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18 Microcirculation in Chronic Venous Insuffi ciency
The fi brin cuff hypothesis was modifi ed by Falanga and Eaglstein,
12
who
confi rmed that fi brinogen, α
2
-macroglobulin, and other large molecules
were present in the pericapillary cuff. They suggested that this cuff might
interfere with and “trap” growth factors and other stimulatory factors. The
trapped molecules were unavailable for the maintenance of tissue strength
and the repair process. α
2
-macroglobulin is known to be a scavenger of
growth factors such as transforming growth factor-β (TGF-β). An absence
of TGF-β in the venous ulcer bed compared with normally healing graft
donor sites has been found. Markedly increased levels of TGF-β within the
pericapillary fi brin cuffs have provided further evidence for a possible
“trapping” of growth factors in venous ulcers.
13
WHITE CELL TRAPPING
Moyses, in 1987, demonstrated that blood returning from the lower limb
following a period of dependency contained fewer leukocytes than the
normal control limbs. Thomas et al. found that these changes were more
marked in patients with chronic venous disease. Leukocytes are larger and
less deformable than red blood cells and have the potential to block capil-
laries (Figure 2-2). The reduced pressure gradient between the arterial and
venous systems in venous hypertension might encourage leukocytes to plug
in capillaries and block the passage of erythrocytes.
14
This phenomenon
could cause local ischemia.
15
A hypothesis known as the “leukocyte trap-
ping hypothesis” was proposed in which leukocytes were thought to occlude
venular capillaries and predispose to venous (ischemic) ulceration.
16
Attempts to directly demonstrate capillary occlusion by leukocytes were
FIGURE 2-2 Illustration of one leukocyte and erythrocytes aggregating behind it in
normal venular capillary. This has never been directly observed in capillaries in the vicinity
of venous ulcers.
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Microcirculation in Chronic Venous Insuffi ciency 19
unsuccessful, casting doubts on the validity of this theory.
17
This theory
therefore was adjusted, and it was proposed that trapped leukocytes
migrated into the pericapillary and dermal tissue, activating the infl amma-
tory response.
LEUKOCYTES AND ENDOTHELIAL
CELLS’ ACTIVATION
The theory that leukocytes had a role in the development of venous
ulceration has led to further studies to identify the types and functions of
leukocytes that might be responsible.
Studies reporting the association of leukocytes and venous ulcers vary.
Skin biopsies taken from patients with venous ulcers have demonstrated
abundant T-lymphocytes and macrophages with few neutrophils and B-
lymphocytes.
17
Macrophages and mast cells were the main leukocytes
found in the environs of venous ulcers in a quantitative morphometric
study using electron microscopy.
18
Mast cells were increased around arte-
rioles and postcapillary venules but not increased in the capillaries of
ulcer-bearing skin of patients with lipodermatosclerosis or healed ulcers.
Patients with active ulceration had a similar number of mast cells com-
pared with controls. Macrophages were increased around the arterioles
and postcapillary venules in patients with active and healed ulcerations.
Pappas et al. also assessed the capillary endothelial cells structure in
the vicinity of venous ulcers. The endothelial cells had euchromatic nuclei
indicative of active transcription and protein production. There were no
other structural changes found in the endothelial cells.
18
The tight gaps
between the endothelial cells junction were well maintained, which seemed
to refute the stretch pore phenomenon.
Endothelial cell binding and interaction with leukocytes is dependent
on adhesion molecules. Changes in adhesion molecules can therefore mod-
ulate leukocytes’ migration and activation. Expression of intracellular
adhesion molecules (ICAM-1) and vascular adhesion molecules (VCAM-1)
on the endothelial cell increases as lipodermatosclerosis deteriorates.
19,20
Pappas et al. measured the activity of circulating leukocytes in patients
with venous ulceration using fl ow cytometric analysis of activation markers
on the monocytes and T-lymphocytes. A decrease in activated T-lympho-
cytes and an increase in activated monocytes were found in patients with
venous ulcers compared with normal patients.
21
The possibility that leukocytes were dysfunctional has also been
assessed. A signifi cant attenuation in the proliferation of cultured mono-
cytes and lymphocytes taken from the blood of patients with venous ulcers
was observed compared with monocytes and lymphocytes extracted from
patients with no ulcer. The dysfunction of these cells was associated with
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20 Microcirculation in Chronic Venous Insuffi ciency
clinical venous disease progression.
22
It was therefore hypothesized that
altered leukocyte activity and decreased mononuclear cell proliferation
contributed to poor wound healing.
