CHRONIC VENOUS INSUFFICIENCY

(Rutherford`s Vascular Surgery, 8th edition, Chapter 12, Venous Patology, 170-173, 2014)

Limb manifestations of CVI are easy to recognize: variable swelling, varicosities,

hyperpigmentation, stasis dermatitis, ulceration, and pain (Figure 12-5). The symptoms are
widespread in the general population and are not always directly related to the magnitude of
venous insufficiency (e.g., degree of reflux). However, the most severe CVI symptoms are
related to venous reflux with an obstructed venous segment.
The best way to categorize CVI is with the CEAP (clinical, etiologic, anatomic,
pathologic) classification. This system is discussed in detail in Chapter 53; in brief, it is a
standardized system to grade CVI on the basis of symptoms, etiology, anatomy, and
pathophysiology. The higher the class, the more severe the symptoms and the patient’s disability.
For clarity of discussion, this section separately focuses on the pathology of class 2 to 3 and class
4 to 6 CVI, although there are many common factors and the pathology clearly represents a
spectrum.
Mechanisms of chronic vein injury with primary and secondary valve damage have been
reasonably well described (Table 12-3). The common mechanism is venous reflux between the
superficial and deep systems, either at the site of perforators or through other deep and
superficial system connections, which accounts for the increased venous hydrostatic pressure
transmitted to the superficial veins and tissues. An obstructed vein segment worsens this process.
Experimentally, venous hypertension activates leukocytes, although the activation is probably a
local phenomenon. The process of vein wall fibrosis plays a contributing role in valvular
damage, which then worsens the hydrostatic pressure regulation and consequently promotes
greater venous hypertension with the upright position. The molecular and cellular eventsseem to
point to adaptive responses to injury as well as abnormal healing.
Historical Perspective and General Background
Several important theories have been postulated regarding the etiology and
pathophysiology of CVI. In 1917, John Homans produced a clinical treatise on the diagnosis and
the management of patients with CVI and coined the term “post thrombotic syndrome.” Dr.
Alfred Blalock put forth the hypothesis that local hypoxia precipitated CVI. Local tissue hypoxia
and alterations in nutrient blood flow were proposed as an underlying etiology by Browse and
Burnand. Their important study directly demonstrated the effect of venous hypertension on the
venous microcirculation, and they observed histologically that in large capillaries, pericapillary
fibrin deposition, which they called the “fibrin cuff,” occurred (Fig. 12-6). Dr. P.D. Coleridge
Smith proposed that leukocyte trapping in slow-flow and distended venous segments may
underlie much of CVI development. Burnand et al also showed a positive correlation between
the inability of the calf pump to reduce foot vein pressure during exercise and the number of
capillaries in the skin.

Varicose Veins (CEAP Class 2 to 3 Disease)

