phlebectatica
paraplantaris)
Fan-shaped pattern of numerous small intradermal veins
on the medial or lateral aspects of the ankle and foot.
9.3.1.5 Eczema (venous eczema, stasis dermatitis)
An inammatory and pruriginous condition of the skin of
the lower legs resulting from venous hypertension (reux,
obstruction, obesity, articular ankylosis). It may be acute
(redness, exudation, oozing) or chronic (dry and lichenied skin). Contact dermatitis is quite often associated with
venous eczema; allergological investigations are mandatory to detect sensitization.
9.3.1.6 Edema (venous edema, phlebedema)
Limb swelling observed mainly in the evening. It is relieved
by elevating the legs, using compression stockings, or taking venoactive drugs. Venous edema occurs as a result of
supercial and/or deep venous insufciency or venous outow obstruction.
9.3.1.7 Incompetent vein
A vein where the blood ow could move both along
its usual antegrade path and backward in the opposite
direction due to malfunctioning (incompetent) venous
valves.
9.3.1.8 Outflow obstruction
Hemodynamic concept. Abnormal venous ow caused by
venous occlusion, stenosis, or compression.
9.3.1.9 Pigmentation or hyperpigmentation
Darkening of an area of the skin that may be due to an
excess of melanin or, in the context of venous disease,
increased hemosiderin deposits. It is one of the clinical
signs of chronic venous insufciency.
9.3.1.10 Reticular vein
Dilated bluish subdermal veins that range from 1mm to
<3mm in diameter and are usually tortuous. This excludes
normal visible veins in people with thin, transparent skin.
Synonyms include blue veins, subdermal varices, and
venulectases.
9.3.1.11 Telangiectasia
Small, dilated, at, thin-walled, blue or red veins <1mm in
diameter that are seen near the surface of the skin. Numerous telangiectasias near the foot and ankle are termed
corona phlebectatica paraplantaris. Commonly termed
spider veins, they are distinguished from reticular veins by
having no prole.
9.4 CEAP 2020
9.4.1 Clinical class
Several manifestations of CVD tend to recur. Recurrent
disease is a clinical term that includes residual veins and/or
varicose veins occurring as a disease progression after prior
treatment.[11] Venous ulcers also have a high recurrence
rate.[12] Recurrent disease has a different natural history
and frequently requires different treatment strategies. For
these reasons, the subscript (r) for recurrence has been
added to the C2 and C6 classes designation (C2r or C6r).
Corona phlebectatica would likely be classied as C1
clinical class in the 2004 revision of CEAP. However, corona
phlebectatica can be an early sign of advanced venous disease. Aclinical series of 872 patients evaluated by 49 venous
specialists demonstrated high prevalence of more advanced
C clinical class in limbs with corona phlebectatica.[13] The
presence of corona phlebectatica has also been shown to
be a highly sensitive predictor of C4–C6 clinical classes of
CVD.[14] More importantly, similar to C4 patients, patients
with corona phlebectatica are more than ve times more
likely to develop an ulcer.[15] Based on this evidence, a designation of corona phlebectatica as C4c was made. Since
CEAP is a descriptive classication, not intended to reect
the severity of CVD, C4a, b, and c subclasses should not be
interpreted as a progression to more severe disease. A4c
designation for corona phlebectatica was mainly based on
the principle of compatibility with prior versions, leaving
hyperpigmentation or eczema as C4a and lipodermatosclerosis or atrophe blanche as C4b unchanged.
9.4.2 Etiology
Understanding the etiology of CVD is important, as it determines the prognosis, guides treatment choices, and affects
outcomes. Previous versions of CEAP stratied etiology, “E,”
into congenital, primary, and secondary categories.
Ample evidence of the diverse nature of the secondary CVDs (Es) and development of new treatment options
addressing these causes dictated the need to subcategorize
Es into two subclasses. The subclass Esi is included to recognize intravenous causes of CVDs, such as post-thrombotic
changes, traumatic arteriovenous stulas, primary intravenous sarcoma, or other luminal changes inside the vein. The
subclass Ese is included to denote secondary CVD caused by
extravenous factors. The signs and symptoms of CVD in the
case of Ese are due to a condition affecting venous hemodynamics with no or resulting secondary changes in the venous
wall. These conditions may be either systemic (e.g., obesity
and congestive heart failure), locally caused by extrinsic compression (e.g., extravenous tumor), or caused by a distant process, such as muscle pump dysfunction due to motor disorders
(paraplegia, arthritis, chronic immobility, and frozen ankle).
