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a problem where wound care clinics treat the wound and not the cause of
the problem. In this volume, the fundamental molecular mechanisms, which
lead to chronic venous insuffi ciency on one hand and venous ulceration on
the other, are well described by the essays of Geert Schmid-Schönbein and
Luigi Pascarella. Taking a cue from those studies, Kevin Burnand has
described the microenvironment of venous ulcerations and Olle Nelzén has
collected information on the epidemiology of such ulcerations.
Dominating the new knowledge of cause and development of venous
ulceration have been the studies by ultrasound of the lower extremities.
Among the leading investigators in this fi eld is Nicos Labropoulos, who
has contributed a chapter here on the evaluation of limbs with venous
ulceration.
In many instances, previous deep venous thrombosis has led to chronic
venous insuffi ciency, which eventuates in venous ulceration. Jeffrey Lawson
of Duke University has described the hypercoagulable states that lead to
venous ulcer, and to round out the evaluation of such problems, Warner
Bundens of UCSD has provided a chapter on the differential diagnosis of
the swollen leg.
The fundamental treatment of venous ulceration begins with compres-
sion therapy, and the best-informed individual in that area of treatment is
Hugo Partsch of Vienna, who has provided a succinct chapter on the
subject of compression in treating chronic venous insuffi ciency. Such com-
pression is most often combined with topical agents in wound healing, and
Dale Buchbinder of Baltimore has summarized important information on
this subject in his contribution.
To prevent the need for treatment of venous ulcers, it is necessary to
prevent recurrent deep venous thrombosis, and this is the subject of Joseph
Caprini’s essay from the Northwestern Healthcare System where his infl u-
ence is pervasive.
With the new knowledge of venous ulcers and their cause have come
new methods of treatment. Negative pressure dressings and wound vacuum
systems have come into play, and Jonathan Towne has summarized his
experience with these in his chapter. But, of course, compression combined
with surgery has been the mainstay of treatment of venous ulcerations
during the last century. Results comparing compression to compression
and surgery have been an interest of Keith Poskitt of Gloucester in the
UK. He has described his studies on this subject in an erudite chapter seen
here. But, of course, harking back to experience of the last century in treat-
ment of venous ulcers with perforator interruption, William Marston of
Chapel Hill has described his experience with this technique. In addition
to treatment of perforating veins and superfi cial incompetence are the
endovenous techniques, which are used to treat axial incompetence in the
care of venous ulcers. Cynthia Shortell, also of North Carolina, has pro-
vided a chapter on this subject.
xx Preface
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Among the new methods of leg ulcer treatment, and perhaps the most
important, is the use of foam sclerotherapy. This technique has now crossed
the Atlantic, but much of the new knowledge still resides overseas. Ales-
sandro Frullini, of Florence, Italy, has explained his experience with the
development of foam therapy for venous insuffi ciency. The modern era of
foam treatment of venous insuffi ciency began with Juan Cabrera in
Granada, Spain, and here he has described the initial experience in treat-
ing venous ulcerations with sclerosant foam. This experience has been
carried further at the Vein Institute in La Jolla, where we described the
foam treatment of venous leg ulcers not knowing of the experience of
Cabrera.
Both the endovenous techniques and foam sclerotherapy depend on
ultrasound evaluation and management. Luigi Pascarella has long experi-
ence with these techniques and has described them in his chapter on this
subject.
There has been some experience with the repair of venous valves in
severe chronic venous insuffi ciency, and Michel Perrin, a truly distin-
guished French surgeon, has described his experience and that of others
in developing these techniques.
Excision of the ulcer bed and then fi nding coverage has drifted from
general surgery into plastic surgery, where Scott Levin of Duke University
has a provided an interesting chapter on this subject.
A few cases of venous ulcer have as the fundamental cause venous
obstructive disease. Patricia Thorpe has a long experience with this subject
and has described that in her contribution on treatment of major venous
obstruction in chronic venous insuffi ciency.
Lastly, venous ulcers are not isolated entities. They can be present in
limbs with arterial insuffi ciency. It is the arterial insuffi ciency and its treat-
ment that dominate. An experience with these conditions is well described
by Robert McLafferty of Springfi eld.