Varicose veins (VVs) have been described since before the Common Era and are obvious
on the lower limbs of many people. The fact that varicose veins primarily affect the lower limb
directly implicates the upright nature of humans— specifically, the effect of hydrostatic pressure
on the pathophysiology of such veins. The relationship between body weight and extent of
varicose veins and symptoms is variable. Limb symptoms are generally local and consist of
pruritus and swelling. Occasionally, varicose veins can erode and bleed. Conversely, most such
veins do not thrombose, despite relatively slow blood flow through these torturous structures,
and this fact underlies the natural anticoagulant nature of venous endothelium, even in
structurally abnormal vessels.
The initial anatomic location of varicose veins is typically in the great and small
saphenous distributions and their tributaries in the superficial system. Related risk factors are
multiple, including primary etiologies associated with pregnancy, prolonged standing, female
gender, and, rarely, congenital absence of valves. In addition, varicosities may develop as a
result of prior DVT or trauma.
 Studies support a genetic predisposition to varicose veins. In a prospective study of 402
subjects, the risk of development of varicose veins was 90% if both parents were affected, 25%
for males and 62% for females if one parent was affected, and 20% if neither parent was
affected. These data suggest an autosomal dominant with variable penetrance mode of genetic
transmission.
Studies are generally lacking in relation to early vein wall changes associated with
varicose veins, because most histologic studies are limited to end-stage surgical specimens. In
varicose veins, the orderly appearance of the medial layer is replaced by an intense and
disorganized deposition of collagen that separates the closely apposed muscle cells. Smooth
muscle cells appear elliptical and are likely a secretory phenotype, and both TGF-β and basic
fibroblast growth factor (bFGF) have been documented to be significantly increased in
hypertrophic segments of varicose veins. The underlying mechanism for these histologic changes
is unknown, but the inciting event of increased hydrostatic pressure or an intrinsic genetic defect
is probably primary.
Active vein wall remodeling is consistently observed in specimens of varicose veins with
abnormal matrix collagen metabolism. Quantitatively, higher collagen content and lower elastin
content in varicose veins have been measured in human samples, suggesting an imbalance in
connective tissue matrix regulation and turnover. Specific alteration in the type of collagen may
also contribute to vessel weakening, with an observed increase in tissue water and collagen type I
content in comparison with normal saphenous veins.
Conversely, collagen types III and V levels were lower than in normal veins, and less
type III collagen is associated with decreased elasticity. Similarly, in a separate study, varicose
veins had increased type I and decreased type III collagen gene expression. Comparison of
smooth muscle cells from varicose veins with controls has shown matrix dysregulation as well as
regional differentiation as measured by antigen markers in the cells from varicose veins.
Interestingly, a similar collagen dysregulation pattern has also been observed in patients with
varicose veins after dermal biopsies, suggesting an intrinsic genetic abnormal response to injury.
The observed pathology suggests a net effect of matrix deposition. One mechanism for
these changes may be local upregulation of MMPs and fibrinolytic activity within the
microenvironment. The upstream regulators of MMPs are in part, the plasmin system. Urinary
PA levels are three to five times higher than in controls, as assessed from media of specimen
organ culture from varicose veins. Interestingly, there is no difference in tPA activity or PAI-1
levels. Investigators have found that TIMP-1 and MMP-1 protein levels are higher at the
saphenofemoral junction in patients with varicose veins and that MMP-2 activity is lower in
normal controls. Similarly, high TIMP-1 activity and low MMP-2 activity have been observed in
varicose vein segments, with a threefold significant difference in comparison with normal
controls. Overall differences in MMP-9 protein have also been identified, and it is likely, with
the inflammatory influx, that MMP-9 is released primarily from PMNs but may be less important
than MMP-2.
This disordered vein structure also correlates with altered vasoreactivity. The contractual
response of varicose and normal great saphenous rings to various alpha-adrenergic and non–
alpha-adrenergic receptors has shown decreased contractility as compared with controls. This
lower contractility may be due to repeated overdistention or impaired contractility related to
persistent vein wall tension. However, it is a segmental response and likely adaptive. Receptor
downregulation may also play a role. For example, feedback inhibition of ETA receptor
secondary to increased endothelin-1 is also postulated to mediate the lower vasoreactivity
content in the walls of varicose veins. The ratio of prostacyclin to thromboxane A2 is also lower,
suggesting an increased basal contractile state. Finally, one investigation has suggested that
MMP-2 may act to dilate the vein by direct hyperpolarization effects, via a Ca+2 channel
mechanism.

Pathophysiology of Stasis Dermatitis and Dermal Fibrosis (CEAP Class 4 to 6 Disease)

