Materiały źródłowe

• #1 Pathogenesis of venous ulcer – PubMed

  https://pubmed.ncbi.nlm.nih.gov/26358304/

  The underlying pathophysiology of venous ulceration is venous hypertension, which initiates a complex cascade of cellular humeral events that are then magnified by genetic factors. […] Hemodynamic abnormalities are features of primary and secondary chronic venous diseases that lead to disease progression. […] Through a sequence of events, some patients develop venous leg ulcers, if the process is not interrupted. […] The exact science of the pathophysiology of the progression of chronic venous disease to venous leg ulcers is still in its infancy, but the framework for future study has been established.

• #1 Venous Ulcers: Diagnosis and Treatment | AAFP

  https://www.aafp.org/pubs/afp/issues/2019/0901/p298.html

  Venous hypertension as a result of venous reflux (incompetence) or obstruction is thought to be the primary underlying mechanism for venous ulcer formation. […] Venous hypertension is defined as increased venous pressure resulting from venous reflux or obstruction. This process is thought to be the primary underlying mechanism for ulcer formation. […] Valve dysfunction, outflow obstruction, arteriovenous malformation, and calf muscle pump failure contribute to the pathogenesis of venous hypertension. […] Venous ulcers result from a complex process secondary to increased pressure (venous hypertension) and inflammation within the venous circulation, vein wall, and valve leaflet with extravasation of inflammatory cells and molecules into the interstitium.

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

  https://www.mdpi.com/2077-0383/10/1/29

  Venous leg ulcers (VLUs) are one of the most common ulcers of the lower extremity. 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. […] VLU can be defined as a full-thickness defect of the skin frequently seen in the ankle region that fails to heal spontaneously and is sustained by chronic venous disease (CVD, the spectrum of venous diseases affecting the lower limbs). The macrovasculature involves abnormalities with hemodynamics, leading to venous hypertension that involves superficial venous insufficiency that can overwhelm the deep system, junctions, and reentry points in compartments of the lower extremity and cause outflow obstruction via the iliofemoral venous system, calf muscle pump dysfunction, and perforator venous insufficiency. The majority (70–80%) of patients with VLU have primary venous insufficiency (reflux) from varicose vein disease, and about 20–30% have secondary venous insufficiency from post thrombotic syndrome (PTS).

• #1 :: Journal of Wound Management and Research

  https://www.jwmr.org/m/journal/view.php?number=414

  Defined as an ulceration in a lower extremity caused by venous hypertension, venous ulcers are a common condition which are known to affect approximately 1% of the population. […] The pathophysiology of venous ulcers is a complex process with various associated signs such as varicose veins, chronic discharge, dermatitis, skin hyperpigmentation and fibrosis. […] Obstruction is an important factor in the pathogenesis of venous ulcers. […] The theory of the calf muscle pump concept is a crucial component of venous physiology. […] Genetic mutation can be a predisposing factor for developing venous ulcers. […] Introduced in 1917 by Homans, the term postphlebitic syndrome was used to explain the etiology of venous ulcerations. […] Blalock postulated the arteriovenous fistula theory from an analysis of hypoxia from chronic venous insufficiency. […] Proposed by Burnand et al., the fibrin cuff theory is based on a study of skin biopsies from patients with chronic venous disease. […] Early activation of white blood cells resulting from venous hypertension has been demonstrated in previous studies.

• #1 Cited

  https://www.koreamed.org/SearchBasic.php?RID=1940980

  Venous ulcer is a severe clinical manifestation of chronic venous insufficiency (CVI). […] The pathophysiology of venous ulcer and CVI are directly related. CVI is caused by a dysfunction in the muscular pump of the calf which is the primary mechanism to return blood from the lower limbs to the heart. This dysfunction leads to the ambulatory venous hypertension (AVH). AVH is the primary event result in the venous ulcer. […] There are many theories regarding the pathogenesis of venous ulcer. The oldest theories are venous stasis and arteriovenous shunts. The more recent theories have associated CVI with microcirculatory abnormalities, with the generation of an inflammatory response: pericapillary fibrin cuff formation; leukocyte adhesion and activation; tumor necrosis factor alpha (TNF-alpha); macromolecules, extravasation and fibrinolysis abnormalities; aggregate monocyte-platelet formation. Despite the many studies, the real mechanism of venous ulcer is still unknown. It is possible that each mechanism is important in some cases. Therefore, the pathophysiology of venous ulcer is still the subject of many current studies.

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

  https://www.mdpi.com/2077-0383/10/1/29

  Both the macrovenous and microvenous components of the venous system are affected. In the macrovenous component, there are several abnormalities including venous valve dysfunction and obstruction, that have a common pathway leading to venous hypertension and skin changes including venous leg ulcers. In microvenous circulation endothelial dysfunction, glycocalyx injury, and activation of chemokines (e.g., MCP-1 and MIP-1), adhesion molecules (e.g., ICAM-1, VCAM-1, and selectins) and endothelial regulators (NO) are potent molecules to allow for leukocytes migration within the venous wall and valve and eventually in the interstitium. […] A clear understanding of inflammatory pathways allows for detailed understanding of the pathophysiology and for areas of research for treatment targets. In addition, there are significant metabolic changes that occur in the VLU cell and tissues, which affect cell function and potential for healing and also present systemically, indicating that metabolic changes are dynamic and opportunity for novel therapeutic targets.

