Venous ulcer is defined as a full-thickness defect, which occurs mostly commonly in the ankle region. Venous ulcer does not heal naturally and persists due to chronic venous disorder.

Moreover, venous ulcer is an open skin lesion in the leg or feet affected by venous hypertension. Venous hyper-tension, a cause of venous ulcer, occurs as a result of venous reflux and obstruction. However, venous ulcer is not caused solely by reflux or obstruction and additional bio-chemical factors due to activation of inflammatory cascade can also contribute to the development of venous ulcer.

Such venous ulcer is the most common form of leg ulcer, known to account for approximately 70% of all ulcer cases (1). Venous ulcers typically occur in the lateral and medial malleolar regions of the ankle. However, they are also known to occur in the supra- and infra-malleolar regions of the leg or foot. In the US alone, there are approximately 2.5 million patients with CVI with progression to venous ulcer found in nearly 20% of the patients (2). Moreover, the prevalence of non-healing venous ulcer is known to be approximately 0.3% (3).

Venous ulcer is known to have significant molecular changes, including cellular alterations associated with trans-forming growth factor, mitogen-activated protein kinase pathway, and matrix metalloproteinase (MMP) production (4-6). In addition, recent studies have demonstrated that cytokine production and metabolism are closely associated with venous ulcer healing (7,8). Appropriately defining venous ulcer is of utmost importance to enable accurate characterization and standardization that may influence the study outcome. when assessing the natural history, epide-miology, genetics, prognostic indicators, and predictors of healing of venous ulcer, which can ultimately improve healing and reduce recurrences of venous ulcer.

Venous ulcers are most commonly found among the elderly with CVI. Moreover, various studies have reported that the prevalence of venous ulcer ranges between 0.06% and 2%. The average healing rate for venous ulcer is 60% after 12 weeks, and even after being treated, recurrence within three weeks is found in approximately 75% of cases (3).

Chronic venous disease may cause varicose veins or progress into severe skin change or venous ulcer. Reflux and obstruction both explain the pathophysiology of chronic venous disease. Valvular reflux and obstruction due to secondary venous disease are associated with much faster disease progression and higher rate of progression to venous ulcer.

1) Normal venous function

The peripheral venous system functions as a reservoir for storing blood and a conduit for return blood to the heart. Appropriate functioning of the peripheral venous system depends on vascular patency, including a series of one-way valves and muscle pumps.

Veins in the legs are classified as superficial, deep, and perforating veins. Superficial veins are located above the muscular facial layer and include great and small saphenous veins. The deep venous system is located below the muscular facial layer and plays a role in collecting venous blood and effluents from the limbs. Perforator veins crosses the anatomic fascial layer and connects the superficial and deep venous systems. There is a series of one-way bicuspid valves throughout superficial and deep veins. These valves allow blood to flow toward the heart, but closes to prevent reflux back to the feet. Valve function has four stages: opening, equilibrium, closing, and closed. An important factor in valve function is the vertical velocity of valve cusp, which increases the mural pressure relative to the luminal pressure that causes valve closing and vortical flow that causes valve opening. Basically, these valves work in conjunction with the venous muscle pumps. Typically, the contraction of the calf muscle pump facilitates the move-ment of blood from the venous plexi to the deep venous system. In this process, the valves prevent blood from flowing further distally in the deep venous system or through the perforating veins.

Relaxation of the muscle pump allows blood to refill into the deep venous system. Prolonged standing allows the veins to be filled by antegrade flow, and as the veins dilate, valves open and pressure is applied.

2) Venous dysfunction

Venous dysfunction occurs when venous pressure increases and blood circulation is impaired by various mechanisms. This is caused by valvular dysfunction due to axial veins, superficial vein, venous tributaries, venous obstruction, or combination of these mechanisms. These mechanisms play a role in causing systemic or local venous hypertension, especially when standing or walking.

Persistent venous hypertension causes skin change due to hyperpigmentation, which lead to subcutaneous tissue fibrosis called lipodermatosclerosis that ultimately progress to ulcer.

