The chronic venous disease covers a wide spectrum of venous disorders that are characterized by severely impaired blood return that primarily affects veins in the lower extremities. Morphological and functional abnormalities of the venous system led to chronic venous insufficiency (CVI), and present as leg heaviness/achiness, edema, telangiectasia, and varices. The term 'chronic venous insufficiency' (CVI) refers to a disease of greater severity. Venous dysfunction is associated with venous hypertension and is associated with venous reflux due to poorly functioning or incompetent venous valves, which ultimately reduces venous return, leading to a cascade of morphological, physiological, and histologic abnormalities such as blood pooling, hypoxia, inflammation, swelling, skin changes (lipodermatosclerosis), and in severe cases, venous leg ulcers (VLU). This review summarizes recent knowledge about the aetiology, risk factors, and pathophysiology of VLU and compared the possibilities of their treatment.

Department of Burns and Plastic Surgery Faculty of Medicine Masaryk University and University Hospital Brno Czech Republic

Department of Chemistry Faculty of Natural Sciences University of Ss Cyril and Methodius Trnava Slovakia

Department of Health Sciences Faculty of Medicine Masaryk University Brno Czech Republic

Department of Physiology Faculty of Medicine Masaryk University Brno Czech Republic

Institute of Clinical and Translational Research Biomedical Research Center SAS Bratislava Slovakia

See more in PubMed

Hyder ON, Soukas PA. Chronic venous insufficiency: novel management strategies for an under‐diagnosed disease process. R I Med J. 2017;100(5):37‐39. PubMed

Eberhardt RT, Raffetto JD. Chronic venous insufficiency. Circulation. 2014;130(4):333‐346. PubMed

Musil D, Kaletova M, Herman J. Venous thromboembolism—prevalence and risk factors in chronic venous disease patients. Phlebology. 2017;32(2):135‐140. PubMed

Taengsakul N. Risk factors for and treatment of chronic venous disease in Thai patients. Vasc Health Risk Manag. 2022;18:667‐676. PubMed PMC

Ferreira AP, Furtado SRC, Carceroni LL, et al. Variation in sociodemographic, clinical and functional characteristics of patients with chronic venous insufficiency in a single public health center. J Vasc Nurs. 2023;41(2):72‐76. PubMed

Mansilha A, Sousa J. Benefits of venoactive drug therapy in surgical or endovenous treatment for varicose veins: a systematic review. Int Angiol. 2019;38(4):291‐298. PubMed

Probst S, Saini C, Gschwind G, et al. Prevalence and incidence of venous leg ulcers‐a systematic review and meta‐analysis. Int Wound J. 2023. doi:10.1111/iwj.14272. PubMed DOI PMC

Slonkova V, Vasku A, Vasku V. Genetic predisposition for chronic venous insufficiency in several genes for matrix metalloproteinases (MMP‐2, MMP‐9, MMP‐12) and their inhibitor TIMP‐2. J Eur Acad Dermatol Venereol. 2017;31(10):1746‐1752. PubMed

Chen YF, Peng W, Raffetto JD, Khalil RA. Matrix metalloproteinases in remodeling of lower extremity veins and chronic venous disease. In: Khalil RA, ed. Matrix Metalloproteinses and Tissue Remodeling in Health and Disease: Cardiovascular Remodeling; 2017:267‐299. Academic Press. PubMed PMC

Raffetto JD. Pathophysiology of chronic venous disease and venous ulcers. Surg Clin North Am. 2018;98(2):337. PubMed

Ortega MA, Fraile‐Martinez O, Garcia‐Montero C, et al. Contribution of the elastic component and Venous Wall arterialization in patients with venous reflux. J Pers Med. 2022;12(2):260. PubMed PMC

Caliskan S, Atay M, Gunay‐Polatkan S, Sigirli D. The relationship between venous insufficiency and serum magnesium level. Magn Res. 2022;35(4):108‐117. PubMed

Jarošíková R, Roztočil K, Husáková J, et al. Chronic venous disease and its intersections with diabetes mellitus. Physiol Res. 2023;72(3):280‐286. PubMed PMC

Caggiati A, Rosi C, Franceschini M, Innocenzi D. The nature of skin pigmentations in chronic venous insufficiency: a preliminary report. Eur J Vasc Endovasc Surg. 2008;35(1):111‐118. PubMed

Falanga V, Eaglstein WH. The trap hypothesis of venous ulceration. Lancet. 1993;341(8851):1006‐1008. PubMed

Latha KC, Sreekumar A, Beena V, et al. Shear stress alterations activate BMP4/pSMAD5 signaling and induce endothelial mesenchymal transition in varicose veins. Cell. 2021;10(12):3563. PubMed PMC