While the fi nal words on diagnosis and treatment of venous ulceration
will not be provided in this volume, in fact much light is thrown on various
entities by the information supplied in these chapters. We, as editors, hope
that the contents of this book will stimulate investigations in the solution
of the problems caused by venous ulcerations so that diagnosis can be more
precise, treatment more standardized, and results to the patient more uni-
formly benefi cial.
John Bergan, La Jolla
Cynthia Shortell, Durham
Preface xxi
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SECTION
I
Etiology and Initial
Evaluation of the
Patient with Chronic
Venous Insuffi ciency
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3
1
Infl ammation and the
Pathophysiology of
Chronic Venous Disease:
Molecular Mechanisms
Geert W. Schmid-Schönbein and
Luigi Pascarella
INTRODUCTION
Increasing evidence supports the hypothesis that chronic venous disease
is associated with an i nfl ammatory cascade. Classical signs of infl ammation
have been observed in human biopsies and plasma samples and in acute
and chronic experimental models of venous disease. The cascade starts
with a relatively innocent elevation of permeability, mast cell degranula-
tion, and progresses to adhesion of leukocytes and platelets to the endo-
thelium. There is early release of infl ammatory mediators, such as
cytokines, oxygen radicals, nitric oxide products, and lipid mediators.
Eventually, the disease may progress to overt cell apoptosis, enzymatic
degradation of basement membrane and extracellular matrix proteins,
accumulation of extracel lular tissue fragments, a lack of c ell responsiveness
in the skin, and a prominent vascular restructuring in the form of telangi-
ectases and venous varicosities, which serve as a key index for classifi cation
of different stages of the disease. Lymphatic transport to remove the extra-
cellular fragments may be compromised, and in the most severe manifesta-
tions of the disease, complete breakdown of the skin and subdermal tissues
leads to ulceration.
The progression of these steps in the infl ammatory cascade is different
among individual patients, both in terms of the time course and their sever-
ity. The individual steps progress spatially nonuniform so that early and
late stages may occur simultaneously in the same leg. Current macroscopic
Venous Ulcers
Copyright © 2007 by Academic Press, Inc.
All rights of reproduction in any form reserved.
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4 Infl ammation and the Pathophysiology of Chronic Venous Disease
clinical manifestations of the disease are relatively late-stage manifesta-
tions of the infl ammatory reactions; observations at the microvascular level
may serve to detect the infl ammatory events at earlier stages. In the fol-
lowing we will focus on selected infl ammatory steps in which molecular
mechanisms have been identifi ed. The analysis is still at an early stage, but
opportunities arise with new ideas for early intervention.
LEUKOCYTE ACTIVATION AND
MICROVASCULAR INFILTRATION
Chronic venous disease is accompanied by enhanced infi ltration of cir-
culating leukocytes into the affected leg.
1
Circulating leukocytes infi ltrate
the microcirculation predominantly by entrapment in true capillaries and
by attachment to the endothelium of venules. The two processes are dif-
ferent in several respects. Entrapment in capillaries occurs as a result of
either a reduction of the pressure drop across the length of capillaries and
an inadequate pressure to deform the relatively stiff viscoelastic leukocytes
in the circulation and/or by activation of endothelial cells or leukocytes.
The activation may be accompanied by polymerization of the cytoplasmic
actin with formation of rigid pseudopods, a process that is under control
of soluble agonists (e.g., complement fragments, leukotrienes, platelet acti-
vating factor, interleukin-8) by means of G-protein coupled receptors.
2
Recent evidence indicates that pseudopod formation in circulating leuko-
cytes is also under the control of purely mechanical factors, such as the
fl uid shear stress (force parallel to the area/area, dyn/cm
2
) generated by
the fl ow of plasma.
3
Reduced fl uid shear stresses, the presence of infl am-
matory agonists, or their combination serves to enhance entrapment of
leukocytes in capillaries. The capillaries become permanently obstructed
since the leukocyte completely fi lls the vessel lumen, and the process is
frequently followed by red cell aggregation and thrombus formation.
In contrast, attachment of leukocytes to endothelium in postcapillary
venules or larger veins may occur without vessel obstruction. In this case
membrane attachment between leukocyte and endothelium is required and
facilitated by selectins (e.g., P-, L-selectin, P-selectin glycoprotein ligand-1,
sialyl Lewis X), integrins (CD11/CD18), and members of the immuno-
globulin family (ICAM-1).
