Development Of Chronic Venous Insufficiency Research Articles

Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs.

One of the early symptoms of chronic venous disease (CVD) is varicose veins (VV) of the lower limbs. There are many etiological environmental factors influencing the development of chronic venous insufficiency (CVI), although genetic factors and family history of the disease play a key role. All these factors induce changes in the hemodynamic in the venous system of the lower limbs leading to blood stasis, hypoxia, inflammation, oxidative stress, proteolytic activity of matrix metalloproteinases (MMPs), changes in microcirculation and, consequently, the remodeling of the venous wall. The aim of this review is to present current knowledge on CVD, including the pathophysiology and mechanisms related to vein wall remodeling. Particular emphasis has been placed on describing the role of inflammation and oxidative stress and the involvement of extracellular hemoglobin as pathogenetic factors of VV. Additionally, active substances used in the treatment of VV were discussed.

The Role of the Vegfa C936t Polymorphism in the Development of Chronic Venous Insufficiency of the Legs And Its Analysis

In 98 patients, an analysis of the genetic risk factor for the development of chronic venous insufficiency was carried out by studying the frequency of distribution of alleles and genotypes of the C936T polymorphism in the VEGFA gene. In both groups, the actual distribution of C807T polymorphism genotypes corresponded to those expected under the Hardy-Weinberg equilibrium (p
 <0.05). A significant relationship was established between the risk of developing chronic venous insufficiency and the distribution of predisposing/protective variants of the C807T polymorphism genotypes in the VEGFA gene. These data allow us to suggest testing this locus to predict the risk of occurrence and progression of chronic venous insufficiency>

Evolution of deep vein thrombosis treatment from leeches to mechanical thrombectomy.

Deep vein thrombosis (DVT) is one of the most common diseases in developed countries with significant socioeconomic consequences. The severity of DVT lies in the potential for life-threatening pulmonary embolism and the development of chronic venous insufficiency, referred to as post-thrombotic syndrome. Virchow contributed to the understanding of the pathophysiological events that lead to thrombosis by describing three basic risk mechanisms. The first therapeutic attempts in the 17th century included venepuncture and the application of leeches. The first anticoagulant drug was heparin, which entered clinical practice after 1935. Subsequent commercialization of oral vitamin K antagonists (warfarin) and the advent of low molecular weight heparin along with compression therapy allowed the expansion of outpatient treatment of DVT. Recently, new oral anticoagulants have been introduced, leading to improved safety due to lower risk of bleeding complications and simplification of the treatment process. The next step in the development of therapeutic options are invasive methods of early thrombus removal, which significantly shorten the process and aim to reduce the occurrence of late complications. These methods include local catheter-directed thrombolysis using tissue plasminogen activator, mechanical thrombectomy and their combination called pharmaco-mechanical thrombectomy. The latter is currently used in patients with acute ilio-femoral DVT.

The relationship between venous insufficiency and serum magnesium level

Magnesium is the second most common cation in the cell. In addition to its role as a cofactor in many enzymatic pathways in physiological processes, it is necessary for the regular functioning of vascular smooth muscle cells. Magnesium deficiency has been associated with exacerbation of inflammation, which plays a role in the aetiopathogenesis of many diseases. To investigate the potential relationship between serum magnesium level and the development of chronic venous insufficiency by comparison with healthy individuals. The study included 394 patients with venous insufficiency based on physical examination findings and colour Doppler ultrasonography, and 206 controls without venous insufficiency. Venous insufficiency was defined by colour Doppler as reflux lasting 0.5 seconds or more in superficial veins, and longer than one second in femoral and popliteal veins. Clinical, haematological and biochemical parameters, including serum magnesium level and indicators of inflammation, were compared between groups. A total of 600 participants were included. There was no significant difference between the groups in terms of age and gender. In total, 187 (47.46%) patients with chronic venous insufficiency and 105 (50.97%) of the control group were male (p=0.414). The median age of the patients with chronic venous insufficiency was 48 (min-max: 41-49), and the median age of the control group was 49.00 (min-max: 45.00-60.25) (p=0.064). Serum magnesium level was found to be significantly lower in the group with chronic venous insufficiency compared to the control group; 1.90 mg/dL (min-max: 1.82-2) versus 2.1 mg/dL (min-max: 2-2.2) (p<0.001), respectively. Low serum magnesium levels may pose a potential risk for the development of chronic venous insufficiency, which is common in the community.

Th17-Gene Expression Profile in Patients with Chronic Venous Disease and Venous Ulcers: Genetic Modulations and Preliminary Clinical Evidence.

