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Page 18 of 30 Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16

the dilated VVs. Other sclerosing agents approved by the Food and Drug Administration (FDA) include the
[172]
liquid detergent sodium tetradecyl sulfate (STS) and polidocanol . STS and polidocanol produce foam
that displaces blood, and causes vasoconstriction and eventually thrombosis and occlusion of VVs. VVs
patients treated with proprietary polidocanol endovenous microfoam have reported good benefits and
improved quality of life .
[173]
Other surgical approaches include endovenous ablation with a radiofrequency or infrared laser at
wavelengths ranging between 810 and 1320 nm, but could be as high as 1470 and 1550 nm. The high
endovenous heat denatures endothelial cell proteins and occludes VVs . Ablation therapy has shown
[174]
acceptable vein occlusion rates, good clinical outcomes, and ~2% vein recanalization rate 4 years following
[175]
radiofrequency therapy and only 3%-7% VVs recurrence rate 2-3 years following infrared laser
[176]
therapy . Stripping of the saphenous vein and high ligation of the saphenofemoral junction are also
commonly used surgical approaches with a low VVs recurrence rate . Ambulatory micro-phlebectomy
[177]
involves avulsion of clusters of large VVs and incompetent saphenous vein. Transilluminated power
phlebectomy is also used to remove clusters of VVs through fewer incisions and a shorter surgical
procedure .
[178]

Innovative endovenous treatment of VVs involves the use of non-thermal and non-tumescent approaches
including cyanoacrylate glue and related mechanochemical techniques [179,180] . Initial clinical outcomes are
promising, but further studies are needed to evaluate the potential benefits of these new approaches vs. the
thermal ablation and surgical procedures.

SDX in venous leg ulcer
SDX is a highly-purified glycosaminoglycan with antithrombotic and profibrinolytic effects, which has
shown benefits in atherosclerotic and thrombotic vascular disease. SDX-mediated decrease in blood
viscosity together with its fibrinolytic and lipolytic properties has made it beneficial in vascular disorders
such as atherosclerotic peripheral arterial disease, chronic leg ischemia, post-thrombotic venous syndrome,
and venous thromboembolism [181-186] . SDX has also shown some benefits in diabetic microangiopathy and
nephropathy, advanced CVI and VLU [182,185,187] . Experimental studies have also shown beneficial actions of
SDX including reduction of oxidative stress , modulation of growth factors, decreased MMP expression,
[188]
[189]
reduced inflammation, anti-angiogenic effects , and protection of endothelial cells [14,75,190-195] .
Recent studies have shown that in CVD patients at CEAP stage C5, SDX treatment for 2 months was
associated with reduction in MMP-9 serum level . Also, treatment of leukemia white blood cells in culture
[196]
with SDX causes reduction in the proMMP-9 and complexed MMP-9 in a concentration-dependent
manner . We have recently shown that SDX could improve venous contraction. In IVC segments under
[14]
control basal tension, SDX caused concentration-dependent (0.001-1 mg/mL) contraction. In IVC segments
under prolonged stretch, high KCl-induced contractile response and phenylephrine-elicited contraction
were reduced. In IVC under prolonged stretch and pretreated with SDX, the high KCl-induced contractile
response was restored and phenylephrine-induced contraction was improved. MMP-2 and MMP-9 levels
and activity were increased in IVC segments under prolonged stretch, and reversed to control levels in IVC
segments under prolonged stretch and pretreated with SDX. These observations suggest that SDX enhances
contraction in veins under protracted stretch likely through decreases in MMP-2 and MMP-9 activity, and
[14]
these effects could contribute the potential benefits of SDX in CVI and VVs .
Interestingly, SDX shows different effects in arteries vs. veins. In contrast with the contractile effect of SDX
in rat IVC, our recent experiments showed that phenylephrine caused contraction in rat aortic and