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

  https://www.mdpi.com/2077-0383/10/1/29

  In fact, the pooling of venous blood due to valve dysfunction together with increased venous pressure on the vein walls lead to an alteration of the physiological shear stress, which normally maintain blood fluidity and inhibit blood cell attachment. These mechanical stress forces alter the endothelium integrity both by disrupting the protective glycocalyx layer and by promoting endothelial cell fenestration/activation. Endothelial cell activation, through the expression of adhesion molecules (e.g., ICAM-1, VCAM-1, and E-selectins) and the release of chemoattractant molecules favor white blood cell (WBC) recruitment, attachment, and migration within the vein wall and interstitial tissue. […] As a consequence, VSMCs proliferate and lose their contractility and their ability to synthesize collagen fibers, thus resulting in the appearance of hypertrophic areas, with reduced contractility, increased rigidity, and impaired elasticity, which altogether worsen the ability of the vein wall to respond to increased venous pressures and to preserve the physiological shape.

• #1 Venous Leg Ulcer – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK567802/

  Venous leg ulcers (VLUs) are late indicators of chronic venous insufficiency (CVI) and venous hypertension. […] However, when retrograde flow, obstruction, or both exist, chronic venous hypertension is responsible for the dermatologic and vascular complications that form a VLU. […] The increased intraluminal pressure causes protein extravasation and fibrin cuff formation, which impedes the diffusion of oxygen and growth factors and activates the inflammatory response. […] The proinflammatory microenvironment is maintained by M1 macrophages, mainly by releasing interleukin-1, interferon-gamma, and transforming growth factor-beta 1. Chronic inflammation and incompetent blood flow favor thrombus formation, causing further fibrosis and valvular destruction. […] Together, this inflammatory cascade of events impairs healing processes, which results in ulcer formation upon wounding.

• #1 Vascular Ulcers: Practice Essentials, Epidemiology, Etiology

  https://emedicine.medscape.com/article/1298345-overview

  Venous (or stasis) ulceration is initiated by venous hypertension that develops because of inadequate calf muscle pump action and after the onset of either primary (with no obvious underlying etiology) or secondary (as seen after deep venous thrombosis) valvular incompetence. […] Two hypotheses have been proposed to explain venous ulceration once venous hypertension develops. […] The first states that distention of the capillary beds occurs because of increased stasis. This leads to leakage of fibrinogen into the surrounding dermis. Over time, a fibrinous pericapillary cuff is formed, impeding the delivery of oxygen and other nutrients or growth factors to the affected tissue. The resulting hypoxic injury leads to fibrosis and then ulceration. […] The other hypothesis suggests that the endothelium is damaged by increased venous pressure and leukocyte activation. Proteolytic enzymes and free radicals are released, escape through the leaky vessel walls, and damage the surrounding tissue, leading to injury and ulceration.

• #1 Prevention and Treatment of Leg and Foot Ulcers in Diabetes Mellitus

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/endocrinology/prevention-treatment-diabetic-leg-and-foot-ulcers/

  Venous ulceration is the eventual result of venous hypertension. This has multiple causes, but the most common cause is venous valvular incompetence or insufficiency, which may be congenital or acquired. Failure of the venous or muscle pump or venous obstruction may also contribute to venous hypertension. The end result is transmission of elevated venous pressure from the deep to superficial system of the veins, with local effects leading to ulceration. Although it is accepted that venous hypertension plays a dominant role in the development of ulceration, there are multiple hypotheses attempting to explain the direct cause of ulceration. […] The fibrin cuff theory, proposed by Browse and colleagues, has asserted that as a result of increased venous pressure, fibrinogen is leaked from capillaries. This results in the formation of pericapillary fibrin cuffs that serve as a barrier to the diffusion of oxygen and nutrients. This theory has lost favor as the sole cause, because fibrin is probably not as significant a barrier to diffusion as previously believed.

• #1 Venous ulcer – Wikipedia

  https://en.wikipedia.org/wiki/Venous_ulcer

  Venous ulcers are wounds that are thought to occur due to improper functioning of venous valves, usually of the legs (hence leg ulcers). […] The exact cause of venous ulcers is not certain, but a common denominator is generally venous stasis, which may be caused by chronic venous insufficiency, and/or congestive heart failure. Venous stasis causes the pressure in veins to increase. […] Venous hypertension may also stretch veins and allow blood proteins to leak into the extravascular space, isolating extracellular matrix (ECM) molecules and growth factors, preventing them from helping to heal the wound. […] Venous insufficiency may also cause white blood cells (leukocytes) to accumulate in small blood vessels, releasing inflammatory factors and reactive oxygen species (ROS, free radicals) and further contributing to chronic wound formation.