Chronic venous disease is a condition globally widespread, resulting in a disabling pathological disorder. The CD4 + Th17+ (Cluster Differentiation 4) lymphocytes represent a regulative factor for innate immunity related to the development of complex diseases. Recently, these mechanisms have been associated with vascular disease. The aim of this work is to validate whether the Th17 response correlates with the development of CVI (Chronic venous insufficiency)and CVLUs (chronic venous limbs ulcers) and whether Th17 markers can be used, both as intrinsic risk factors and diagnostic markers, for disease development. PBL derived from peripheral blood samples of patients and controls were subjected to gene expression analysis for IL23R, IL17, SGK1, TGFβ, RORγ, FOXO1, and RANBP1 by qRT-PCR and immunoblot. A post hoc correlation, the diagnostic performance of the target genes, and multivariable analyses were properly conducted. The main expression markers of the CD4 + Th17+ switch were strongly activated in chronic venous insufficiency and in advanced ulceration. The correlation analysis demonstrated the inter-dependence on Th17’s signature modulation. ROC (Receiver Operating Characteristic) analysis defined, for the examined genes, a clinical value as the potential diagnostic markers. Multi-logistic regression studies showed that Th17 markers behave as empirical risk factors for CVD (chronic venous disease) development. Taken together, the present data provide a new hypothesis for the TH17-dependent pathogenesis of CVD, favoring the possibility for the development of new diagnostic, preventive, and therapeutic approaches.

ЭПИДЕМИОЛОГИЯ ГОСПИТАЛИЗИРОВАННОЙ ЗАБОЛЕВАЕМОСТИ ВАРИКОЗНОЙ БОЛЕЗНЬЮ В МЕГАПОЛИСЕ

Chronic venous insufficiency of the lower extremities is currently one of the most common pathologies of the human vascular system and represents an important socio-economic problem for developed countries both due to its high prevalence and due to the cost of diagnosis and treatment. In the medical literature, the analysis of treated patients in a hospital is limited only to a certain contingent of patients in a given hospital or to the study of specific degrees of chronic venous insufficiency. We did not find data on the hospitalized morbidity of varicose veins, which would indicate its structure, in the literature available to us. We studied 10326 statistical maps and case histories of patients with varicose veins with venous insufficiency C2-C6 according to CEAP classification, treated from 2010 to 2019 in the city vascular center operating on the basis of the city clinical hospital of Minsk, all patients underwent various surgical procedures. interference. The structure of hospitalized morbidity, its growth over the years, the influence of the age of men and women on the development of chronic venous insufficiency are shown. The main reasons for the development of chronic venous insufficiency have been analyzed.

Modern views on the development of varicose and post-thrombotic diseases

Chronic diseases of the veins of the lower extremities include vascular pathologies within the venous system and exclude those, in which the veins suffer secondarily (chronic heart failure, iatrogenic damage, tumour occlusion). The main clinical and morphological forms of chronic diseases of the veins of the lower extremities include: varicose veins, post-thrombotic disease and phlebodysplasia. Moreover, according to publications, varicose disease accounts for the main percentage of occurrence, i.e. from about 70 to 86 %. Post-thrombotic disease occurs from 14 to 29 % of cases and develops, as a rule, during the first two years after an episode of deep vein thrombosis of the lower extremities in 20–50 % of patients. These two diseases are the main reason for the development of chronic venous insufficiency with a significant decrease in working capacity and quality of life under the age of 60. Despite the achievements of modern science, the ethiopathogenesis of these diseases is yet to be understood. Instrumental diagnostics allows a pathological retrograde blood fl ow due to the failure of the valves of the venous system of the lower extremities to be determined. However, the issue of what is primary — valvular insufficiency or venous wall deformation — remains open at the present time. This article is devoted to a review of modern theories about the mechanisms underpinning the formation of valvular insufficiency in varicose and post-thrombotic diseases. The review also addresses systemic hemodynamic disorders (heart morphology and hemodynamics) against the background of chronic diseases of the veins of lower extremities.

High prevalence of chronic venous disease among health care workers in the United States

BackgroundHealth care workers spend extended times standing and walking short distances and are at risk for development of chronic venous insufficiency (CVI). We conducted a hospital-wide venous screening program designed to measure the prevalence of and risk factors for clinical manifestations of CVI and ultrasound evidence of venous reflux or obstruction in health care workers. We also determined their risk for deep venous thrombosis (DVT). MethodsFree venous screening and education were offered to all hospital employees; the program started in April 2016, and results are presented from the first year. Demographics, medical history, and use of compression stockings were recorded. A physical examination determined the clinical class of the Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) classification for clinical disease, and an ultrasound test evaluated for reflux or obstruction in the common femoral vein, popliteal vein, and saphenofemoral junction. The Caprini score was recorded to evaluate risk of DVT. Descriptive statistics were reported, and logistic regression was used for multivariate analysis of risk factors. ResultsWe enrolled 636 participants (1272 legs); 93.0% were women. The median age was 42 years (interquartile range, 31-52 years), mean body mass index was 29.2 ± 6.6 kg/m2, and most participants were white (49.1%) or African American (39.5%); 18% reported having hypertension, 7.1% had diabetes, and 6.1% were current smokers. The majority reported occasional leg pain (72.7%) and evening leg swelling (42.3%). Only 2.7% used daily compression stockings. Clinical evidence of CVI was present in at least one leg in 69.1% (C1, 49.0%; C2, 17.7%; C3, 1.9%; C4, 0.2%; C5, 0.2%). Venous reflux was present in at least one leg in 82.1%; obstruction was rare (0.2%). Reflux in either the superficial (saphenofemoral junction) or the deep (femoral or popliteal) venous system was present in the majority (71.0%) of patients with CVI (clinical class ≥C1). Reflux and white race were risk factors for clinical disease; clinical disease, age, female sex, and white race were risk factors for reflux. On the basis of the Caprini score, 14.1% of participants were in the highest risk category for DVT when experiencing a high-risk situation (including 2.2% with history of DVT). ConclusionsPrevalence of clinical CVI and venous reflux is high among health care workers despite a low frequency of cardiovascular comorbidities. Increased awareness about CVI and DVT and preventive strategies for venous disease must be instituted in this high-risk cohort.