Pastar I, Stojadinovic O, Krzyzanowska A, et al. Attenuation of the transforming growth factor beta‐signaling pathway in chronic venous ulcers. Mol Med. 2010;16(3–4):92‐101. PubMed PMC

Krizanova O, Penesova A, Sokol J, Hokynkova A, Samadian A, Babula P. Signaling pathways in cutaneous wound healing. Front Physiol. 2022;13:1030851. PubMed PMC

Ortega MA, Romero B, Asunsolo A, et al. Patients with incompetent valves in chronic venous insufficiency show increased systematic lipid peroxidation and cellular oxidative stress markers. Oxid Med Cell Longev. 2019;2019:1‐9. PubMed PMC

Kuhn J, Sultan DL, Waqas B, et al. Nrf2‐activating therapy accelerates wound healing in a model of cutaneous chronic venous insufficiency. Plast Reconstruct Surg Glob Open. 2020;8(11):e3006. PubMed PMC

Lichota A, Gwozdzinski L, Gwozdzinski K. Therapeutic potential of natural compounds in inflammation and chronic venous insufficiency. Eur J Med Chem. 2019;176:68‐91. PubMed

Casili G, Lanza M, Campolo M, et al. Therapeutic potential of flavonoids in the treatment of chronic venous insufficiency. Vascul Pharmacol. 2021;137:106825. PubMed

Lal BK. Venous ulcers of the lower extremity: definition, epidemiology, and economic and social burdens. Semin Vasc Surg. 2015;28(1):3‐5. PubMed

Stucker M. Superficial venous thrombosis, varicose veins, and chronic venous insufficiency: an update for clinical practice. Inn Med (Heidelb). 2022;63:612‐618. PubMed

Raju S, Neglen P. Chronic venous insufficiency and varicose veins. N Engl J Med. 2009;360(22):2319‐2327. PubMed

Fife CE, Eckert KA, Carter MJ. Publicly reported wound healing rates: the fantasy and the reality. Adv Wound Care. 2018;7(3):77‐94. PubMed PMC

Mayrovitz HN, Wong SM, Mancuso C V. Arterial, and neuropathic leg ulcers with emphasis on the geriatric population. Cureusl. 2023;15(4):e38123. PubMed PMC

Santler B, Goerge T. Chronic venous insufficiency—a review of pathophysiology, diagnosis, and treatment. J Dtsch Dermatol Ges. 2017;15(5):538‐557. PubMed

Silverberg J, Jackson JM, Kirsner RS, et al. Narrative review of the pathogenesis of stasis dermatitis: an inflammatory skin manifestation of venous hypertension. Dermatol Ther. 2023;13(4):935‐950. PubMed PMC

O'Donnell TF, Passman MA, Marston WA, et al. Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery (R) and the American venous forum. J Vasc Surg. 2014;60(2):3S‐59S. PubMed

Swoboda SJ, Schumann H, Kiritsi D. A leg ulcer with pulsating varicose veins—from the legs to the heart. Int Wound J. 2018;15(1):62‐64. PubMed PMC

Cavadas PC, Padial B. Circumferential radical debridement and omental free flap in the treatment of severe chronic venous ulcers. Ann Plast Surg. 2023;90(6):568‐574. PubMed

Millan SB, Gan R, Townsend PE. Venous ulcers: diagnosis and treatment. Am Fam Physician. 2019;100(5):298‐305. PubMed

Andriessen A, Apelqvist J, Mosti G, Partsch H, Gonska C, Abel M. Compression therapy for venous leg ulcers: risk factors for adverse events and complications, contraindications—a review of present guidelines. J Eur Acad Dermatol Venereol. 2017;31(9):1562‐1568. PubMed

Karanikolic V, Ignjatovic A, Marinkovic M, Djordjevic L. The effectiveness of two different sub‐bandage pressure values on healing and quality of life outcomes for patients with venous leg ulcers. Postepy Dermatol Alergol. 2023;40(1):47‐53. PubMed PMC

Milic DJ, Zivic SS, Bogdanovic DC, Lazarevic MV, Ademi BN, Milic ID. The influence of different sub‐bandage pressure values in the prevention of recurrence of venous ulceration‐a ten year follow‐up. Phlebology. 2023;38:458‐465. PubMed

Mutlak O, Aslam M, Standfield NJ. An investigation of skin perfusion in venous leg ulcer after exercise. Perfusion‐Uk. 2018;33(1):25‐29. PubMed