• #1 Venous ulcer – Wikipedia

  https://en.wikipedia.org/wiki/Venous_ulcer

  Buildup of white blood cells in small blood vessels may also plug the vessels, further contributing to ischemia. […] This blockage of blood vessels by leukocytes may be responsible for the „no reflow phenomenon”, in which ischemic tissue is never fully reperfused. […] It is in the crus that the classic venous stasis ulcer occurs. Venous stasis results from damage to the vein valvular system in the lower extremity and in extreme cases allows the pressure in the veins to be higher than the pressure in the arteries. This pressure results in transudation of inflammatory mediators into the subcutaneous tissues of the lower extremity and subsequent breakdown of the tissue including the skin. […] Wounds of the distal lower extremities arising from causes not directly related to venous insufficiency (e.g., scratch, bite, burn, or surgical incision) may ultimately fail to heal if underlying (often undiagnosed) venous disease is not properly addressed.

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

  https://www.mdpi.com/2077-0383/10/1/29

  The increased permeability of endothelial cells leads also to the extravasation of red blood cells, the degradation of which within the interstitium entails the release of hemoglobin and ferric iron, which amplify oxidative stress and inflammation of the surrounding tissues, further impairing wound healing. […] In this complex network of hemodynamic, cellular, and molecular processes, proteolytic enzymes and, in particular, the members of the MMP family, released by infiltrating leukocytes as well as by resident fibroblasts, VSMC, and keratinocytes, regulate both pathological remodeling of the extracellular matrix and the availability of signaling molecules. […] Despite conflicting results that have been occasionally reported, the impact of inflammatory and proteolytic mediators has been widely documented by a number of preclinical and in vitro studies. In this respect, circulating biomarkers have been found both in blood samples and VLU exudate.

• #1 Mechanism of disease: the inflammatory chain in chronic venous disorders and genetic screening for prevention of venous leg ulcers – Acta Phlebologica 2006 August;7(2):39-44 – Minerva Medica – Journals

  https://www.minervamedica.it/en/journals/acta-phlebologica/article.php?cod=R43Y2006N02A0039

  The inflammatory chain following venous outflow obstruction/reflux, and consequent microcirculatory overload, can be nowadays considered practically deciphered. […] Increased TMP determines expression of adhesion molecules on the endothelial cells, promotes red blood cells extra-vasation and either dermal hemosiderin deposits or iron laden-phagocites. […] Iron plays a role in the pathogenesis of venous leg ulcers: local iron overload may generate free radicals or activates a proteolytic hyperactivity of metalloproteinases (MMPs) or else down regulate tissue inhibitors of MMPs. […] It has been proven that these mutations increase the risk of ulcers and advance the age of ulcer onset, respectively. […] The inflammatory iron-dependent chain in CVD paves the way to new therapeutic strategy including the deliberate induction of iron deficiency as a treatment modality for non healing and/or recurrent venous leg ulcers. […] In addition, relatives of ulcers patients, carriers of the HFE mutation, when affected by CVD could undergo to genetic screening followed by a prevention program of venous leg ulcers.

• #1 Compression therapies for chronic venous leg ulcers: interventions and | CWCMR

  https://www.dovepress.com/compression-therapies-for-chronic-venous-leg-ulcers-interventions-and–peer-reviewed-fulltext-article-CWCMR

  Ulcers trapped in the inflammatory phase are unlikely to heal. This may be caused by an imbalance between matrix metalloproteinases (MMPs) and elastase and the MMP inhibitors. Certain dressings can trap MMPs in the form of oxidized regenerated collagen and cellulose, and may help to promote wound healing.

• #1 Venous Leg Ulcer – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK567802/

  Compared with healing VLUs, the gene expression profile of non-healing VLUs showed upregulation of secreted frizzled-related protein 4, branched-chain aminotransferase 1, dermatopontin, cytochrome P450, and 17 B hydroxysteroid dehydrogenase genes, which are involved in inflammation control, Wnt signaling, cell growth, extracellular matrix assembly, and steroidogenesis. […] A gene expression study’s results showed that VLUs treated with a bioengineered bilayered living cellular construct skin substitute displayed a shift from a chronic non-healing inflammatory profile to acute healing inflammation, highlighting the negative effects of chronic inflammation in wound healing.

• #1 Association Between Venous Leg Ulcers and Sex Chromosome Anomalies in Men | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-0949

  We report here two cases of men, aged 46 and 23 years, with refractory chronic venous leg ulcers in association with sex chromosome aberrations: one with a 47,XXY/48,XXXY karyotype (Klinefelter syndrome) and the other with a 47,XYY karyotype (Jacob syndrome). […] The pathophysiology behind the occurrence of venous leg ulcers in patients with numerical aberrations of the sex chromosomes is incompletely understood. Involvement of elevated plasminogen activator inhibitor-1 levels in the pathogenesis of venous leg ulcers has been reported in patients with Klinefelter syndrome. […] Leg ulcers in Klinefelter syndrome have been proposed to be caused by CVI and complicated by recurrent phlebothromboses. […] Some clinical reports have suggested a causal relationship with abnormalities in the fibrinolytic pathway, such as platelet hyper-aggregability, factor V Leiden mutation, decreased anti-thrombin III level, elevated factor VIII activity and particularly elevated levels of PAI-1 activity.