Valvular insufficiency in the superficial venous system refers to the retrograde flow known as “reflux,” which contributes to an increase in hydrostatic pressure. Speci-fically, valvular insufficiency at the junction between the deep and superficial systems, such as the sapheno-femoral-saphenopopliteal junction, can result in reflux that leads to chronic venous insufficiency (CVI). Superficial venous valvular insufficiency with reflux is found in up to 90% of patients with chronic venous disorder (typically 70∼ 80%) and approximately 84% of patients with venous ulcer (9,10). However, the precise mechanisms underlying the progression of chronic venous disease and venous ulcers are not yet fully understood.

Valvular insufficiency in the deep venous system occurs mostly due to damage caused by deep vein thrombosis. Damage to deep venous valves causes rapid refilling due to pathologic retrograde venous flow and reduces the amount blood flowing from the limbs. While the venous pressure may be slightly elevated or even normal after walking, but without continued muscle contraction, venous pressure increases to cause rapid refilling. In particular, deep venous valvular insufficiency accelerates the progres-sion of venous disorder, leading to venous ulcer at a high frequency (11,12). Moreover, valvular insufficiency in the communicating perforating vein can cause high pressure in the superficial system (13,14). Perforating venous valvular insufficiency causes reflex of blood from deep veins to superficial system due to high pressure generated by muscle pumps.

1) Inflammation

Both reflux and obstruction are major pathophysiology factors of venous ulcer. In particular, obstruction causes venous ulcer at a high frequency and accelerates disease progression. Under both of these conditions, ambulatory venous pressure is elevated.

The fundamental pathophysiology process of venous ulcer involves inflammation within the venous circulation, which causes increased hydrostatic pressure that leads to increased ambulatory venous pressure. Such inflammatory response includes macrophages and monocytes, as well as T-lymphocytes, inflammatory modulators, chemokines, cytokine expression, growth factors, metalloproteinase activity, and various regulatory pathways that perpetuate inflammation.

2) Genetic influences

HFE gene mutation has been proven to increase the risk of venous ulcers in patients with primary chronic venous disorder (15). Moreover, factor XIII is a cross-linking protein that plays an important role during ulcer healing (16). While specific factor XIII genotypes have a beneficial influence on ulcer healing time, whereas HFE gene mutation does not influence healing time, despite its impor-tance with respect to the risk of venous ulcer (17).

3) Cytokines and chemoattractants

Both venous wall and valves become pathologically altered to cause primary venous disorder. The perturbance of microcirculation is a very important component of pathophysiology of chronic venous disorders.

An essential factor in chronic venous disorders is persistently elevated ambulatory venous pressure. The effect on the microcirculation begins with altered shear stress on endothelial cells that leads to release of vasoactive agents and expression of E-selectin, inflammatory molecules, chemokines, and prothrombotic precursors (18,19).

Patients with chronic venous disorder exhibit increased expression of ICAM-1, which is expressed on endothelial cells. This initiates an inflammatory cascade, activating leukocyte recruitment and initiating endothelial trans-migration (20,21). Initially, altered shear stress and mechanical stress forces affect the endothelium and glycocalyx, likely accompanied by the expression of nitric oxide production, release of vasoactive substances, macro-phage chemoattractant protein-1, vascular cell adhesion molecule-1 (VCAM-1; CD-106), L-selectins, E-selectins, ICAM-1, and recruitment of leukocytes that induce trans-migration into the venous wall and valves (22). This series of events establishes an inflammatory cascade, leading to increased expression of various cytokines, including trans-forming growth factor-beta 1 (TGF-b1), tumor necrosis factor-a, IL-1, and MMPs (19,23,24). The glycocalyx plays a crucial role in preventing leukocyte adhesion, inflam-mation, and thrombus formation. However, altered shear stress and mechanical stress on the venous walls cause leukocyte adhesion and inflammation, leading to damage and loss of the glycocalyx (25,26).

In venous leg ulcer (VLU) cases, a major element of inflammation is expression of MMPs and cytokines, which causes serious harm to the venous walls, venous valves, endothelium, glycocalyx, and surrounding tissues, including destruction of the dermis that ultimately leads to skin changes and ulcer formation (23). MMPs have a significant effect on chronic inflammation and degradation of extra-cellular matrix in VLU cases. Pro-inflammatory cytokines are also believed to be powerful inducers of MMP expres-sion in chronic wound cases.