Rerkasem A, Nantakool S, Kulprachakarn K, et al. The effect of standard compression adjuvant with a tailored exercise training program on health‐related quality of life outcomes in treating adults with venous leg ulcer: a randomized controlled trial. Int J Low Extrem Wounds. 2023. doi:10.1177/15347346231172566. PubMed DOI

Tew GA, Gumber A, McIntosh E, et al. Effects of supervised exercise training on lower‐limb cutaneous microvascular reactivity in adults with venous ulcers. Eur J Appl Physiol. 2018;118(2):321‐329. PubMed PMC

Jull A, Slark J, Parsons J. Prescribed exercise with compression vs compression alone in treating patients with venous leg ulcers a systematic review and meta‐analysis. JAMA Dermatol. 2018;154(11):1304‐1311. PubMed PMC

Zhang QT, Lu L, Song JL, Wang L. Effects of exercise in treating patients with venous leg ulcers: a systematic review and meta‐analysis. Int Wound J. 2023;20(5):1776‐1783. PubMed PMC

Nantakool S, Chuatrakoon B, van der Veen M, Rerkasem A, Rerkasem K. Exercise training as an adjunctive therapy for chronic venous insufficiency patients: evidence from research to practice. Int J Low Extrem Wounds. 2021. doi:10.1177/15347346211060126 PubMed DOI

Bush R, Comerota A, Meissner M, Raffetto JD, Hahn SR, Freeman K. Recommendations for the medical management of chronic venous disease: the role of micronized purified Flavanoid fraction (MPFF). Phlebology. 2017;32:3‐19. PubMed

Martinez MJ, Bonfill X, Moreno RM, Vargas E, Capella D. Phlebotonics for venous insufficiency. Cochrane Database Syst Rev. 2005;3:CD003229. PubMed

Martinez‐Zapata MJ, Vernooij RWM, Tuma SMU, et al. Phlebotonics for venous insufficiency. Cochrane Database Syst Rev. 2016;4:CD003229. PubMed PMC

Raffetto JD, Eberhardt RT, Dean SM, Ligi D, Mannello F. Pharmacologic treatment to improve venous leg ulcer healing. J Vasc Surg Venous Lymph Disord. 2016;4(3):371‐374. PubMed

Margolis DJ. Pentoxifylline in the treatment of venous leg ulcers. Arch Dermatol. 2000;136(9):1142‐1143. PubMed

Cwajda‐Bialasik J, Moscicka P, Jawien A, Szewczyk MT. Microbiological status of venous leg ulcers and its predictors: a single‐center cross‐sectional study. Int J Environ Res Public Health. 2021;18(24):12965. PubMed PMC

Miron A, Giurcaneanu C, Mihai MM, et al. Antimicrobial biomaterials for chronic wound care. Pharmaceutics. 2023;15(6):160. PubMed PMC

O'Meara S, Al‐Kurdi D, Ologun Y, Ovington LG, Martyn‐St James M, Richardson R. Antibiotics and antiseptics for venous leg ulcers. Cochrane Database Syst Rev. 2013;12:CD003557. PubMed

Shaydakov ME, Ting W, Sadek M, et al. Review of the current evidence for topical treatment for venous leg ulcers. J Vasc Surg Venous Lymph Disord. 2022;10(1):241‐+. PubMed

Kemaloglu CA. Nanofat Grafting Under a Split‐Thickness Skin Graft for Problematic Wound Management. Springerplus; 2016:5. PubMed PMC

Bowers S, Franco E. Chronic wounds: evaluation and management. Am Fam Physician. 2020;101(3):159‐166. PubMed

Orlov A, Gefen A. Fluid handling performance of wound dressings tested in a robotic venous leg ulcer system under compression therapy. Int Wound J. 2023;20(5):1384‐1392. PubMed PMC

Keohane C, Westby D, Nolan FC, Twyford M, Tawfick W, Walsh SR. Hyperbaric oxygen as an adjunct in the treatment of venous ulcers: a systematic review. Vasc Endovascular Surg. 2023;57(6):607‐616. PubMed PMC

Hong KP. Midterm results of radiofrequency ablation with multiple heat cycles for incompetent saphenous veins. J Vasc Surg Venous Lymph Disord. 2023;11(3):483‐487. PubMed

Brehmer F, Haenssle HA, Daeschlein G, et al. Alleviation of chronic venous leg ulcers with a hand‐held dielectric barrier discharge plasma generator (PlasmaDerm (R) VU‐2010): results of a monocentric, two‐armed, open, prospective, randomized and controlled trial (NCT01415622). J Eur Acad Dermatol Venereol. 2015;29(1):148‐155. PubMed