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

  https://www.mdpi.com/2077-0383/10/1/29

  VLU is the result of an intricate series of pathological events involving hemodynamic, cellular, and biomolecular alterations of macro- and microcirculation, which are eventually transmitted to the skin. In this complex picture, the common finding is the presence of ambulatory venous hypertension. Several predisposing factors (e.g., advanced age, female sex, genetic predisposition, family history, pregnancy, estrogen levels, obesity, prolonged standing, sitting, and environmental/occupational factors) have been highlighted to promote venous hypertension. […] Venous hypertension in association with the onset of cellular, molecular, and hemodynamic alterations in the microcirculatory system, through the activation of a cascade of events involving inflammatory processes, proteolytic activity, reduction of the physiological shear stress, and loss of glycocalyx glycosaminoglycans, leads to venous structural changes which finally exacerbate venous hypertension resulting in clinical manifestations of CVD, skin changes, and VLU.

• #1 Vascular Ulcers: Practice Essentials, Epidemiology, Etiology

  https://emedicine.medscape.com/article/1298345-overview

  In addition, studies have shown a relationship between obesity, chronic venous disease, and popliteal venous compression (PVC). […] A study by Rasmussen et al using near-infrared fluorescence lymphatic imaging found impaired lymphatic function occurring early in the development of venous leg ulcers and revealed bilateral dermal backflow in the presence of chronic venous insufficiency, including in patients without ulcers in the contralateral limb. […] A study by Polak et al indicated that in patients with deep venous thrombosis, denser fibrin clots that are resistant to lysis not only increase the risk of postthrombotic syndrome but also raise the likelihood of postthrombotic venous ulcer development.

• #1 Lower Leg Ulcers – Dermatology Advisor

  https://www.dermatologyadvisor.com/ddi/lower-leg-ulcers/

  At the cellular level, mast cells, leukocytes, matrix metalloproteinase inhibitors, prostacyclins, and myofibroblasts create a proinflammatory microenvironment with eventual remodeling of vessel walls. Chronic inflammation combined with blood pooling in the lower limbs favors thrombus formation, fibrosis, and destruction of intraluminal valves. When all of these factors are present they impair proper healing and result in ulcer formation within chronic wounds. […] The following are risk factors for venous insufficiency and the subsequent development of venous ulcers: advanced age, female sex, obesity, immobility, congenitally absent or incompetent valves, and history of either deep vein thrombosis or phlebitis. […] Clinically, venous ulcers typically affect the gaiter area of the legs, defined as the area between the mid-calf and ankle. The most common location is the medial malleolus. The wound normally appears as a shallow, well-defined ulcer with an irregular shape and a base of fibrin and granulation tissue.

• #1 The impact of venous leg ulcers on a patient’s quality of life: considerations for dressing selection – Wounds International

  https://woundsinternational.com/journal-articles/the-impact-of-venous-leg-ulcers-on-a-patients-quality-of-life-considerations-for-dressing-selection/

  A vast majority (70%) of lower-extremity ulcers are caused by chronic venous insufficiency (CVI). […] VLUs generally originate from minor traumatic injuries that do not follow the normal healing process as a consequence of CVI and the inflammatory status of the skin in the affected lower limbs. […] The main goals of VLU treatment are to reverse the underlying venous hypertension and the pro-inflammatory environment. […] Compression therapy remains the gold standard of the conservative treatment of CVI in all stages, because of its non-invasive nature, ease of use, and efficacy in reducing venous hypertension, which is a main pathophysiological mechanism of CVI. […] In the presence of venous hypertension, the increase in lymphatic flow can overwhelm the lymph transport capacity, leading to phlebolymphoedema.

• #1 Efficacy and safety of pentoxifylline for chronic venous leg ulcers: study protocol for a multicenter randomized controlled trial in China (ESPECT study) | Trials | Full Text

  https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-023-07547-y

  Pentoxifylline is used as a drug to treat peripheral artery disease and has been used in the treatment of VLUs. It could inhibit the synthesis of inflammatory mediators, decrease cytokine release, and suppress leukocyte function. […] The anti-inflammatory effect of pentoxifylline may offer a promising avenue to treat VLUs. […] In fact, there have been several trials suggesting that pentoxifylline could improve the healing rates of VLUs. […] In addition, other possible mechanisms of pentoxifylline might improve wound healing. Briefly, pentoxifylline could increase cAMP levels in the smooth muscle of vessels, increase erythrocyte flexibility, and then improve microcirculation and oxygen delivery. […] The fibrinolytic property might degrade microcirculation fibrin, improve skin and subcutaneous nutrition, and then improve wound healing. […] However, the evidence that currently recommends the use of pentoxifylline in VLUs is relatively weak. […] Therefore, it is imperative to investigate the efficacy and safety of pentoxifylline for VLUs in the Chinese population.