Collagen type III turnover is an important event needed during venous ulcer healing. MMP-1 activity is also higher in healing ulcer than in resistant ulcer and normal skin. Rapidly healing venous ulcer has increased collagen turn-over rate and MMP-1 activity.

Cytokines play an important role in all aspects of chronic venous disorder, starting with inflammation, leukocyte activation, expression of cytokines in interstitial space, and MMP activation in the wound bed of VLU that causes tissue wound degradation (27). Although there is a cor-relation between ulcer size and initial concentration of basic fibroblast growth factor (bFGF) in wound fluid, ulcer healing is correlated only with increase in TGF-b1 con-centration, while TGF-b1 is involved in fibrogenesis, matrix deposition, and proliferation (28). In fact, TGF-b1 level increases significantly as ulcer improves after compression therapy. When specific cytokine levels were associated with the healing rate, individuals with higher levels of pro- inflammatory cytokines, including IL-1 and IFN-g, showed much better healing than individuals with lower cytokine levels prior to compression therapy (8).

4) Microvalves

A noteworthy aspect is the system of sequentially smaller generations of tributaries leading to a small venous network with competent and incompetent microvalves. The regions are divided into six generations before reaching the small venous network. In regions with incompetent microvalves up to the third-generation tributary, resin is able to penetrate deeper into the micro-venous network. Once the third gene-ration microvalves are damaged, there is a greater risk of developing dermal ulcer.

Once third generation microvalves are damaged, the risk of developing venous skin ulcer increases further. This fact explains why some patients do not develop VLU despite having persistent varicose vein for a long time. In such cases, microvalves may not be damaged in the third-gene-ration network, thus, preventing clinical deterioration.

The diagnosis of VLU is based mostly on medical history, clinical presentations, and physical examination. Detailed history taking and physical examination enable differentiation of leg ulcer due to other causes. History of superficial or deep vein thrombosis, pulmonary embolism, and recurrent ulcers must be checked along with comor-bidities the patient may have.

Venous leg ulcer is caused by venous lesions, such as venous reflux or obstruction, and thus, accurate diagnosis of comorbid venous disorder is very important for future treatment. In other words, VLU is caused by venous hypertension due to CVI, and thus, diagnosing and assessing the severity of CVI that causes VLU are the most important factors for successful treatment of VLU. Moreover, because CVI itself may or may not play a major role in the development of leg ulcer, management of comorbidities may be just as important as treating CVI for successful ulcer treatment. Therefore, early non-invasive tests, including not just comprehensive duplex ultrasono-graphy, but also arterial pulse examination and ankle- brachial index test, are recommended for all patients suspected of having venous ulcer.

1) Clinical presentations

Firstly, the ulcer typically has an irregular shape but clearly defined boundaries. Specific findings suggestive of venous ulcer are location of the ulcer and associated findings. Venous ulcers typically occur in the lateral and medial malleolar regions of the ankle and are often accompanied by telangiectasia, corona phlebectatica, atrophic blanche, and lipodermatosclerosis (Fig. 1). Sur-rounding skin has erythematous or hyperpigmented ap-pearance with various indurations, while yellow exudate is also generally observed. Moreover, leg heaviness, pruritis, pain, and edema are also found and these symptoms become worse during daytime, but improve when elevated. Signs of varicose veins, edema, and venous dermatitis may also be found during a physical examination.

Figure 1. Venous leg ulcers. Irregular and shallow wound on the lateral (A) and medial (B) malleolar region.

Although venous ulcer is the most common type of chronic leg ulcer among all leg ulcers, it must be dif-ferentiated from arterial occlusive disease, diabetic neuro-pathy, malignancy, pyoderma gangrenosum, and other inflam-matory ulcers. In fact, 20∼30% of chronic ulcers that do not respond to vascular intervention are said to be caused by vasculitis, sickle cell disease, pyoderma gangrenosum, calciphylaxis, or autoimmune disease (29).

