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

Compression therapy performed with both bandages and elastic stockings has multiple actions on the
microcirculation, such as a reduction in venulo-capillary permeability, an increase in skin capillary
perfusion with increased nitric oxide and activation of fibrinolysis, and an increase in cutaneous
vasodilation through the activation of capsaicin receptors [33-36] . Histological studies have shown that
compression reduces edema and venulo-capillary ectasia . Studies with CapiFlow have shown a reduced
[38]
[37]
endolymphatic pressure. A reduction in leukocyte adhesion and oxidative stress has also been
demonstrated.

Pharmacological therapy
Two classes of drugs have been shown to significantly interfere with stasis microangiopathy: the purified
micronized flavonoic fraction (FFPM) and glycosaminoglycans (GAGs).

FFPM increases sympathetic-mediated venular contractility, reduces leukocyte adhesion by reducing the
production of adhesion molecules, and reduces the production of pro-inflammatory molecules.
Furthermore, FFPM increases the production of antioxidant factors; reduces the concentration of ICAM-1,
vascular cell adhesion molecule 1 (VCAM-1), and vascular endothelial growth factor (VEGF); and reduces
the permeability of capillaries.

GAGs (sulodexide and mesoglycan) restore the glycocalyx, activate fibrinolysis by acting on plasminogen
activator inhibitor and tissue plasminogen activator, have antithrombotic action by acting on antithrombin
and heparin cofactor II, and reduce thrombin-induced platelet aggregation. GAGs also have anti-
inflammatory action by acting on cytokines, tumor necrosis factor α (TNF-α), TGF-β1, VEGF, and
interferon gamma (IFN-γ); blocking chemokines; modulating macrophages; and blocking MMPs
(sulodexide) [2,39,40] .

[41]
Maresca et al. studied the effect of mesoglycan on cutaneous blood flow measured by laser Doppler
fluometry (LDF) in a group of 75 female patients (aged 45.5 ± 9.6 years) in different stages of CVD,
according to the CEAP classification. The active group (N = 37) received mesoglycan 50 mg twice daily in
adjunct to standard care. After 90 days of treatment, mesoglycan obtained a significative increase in peak
[41]
flow at LDF in the entire group of treated women . In a systematic review and meta-analysis, Bignamini
et al. assessed the efficacy and safety of sulodexide for treatment of signs and symptoms of lower
[42]
extremity CVD. Sulodexide was found to have a beneficial venoactive effect on the major signs and
symptoms of CVD such as pain, cramps, heaviness, and oedema, with the exception of discoloration, which
appeared unaffected by the treatment. Furthermore, sulodexide was found to be effective in decreasing the
release of inflammatory markers present in CVD, such as interleukin-6, monocyte chemoattractant protein-
1, soluble intercellular adhesion molecule-1, and free radicals.

Interestingly, it has been shown that vasoactive and anti-inflammatory properties of aminaphtone may be
useful in treatment of chronic venous and lymphatic stasis . Aminaphtone reduces the expression of
[43]
endothelial-leukocyte adhesion molecule 1 (ELAM-1), VCAM-1, and ICAM-1, as well as the production of
cytokines and vasoconstrictor agent endothelin-1, playing a potential role in treatment of other vascular
[44]
diseases such as Raynaud’s phenomenon .
The combination of Ruscus, hesperidin methylchalcone (HMC), and vitamin C has recently been awarded a
[45]
Grade 1A recommendation by the international guidelines . A review of clinical studies and a meta-
analysis have confirmed its clinical efficacy across a wide spectrum of CVD clinical classes: C0S, C1S, C2,
C3 and C4 . The combination of Ruscus, HMC, and vitamin C acts by increasing venous and lymphatic
[46]