Endovascular correction of venogenic erectile dysfunction in May–Thurner syndrome (clinical case)

Introduction. Secondary varicose small pelvic veins with the development of chronic venous insufficiency due to obstruction of the magistral venous vessels, in particular, the left common iliac vein and the right common iliac artery (May–Thurner syndrome), occupy a special place in the structure of the causes of venogenic erectile dysfunction (ED).The study objective is to present the clinical case of arteriovenous conflict (May–Thurner syndrome), leading to the development of secondary varicose small pelvic veins in men and venogenic ED, as well as modern methods of its verification and endovascular surgical repair.Clinical case. A clinical case of successful endovascular correction of venogenic ED is presented. The patient is diagnosed with: May– Thurner syndrome. Pelvic varicose disease С3 (according to CEAP Classification). Condition after endovascular balloon angioplasty and stenting of the left common iliac vein. Bilateral varicocele. Condition after bilateral varicocelectomy in 2018. Severe venogenic ED (pathological venous drainage, proximal type, International Index of Erectile Function (v. 5) – 12 points; Er3 according to the Unem Scale) in accordance with the Comprehensive Classification System for Chronic Venous Disorders. On July 24, 2019 endovascular occlusion of the Santorini’s plexus veins was performed with the installation of occlusion spirals in their lumen according to Gianturco. In order to provide visualization of the veins in the Santorini’s plexus, given the impossibility of cannulation of the deep vein of the penis, bilateral symmetrical cannulation of the cavernous bodies of the penis was carried out to perform cavernosophlebography. The left common iliac vein was catheterized according to the Crossover technique. Under phlebography control we ensured that the stent in the common iliac vein passed without signs of loss of its lumen. The internal pudental vein on the left was selectively catheterized. Hydrophilic guidewire was introduced through the veins of the periprostatic plexus into the right internal pudental vein. Selective catheterization of the periprostatic venous plexus was not possible due to pronounced tortuosity, valve flaps of the veins and small diameter of the catheterized veins. It was decided to pass the guidewire further through the right iliac vein system with access to the inferior vena cava. Further, the guidewire was again transferred to the left common iliac vein (double crossover). The left common femoral vein was punctured followed by the placement of 5 Fr introducer sheath according to Seldinger. The guidewire tip was fixed by the loop in the left common iliac vein, then captured and brought out through the introducer in the left common femoral vein. A catheter Сobra15 Fr was inserted through a crossover guide from the left common femoral vein into the right internal iliac vein and further into the periostatic venous plexus. Gradually veins of the Santorini’s plexus were selectively catheterized followed by Gianturco coils embolization.Conclusion. The first choice surgery for verified proximal type ED is endovascular occlusion of the veins in the Santorini’s plexus through the deep vein of the penis, which allows to change the hemodynamics in the penis and provide sufficient erection without resorting to endofalloprosthesis of the penis. Single or double-sided transfemoral access is suggested for patients when access through the deep vein of the penis is rather challenging or absent. 

Protocol for a systematic review and meta-analysis of interventions for pathologic perforator veins in chronic venous disease

IntroductionPerforator veins (PVs) play an important role in the development of chronic venous insufficiency and ulceration. Procedures to eliminate incompetence and reflux in PV may include open surgery, subfascial endoscopic...

УЛЬТРАЗВУКОВАЯ ДОППЛЕРОГРАФИЯ ХРОНИЧЕСКОЙ ВЕНОЗНОЙ НЕДОСТАТОЧНОСТИ НИЖНИХ КОНЕЧНОСТЕЙ

Мета дослідження - вивчити можливості ультразвукової доплерографії в діагностиці хронічної венозної недостатності (ХВН) нижніх кінцівок.Матеріали та методи. Проведено обстеження 176 пацієнтів з ХВН. Використаний метод колірної доплерографії.Результати та обговорення. ХВН у обстежених пацієнтів виявлявся різноманітної клінічної симптоматикою. Для оцінки тонусу венозної стінки визначали індекс еластичності (ІЕ) загальної стегнової і підколінної вен, для визначення «нормальності» анатомічної будови великої підшкірної вени на стегні визначали індекс гіпоплазіі.Характерізова гемодинамичну значимість, розділили всіх обстежених хворих за ступенями тяжкості на три групи. У першій групі при проведенні проб на клапанах в сафенофеморальному сполученні ретроградний кровотік не фіксували, що підтверджувало відсутність клапанної недостатності. Значення ІЕ не перевищував 1,37 ± 0,09. У другій групі реєстрували ретроградний потік крові тривалістю не більше 2 секунд, що свідчить про гемодинамично незначну недостатність. Значення ІЕ був вище 1,37. У пацієнтів третьої групи при проведенні проб на клапанах в сафенофеморальне сполучення реєструвався ретроградний потік крові, що дозволило виявити гемодинамічно значиму клапанну недостатність, при якому показана хірургічна корекція. Середні показники ІЕ глибоких вен перевищували нормальне значення і становили для загальної стегнової вени 1,7 ± 0,042, для підколінної вени -1,6 ± 0,028.Висновки. Ультразвукова доплерографія дозволила виявити клапанну недостатність різних відділів венозного русла нижніх кінцівок і зробити висновок про ступінь порушення венозного відтоку вен нижніх кінцівок. Вивчення за допомогою ультразвукової доплерографії тоніко-еластичних властивостей венозної стінки є одним з важливих моментів в діагностиці стану венозної системи нижніх кінцівок і має важливе практичне значення. Розвиток ХВН - процес, протяжний в часі, тобто за умови виявлення і лікування захворювання на ранніх стадіях можна реально скоротити кількість хворих або пролонгувати в часі розвиток важких форм хвороби.