The most crucial complications of chronic venous ulcer are osteomyelitis and, very rarely, neoplastic transformation, especially squamous cell carcinoma. The average duration of an ulcer before tumor diagnosis is 25 years. Although osteomyelitis is found in patients with longstanding ulcer, the incidence of osteomyelitis in patients with chronic venous ulcer is still unknown. Therefore, if the base of the ulcer has palpable bone and no soft tissue, then additional tests may be needed due to high probability of osteo-myelitis.

2) Diagnosis of CVI

For the diagnosis of CVI, a complete assessment of venous segments for reflux is needed for hemodynamic evaluation. Additionally, an assessment of deep vein throm-bosis by compression ultrasound, which is a diagnostic criterion for venous thrombosis, is necessary.

3) Duplex ultrasonography

Duplex ultrasonography is the test method most com-monly used today for diagnosing CVI and assessing its etiology and anatomy. The usefulness of duplex ultra-sonography of the legs in patients with suspected venous ulcer has been widely reported, where the severity and distribution of reflux identified by duplex ultrasonography are strongly associated with the clinical severity of CVI. However, skin changes and ulcer formation are not prerequisites for deep vein thrombosis.

Reflux is diagnosed based on reflux time of ≥0.5 seconds in superficial veins and ≥1 second in deep veins. However, although longer reflux time is typically observed in CVI, it is not always consistent with the clinical pre-sentations.

4) Air plethysmograpy (APG)

APG offers the advantages of being able to assess potential components of the pathophysiologic mechanisms of CVI, including reflux, obstruction, and muscle pump dysfunction (30,31). APG measures changes in leg volume by air displacement in a cuff wrapped around the calf during emptying and filling of the venous system.

Venous outflow at 1 second, expressed as a percentage of the total venous volume, can be utilized to evaluate the adequacy of outflow. The rate of refill, indicated as the venous filling index, can be employed to determine the presence and severity of reflux. A normal venous filling index is 2 ml/s, while ≥4 ml/s is considered abnormal (32,33). An abnormal venous filling index is an excellent parameter for assessing reflux and has been found to be correlated with the severity of chronic venous insufficiency (CVI) (31-34).

The blood ejection function of the calf muscle pump is determined by one contraction and ten contractions during toe raise. The volume of blood ejected by one toe maneuver divided by the venous volume is referred to as the ejection fraction. CVI-related complications, including venous ulcer, are correlated with the severity of venous disorder assessed by the venous filling index and ejection capacity (30,32,35). This testing method not only provides quan-titative information about various aspects of overall venous function but also aids in selecting the appropriate inter-vention and evaluating the response to it. However, the role of this test is diminishing as it is being mostly replaced by duplex ultrasound.

5) CT venography and MR venography

These diagnostic methods are useful for assessing more proximal veins and their surrounding structures for obstruc-tion or external compression. Moreover, these methods are also used for defining complex venous anatomy, such as iliofemoral vein occlusion, prior to intervention.

6) Intravascular ultrasound

Intravascular ultrasound utilizes a catheter-based ultra-sound probe to visualize the surrounding anatomy and assess venous obstruction or stenotic lesions. This technique is rapidly gaining adoption due to its capability of providing more accurate diagnosis and its effectiveness in guiding endovascular interventions. However, despite its benefits, it is not reimbursed in Korea, which restricts its clinical appli-cation.

7) Venography

Ascending venography is the “gold standard” for diag-nosing deep vein thrombosis, but it is rarely used today. It can be used for objective assessment of the anatomy and hemodynamic status of the venous system. It also provides anatomical details of the venous system that are useful for surgical procedures, while also being helpful in differen-tiating between primary and secondary diseases. While this method is most useful for identify reflux in the femoral vein and saphenofemoral junction, it can also to use to assess other locations.

Treatment of VLU is based on conservative therapy, such as mechanical and pharmacologic therapy. In patients with venous ulcer, the treatment goals are reducing edema, promoting ulcer healing, and preventing recurrence of ulcer.