CYTOKINES AND GROWTH FACTORS
The changes that have been found in leukocytes and endothelial cells
with the environs of venous ulcers and circulating blood have led to specu-
lation that their role in cytokine activation and growth factor production
could lead to tissue death and infl ammation.
Tumor necrosis factor-α (TNF-α), an important mediator of cell apop-
tosis, was found to be upregulated in serum during active ulceration, and
its levels declined with healing.
23
TNF-α and interleukins (IL) such as IL-
1α and IL-6 were found to be reduced in the wound fl uid taken from
healing chronic venous ulcers when compared with nonhealing ulcers.
24
Transforming growth factor-β (TGF-β) is known to stimulate dermal fi bro-
blast proliferation, which may lead to excessive tissue fi brosis if overex-
pressed. An excess of TGF-β has been found in some venous ulcers. This
has been confi rmed at transcriptional and translational levels.
25
Vascular endothelial growth factor (VEGF) and platelet derived growth
factor receptor α and β (PDGFR-α and -β) are well known to be produced
by endothelial cells. These factors have been found to be overexpressed in
the microenvironment of some venous ulcers.
26,27
It has been suggested that
some of these growth factors are ineffectual. Endothelial cell proliferation
studies have found that ulcer exudates had no effect on the ulcer healing
despite the increase of VEGF in nonhealing ulcers. This suggests that there
is posttranslational inhibition of some growth factors in the ulcer environ-
ment.
26,28
Ulcer healing appears to be a polygenic complex process involv-
ing alterations in cellular function and infl ammatory mediators.
It is often diffi cult to know whether the observed changes are cause or
effect or simply the result of local infl ammation. They also do not explain
why ulcers develop in the gaiter region of the calf or why ulcer healing is
achieved by compression treatment. Ideally, leukocyte/endothelial cell
interactions and growth factor changes should be studied before skin
changes develop in a high-risk group of patients (e.g., following a deep vein
thrombosis).
OXIDATIVE STRESS IN VENOUS ULCERS
Reactive oxygen species are present in the ulcer tissue and exudate.
Their release is probably mediated by infl ammatory cells, fi broblasts, and
endothelial cells, which are known to produce superoxidants. These cells
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Microcirculation in Chronic Venous Insuffi ciency 21
are commonly present in chronic venous leg ulcers’ environs, leading to
hostile oxidative stress and consequent tissue destruction.
29
Oxidative stress is dependent on the presence of free ion radicals such
as iron in the tissue around venous ulcers. Increased iron deposition may
cause an elevation of toxic free radicals in venous ulcers’ environs. Iron is
toxic because of its ability to undergo cyclic oxidation and reduction, gen-
erating free radicals via Fenton reaction. Antioxidants have been shown to
be upregulated in chronic wounds, perhaps to counterbalance the increased
risk of oxidative damage to the tissue.
29,30
MMP AND VENOUS ULCER FORMATION
Venous ulcers contain a number of protolytic enzymes, especially potent
matrix remodeling enzymes, which are capable of degrading the different
types of collagen and regulating dermal matrix turnover. The matrix metal-
loproteinase (MMP) family appears to be involved in different stages of
the ulcerative and healing process in chronic venous ulcers.
31
Analysis of
venous ulcer exudates found an elevated expression and activation of dif-
ferent subtypes of MMP at different stages of ulcer healing.
32
Elevated levels of mRNA expression of MMP-1 and MMP-2 have been
found in lipodermatosclerotic skin, but only the MMP-2 was found in its
active form. These were mainly present particularly in the perivascular
regions, basal and suprabasal epidermal layers, and associated with reduced
expression of tissue inhibitor metalloproteinase-2 (TIMP-2).
33
Matrix
metalloproteinase-2 (MMP-2) digests type I collagen, type III collagen,
and fi bronectin, all of which are present in the perivascular fi brin cuffs of
lipodermatosclerosis. MMP-2 can also degrade elastic fi bers that are found
fragmented in the reticular dermis of patients with lipodermatosclerosis,
indicating perhaps that MMP-2 contributes to the hardening of the skin in
this condition. The expression of membrane type metalloproteinases (MT-
MMPs) is also elevated in the environs of venous ulcers.
34
These mem-
brane-bound proteinases not only degrade extracellular matrix but are also
known to activate other collagenolytic and gelatinolytic enzymes such as
MMP-2 and MMP-9. Levels of MMP-9 may also decrease as the wound
progresses toward healing.