• #1 Clinical Trial for Leg Ulcer Patients | Clinical Trial against Leg Ulcers

  https://leg-ulcer-study.co.uk/

  The investigational medicine has a new mechanism of action to treat chronic venous leg ulcers. […] The investigational medicine allo-APZ2-CVU contains ABCB5-positive mesenchymal stromal cells (MSC) obtained from a skin tissue donation and multiplied. This highly purified cell population is applied once to the surface of the affected wound. The application transforms the inflammatory environment of the wound tissue into an anti-inflammatory environment, which is intended to create better conditions for wound healing. […] Initial data from a single-arm multicentre Phase I/IIa study in patients with leg ulcers support the efficacy and safety of allo-APZ2-CVU. The study comprised 31 treated patients with chronic venous leg ulcers. Within 12 weeks, wound size shrunk by an average of 82% in 70% of the patients. In 6 patients, the wound had even entirely closed after 12 weeks. None of the patients experienced any serious adverse events. […] The treatment of the wound with active wound care products must also be paused 14 days before the administration of the trial medicine or placebo.

• #1 Association Between Venous Leg Ulcers and Sex Chromosome Anomalies in Men | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-0949

  The serine protease inhibitor PAI-1 is the primary physiological inhibitor of tissue plasminogen activator and urokinase, the activators of plasminogen and hence fibrinolysis. […] Increased PAI-1 activity thus appears to indicate diminished fibrinolysis in Klinefelter syndrome and this inverse relationship supports the beneficial role of androgen therapy in XXY patients with venous leg ulcers. […] Jacob syndrome (47,XYY syndrome) has an incidence of approximately 0.51.5 per 1000 live male births, but may well also be underdiagnosed. […] It has been suggested that the prevalence of venous ulceration is increased in males with XYY syndrome. However, clear evidence of a disease-specific (hormonal) pathogenesis is lacking, and the occurrence might thus be related to the greater height of these patients. […] Treatment of venous leg ulcers in patients with sex chromosomal anomalies involves the same medical and surgical methods as in other patients. […] Furthermore, androgen replacement therapy may be a promising approach in the long-term treatment of PAI-1 related venous leg ulcers in XXY patients.

• #1 SciELO Brasil – Abordagem de pacientes com úlcera da perna de etiologia venosa Abordagem de pacientes com úlcera da perna de etiologia venosa

  https://www.scielo.br/j/abd/a/sKS9Vk77SrYD3LwT6cyjvvz/?lang=en

  Venous ulcers are common in adult population. They cause significant socioeconomic impact due to recurrence and the long interval between onset and healing. If venous ulcers are not appropriately managed, they present high rates of healing failure and recurrence. […] Advanced knowledge on the venous ulcer physiopathogenesis has led to development of new clinical and surgical treatments. […] The major advance in understanding the pathophysiology of venous ulcers has led to the development of new modalities of clinical and surgical treatments.

• #1 Venous ulcers of the shin | Leg ulcers | Phlebology clinic

  https://klinikaflebologii.pl/en/diseases/lower-limb-venous-insufficiency/venous-leg-ulcers/

  It is worth noting that treating venous disease at an early stage of development (C2-C3) significantly reduces the risk of its skin and thrombotic complications, significantly reducing the incidence of venous ulcers of the shin. Early intervention, e.g. in the form of compression therapy (compression therapy) or causal intravenous treatment can effectively reduce venous hypertension and prevent the development of inflammatory lesions in the skin.

• #2 SciELO Brasil – Abordagem de pacientes com úlcera da perna de etiologia venosa Abordagem de pacientes com úlcera da perna de etiologia venosa

  https://www.scielo.br/j/abd/a/sKS9Vk77SrYD3LwT6cyjvvz/?lang=en

  Venous ulcers are common in adult population. They cause significant socioeconomic impact due to recurrence and the long interval between onset and healing. If venous ulcers are not appropriately managed, they present high rates of healing failure and recurrence. […] Advanced knowledge on the venous ulcer physiopathogenesis has led to development of new clinical and surgical treatments. […] The major advance in understanding the pathophysiology of venous ulcers has led to the development of new modalities of clinical and surgical treatments.

• #2 Efficacy and safety of pentoxifylline for chronic venous leg ulcers: study protocol for a multicenter randomized controlled trial in China (ESPECT study) | Trials | Full Text

  https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-023-07547-y

  Venous leg ulcers (VLUs) are the most severe manifestation of chronic venous disease, with long healing time and a high recurrence rate. […] Chronic inflammation triggered by sustained venous hypertension is now recognized as the hallmark of chronic venous disease. […] The main pathophysiology of VLUs is venous reflux or obstruction, venous hypertension, and chronic inflammation. […] In recent years, it has been increasingly recognized that chronic inflammation, possibly triggered by sustained venous hypertension, is the principal basis that potentiates the disease progression of CVD. Chronic inflammation of the venous vessel wall could lead to degradation of venous integrity and function, resulting in diminished venous return, fluid accumulation, tissue fibrosis, atrophy, and ulceration in severe cases.

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

  https://www.mdpi.com/2077-0383/10/1/29

  Both the macrovenous and microvenous components of the venous system are affected. In the macrovenous component, there are several abnormalities including venous valve dysfunction and obstruction, that have a common pathway leading to venous hypertension and skin changes including venous leg ulcers. In microvenous circulation endothelial dysfunction, glycocalyx injury, and activation of chemokines (e.g., MCP-1 and MIP-1), adhesion molecules (e.g., ICAM-1, VCAM-1, and selectins) and endothelial regulators (NO) are potent molecules to allow for leukocytes migration within the venous wall and valve and eventually in the interstitium. […] A clear understanding of inflammatory pathways allows for detailed understanding of the pathophysiology and for areas of research for treatment targets. In addition, there are significant metabolic changes that occur in the VLU cell and tissues, which affect cell function and potential for healing and also present systemically, indicating that metabolic changes are dynamic and opportunity for novel therapeutic targets.