Stasis venous dermatitis is a disease of chronic dermal inflammation due to persistent and
sustained cutaneous and dermal injury secondary to venous hypertension. The primary injury
may be extravasation of macromolecules and red blood cell products into the dermal interstitium,
which creates a secondary inflammatory response, and multiple pathophysiologic hypotheses
have been proposed. The clinical appearance is that of brawny induration, skin thickening,
swelling, and tissue breakdown with ulceration in the gaiter regions. Alteration in extracellular
matrix is clear on histologic assessment, with dermal space extracellular disorganized collagen
deposition and perivascular tissue cuffs.
The role of the common growth factor TGF-β1, which is secreted by activated endothelial
cells, fibroblasts, and platelets and stimulates matrix protein production, has been studied in
relation to venous ulcer development. TGF-β is an inducer of TIMP-1 and collagen production
and inhibits MMP activity and gene expression. The local upregulation of TGF-β1 thus favors
net collagen and matrix accumulation and is supported by histologic and clinical analysis,
although gene upregulation may occur at an earlier stage than protein production. Whether TGF-
β is acting directly or is associated with this process has not been substantiated in human studies
to date. Several other growth factors are elevated in the dermis of patients with CVI, including
platelet-derived growth factors α and β and VEGF. These various molecules are found within the
capillaries surrounding fibroblasts and inflammatory cells in patients with venous skin changes.
Further studies have suggested that endothelial activation results from venous
hypertension. A significant rise in plasma levels of endothelial leukocyte adhesion molecule-1
(ELAM-1), ICAM-1, and vascular cell adhesion molecule-1 were observed in patients with
venous hypertension, indirectly suggesting a role of these molecules in the pathogenesis.
Similarly, increased endothelial expression of ICAM-1, vascular cell adhesion molecule-1, and
leukocyte function-associated antigen-1 (LFA-1) has been documented in patients with dermal
disease.
Several studies suggest conflicting data with regard to whether MMP-2, MMP-9, and
TIMP-1 levels are higher or unaltered in patients with venous ulcers. This uncertainty may have
to do with the measurement of MMP gene, protein, or activity expression as well as with the
ulcer stage and patient characteristics that may not be controlled for. Another important
proteinase is elastase, primarily derived from PMNs. Higher levels of plasma elastase were
found in patients with venous ulceration than in those with uncomplicated varicose veins,
perhaps reflecting active degranulation in those with ulcers. However, this evidence is only
indirect, and whether proteinases are directly responsible for venous ulcer development is not
known.
Consistent with the tissue inflammation, leukocytes are markedly elevated in the gaiter
region in association with the venous ulcers. This finding correlates with preceding elevation of
IL-1α and ICAM-1 in the tissue of lipodermatosclerotic skin. The type and distribution of
leukocytes in patients with CEAP class 5/6 CVI have been studied histologically. Numbers of
mast cells and macrophages were two to four times greater around arterioles and postcapillary
venules in patients with CEAP class 4/5 CVI than in controls. Similarly, increased macrophages
are demonstrated around arterioles and postcapillary venules, although fibroblasts are the most
common cell observed in both gaiter and thigh biopsy specimens. It is likely that these
leukocytes regulate the tissue remodeling that results in dermal fibrosis.
Sluggish venous blood flow related to increased hydrostatic pressure leads to hypoxia and
PMN activation, with degranulation of mediators and proteinases that cause endothelial damage.
Skin hypoxia also occurs on the gaiter areas of limbs with severe venous disease and is
significantly different from controls, oxygen tension (tcPO2) differing by more than 20 mm.
Although leukocyte trapping within the capillaries is probably not the sole cause, it is likely that
leukocytes become activated, transmigrate into the vein walls, and mediate some of the observed
damage. Consistently, findings in punch biopsy specimens of ulcers suggest that leukocytes play
a role in the dermal manifestations of CVI. For example, leukocytes, macrophages, and mast
cells have all been observed in immunohistochemical and electron microscopic examinations of
affected tissue.
The dermal fibroblast may also be dysfunctional and allow perpetuation of the disease.
Decreased motility, in part mediated by the microenvironment, plays a role in the impaired
healing process of ulcer tissue. Comparison of venous ulcer fibroblasts with control fibroblasts
with stimulation with TGF-β suggested that there are differences in collagen production. With
stimulation, collagen production was increased 60% in controls, whereas the venous ulcer
fibroblasts were unresponsive. This finding may be related to an end-stage process,
overstimulation of the ulcer fibroblast, or an intrinsically dysfunctional fibroblast. Consistently,
the proliferative responses of fibroblasts from patients with CVI to TGF-1β correlated with
disease severity. Fibroblasts in patients with CEAP class 2 or 3 CVI retained agonist induce
proliferative capacity, whereas those from patients with class 4 or 5 CVI showed diminished
agonist-induced proliferation. Fibroblasts from patients with class 6 CVI and active ulcers did
not proliferate with TGF-1β, suggesting that these ulcer fibroblasts are refractory to stimulation
and may contribute to the inability to promote healing. Histologically, these fibroblasts appear
morphologically similar to fibroblasts undergoing cellular senescence, and therefore may be
proapoptotic from repeated injury. Another study showed similar impairment of dermal wound
fibroblast proliferation response to both basic fibroblast growth factor and EGF.
An interesting but unanswered question is which patients with similar degrees of reflux
and hydrostatic pressures from CVI are more predisposed to development of venous ulcers. Data
now suggest that iron metabolism and ulcer development are interrelated. Although commonly
thought of as a consequence of all the other mechanisms of CVI, the iron deposition itself may
cause tissue damage. More onvincingly, the risk of ulcer development among patients with class
4 to 6 CVI was sevenfold higher in those with the C282Y genotype, a mutation related to iron
processing.
Taken together, venous insufficiency and secondary cutaneous manifestations suggest
that active tissue remodeling occurs, likely via multiple mechanisms and in different stages.
Whether the growth factors, cytokines, and proteinases are directly responsible or secondary to
other factors of the disease has not been definitively answered. Regardless, the significant benefit
of compression in ulcer healing suggests these factors may play a secondary role. In one study
the benefit of compression therapy and how it may alter histologic and biochemical features was
shown after 4 weeks. Complete epithelialization was frequent, the hemosiderin and red blood
cell extravasation products had decreased, and fibrin cuffs were reversed. However, a single
“silver bullet” approach to therapy is unlikely to be successful. Rather, identifying patients at risk
for CVI with biomarkers (via genomics and proteomics) may be the best immediate translational
approach.