4
Their expression in turn is constitutive either
on the membrane of postcapillary venules, in the endothelial Weibel-
Palade bodies of endothelial cells, or in secondary granules in the case of
granulocytes.
Entrapment of neutrophilic leukocytes in the microcirculation reduces
local capillary perfusion and at the same time serves to enhance oxygen
free radical formation and delivery of proteolytic enzymes, most of which
enhance tissue degradation. While acute interventions against the accumu-
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Infl ammation and the Pathophysiology of Chronic Venous Disease 5
lation of the leukocytes in the microcirculation have been shown repeat-
edly to reduce tissue injury, the utility of chronic intervention against
leukocyte infi ltration remains to be explored. In general, methods that
serve to reduce progression of venous disease (e.g., compression banding,
anti-infl ammatory medication) are accompanied by a reduction of leuko-
cyte activation and infi ltration.
5
Besides the acute infi ltration of the venous and venular wall with granu-
locytes, infl ammation in chronic venous disease is accompanied by infi ltra-
tion with B- and T-lymphocytes, monocytes, and by mast cells. There is
also infi ltration of monocyte/macrophages into the venous valves,
6
and
valve destruction may in fact be mediated by these cells. The particular
membrane adhesion molecules involved are less well defi ned, although
there is evidence for VCAM-1, ICAM-1, and E-selectin on the endothelial
surface binding specifi c leucocytes receptors (e.g., L-selectins, VLA 4, and
LFA 1).
7,8
The adhesion molecules may be vessel specifi c, and effective
interventions against enhancement of the infl ammatory reaction by leuko-
cyte infi ltration may require a more detailed understanding of the actual
sequence of adhesion molecules expressed in specifi c tissues.
9
INFLAMMATORY MEDIATORS
Patient plasma contains an activating factor for granulocytes and also
spontaneously produces a higher level of hydrogen peroxide.
5,10
The iden-
tifi cation of the particular factor(s) involved is an important unresolved
issue.
Leukocyte activation is characterized by synthesis and release of many
infl ammatory molecules such as leukotrienes, prostaglandin, bradykinin,
free oxygen radicals, and cytokines. Cytokines act to regulate and perpetu-
ate the infl ammatory reaction by paracrine and autocrine mechanisms.
TNF-α, whose expression is enhanced in many infl ammatory reactions,
stimulates the expression of membrane adhesion molecules, the synthesis
and release of other cytokines, and the chemotactic migration of neutro-
phils and macrophages. The expression of TNF-α appears to be upregu-
lated in patients with venous ulcers, and healing of the ulcer is accompanied
by reduced levels of TNF-α.
Vascular endothelial growth factor (VEGF), by defi nition, is a potent
angiogenic factor and also enhances endothelial permeability. Both VEGF
expression and its receptor expression (Flk-1/KDR) are upregulated during
the infl ammatory reaction. Patients with chronic venous insuffi ciency and
skin changes (CEAP 4) exhibit higher levels of VEGF than those in CEAP
Classes 2 and 3 and normal control individuals. The expression of VEGF
and other growth factors does not correlate with capillary density of lipo-
sclerotic skin or with the slow or poor healing of venous ulcers. Venous
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6 Infl ammation and the Pathophysiology of Chronic Venous Disease
ulcer exudates have been found to inhibit the growth of human endothelial
cells. Possible degradation of VEGF and other growth factors may be
related to these observations.
Transforming growth factor beta (TGF-β) is another cytokine whose
expression has been found upregulated in patients with venous ulcers.
TGF-β is related to tissue remodeling by stimulating the formation of the
granulation tissue, proliferation of fi broblasts, and synthesis of collagen
fi bers.
11
TISSUE RESTRUCTURING
Varicose veins undergo a major collagen and elastin fi ber restructuring
with synthesis as well as degradation.
12
There is evidence for increased
levels of hydroxyproline, suggesting an increased content of collagen type
I but a decrease of collagen type III.
13
Restructuring also involves the
integrin binding of tissue cells to extracellular matrix proteins. Besides the
control of the acute reactions of smooth muscle cells in the vascular wall,
such integrin binding sites have the ability to slide under mechanical
stresses.
