Why Venous Leg Ulcers Have Difficulty Healing: Overview on Pathophysiology, Clinical Consequences, and Treatment

Abstract

Venous leg ulcers (VLUs) are one of the most common ulcers of the lower extremity. VLU affects many individuals worldwide, could pose a significant socioeconomic burden to the healthcare system, and has major psychological and physical impacts on the affected individual. VLU often occurs in association with post-thrombotic syndrome, advanced chronic venous disease, varicose veins, and venous hypertension. Several demographic, genetic, and environmental factors could trigger chronic venous disease with venous dilation, incompetent valves, venous reflux, and venous hypertension. Endothelial cell injury and changes in the glycocalyx, venous shear-stress, and adhesion molecules could be initiating events in VLU. Increased endothelial cell permeability and leukocyte infiltration, and increases in inflammatory cytokines, matrix metalloproteinases (MMPs), reactive oxygen and nitrogen species, iron deposition, and tissue metabolites also contribute to the pathogenesis of VLU. Treatment of VLU includes compression therapy and endovenous ablation to occlude the axial reflux. Other interventional approaches such as subfascial endoscopic perforator surgery and iliac venous stent have shown mixed results. With good wound care and compression therapy, VLU usually heals within 6 months. VLU healing involves orchestrated processes including hemostasis, inflammation, proliferation, and remodeling and the contribution of different cells including leukocytes, platelets, fibroblasts, vascular smooth muscle cells, endothelial cells, and keratinocytes as well as the release of various biomolecules including transforming growth factor-β, cytokines, chemokines, MMPs, tissue inhibitors of MMPs (TIMPs), elastase, urokinase plasminogen activator, fibrin, collagen, and albumin. Alterations in any of these physiological wound closure processes could delay VLU healing. Also, these histological and soluble biomarkers can be used for VLU diagnosis and assessment of its progression, responsiveness to healing, and prognosis. If not treated adequately, VLU could progress to non-healed or granulating VLU, causing physical immobility, reduced quality of life, cellulitis, severe infections, osteomyelitis, and neoplastic transformation. Recalcitrant VLU shows prolonged healing time with advanced age, obesity, nutritional deficiencies, colder temperature, preexisting venous disease, deep venous thrombosis, and larger wound area. VLU also has a high, 50–70% recurrence rate, likely due to noncompliance with compression therapy, failure of surgical procedures, incorrect ulcer diagnosis, progression of venous disease, and poorly understood pathophysiology. Understanding the molecular pathways underlying VLU has led to new lines of therapy with significant promise including biologics such as bilayer living skin construct, fibroblast derivatives, and extracellular matrices and non-biologic products such as poly-N-acetyl glucosamine, human placental membranes amnion/chorion allografts, ACT1 peptide inhibitor of connexin 43, sulodexide, growth factors, silver dressings, MMP inhibitors, and modulators of reactive oxygen and nitrogen species, the immune response and tissue metabolites. Preventive measures including compression therapy and venotonics could also reduce the risk of progression to chronic venous insufficiency and VLU in susceptible individuals.

Human Wound and Its Burden: Updated 2020 Compendium of Estimates

“…Venous ulcers (VUs) are caused by chronic venous insufficiency and have a preponderance for the lower extremity. 53,54 The United Kingdom leads research on VU and studies by the National Health Service (NHS) identified that 1 in 500 UK residents have VU costing an estimated £400-600 million in health care costs. 55 In the United States, an estimated 500,000-600,000 people have venous leg ulcers resulting in a nearly $1 billion burden on health care.…”

High Na+ Salt Diet and Remodeling of Vascular Smooth Muscle and Endothelial Cells

“…These structural changes may be eccentric (increased remodeled arterial lumen) to accommodate reduced luminal space due to atherogenic lesions or post-intraluminal restenosis, to maintain adequate blood flow [ 14 ]. However, these changes may be concentric (reduction in remodeled arterial lumen) due to prolonged wall tension and vasoconstriction as in hypertension [ 14 , 16 , 17 ].…”

Mechanisms of lower extremity vein dysfunction in chronic venous disease and implications in management of varicose veins

“…Altered shear stress could lead to injury to the glycocalyx, endothelial dysfunction and progression of CVD. The glycocalyx structure is markedly altered and is associated with increased inflammation in CVD and VVs [75] . The glycocalyx is composed of glycoproteins with acidic oligosaccharides and terminal sialic acid, proteoglycans (heparan sulfate proteoglycan, syndecans and glypican core proteins), and glycosaminoglycan side chains that are sulfated (chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, and heparin), and nonsulfated (hyaluronic acid).…”

“…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 [188] , modulation of growth factors, decreased MMP expression, reduced inflammation, anti-angiogenic effects [189] , and protection of endothelial cells [14,75,[190][191][192][193][194][195] .…”