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Bilancini et al. Vessel Plus 2021;5:39 https://dx.doi.org/10.20517/2574-1209.2021.14 Page 3 of 8

microcirculation. The microvalves are located in venules, and they reach their maximum number in the
[5]
[2]
vessels with a caliber less than 100 microns . In 2011, Vincent et al. showed the incompetence of these
valves in patients with severe chronic venous insufficiency using retrograde resin venography. Therefore,
venous hypertension is transmitted from the macrocirculation to the microcirculation by the post-capillary
venular system. Lesions of microvalves secondary to venous pressure overload lead to the phenomenon of
venulo-capillary stasis. The stasis causes a reflex constriction in the pre-capillary arterioles with a blood flow
reduction . Venulo-capillary stasis causes an increase in endothelial permeability, with opening of the
[1]
intercellular spaces, slipping of the basement membrane, extravasation of liquids from the capillaries, and
interstitial flooding . The increased shear stress secondary to venous hypertension causes damage to the
[6]
glycocalyx that covers the endothelium and consequent activation of inflammatory events, which we discuss
in a dedicated section .
[7]
The role of the lymphatic system
The drainage of interstitial fluids is an almost absolute prerogative of the lymphatic circulation, which acts
as a “safety valve” against inflammation, removing proinflammatory molecules from interstitium, and
edema . In fact, edema develops only when the production of interstitial fluid exceeds the drainage capacity
[8]
of the lymphatic vessels. The increased intra-capillary pressure is initially counteracted by the increase in
interstitial pressure, secondary to the accumulation of interstitial fluid, and by the decrease in colloid
osmotic pressure, which determines a pressure gradient that favors the entry of liquid into the capillaries.
The balance is altered when a condition characterized by a progressive increase in intra-capillary pressure
occurs, such as in case of inflammation (e.g., stasis dermatitis and lipodermatosclerosis). At this point, the
[9]
lymphatic system reacts to avoid edema by increasing its drainage capacity . It is interesting to understand
why edema still occurs despite this compensation mechanism. Studies with fluorescence
microlymphography have shown an obstruction of the superficial lymphatic vessels, a reflux from the deep
[10]
to the superficial lymphatic system, and an increased capillary permeability . Studies with CapiFlow have
shown an absence of flow motion and an activation of deep lymphatics due to interstitial hypertension . At
[11]
the histological level, lesions of the anchoring filaments opening the lymphatic vessels and collapses of the
lymphatic vessels of the dermis have been reported . Other histological studies at the bed of venous ulcer
[6]
and its edges revealed a severe loss of lymphatic vessels that resulted totally absent in the bed of the ulcer .
[12]
This severe alteration of the lymphatic circulation also causes a localized immune deficit, secondary to loss
of immune surveillance, and susceptibility to infections. This finding would provide an explanation for the
susceptibility to skin infections observed in patients with chronic venous disease (CVD) at Clinical
Etiological Anatomical Pathophysiological (CEAP) classification C6 stage .
[6]
Hemorheological aspects
When stasis occurs, there is a marked increase in the aggregation of erythrocytes with consequent
obstruction of the capillaries, altered distribution, and slowing of tissue blood flow until it stops. In addition,
the erythrocytes lose their discoid shape, transform into spherocytes and echinocytes, and become rigid,
with further reduction in tissue blood flow. This phenomenon was described in 1975 by Schmidt and
Schombein as “collateral blood viscidation” . In this setting, there is an increased erythrocyte diapedesis
[13]
with deposition of erythrocytes in the interstitium, deposition of hemosiderin, and release of iron, which
causes both direct tissue lesions secondary to toxicity and production of free radicals that activate
inflammation .
[14]

The fibrin caps
In 1982, Burnand et al. showed the presence of fibrin deposits in the pericapillary space secondary to the
[15]
increased capillary permeability and hypothesized that these “fibrin caps” reduced exchanges between blood
and tissues, contributing to the formation of the venous ulcer. However, this hypothesis was rejected by