Approach to venous diseases in the elderly

Incidence and severity of both deep vein thrombosis and chronic venous insufficiency are increased with age. Today, however, the significance of these diseases in the elderly patient population are still poorly comprehended. Although most patients have a history of previous treatment, chronic venous insufficiency is usually encountered in the advanced clinical stage. As a result, there is an increase in mobility restrictions, the need for assistance in daily activities and the risk of falls in elderly patients. The quality of life is negatively affected in patients. Age, immobilization and obesity are the main risk factors for the development of chronic venous insufficiency in the elderly. Patients present with complaints such as pain, edema, burning, bloating, weight sensation, restless leg syndrome, night cramps, varicosities, color change and open wound in the legs. In diagnostic procedures, color Doppler ultrasonography examination is used together with patient's staging as well as history and physical examination. Classification of "Clinical-Etiology- Anatomy-Pathology (CEAP)" is used in defining venous insufficiency patients. Among the leading differential diagnoses are congestive heart failure, renal failure, liver dysfunction, antihypertensive, non-steroidal anti-inflammatory and some antidiabetic medications and lymphedema and deep vein thrombosis. Patients underwent early diagnosis and long-term regular follow-up after appropriate therapeutic interventions reduce the risk of developing advanced complicated clinical conditions. The main components of treatment include patient education, mobilization, leg elevation, prevention of obesity, use of venous compression stockings, use of venoactive agents, and catheterbased/ surgical interventions. Endovenous radiofrequency or laser ablation techniques and endovenous chemical ablation techniques in superficial venous insufficiency are preferential interventional modalities due to low morbidity risks in older age group of chronic superficial venous insufficiency patients. Foam sclerotherapy for superficial truncal varicosities can also be considered as an alternative for older age groups. In any treatment decision to be taken, the risk-benefit ratio, the patient's clinical status, the available treatment options as well as the patientspecific risks and the patient's expectation and decision should be the main determinant. It is important to remember that what is more important than the age of the patient is the patient's own physical condition and that the quality of life is improved.

Elastic stockings effect on leg volume variability in healthy workers under prolonged gravitational gradient exposure

The aim of this study was to determine the elastic stockings effect on healthy workers (HW) who are exposed to a prolonged hydrostatic pressure overload for professional reasons. The cohort was composed by 20 HW who voluntarily underwent a water plethysmography test before and after eight hour of standing up in an operating room, wearing elastic stockings. After 8 h of gravity exposure, we demonstrated the absence of leg volume increase in case of elastic stockings use. In the morning measurement we found that the lower limb volume was 1967.5 mL±224, while in the evening it was 1962.5 mL±227 (P&amp;lt;0.0828). The decreased volume is significantly correlated with the time that was spent under gravity forces for working purpose wearing elastic stockings (R&lt;sup&gt;2&lt;/sup&gt;=0.99, P&amp;lt;0.0001). Our experiment demonstrates that elastic stockings may effectively counteract the increased leg volume over time in workers who are exposed to prolonged gravitational gradient. Further longitudinal studies are needed to determine if the above effect could correct one of the major risk factors for the development of chronic venous insufficiency.

Current state of the treatment of perforating veins.

Perforating veins may play a role in the development of chronic venous insufficiency and ulceration. There is renewed interest in minimally invasive treatments vs historic surgical options. Current indications for treatment, technical success, and evidence for clinical efficacy are summarized. Existing recommendations include perforator closure in Clinical, Etiology, Anatomy, and Pathophysiology class 5 or class 6 disease through percutaneous thermal ablation, subfascial endoscopic perforator surgery, open surgery, or sclerotherapy. Closure rates for percutaneous thermal ablation are reported as 60% to 80% initially. More recanalization and de novo perforator formation have been reported than after thermal saphenous closure. Ultrasound-guided foam sclerotherapy has shown promise in perforator closure and wound healing, but with variable success rates. Regardless of method used, successful closure of perforators appears predictive of wound healing with minimal morbidity. However, the power and design of all studies supporting this are far from robust, and more work is needed.

Incidence of chronic venous disease in the Edinburgh Vein Study.