14
PROTEOLYTIC DEGRADATION
An important link between infl ammation and skin changes may be by
way of Ca/Zn-dependent endoproteinases (matrix metalloproteinases,
MMPs) and serine proteinases. Chronic dermal ulcers are characterized
by excessive proteolytic activity, which degrades extracellular matrix and
growth factors and their receptors. The MMP family of proteases (there
are at least 26 MMPs, in addition to six membrane-bound membrane-type
metalloproteinases, MT-MMPs, and in addition to four tissue inhibitors of
metalloproteinases, TIMPs) are positioned on extracellular matrix pro-
teins in an inactive proform. MMPs play an important role in cell differ-
entiation and development. MMPs may be released from preexisting pools
(cytoplasmic granules) upon stimulation and endocytosis or may be newly
synthesized by several types of cardiovascular cells. The inactive proen-
zymes can be activated by other proteinases, including those produced by
mast cells. MMPs have multiple binding sites but cleave collagen at unique
sites. The MMP levels in wound fl uids from chronic wounds tend to be
signifi cantly higher than from acute wounds, and healing is associated with
reduced MMP activity.
The expression levels of MMPs can be controlled by mechanical stretch
(strain), but in a way that depends on the time course of the strain. This
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Infl ammation and the Pathophysiology of Chronic Venous Disease 7
has been studied on smooth muscle cells in an in vitro chamber subject to
oscillatory and constant strain.
15
Stationary strain signifi cantly increases
MMP-2 mRNA levels at all time points, whereas cyclic strain decreases it
after 48 hours. Both secreted and cell-associated pro-MMP-2 levels are
increased by stationary strain at all times, whereas cyclic strain decreases
secreted levels after 48 hours. MMP-9 mRNA levels and pro-MMP-9
protein are increased after 48 hours of stationary strain compared with
both no strain and cyclic strain.
There is an increase of neutrophil elastase and lactoferrin from
activated neutrophils in patients under transient conditions of venous
hypertension and with chronic venous insuffi ciency. Neutrophils and
macrophages also release several MMPs. There is gelatinolytic activity
discharged by MMP-9; MMP-8, a neutrophil collagenase and leukolysin,
a membrane-type MT-MMP. Evidence from knockout experiments sug-
gests that MMP-9 acts upstream of neutrophil elastase by proteolytically
inactivating neutrophil elastase inhibitor a1-PI
16
and that it can activate
other MMPs. Extracellular MMP inducer (EMMPRIN; CD147) has
been observed to increase MMP expression, and membrane type 1 MMP
(MT1-MMP) has been implicated in the activation of MMPs. Venous leg
ulcers have elevated expression of EMMPRIN, MMP-2, MT1-MMP, and
MT2-MMP.
17
Clearly, these proteases will remain of major interest because of their
involvement in the remodeling of cutaneous tissue.
18
Examples of interest
are MMP-1, MMP-2, MMP-9, MMP-12, MMP-13, and the tissue inhibitors
of metalloproteinases (e.g., TIMP-1 and TIMP-2). Overexpression of
MMP-3 (stromelysin-1) and MMP-13 (collagenase-3) is associated with
nonhealing wounds. Venous leg ulcers have an increased expression of
MMP-2 and TIMP-1 in liposclerotic skin and in wound fl uid from nonheal-
ing venous ulcers.
17,19
Expression of MMP-9 has been observed to be upreg-
ulated on the edges of intractable venous ulcers, and the rate of MMP-9
activation in plasma of patients with severe CVD is elevated. Levels of
TIMP-2 are lower in lipodermatosclerotic skin and ulcers. Unrestrained
MMP activity may contribute to impaired healing. The presence of gelati-
nase (MMP-2 and MMP-9) activity may lead to breakdown of interstitial
collagen (e.g., III, IV, V, and IX). MMP-2 and MMP-9 are also expressed
in venous valves preceding the time period of valve remodeling,
20
support-
ing the hypothesis that enzymatic degradation of the valve leafl ets and
venous wall by MMPs plays a key role in valve degradation, the inability
of the valve to close, and therefore the venous pressure elevation.
A critical issue is not only the mechanisms that cause expression of these
proteases, but also the mechanisms that cause their activation from the
inactive proform and the potential lack of antiprotease activity. Among
the mechanisms that have been proposed to activate MMPs are plasmin,
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