• #2 Vascular Ulcers: Practice Essentials, Epidemiology, Etiology

  https://emedicine.medscape.com/article/1298345-overview

  Venous (or stasis) ulceration is initiated by venous hypertension that develops because of inadequate calf muscle pump action and after the onset of either primary (with no obvious underlying etiology) or secondary (as seen after deep venous thrombosis) valvular incompetence. […] Two hypotheses have been proposed to explain venous ulceration once venous hypertension develops. […] The first states that distention of the capillary beds occurs because of increased stasis. This leads to leakage of fibrinogen into the surrounding dermis. Over time, a fibrinous pericapillary cuff is formed, impeding the delivery of oxygen and other nutrients or growth factors to the affected tissue. The resulting hypoxic injury leads to fibrosis and then ulceration. […] The other hypothesis suggests that the endothelium is damaged by increased venous pressure and leukocyte activation. Proteolytic enzymes and free radicals are released, escape through the leaky vessel walls, and damage the surrounding tissue, leading to injury and ulceration.

• #2

  https://dermnetnz.org/topics/leg-ulcer

  Venous insufficiency refers to improper functioning of the one-way valves in the veins. Veins in the feet and lower legs drain blood uphill to the heart. Two mechanisms assist this uphill flow, the calf muscle pump which pushes blood towards the heart during exercise, and the one-way valves which prevent the flow of blood back downhill. Reflux through the valves, obstruction of the veins and/or impaired calf pumping action results in pooling of blood around the lower part of the leg to just below the ankle. The increased venous pressure causes fibrin deposits around the capillaries, which then act as a barrier to the flow of oxygen and nutrients to muscle and skin tissue. The death of tissue cells leads to ulceration. […] Venous leg ulcer, in the absence of arterial disease, is usually treated with exercise, elevation at rest, and compression. Compression must not be used if there is significant arterial disease, as it will aggravate an inadequate blood supply.

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

  https://www.mdpi.com/2077-0383/10/1/29

  In fact, the pooling of venous blood due to valve dysfunction together with increased venous pressure on the vein walls lead to an alteration of the physiological shear stress, which normally maintain blood fluidity and inhibit blood cell attachment. These mechanical stress forces alter the endothelium integrity both by disrupting the protective glycocalyx layer and by promoting endothelial cell fenestration/activation. Endothelial cell activation, through the expression of adhesion molecules (e.g., ICAM-1, VCAM-1, and E-selectins) and the release of chemoattractant molecules favor white blood cell (WBC) recruitment, attachment, and migration within the vein wall and interstitial tissue. […] As a consequence, VSMCs proliferate and lose their contractility and their ability to synthesize collagen fibers, thus resulting in the appearance of hypertrophic areas, with reduced contractility, increased rigidity, and impaired elasticity, which altogether worsen the ability of the vein wall to respond to increased venous pressures and to preserve the physiological shape.

• #2 Venous ulcer – Wikipedia

  https://en.wikipedia.org/wiki/Venous_ulcer

  Venous ulcers are wounds that are thought to occur due to improper functioning of venous valves, usually of the legs (hence leg ulcers). […] The exact cause of venous ulcers is not certain, but a common denominator is generally venous stasis, which may be caused by chronic venous insufficiency, and/or congestive heart failure. Venous stasis causes the pressure in veins to increase. […] Venous hypertension may also stretch veins and allow blood proteins to leak into the extravascular space, isolating extracellular matrix (ECM) molecules and growth factors, preventing them from helping to heal the wound. […] Venous insufficiency may also cause white blood cells (leukocytes) to accumulate in small blood vessels, releasing inflammatory factors and reactive oxygen species (ROS, free radicals) and further contributing to chronic wound formation.

• #2 Cited

  https://www.koreamed.org/SearchBasic.php?RID=1940980

  Venous ulcer is a severe clinical manifestation of chronic venous insufficiency (CVI). […] The pathophysiology of venous ulcer and CVI are directly related. CVI is caused by a dysfunction in the muscular pump of the calf which is the primary mechanism to return blood from the lower limbs to the heart. This dysfunction leads to the ambulatory venous hypertension (AVH). AVH is the primary event result in the venous ulcer. […] There are many theories regarding the pathogenesis of venous ulcer. The oldest theories are venous stasis and arteriovenous shunts. The more recent theories have associated CVI with microcirculatory abnormalities, with the generation of an inflammatory response: pericapillary fibrin cuff formation; leukocyte adhesion and activation; tumor necrosis factor alpha (TNF-alpha); macromolecules, extravasation and fibrinolysis abnormalities; aggregate monocyte-platelet formation. Despite the many studies, the real mechanism of venous ulcer is still unknown. It is possible that each mechanism is important in some cases. Therefore, the pathophysiology of venous ulcer is still the subject of many current studies.