Epidemiologic research in chronic venous disease has focused on prevalence and associated risk factors. Evidence on the risks and incidence that this condition will develop is limited. The aim of this study was to measure the incidence of new varicose veins and chronic venous insufficiency (CVI) in an adult population and to investigate risk factors associated with the development of these conditions. The Edinburgh Vein Study is a cohort study of a random sample of the general population. Invitations were sent to 1456 men and women at baseline to participate in a 13-year follow-up examination. Each participant completed a questionnaire on lifestyle and medical history and underwent an examination that included clinical classification of venous disease. After a mean follow-up of 13.4 (standard deviation, 0.4) years, 880 of 1456 individuals participated (60.4% response). The overall incidence (95% confidence interval [CI]) of C2 varicose veins was 18.2% (15.2%-21.6%), giving an annual incidence rate of 1.4% (1.1%-1.7%), with incidence rates similar in men and women: the 13-year age-adjusted incidence of varicose veins was 15.2% (10.4%-20.0%) in men and 17.4% (13.1%-21.7%) in women (P=.97). The 13-year incidence of varicose veins increased consistently with age from 9.8% in those aged 18 to 34 years to 25.7% in those aged 55 to 64 years (P< .001). The 13-year incidence (95% CI) of CVI was 9.2% (7.0%-11.9%), and the annual incidence rate was 0.7% (0.5%-0.9%). The incidence of CVI was similar in men and women and increased consistently with age (P< .001). Participants with a family history of venous disease were more likely to develop C2 varicose veins (odds ratio, 1.75; 95% CI, 1.12-2.71). Obesity was associated with the development of CVI: the 13-year incidence (95% CI) was 6.1% (3.7%-9.6%) in those who were of normal weight and 23.6% (14.2%-37.0%) in obese participants, with an age-adjusted odds ratio of 3.58 (1.70-7.56). The Edinburgh Vein Study is one of a few cohort studies to report the incidence of varicose veins and CVI in the general population. The incidence of varicose veins and CVI did not differ significantly by sex and was strongly associated with increasing age. The risk of developing varicose veins was increased in those with a family history, and the risk of CVI was increased in those with higher body mass index.

Technical procedure of two-port system subfascial endoscopic perforator vein surgery (TPS-SEPS)

It has long been noted that incompetent perforating veins contribute to the development of chronic venous insufficiency and recurrent varicose veins that are complicated by skin ulcerations or liposcleroderma. For these conditions, severing of incompetent perforating veins is an effective surgical treatment. However, severing of incompetent perforating veins by a direct approach has become less commonly performed because of the excessive invasiveness of the procedure itself. We referred to 37 cases (44 legs) of varicose veins with or without active venous dermatitis, who underwent the two-port system subfascial endoscopic perforator surgery, which we devised (hereafter referred to as TPS-SEPS). According to this method, incompetent perforating veins can be severed without surgical intervention in the lesion. The criteria for insufficiency of the perforating veins (IPVs) are reverse flow demonstrated on a color-flow duplex and a caliber more than 3 mm in diameter. One hundred forty one out of one hundred fifty two IPVs were processed. A mean of 3.21 perforating veins per patient was severed using ultrasonic coagulation-incision apparatus. From these 37 cases we conclude that TPS-SEPS provides a useful tool for the surgeon interested in treating severe chronic venous insufficiency same as the single-port technique. Our TPS-SEPS is a relatively simple operation, but its skill is dependable and provides lower invasiveness than other operation procedure. From now on, it is necessary to unify the authorized name of the endoscopic surgery of perforating veins and is also important to define the indication of this method for the primary varicose veins without stasisdermatitis.

