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Page 4 of 8 Bilancini et al. Vessel Plus 2021;5:39 https://dx.doi.org/10.20517/2574-1209.2021.14

other studies which showed that fibrin caps were also present in healed ulcers and that application of
Xenon-133 to the skin of patients with fibrin caps had the same clearance as healthy subjects [13,16] . Falanga
[17]
et al. hypothesized that fibrin trapped growth factors, making them unavailable for ulcer healing, thereby
delaying reparative processes.

Inflammation
The lesions of the glycocalyx secondary to the venulo-capillary stasis and the consequent increase in shear
stress cause the activation of endothelial mechanoreceptors and the endothelial production of E-selectins
that interact with the L-selectins produced by leukocytes, leading to rolling of these cells along the
endothelial surface. When leukocytes are activated, they express integrins, which bind to intercellular
adhesion molecule 1 (ICAM-1) expressed by endothelial cells, and this event represents the starting point
for their migration into the interstitium and for their subsequent degranulation [18-19] . The activation of
matrix metalloproteinases (MMPs), especially MMP-2 [20-22] , is a subsequent event. On the other hand, the
tissue inhibitor of MMP-2 (TIMP-2) is reduced [20-22] . The reduction of TIMP-2 activates inflammation and
causes damage to the intercellular matrix by MMPs. The deposition of iron in the tissues further activates
the MMPs, which, together with free radicals, accentuate the tissue damage. On the other hand, the
production of transforming growth factor β1 (TGF-β1) in the context of inflammation stimulates collagen
[14]
production leading to fibrosis .
Functional alterations
Inflammation does not spare the peripheral nerves, and for this reason a neuropathy secondary to venous
stasis also develops leading to vasomotor changes , consisting of abolition of the veno-arteriolar reflex ,
[24]
[23]
reduction of reactive hyperemia, heating hyperemia, and neuro-mediated vasodilation [25-27] . At the level of
the venous ulcer, laser Doppler imaging has allowed detecting a high blood flow in the areas with
granulation tissue, a low blood flow in the areas without granulation tissue, and a high blood flow both at
[28]
the edges of the ulcer and at the adjacent areas of lipodermatosclerosis . On the other hand,
transcutaneous carbon dioxide tension was very low both at the bed of the ulcer and at the edges . These
[29]
two apparently conflicting observations led Partsch to define this condition as “hyperemic hypoxia” . At
[30]
the capillaroscopic level, different conditions have been described in the areas of lipodermatosclerosis
depending on the clinical stage of the ulcer. The initial stages are characterized by a pericapillary halo
secondary to increased permeability, a moderate capillary dilation, and capillary tortuosity. In the
intermediate stages, the pericapillary halo and capillary dilation are accentuated. The advanced stages are
instead characterized by a reduction in the number of capillaries. In the zones of atrophie blanche (white
scar tissue), there are avascular areas and few huge and convoluted capillaries. In the ulcerated areas without
granulation tissue, there are no capillaries, while, in the areas with granulation tissue, there are few giant
capillaries and edema [31-32] . The histological examination revealed micro-vessels occlusions, dilation of
endothelial junctions, alteration of lymphatic vessels and anchoring filaments, and fibrosis of the interstitial
matrix .
[23]

STASIS MICROANGIOPATHY: TREATMENT
Compression therapy
It has been reported that compression therapy can significantly improve symptoms and reduce lower limb
volume in patients with CVD by improving the function of cutaneous microcirculation . Grenier et al.
[33]
[34]
investigated the relationship between skin microcirculatory activities and external compression provided by
elastic compression stockings by measuring skin thermal conductivity in a group of 30 female subjects
having minor symptoms of CVD (CEAP C0S and C1S) and observed an improvement of microcirculatory
activities in 83% of them.