• #2 Wound Care Today | May 2025

  https://www.woundcare-today.com/journals/issue/wound-care-today/article/differential-diagnosis-leg-ulcers-focus-atypical-ulcers

  Most leg ulcers seen in practice are venous in aetiology. […] Although vascular disorders are the major cause of leg ulcers, there are other aetiologies that should be considered when the leg ulcer has failed to respond to evidence-based therapy. […] The lack of an accurate diagnosis means that a leg ulcer will be challenging to treat effectively. […] The hard woody feel of the tissues is thought to result as fibrin gets excessively deposited around capillary beds leading to elevated intravascular pressure. This causes enlargement of endothelial pores resulting in further increased fibrinogen deposition in the tissues. The fibrin cuff, which surrounds the capillaries in the dermis, decreases oxygen permeability and inhibits diffusion of oxygen and other nutrients, leading to impaired wound healing.

• #2 Prevention and Treatment of Leg and Foot Ulcers in Diabetes Mellitus

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/endocrinology/prevention-treatment-diabetic-leg-and-foot-ulcers/

  The trapping of white cells to capillary endothelium is another hypothesis. Venous hypertension results in decreased flow in the capillaries, resulting in the accumulation of white cells. These white cells may then release proteolytic enzymes, as well as interfere with tissue oxygenation. […] A different trap hypothesis has been proposed. This suggests that venous hypertension causes various macromolecules to leak into the dermis and trap growth factors. These growth factors are then unavailable for repair of damaged tissue.

• #2 Venous ulcers of the shin | Leg ulcers | Phlebology clinic

  https://klinikaflebologii.pl/en/diseases/lower-limb-venous-insufficiency/venous-leg-ulcers/

  A key role in the development of venous ulcers is played by the processes of inflammation of the subcutaneous tissue and tissue overload with iron, which is a breakdown product of haemoglobin from extravasated blood. Chronic venous hypertension causes inflammation which damages not only capillaries but also skin cells, fibroblasts. Fibroblasts change their phenotype to myofibroblasts which, by contracting, increase the tension in the dermis. This increased tension causes the skin to become more susceptible to injury and impedes wound healing. […] Cutaneous haemosiderosis (iron overload) sustains inflammation and hinders the healing. Iron, derived from haemoglobin, accumulates in the intercellular space of the skin and activates macrophages (foraging cells), keeping them ready to respond chronically to inflammation. This mechanism blocks the conversion of macrophages into other beneficial ones, which are responsible for repair mechanisms in our tissues. The protracted inflammatory process also changes the structure of the extracellular matrix (ECM) which provides a scaffolding for the skin cells. Damage to this scaffolding impedes the migration of keratinocytes, i.e. those cells responsible for epidermal regeneration. This is a mechanism that further delays ulcer healing.

• #2 Association Between Venous Leg Ulcers and Sex Chromosome Anomalies in Men | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-0949

  The serine protease inhibitor PAI-1 is the primary physiological inhibitor of tissue plasminogen activator and urokinase, the activators of plasminogen and hence fibrinolysis. […] Increased PAI-1 activity thus appears to indicate diminished fibrinolysis in Klinefelter syndrome and this inverse relationship supports the beneficial role of androgen therapy in XXY patients with venous leg ulcers. […] Jacob syndrome (47,XYY syndrome) has an incidence of approximately 0.51.5 per 1000 live male births, but may well also be underdiagnosed. […] It has been suggested that the prevalence of venous ulceration is increased in males with XYY syndrome. However, clear evidence of a disease-specific (hormonal) pathogenesis is lacking, and the occurrence might thus be related to the greater height of these patients. […] Treatment of venous leg ulcers in patients with sex chromosomal anomalies involves the same medical and surgical methods as in other patients. […] Furthermore, androgen replacement therapy may be a promising approach in the long-term treatment of PAI-1 related venous leg ulcers in XXY patients.

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

  https://www.mdpi.com/2077-0383/10/1/29

  VLU is the result of an intricate series of pathological events involving hemodynamic, cellular, and biomolecular alterations of macro- and microcirculation, which are eventually transmitted to the skin. In this complex picture, the common finding is the presence of ambulatory venous hypertension. Several predisposing factors (e.g., advanced age, female sex, genetic predisposition, family history, pregnancy, estrogen levels, obesity, prolonged standing, sitting, and environmental/occupational factors) have been highlighted to promote venous hypertension. […] Venous hypertension in association with the onset of cellular, molecular, and hemodynamic alterations in the microcirculatory system, through the activation of a cascade of events involving inflammatory processes, proteolytic activity, reduction of the physiological shear stress, and loss of glycocalyx glycosaminoglycans, leads to venous structural changes which finally exacerbate venous hypertension resulting in clinical manifestations of CVD, skin changes, and VLU.