Critical issues in preventing post-thrombotic re-ulceration

The lack of effective therapies and the recurrent nature of chronic venous insufficiency (CVI) place a heavy burden on the United States healthcare system. The population-based costs in the United States for treatment of CVI and venous ulcer care has been estimated at over one billion dollars a year. The high incidence and increasing cost of CVI care has renewed interest in this disease process and much has been learned in the past decade. Primary valvular incompetence with or without obstruction causes ambulatory venous hypertension in the lower extremity. Increased pressure is transmitted to the dermal microcirculation resulting in extravasation or red blood cells (RBCs) and macromolecules. RBCs and macromolecules cause an injury to the dermal architecture resulting in microcirculatory activation of adhesion molecules and leukocyte recruitment. Activated leukocytes in conjunction with increased extra-cellular matrix tension may be the underlying cause of venous ulcer formation. Recently published data from our laboratory indicates that CVI disease progression is associated with increased fibroblast mediated contractile properties and a potential ability to accelerate venous ulcer healing. A consequence of this adaptive wound healing response is increased stored kinetic energy and tension in dermis of patients with CVI. In our experiments, we observed gel contraction in unstipulated gels indicating that fibroblasts surrounded by an extracellular matrix, exert a baseline degree of tension on their surrounding environment. This tension is increased when stimulated with transforming growth factor-β1 and/or extracellular signal-regulated kinase inhibition. We believe that an injury to the CVI dermal architecture releases stored kinetic energy in the dermis and clinically manifests itself initially as wound separation. This clinical situation is analogous to a stretched rubber band. When external forces are used to stretch a rubber band, tension is exerted on the elastic fibers within the band. When the rubber band is released, the stored kinetic energy within the elastic fibers is released and the band contracts. It is clear that increased fibroblast contractility is beneficial in healing wounds. However, in patients with dermal fibrosis and increased matrix tension, an injury that causes architectural damage may be the underlying stimulus that releases kinetic energy and causes initial wound separation. If the above hypothesis is true, then it is logical to assume that medical or surgical correction of venous hypertension should prevent RBC and macromolecule extravasation and stops the underlying inflammatory injury event. Given the fact that compression therapy is the mainstay of venous ulcer healing, there seems to be credence to this hypothesis. Therefore, one must assume that venous re-ulceration is partially if not completely related to the persistence of venous hypertension in primary CVI. In patients with PTS, the effectiveness of clot resolution and anticoagulation is another related factor. PTS is the development of CVI after an episode of deep venous thrombosis. Patients with PTS can manifest any of the signs of the CVI from pain and edema to severe lipodermatosclerosis and venous ulceration. Every clinical venous study performed has indicated that PTS patients have worse symptoms and higher venous ulcer recurrence rates. Why the outcomes are poorer is currently unknown. In a recent review by Prandoni in the British Journal of Hematology a proximal venous thrombosis, previous ipsilateral DVT, insufficient oral anticoagulation, and poor vein recanalization after 6 months of anticoagulation were all strong predictors for the development of PTS. Based upon these facts, what are the current road blocks to preventing re-ulceration in patients with PTS?1Pathophysiology of venous ulcer formation. Although great progress has been made over the past 2 decades, the pathophysiology of ulcer formation is still poorly understood. Effective medical and surgical therapies cannot be developed without a better understanding of how end organ damage is caused by venous hypertension.2Ineffective anticoagulation and poor venous recanalization strongly suggest that lytic therapy may play a significant role in decreasing the incidence of PTS. Presumably this effect is secondary to valve function preservation and/or the prevention of venous outflow obstruction. Randomized trials are currently being conducted to evaluate the role of venous lysis in the prevention of PTS.3We have no objective method or good imaging techniques for determining venous obstruction. Current data on surgical valve repairs or valve transplants have all depended heavily on the subjective assessment of vein patency based on venography. Examination of excised, recanalized veins have documented high-grade stenoses in damaged veins despite their patent appearance on venography. To overcome this road block, I suggest the following:(a)Re-assess valve repair in conjunction with stenting and/or endophlebectomy.(b)Consider re-evaluating angioscopy as a method to assess venous obstruction. Perhaps the angioscope can be modified with a side port that can cut endovenous scar tissue and widen lumen patency.(c)Consider a natural history study using an intravascular ultrasound scan to assess venous anatomy in patients with PTS.4Compression therapy is currently the gold standard for ulcer healing and recurrence. Despite this fact, ulcer recurrence is still seen in compression patients for reasons that are currently unknown. I propose the following to overcome this roadblock:(a)We need a different type of stocking. I propose developing smart stockings that can provide clinicians with clinically relevant data. For example, can stocking fibers that change color when the degree of compression decreases be developed? Can we develop remote pressure sensors or holter type pressure sensors that can be interrogated to determine the effectiveness of compression much like holter monitors collect heart rhythm data over a 1-week to 2-week period.(b)Can we develop a technology that measures skin tension? The greater the dermal fibrosis and scarring the higher the skin tension and, therefore, the greater the likelihood of a venous ulcer recurrence.5We need an objective way to assess end organ damage. Imaging that identifies high-risk dermal architecture may help clinicians determine which patients are at risk for developing ulcer recurrences and who are not.

Prevention and treatment of venous ulcers in primary chronic venous insufficiency