1) Compression therapy

Compression therapy is a standard treatment modality for venous ulcer and CVI. Recent Cochrane reviews have also reported that patients who receive compression therapy showed faster venous ulcer healing than those who did not receive compression therapy (36). The goal of compression therapy is to provide gradual external compression on the legs to counteract the hydrostatic force caused by venous hypertension.

While elastic compression therapy provides high com-pression during walking and muscle contraction, it does not provide compression at rest. The methods most often used in non-elastic therapy are Unna boots and zinc oxide-impre-gnated moist bandage. Unna boots have been reported to show higher healing rate than placebo or hydroactive dressing (37,38). Moreover, recent studies have reported that adding elastic compression therapy is more effective than non-elastic compression therapy alone (36). However, because Unna boots are not elastic, they have the dis-advantage of the patient feeling discomfort as the boots cannot adapt to changes in leg size and foul odor due to accumulation of exudate.

Elastic compression therapy offers the advantage of maintaining compression both at rest and during activities according to changes in leg size. A recent meta-analysis also reported that elastic compression therapy was more effective than non-elastic compression therapy (39). Com-pression therapy includes graded elastic compressive stockings with the use of various types of compression garments, paste gauze boots, and adjustable layered com-pression garments. Of these, graded elastic compressive stockings (between 20 and 50 mmHg) comprise the core component of elastic compression therapy. Compressive stockings help reduce residual volume fraction (an indicator of calf muscle pump improvement) and reflux in the venous segments (40,41). Since compressive stockings may lose their compressive capacity due to taking them off at night and regular washing, they should be replaced every six months. Compression therapy with higher compressive force is more effective than lower compressive force and using several overlapping layers of bandage is more effective than using a single layer for treating venous ulcer (36,42,43). Accordingly, using compressive stockings and other compressive bandage therapy can be effective for ulcer healing and preventing recurrences in venous ulcer cases. Surprisingly, it has been reported that complete ulcer healing within an average of 5.3 months can be achieved in over 90% of cases after applying well-structured compression therapy (44). Therefore, compression therapy is recommended for patients with venous ulcer and as an adjuvant therapy to superficial phlebectomy to reduce the risk of ulcer recurrence.

2) Dressings

The wound should be kept moist at all times by using occlusive dressings. Dressings are occasionally used to promote faster healing and prevent bandage from adhering to the ulcer. Many dressing materials are available, inclu-ding hydrocolloids (e.g., Duoderm), foam, hydrogels, pastes, alginates, antimicrobial dressing, and simple nonadherent dressings. In a meta-analysis of randomized controlled trials, there were no significant differences between the types of dressings (45).

Hydrogel dressing, made of 96% water, contains cross- linked insoluble polymers. This dressing method is used on dry wound and promotes autolysis of necrotic tissue.

Hydrocolloid dressing is an occlusive dressing consisting of hydrocolloid matrix bonded to vapor-permeable film or foam scaffold. Upon contact with exudate, this dressing forms a gel to promote rehydration in ulcers with low to moderate drainage.

Foam dressing contains hydrophilic foam, which makes it suitable for all types of exuding wounds. Applying this dressing on the site of ulceration prior to compression therapy can help promote healing and prevent the bandage from adhering to the wound. However, there is no evidence of foam dressing being superior to other types of dressings.

Alginates can be used on cavities and complicated lesions. Upon contact with exudate, this dressing forms a gel to promote rehydration in ulcers with low to moderate drainage to facilitate autolytic debridement of necrotic tissue. Up to now, there is no evidence suggesting dif-ferences in wound healing between different alginate dres-sings or between alginate and hydrocolloid dressings.

Antimicrobial dressings, such as dressing that contain ionized silver, can be used in some patients with suspected infection owing to their broad application and anti-inflam-matory and antimicrobial properties (46,47).

3) Pharmacologic therapy

Because venous ulcer is an inflammatory response attributed to venous hypertension, the goal of pharma-cologic therapy in venous ulcer cases is treating CVI.