The rened denition of Ec, or the congenital category,
now includes any condition present at birth that may manifest later in life with signs and symptoms of venous disease.
These conditions include but are not limited to venous
agenesis, venous malformation (such as Klippel–Trenaunay
syndrome), and arteriovenous malformation.
The primary etiologic subclass Ep is one of the most common causes of CVD. In the original version of CEAP, Ep was
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described as “neither congenital nor having any identiable
cause.” Adding subclass En in the 2004 CEAP caused some
confusion because the denition overlaps with the Ep subclass for primary or idiopathic etiology, which also included
an undetermined cause. Amore precise denition of primary
etiology is that primary disease is a degenerative process of
the venous valve and/or venous wall, leading to valve and/or
vein wall weakness and dilatation that results in pathologic
reux, demonstrated by imaging. The key features of Ep are
the absence of venous obstruction and intralumenal lesions
such as synechia and scarring of the wall.
The En descriptor should be present when no other
venous etiology (Ep, Esi or Ese, Ec) is found, yet there are
clinical signs and symptoms that can be consistent with
those typically associated with venous disease.
Combinations of etiologic states can coexist. Most frequently, both primary and secondary etiologic factors can
be present. For example, primary varicose veins (supercial reux without prior acute venous thrombosis) can be
present prior to occurrence of a DVT. At a later time, the
etiology of CVD symptoms and signs should be described
as both primary and secondary (from the internal causes)
and denoted as “Ep,si.” Another example would be nonthrombotic iliac vein compression (nonthrombotic iliac vein
lesions), with later developed DVT and chronic intraluminal
synechia; the description for this etiology would be Esi,e.
9.4.3 Anatomy
Practicality was the main reason for the revision of the “A”
component of the CEAP. Using numbers to denote venous
segments is believed to be difcult. At the same time, standard abbreviation of the anatomical terms is widely used
in practice, professional communication, and publications.
In addition, the use of the abbreviations instead of numbering should increase the specicity and reproducibility
of the CEAP. To maintain compatibility with prior CEAP
documents, the new abbreviations can be easily linked to
the previous system of segment numbers.
In the basic CEAP, the anatomic sites of the disease
should be described as supercial (As), deep (Ad), or perforating (Ap) vein(s). One, two, or three systems may be
involved in any combination.
9.4.4 Pathology
CEAP 2020 did not change the 2004 CEAP description
of P. The pathophysiologic class has basic and advanced
designations. The basic designation includes r (reux),
o (obstruction), r,o (reux and obstruction), and n (no
venous pathophysiology). The advanced CEAP is the same
with the addition of any (one or more) named specic anatomic venous segments.
9.5 WRITING THE CEAP
9.5.1 Basic CEAP
Basic CEAP limits description of the clinical class to
the numerically highest subclass. The symptomatic status is noted by a subscript (s) for symptomatic or (a) for
asymptomatic immediately after the clinical class. E, A, and
P components include all subscripts; however, P is written
without anatomical location. Each limb is described separately starting with the right limb.
For example, a patient with primary CVD, bilateral varicose veins with left leg swelling, and symptoms only in the
left leg who has reux in both GSVs should be described
as follows:
R: C2(a), Ep, As, Pr
L: C3(s), Ep, As, Pr
A symptomatic patient with post-thrombotic occlusion of
the iliac vein, reux in the femoral vein, and a recurrent
venous ulcer in the right leg and no venous disease in the
left limb will be described as:
R: C6r(s), Esi, Ad, Pr,o
L: C0(a), An, An, Pn
9.5.2 Advanced CEAP
Advanced CEAP includes all subscripts for all components
of CEAP. In addition, the P components lists the specic
anatomical location.
A patient with primary CVD, bilateral varicose veins
with left leg swelling, and symptoms only in the left leg
who has reux in both GSVs should be described as follows:
R: C2(a), Ep, As, Pr(GSV)
L: C2, 3(s), Ep, As, Pr(GSV)
A symptomatic patient with post-thrombotic occlusion of
the external iliac vein, reux in the femoral vein, and a
recurrent venous ulcer in the right leg and no venous disease in the left limb will be described as:
R: C6r(s), Esi, Ad, Pr(FV), o(EIV)
L: C0(a), An, An, Pn
9.6 PRINCIPLES OF CEAP
9.6.1 When should CEAP be used?
Clinical manifestations of CVD are not specic. Similar or
even identical symptoms and signs can affect lower limbs
with diseases and disorders other than venous. Examples
include edema, skin discoloration, and chronic wounds,
which can be present in multiple systemic and focal conditions. CEAP is designed to describe limbs affected only by
CVDs and is not intended to be used in other conditions.