Primary chronic venous disease (PCVD) is a progressive degenerative condition that usually results in vein wall weakness, producing valvular incompetence. The disease most frequently occurs in the superficial veins and presents as asymptomatic cosmetic varicose veins. PCVD may also advance to symptomatic stages with pain, edema, skin changes, or venous ulcerations. Primary venous reflux can also develop in the deep and perforating veins. PCVD may also include a symptomatic obstructive element when a nonthrombotic iliac vein lesion (NIVL) is present. PCVD is defined by the basic CEAP classification as: C2-6 Ep As,d,p Po,r.1Eklöf B. Rutherford R.B. Bergan J.J. Carpentier P.H. Gloviczki P. Kistner R.L. et al.American Venous Forum International Ad Hoc Committee for Revision of the CEAP ClassificationRevision of the CEAP classification for chronic venous disorders: consensus statement.J Vasc Surg. 2004; 40: 1248-1252Abstract Full Text Full Text PDF PubMed Scopus (1431) Google Scholar The letter p (primary) refers to nonthrombotic, noncongenital etiology. The pathology is mainly related to deep and/or superficial valve incompetence creating an axial reflux projecting into the ulcer area.2Bergan J.J. Schmid-Schonbein G.W. Coleridge-Smith P.D. Nicolaides A.N. Boisseau M.R. Eklof B. Chronic venous disease.N Engl J Med. 2006; 355: 488-498Crossref PubMed Scopus (692) Google Scholar Symptomatic NIVL has previously been described as May-Thurner syndrome, Cockett's, or “iliac vein compression” syndrome.3May R. Thurner J. The cause of the predominantly sinistral occurrence of thrombosis of the pelvic veins.Angiology. 1957; 8: 419-427Crossref PubMed Scopus (493) Google Scholar, 4Cockett F.B. The iliac compression syndrome alias “iliofemoral thrombosis” or “white leg.”.Proc R Soc Med. 1966; 59: 360-361PubMed Google Scholar The existence of marked iliac vein compressions (more than 50% obstruction) with or without intraluminal lesions has been shown to be more pathogenic than previously thought. In the past, these lesions have been considered a common finding of little clinical importance.5Raju S. Neglén P. High prevalence of nonthrombotic iliac vein lesions in chronic venous disease: a permissive role in pathogenicity.J Vasc Surg. 2006; 44 (discussion 144): 136-143Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar Primary venous insufficiency should be differentiated from secondary postthrombotic venous insufficiency because the two conditions differ in pathophysiology, management, and prognosis. “Hydrostatic” leg ulcers without venous reflux and/or obstruction (eg, in morbidly obese patients [C5-6 Es An Pn]) are excluded in this discussion.6Bjellerup M. Determining venous incompetence: a report from a specialised leg ulcer clinic.J Wound Care. 2006; 15 (433-6): 429-430PubMed Google Scholar As early as 1948, the Swedish surgeon Gunnar Bauer found a group of patients with venous leg ulceration who had no history of previous deep venous thrombosis (DVT) but a family history of varicose veins. Descending transfemoral venography showed a patent, uniformly wide, deep vein with plentiful valve stations identified, which allowed the contrast to descend into the calf veins.7Bauer G. The etiology of leg ulcers and their treatment by resection of the popliteal vein.J Int Chir. 1948; 8 (937-7)Google Scholar No postthrombotic changes, such as irregular lumen, collaterals, or poorly identified valve stations, were noted. Bauer's interpretation was that there was a loss of elasticity in the vein wall leading to dilatation and subsequent incompetence of the valve. He termed this condition idiopathic deep vein incompetence; this condition today is defined as primary valvular incompetence. Hach et al have later suggested an additional hypothesis (ie, the deep veins will dilate secondary to massive superficial reflux because of “overloading”).8Hach-Wunderle V. Hach W. Invasive therapeutic options in truncal varicosity of the great saphenous vein.Vasa. 2006; 35: 157-166Crossref PubMed Scopus (16) Google Scholar Treatment of the superficial reflux in these patients may correct the deep venous reflux. This normalization of venous flow is frequently seen with segmental primary deep incompetence, but rarely with axial deep reflux.9Adam D.J. Bello M. Hartshorne T. London N.J. Role of superficial venous surgery in patients with combined superficial and segmental deep venous reflux.Eur J Vasc Endovasc Surg. 2003; 25: 469-472Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 10MacKenzie R.K. Allan P.L. Ruckley C.V. Bradbury A.W. The effect of long saphenous vein stripping on deep venous reflux.Eur J Vasc Endovasc Surg. 2004; 28: 104-107Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 11Makarova N.P. Lurie F. Hmelniker S.M. Does surgical correction of the superficial femoral vein valve change the course of varicose disease?.J Vasc Surg. 2001; 33: 361-368Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 12Sharp M.A. Nawabi D.H. Walton J. Hands L. Popliteal venous reflux is not abolished by superficial venous ligation.Phebology. 2003; 18: 143-145Crossref Scopus (6) Google Scholar Mapping of reflux by duplex ultrasound scanning in limbs with primary or secondary reflux and leg ulceration has shown that superficial reflux is present in approximately 80% of limbs, and in half of these limbs it is combined with deep venous reflux.13Grabs A.J. Wakely M.C. Nyamekye I. Ghauri A.S. Poskitt K.R. Colour duplex ultrasonography in the rational management of chronic venous leg ulcers.Br J Surg. 1996; 83: 1380-1382Crossref PubMed Scopus (57) Google Scholar, 14Hanrahan L.M. Araki C.T. Rodriguez A.A. Kechejian G.J. LaMorte W.W. Menzoian J.O. Distribution of valvular incompetence in patients with venous stasis ulceration.J Vasc Surg. 1991; 13 (discussion 811-2): 805-811Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 15Labropoulos N. Giannoukas A.D. Nicolaides A.N. Ramaswami G. Leon M. Burke P. New insights into the pathophysiologic condition of venous ulceration with color-flow duplex imaging: implications for treatment?.J Vasc Surg. 1995; 22: 45-50Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar The prevalence of significant NIVL in these patients is not known. Current evidence suggests that multiple factors may lead to intrinsic structural and biochemical abnormalities of the vein wall in PCVD resulting in remodeling