35
Venous ulcer fl uids, unlike acute wound fl uid, have increased proteolytic
activity. This encourages the degradation of extracellular adhesion pro-
teins like fi bronectin and vitronectin,
36
which are important in the migra-
tion of cells such as keratinocytes. MMP-2 and MMP-9 are mainly
responsible for degrading fi bronectin. They have also been found to be
elevated in venous ulcer fl uids when compared with acute wound fl uids.
Altered levels of collagenases MMP-1 and MMP-8 are also present in
chronic leg ulcer fl uids.
37
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22 Microcirculation in Chronic Venous Insuffi ciency
The overall MMP activity in chronic wound fl uids is infl uenced by the
types of cells that are present in the ulcer base and by the types and amount
of growth factors and cytokines that are present. Ulcers may therefore form
because of an enhanced turnover of the dermal extracellular matrix regu-
lated by specifi c MMPs. It is, however, equally possible that existing local
tissue damage and infl ammation cause activation of the MMPs.
THE ROLE OF FIBROBLASTS IN VENOUS
ULCERS
Fibroblasts are present in abundance in the dermis of patients with
lipodermatosclerosis. Dermal fi broblasts are active skin replacement cells
and are characterized by an ability to produce collagen and induce fi brosis.
Fibroblasts in the dermis of venous ulcers have been found to behave
abnormally. Studies have been carried out on their role in venous ulcer-
ation.
38,39
The dermal fi broblasts in venous ulcers and chronic wounds
appear to have a decreased number of type II receptors to TGF-β and a
reduced ability to phosphorylate TGF-β.
38,40
They exhibit a decreased
dose-dependent response to TGF-β stimulation compared with fi broblasts
taken from normal skin.
38
Decreased collagen production has been demonstrated in cultured
dermal fi broblasts taken from biopsies of the edge of venous ulcers com-
pared with those taken from normal skin, but fi bronectin synthesis was not
different between both cultured cells.
39
Normal fi broblasts exhibited
reduced collagen production although fi bronectin production was
unchanged when cultured under hypoxic conditions. These fi ndings led
Herrick et al. to suggest that fi broblasts’ ability to synthesize collagen is
probably reduced in the presence of hypoxia, which occurs in the venous
ulcer environment. Low fi bronectin levels in venous ulcer tissue may be
caused by increased degradation rather than poor synthesis.
Slow growth of dermal fi broblasts from the venous ulcer edge and
elevated levels of markers of senescence have been demonstrated.
41
It therefore appears that premature “aging” of dermal fi broblasts
in venous ulceration is responsible for their poor proliferation and
dysfunction.
“Senescence” was observed when neonatal fi broblasts were cultured in
a mechanically designed pressure incubator, providing direct in vitro evi-
dence of a relationship between elevated pressure and altered fi broblast
behavior.
42
Dermal fi broblast “senescence” may, however, still be the result rather
than the cause of ulceration. The role of fi broblast senescence in the devel-
opment of venous ulcers remains to be confi rmed.
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Microcirculation in Chronic Venous Insuffi ciency 23
SUMMARY
The mechanisms involved in venous ulceration still need to be fully
elucidated. The process by which skin changes and venous ulcers develop
is complex.
The different hypotheses have generated many further investigations
and studies. A better understanding of the cellular and molecular changes
in microcirculation of venous ulcers may alter potential therapeutic targets
and strategies.
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27
3
Epidemiology of
Venous Ulcers
Olle Nelzén
A leg ulcer is not a disease in itself but rather a symptom that can be
caused by a variety of different diseases with a number of risk factors.
Where venous ulcers are concerned, they can be caused by a variety of
venous diseases. As it appears today, varicose vein disease seems to be the
most common cause, whereas deep vein thrombosis and primary deep vein
disease are becoming less frequent in most studies. In addition, combina-
tions of various venous diseases are far from uncommon, which underlines
the necessity for careful diagnostic measures. Venous ulcers are not a new
problem, since they are well known to have plagued humankind since
ancient times. The fi rst written description of treatment of probable venous
ulcers was found in the Papyrus of Eber originating from Egypt around
1550 bc. In the Milan Cathedral in Italy, four big paintings show miracles
performed by Saint Carlo for patients with leg ulcers in the beginning of
the 17th century, clearly indicating that at that time leg ulcers were already
a huge problem within the population (Figure 3-1). It appears that leg
ulcers have been a voluminous problem for generations, and this problem
still remains. The greatest problem with leg ulcers is that so few people
realize that they really are a problem, and that is why epidemiological
studies are needed.
WHAT IS EPIDEMIOLOGY?
Epidemiology is the science dealing with the distribution and frequency
of diseases or disorders in the population. To have knowledge of the epi-
demiology of a certain disease is of fundamental importance in order to
Venous Ulcers
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