• #2 What are the main venous leg ulcer risk factors? | Richardson Healthcare

  https://richardsonhealthcare.com/venous-leg-ulcer-risk-factors/

  Venous leg ulcers are defined as chronic leg wounds that take longer than 4 to 6 weeks to heal. Venous leg ulcers mostly occur on the inside of the leg, just above the ankle. They are the most common type of leg ulcer and are estimated to account for 60 to 80% of all cases. […] The main venous leg ulcer risk factor is chronic venous insufficiency. […] The valves in the veins tend to weaken as we age. When the valves are damaged, the blood is unable to flow normally through the body. This makes us more susceptible to venous leg ulceration. […] Having a history of venous leg ulceration is one of the biggest risk factors for developing future ulcers. […] These clots can damage the valves in the veins and increase the chances of developing a venous leg ulcer. […] Individuals with varicose veins are at an increased risk of venous leg ulcers because their veins are under high pressure.

• #2

  https://dermnetnz.org/topics/leg-ulcer

  Compression therapy is an important part of the management of venous leg ulcers and chronic swelling of the lower leg. Compression results in healing of 40-70% of chronic venous ulcers within 12 weeks. Compression therapy is achieved by using a stocking or bandage that is wrapped from the toes or foot to the area below the knee. This externally created pressure on the leg helps to heal the ulcer by increasing the calf muscle pump action and reduce swelling in the leg. Compression is not used if the ABPI is below 0.8.

• #2

  https://journals.lww.com/idoj/fulltext/2014/05030/venous_leg_ulcer__systemic_therapy.41.aspx

  Pentoxifylline increases microcirculatory blood flow, oxygenation of ischemic tissues, increase red and white cell filterability and decrease whole blood viscosity, platelet aggregation and fibrinogen levels. […] Doxycycline besides its antibiotic action is known to inhibit proinflammatory cytokines like tumor necrosis factor-alpha and matrix metalloproteinases, which are involved in the pathogenesis of VLU, thereby healing them. […] Phlebotonics are a heterogeneous group of medications both synthetic and plant origin, whose exact mechanism of action is unknown. The postulated benefits include the effect on macrocirculation like improving venous tone and on microcirculation by decreasing capillary hyperpermeability. […] Mesoglycans are glycosaminoglycans extracted from porcine intestine and is composed of heparan sulfate, dermatan sulfate, and chondroitin sulfate. Its exact mechanism of action is not known, but it has a profibrinolytic action, microrheologic, and macrorheologic benefits and has been reported to be useful in treating venous disorders.

• #3 Prevention and Treatment of Leg and Foot Ulcers in Diabetes Mellitus

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/endocrinology/prevention-treatment-diabetic-leg-and-foot-ulcers/

  Venous ulceration is the eventual result of venous hypertension. This has multiple causes, but the most common cause is venous valvular incompetence or insufficiency, which may be congenital or acquired. Failure of the venous or muscle pump or venous obstruction may also contribute to venous hypertension. The end result is transmission of elevated venous pressure from the deep to superficial system of the veins, with local effects leading to ulceration. Although it is accepted that venous hypertension plays a dominant role in the development of ulceration, there are multiple hypotheses attempting to explain the direct cause of ulceration. […] The fibrin cuff theory, proposed by Browse and colleagues, has asserted that as a result of increased venous pressure, fibrinogen is leaked from capillaries. This results in the formation of pericapillary fibrin cuffs that serve as a barrier to the diffusion of oxygen and nutrients. This theory has lost favor as the sole cause, because fibrin is probably not as significant a barrier to diffusion as previously believed.

• #3 Venous leg ulcer | NHS inform

  https://www.nhsinform.scot/illnesses-and-conditions/skin-hair-and-nails/venous-leg-ulcer/

  What causes a venous leg ulcer? […] A venous leg ulcer can develop after a minor injury if there’s a problem with the circulation of blood in your leg veins. If this happens, pressure inside the veins increases. […] This constant high pressure can gradually damage the tiny blood vessels in your skin and make it fragile. As a result, your skin can easily break and form an ulcer after a knock or scratch. […] Unless you have treatment to improve the circulation in your legs, the ulcer may not heal. […] […] […] Whos most at risk of a venous leg ulcer? […] Many factors can increase your risk of developing a venous leg ulcer, including: […] obesity or being overweight this increases the pressure in the leg veins […] if you have difficulty walking this can weaken the calf muscles, which can affect circulation in the leg veins

• #3 What are the main venous leg ulcer risk factors? | Richardson Healthcare

  https://richardsonhealthcare.com/venous-leg-ulcer-risk-factors/

  Surgical procedures such as knee or hip replacements can sometimes cause valve damage. Lower limb surgeries can also lead to reduced mobility, sometimes temporarily, which can increase pressure in the veins. […] Smoking has a negative impact on the flow of blood to the legs. Studies show that smoking can lead to delayed wound healing for existing leg ulcers. […] Standing for a long time can accelerate the backflow of blood into the legs caused by incompetent valves in the veins.

• #4 Venous leg ulcer | NHS inform

  https://www.nhsinform.scot/illnesses-and-conditions/skin-hair-and-nails/venous-leg-ulcer/

  previous deep vein thrombosis (DVT) blood clots that develop in the leg can damage valves in the veins […] varicose veins swollen and enlarged veins caused by malfunctioning valves […] previous injury to the leg, such as a broken or fractured bone, which may cause DVT or affect your walking […] previous surgery to the leg, such as a hip replacement or knee replacement, which can prevent you from moving about […] increasing age some people find it harder to move around as they get older, particularly if they suffer from arthritis

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