Four groups of drugs are used for CVI – coumarins (a-benzopyrenes), flavonoids (g-benzopyrenes), saponosides (horse chestnut extracts), and other plant extracts. While these drugs all have venoactive properties and are widely used in Europe, they have not been approved for use in the US. The principle of action of these venoactive drugs is to improve venous tone and capillary permeability. Of these, flavonoids affect leukocytes and the endothelium by regu-lating the degree of inflammation and reducing edema. A micronized purified flavonoid fraction helps to reduce edema and edema-related symptoms in conjunction with primary or surgical treatment (48).

Horse chestnut seed extract is just as effective as com-pression stockings in the short-term at reducing leg edema and pain in patients with CVI, but the long-term safety and efficacy have not been established to date.

Pentoxifylline has also been found to improve venous ulcer healing rate. Accordingly, its use, along with com-pression therapy, is recommended for treatment of CVI. Recent studies have suggested that using pentoxifylline as an adjuvant to compressive bandage can be effective in treating venous ulcer (49).

4) Wound and skin care

Using topical moisturizers such as lanolin on dry skin can help reduce skin cracking and damage. Stasis dermatitis may need treatment with a topical steroid. Because bacterial overgrowth may lead to venous ulcer, active wound care is needed to minimize infection-related complications.

Actually, a variety of hydrocolloid and foam dressings are used to control wound drainage and maceration of adjacent skin. Silver-impregnated dressings are used to control infection and restoring tissue integrity, but its use still remains controversial (50-52).

There is commercially available tissue-engineered skin product (Apligraf; Novartis, NJ USA), which has shown favorable outcomes for treating venous ulcer. However, this product has the disadvantages of requiring specialize skills and increased cost.

5) Endovenous intervention

The fundamental goal of surgical and interventional treatment for venous ulcer is to achieve venous healing and prevent recurrence. In a trial that compared intervention and compression therapy combined and compression therapy alone for venous ulcer, surgical treatment reduced recur-rence but did not actually improve ulcer healing (53). A recent study reported that early phlebectomy for correction of superficial venous reflux together with compression therapy showed faster venous ulcer healing than compres-sion therapy alone or delayed intervention in cases that were untreated for more than six months (54).

In patients with deep vein thrombosis who have CVI and outflow obstruction, iliac venous stenting showed signi-ficant improvement in clinical presentations with complete pain relief, complete resolution of edema, and complete ulcer healing in approximately 50%, 30%, and 50% of cases, respectively (55). However, stent patency is a potential problem, and as a result, interventional procedure due to in-stent stenosis or obstruction was needed in 25% of cases, especially those involving a thrombotic disease (56).

6) Surgical treatment

The role of saphenous vein stripping in venous ulcer was assessed in the ESCHAR study (57). This study compared the healing and recurrence rates of venous ulcer between monotherapy (compression therapy alone) group and combi-nation therapy (surgery and compression therapy) group. The results showed 64% venous ulcer healing rate in both groups at six months, whereas the recurrence rate was 28% in the monotherapy group and 12% in the combination therapy group. Such findings indicated that the combination therapy group showed no difference in venous ulcer healing rate, but superior results with respect to recurrence rate. Therefore, surgery on superficial veins can be effective for ulcer healing and is recommended even in patients comor-bid with deep vein thrombosis. It has also been reported that endovenous treatment methods using laser or high fre-quency that are being used in recent years can be effective for faster ulcer healing if they are performed early enough (54). Such endovenous treatments are less invasive than conventional surgical methods, and thus, they can be more useful for patients with VLU, especially elderly patients.

Perforator surgery for venous ulcer healing has also been reported. According to the North American Subfascial Endoscopic Perforator Surgery (SEPS) Registry, 1-year venous ulcer healing rate in the group that received SPES was 88%, although many patients also received superficial vein surgery, while the 1- and 2-year ulcer recurrence rate was 16% and 28%, respectively (58). Up to now, the exact role of perforator surgery has not been clearly defined, but it is widely used in conjunction with superficial vein sur-gery in cases with ultrasound findings of perforating vein incompetence.

In addition, free skin graft for venous ulcer has been found to promote venous ulcer healing in most cases, but it still remains controversial due to frequent postoperative recurrences.