It is therefore highly important to use all four components
of CEAP. The etiological class is designed in part to separate limbs with CVD from other conditions. The unique
subclass is En, which should be used when no etiology
(venous or other) cannot be identied. It describes patients
who warrant further in-depth investigation to diagnose a
condition that manifests itself with signs similar to CVD.
Although CVD is not clearly dened in CEAP documents, it should be clear that CEAP describes diseases
and disorders, not syndromes. This difference becomes
clear when comparing the CEAP denition of the secondary etiology of CVD and a commonly used denition of
9.6 Principles of CEAP 91
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post-thrombotic syndrome (PTS). Acute DVT can damage
venous valves, causing reux, which will be classied as Esi;
Ad; Pr by the CEAP, or cause an obstruction to venous ow
by intravenous organized thrombus or synechia, which will
be classied as Esi; Ad; Po. Each of these descriptions are
specic to the sequelae of the DVT. Since CEAP classies
a lower limb at a specic time point, the signs and symptoms may be present in a variety of combinations or not
present at all. For example, a limb with venous obstruction
may exhibit swelling and be symptomatically classied as
C3S, Esi; Ad; Po, or it may have skin discoloration but be
asymptomatically classied as C4A, Esi; Ad; Po. In contrast, the denition of PTS is based on a combination of
symptoms and signs that are not specic and, in more than
50% of patients, are not related to the sequelae of DVT but
are caused by preexisting primary CVD.[16, 17] On the
opposite side of the spectrum, currently asymptomatic or
mildly symptomatic patients would be classied as having
no PTS, although these patients clearly are affected by secondary (post-thrombotic) venous disease and may become
disabled at a later time. This means that studies that use
the PTS instead of a proper classication of the CVD as an
outcome, such as the SOX (Compression Stockings to Prevent Post-Thrombotic Syndrome) and ATTRACT (Acute
Venous Thrombosis: Thrombus Removal with Adjunctive
Catheter-Directed Thrombolysis) trials, are subject to signicant misclassication bias.
9.6.2 CEAP is a descriptive classification
CEAP is a clinical descriptive instrument that serves only
one purpose—to provide a complete clinical description of a lower limb of a patient with CVD at a specic
point in time. CEAP does not address the severity of CVD.
Although the sequence of clinical classes C may be perceived as “stages” or conditions with an increasing severity,
such perception misrepresents the intent and the appropriate use of the CEAP classication. Apatient with varicose
veins as the only sign of CVD may have more severe disease that limits physical activity and negatively impacts her
or his quality of life compared to a patient with a healed
venous ulcer (C5), who is asymptomatic and has no functional limitations. A C0 patient with secondary disease
after iliofemoral venous thrombosis and no signs of CVD
(C0S, Esi, Ad, Po) may suffer from venous claudication,
which is a more severe condition compared to a similar C3
patient with mild edema around the ankle and otherwise
not symptomatic (C3A, Esi, Ad, Po).
Because CEAP is time-specic, the date of examination
should be a part of the limb description. Symptoms and
signs of CVD have complex dynamics. Some patients experience a stable condition over long time intervals, while
others may have changes in appearance quite frequently.
Physical activity has a great impact on the symptoms and
some signs of CVD. Prolonged standing at work may result
in increasing intensity of pain and heaviness and also make
varicose veins more apparent. Fluctuations in ambient
temperature may also change the appearance of the limb.
Such dynamics naturally make CEAP classication of the
same limb variable over time. This variability should not be
seen as a limitation of CEAP, but as a true reection of the
nature of CVD. Proper collection of patient’s history and, if
necessary, follow-up physical examination may reveal the
clinical presentation that is sometimes not obvious at rst
glance.
9.6.3 CEAP is a guide to clinical
management of CVD patients
CEAP addresses all the main domains of the assessment of
a CVD patient that are necessary for clinical decision making and the selection of clinical care. An appropriate examination of a patient with CVD should include assessment of
clinical signs and the presence of venous symptoms, which
is the C of CEAP. It also must include the etiology of these
signs, preferably conrmed by imaging studies, identication, and the anatomical location of pathological changes
in the venous system of the limb, which are E, A, and P
of CEAP. If any of these components of venous diagnosis
are missing, the selection of treatment options and type of
clinical management will be based on insufcient information, and the care for this patient should be considered
substandard. In practice, all this information is routinely
collected by most practitioners, but following CEAP provides a structure and a “check list” to make sure that the
evaluation process is sufcient.