Emmert S, van Welzen A, Masur K, et al. Cold atmospheric pressure plasma for the treatment of acute and chronic wounds. Hautarzt. 2020;71(11):855‐862. PubMed

Edwards R, Harding KG. Bacteria and wound healing. Curr Opin Infect Dis. 2004;17(2):91‐96. PubMed

Jensen JO, Schulz L, Schleusser S, et al. The repetitive application of cold atmospheric plasma (CAP) improves microcirculation parameters in chronic wounds. Microvasc Res. 2021;138:104220. PubMed

Sim P, Strudwick XL, Song YM, Cowin AJ, Garg S. Influence of acidic pH on wound healing In vivo: a novel perspective for wound treatment. Int J Mol Sci. 2022;23(21):13655. PubMed PMC

Ma JH, Sun JL, Guo WS, Li ZR, Wang BL, Wang WG. The effect of platelet‐rich plasma on reducing blood loss after total knee arthroplasty: a systematic review and meta‐analysis. Medicine. 2017;96(26):e7262. PubMed PMC

Ramos‐Torrecillas J, De Luna‐Bertos E, Garcia‐Martinez O, Ruiz C. Clinical utility of growth factors and platelet‐rich plasma in tissue regeneration: a review. Wounds Compend Clin Res Pract. 2014;26(7):207‐213. PubMed

de OliveiraI B, de Carvalho MR, Ribeiro APL. Cost and effectiveness of platelet rich plasma in the healing of varicose ulcer: meta‐analysis. Rev Bras Enferm. 2020;73(4):e20180981. PubMed

Velier M, Magalon J, Daumas A, et al. Production of platelet‐rich plasma gel from elderly patients under antithrombotic drugs: perspectives in chronic wounds care. Platelets. 2018;29(5):496‐503. PubMed

Moneib HA, Youssef SS, Aly DG, Rizk MA, Abdelhakeem YI. Autologous platelet‐rich plasma versus conventional therapy for the treatment of chronic venous leg ulcers: a comparative study. J Cosmet Dermatol. 2018;17(3):495‐501. PubMed

Aziz Z, Cullum N. Electromagnetic therapy for treating venous leg ulcers. Cochrane Database Syst Rev. 2015;7:CD002933. PubMed PMC

Cullum N, Liu ZM. Therapeutic ultrasound for venous leg ulcers. Cochrane Database Syst Rev. 2017;5:CD001180. PubMed PMC

Dumville JC, Land L, Evans D, Peinemann F. Negative pressure wound therapy for treating leg ulcers. Cochrane Database Syst Rev. 2015;7:CD011354. PubMed PMC

Horn C, Fierro A, Lantis JC II. Review of the use of negative pressure wound therapy for the treatment of venous leg ulcers. Wounds. 2023;35(6):117‐125. PubMed

Valbonesi M. Fibrin glues of human origin. Best Pract Res Clin Haematol. 2006;19(1):191‐203. PubMed

Abbade LPF, Ferreira RS, dos Santos LD, Barraviera B. Chronic venous ulcers: a review on treatment with fibrin sealant and prognostic advances using proteomic strategies. J Venomous Anim Toxins Incl Trop Dis. 2020;26:26. PubMed PMC

Kawamura M, Sawafuji M, Watanabe M, Horinouchi H, Kobayashi K. Frequency of transmission of human parvovirus B19 infection by fibrin sealant used during thoracic surgery. Ann Thorac Surg. 2002;73(4):1098‐1100. PubMed

Abbade LPF, Barraviera S, Silvares MRC, et al. Treatment of chronic venous ulcers with heterologous fibrin sealant: a phase I/II clinical trial. Front Immunol. 2021;12:627541. PubMed PMC

Tiryaki T, Cohen SR, Turkay SC, et al. Hybrid stromal vascular fraction (hybrid‐SVF): a new paradigm in mechanical regenerative cell processing. Plast Reconstruct Surg Glob Open. 2022;10(12):e4702. PubMed PMC

Rigotti G, Marchi A, Galie M, et al. Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose‐derived adult stem cells. Plast Reconstr Surg. 2007;119(5):1409‐1422. PubMed

Cervelli V, Gentile P, De Angelis B, et al. Application of enhanced stromal vascular fraction and fat grafting mixed with PRP in post‐traumatic lower extremity ulcers. Stem Cell Res. 2011;6(2):103‐111. PubMed

Gentile P, Orlandi A, Scioli MG, et al. A comparative translational study: the combined use of enhanced stromal vascular fraction and platelet‐rich plasma improves fat grafting maintenance in breast reconstruction. Stem Cells Transl Med. 2012;1(4):341‐351. PubMed PMC