9.6.4 CEAP in clinical research
Introduction and worldwide adaptation of the CEAP classication substantially improved standardization of research
protocols, making it possible to conduct large-scale epidemiological studies and meta-analyses of published clinical trials.[18–20] Despite this progress, publications on
venous disease frequently contain incomplete information,
misunderstandings of the purpose of CEAP, and misuse of
this classication.
The most frequent deciency in published papers is
utilization of a single component of CEAP—clinical class.
It is a serious deciency in describing individual patients
and patient populations. CEAP is designed to describe a
connection between signs and pathology in each lower
limb. Losing a part of this information not only defeats the
purpose and integrity of CEAP but makes it impossible to
correctly comprehend published information. For example,
describing outcomes of supercial vein ablations in patients
with unknown etiology, anatomy, and pathology makes it
impossible to assess the applicability of such data to a specic patient. It remains unknown if such studies included a
mixture of primary and post-thrombotic patients, patients
with deep vein reux or/and obstruction, etc. Inability to
complete the entire CEAP indicates incomplete and substandard patient investigation. The components of CEAP
are not designed as standalones, and CEAP should always
be used in its entirety.
CEAP is a description specic to the time of examination.
Completing CEAP in a series of clinical examinations over
time provides vital information on the natural history of the
CVD in that patient. Not only the C of CEAP but also E, A,
and P may change over time, describing complex relationship between pathology and signs in the course of the natural history of the disease. It is known that varicose veins, and
even venous reux without varicose veins, increases the risk
of DVT.[21, 22] After such an event, the etiological classi-
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cation in the affected limb will change from Ep to Ep,s. The
Aand P may also change if a patient develops an obstruction
to ow in the deep veins. Similar dynamics are not infrequent in the limbs of patients with external compression of
iliac veins. ADVT in such a limb will change the etiological
the severity of CVD. The sequence of clinical classes from
C1 to C6 with all subclasses is made solely for convenience
and should not be interpreted as indicating a decrease or
increase in severity. Again, from the statistical point of view,
clinical class should not be treated as an ordinal variable.
classication from Ese to Ese,si. Capturing these and other
changes is crucial to understanding the natural history of
CVD and for the identication of clinical dynamics related
9.7 CONCLUSION
to different pathological situations.
The descriptive nature of CEAP has a specic impact
on data analysis. From the statistical point of view, all four
components of CEAP are nominal variables and should
be treated as such. Calculating central tendency statistics,
such as means and mediums, is senseless, as it is the same as
attempting to calculate a mean of several different colors or
different shapes. In addition, CEAP has no intent to assess
The updated CEAP 2020 classication is a widely adopted
validated tool describing a lower limb of a patient with CVD
at a specic time point. CEAP includes description of the four
main components of CVD, and all four of these components
must be used for an appropriate description of a lower limb.
As a descriptive tool, CEAP should not be used to assess the
severity of CVD or imply the degree of CVD severity.
Good Practice Statement 9.0 of the American Venous Forum on the classication of chronic venous disorders of the
lower limbs
No. Good Practice Statement
9.1 We recommend the use of the 2020 updated CEAP classication system for chronic venous disorders. The clinical or basic
CEAP classication can be used for clinical practice, and the full CEAP classication system should be used for clinical
research.
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• Randomized controlled trial
* Systematic review or
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PART
Diagnostic evaluations and
https://t.me/med1917
venous imaging studies
Edited by Fedor Lurie
10 Evaluation of hypercoagulable states and molecular markers of acute venous thrombosis
Iva Minga, Alfonso J. Tafur, and Joseph A. Caprini
11 Duplex ultrasound scanning for acute venous disease
Rhusheet Patel and Timothy K. Liem
12 Duplex ultrasound scanning for chronic venous obstruction and valvular incompetence
Pedro J. Furtado Neves, Rafael D. Malgor, and Nicos Labropoulos
13 Evaluation of venous function by indirect noninvasive testing (plethysmography)
Kate Gates, Fedor Lurie, and Thom W. Rooke
14 Direct contrast venography
Haraldur Bjarnason
2
15 Intravascular ultrasound
Paul J. Gagne
16 Computed tomography and magnetic resonance imaging in venous disease
Thanila A. Macedo, Terri J. Vrtiska, and James F. Glockner
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