of the venous wall and valvular incompetence in PCVD (see Critical Issue 2). This process appears to be multicentric; thus, primary valve incompetence develops simultaneously in discontinuous vein segments. Valves may not fail in a progressive descending or ascending uninterrupted order as previously thought.16Lim C.S. Davies A.H. Pathogenesis of primary varicose veins.Br J Surg. 2009; 96: 1231-1242Crossref PubMed Scopus (187) Google Scholar PCVD is widespread in the population and is far more prevalent than secondary (postthrombotic) disease. It is responsible for the development of chronic venous insufficiency (C3-C6) in 20% of the older population. A meta-analysis comprising 390 ulcer patients with PCVD having duplex ultrasound scanning revealed superficial incompetence alone and combination of deep and superficial reflux in 44% and 43% of ulcerated limbs, respectively.17Perrin M. Rationale for surgery in the treatment of venous ulcer of the leg.Phlebolymphology. 2004; 45: 276-280Google Scholar, 18Labropoulos N. Hemodynamic changes according to the CEAP classification.Phlebolymphology. 2003; 40: 103-106Google Scholar The clinical expression of PCVD is indistinguishable from that of postthrombotic disease in its late stages, but the medical and surgical treatment considerations are distinctly different. We have identified four critical issues concerning primary chronic venous disease, which are central in the endeavor to decrease the prevalence of venous leg ulcers by 50% at 10 years. Studies on how to identify patients with PCVD that will progress to ulceration do not exist. It has been shown to be important to correct the underlying pathology in patients with established venous ulcer disease to prevent recurrence.19Gohel M.S. Barwell J.R. Taylor M. Chant T. Foy C. Earnshaw J.J. et al.Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial.BMJ. 2007; 335: 83-88Crossref PubMed Scopus (304) Google Scholar However, there is no standard for evaluation of reflux/obstruction and changes of the microcirculation in CVD by Intersocietal Commission for Accreditation of Vascular Laboratories (ICAVL) in the United States. Standardization is vital to move forward because of its importance to direct treatment in clinical practice as well as to perform research. There is also a lack of basic information on ambulatory venous pressure and hemodynamic changes in the microcirculation.20Pascarella L. Schonbein G.W. Bergan J.J. Microcirculation and venous ulcers: a review.Ann Vasc Surg. 2005; 19: 921-927Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Many laboratories have developed protocols for evaluating reflux and obstruction in the lower limbs, but there is no standardization of method and interpretation. Duplex ultrasound scanning (DUS) is the most common and available test, and, therefore, central in evaluation of CVD, regardless of etiology, in clinical practice. Standardizing the method of scanning and the interpretation of the results would quickly have a major impact on CVD treatment. Primary care physicians would learn when to consult a vascular specialist for assessment and possible intervention. Since DUS of the ilio-caval vein segment is frequently difficult to perform, additional imaging studies may be needed to detect iliofemoral venous outflow obstruction as per institutional preference (eg, transfemoral contrast venography, magnetic resonance venography, computed tomography venography, or intravascular ultrasonography [IVUS]). There are no standard methods of quantification of hemodynamically significant venous outflow obstruction.21Neglén P. Raju S. Proximal lower extremity chronic venous outflow obstruction: recognition and treatment.Semin Vasc Surg. 2002; 15: 57-64Abstract Full Text PDF PubMed Scopus (50) Google Scholar Methods of measuring outflow resistance also need to be developed. There are no known hemodynamic methods to identify which patient with PCVD and limbs with C-class 2 to 4 will progress to develop leg ulcers. To achieve this goal, other hemodynamic tests in addition to ultrasound scanning should be utilized. Duplex ultrasound scanning parameters of interest would be the anatomic extent and distribution of reflux and obstruction (such as the system proposed by Hach),22Hach W. (Diagnosis and surgical methods in primary varicose veins).Langenbecks Arch Chir. 1988; ([in German]): 145-151PubMed Google Scholar and quantification of reflux by peak volume reflux, peak reflux, etc.23Neglén P. Egger 3rd, J.F. Olivier J. Raju S. Hemodynamic and clinical impact of ultrasound-derived venous reflux parameters.J Vasc Surg. 2004; 40: 303-310Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Hemodynamic tests, such as plethysmography (air plethysmography, foot volumetry, or strain-gauge)24Nicolaides A.N. Allegra C. Bergan J. Bradbury A. Cairols M. Carpentier P. et al.Management of chronic venous disorders of the lower limbs: guidelines according to scientific evidence.Int Angiol. 2008; 27: 1-59PubMed Google Scholar and laser Doppler measurements, such as veno-arterial response (VAR) and vasomotor activity (VA),25Shami S.K. Scurr J.H. Smith P.D. The veno-arteriolar reflex in chronic venous insufficiency.Vasa. 1993; 22: 227-231PubMed Google Scholar, 26Chittenden S.J. Shami S.K. Cheatle T.R. Scurr J.H. Coleridge Smith P.D. Vasomotion in the leg skin of patients with chronic venous insufficiency.Vasa. 1992; 21: 138-142PubMed Google Scholar need further evaluation. When these hemodynamic tests are used, the patients need to be followed with clinical severity scores (venous clinical severity, segmental disease, and disability scores or others), which are more sensitive than C-classification to detect symptomatic progression. It is necessary to develop first a protocol for CVD investigation for clinical practice, and then introduce a more sophisticated protocol for longitudinal research of CVD.

Invited commentary

Drs Raju, Darcey, and Neglen add more information about the important role of venous obstruction to the syndrome of chronic venous insufficiency (CVI) in patients with deep venous reflux disease. From my perspective, the most important findings of this study include: venous stenting improved the rates of healed ulcers, freedom of ulcer-recurrence rates in legs with healed ulcers (C5), and freedom from leg dermatitis; venous stenting improved pain and swelling at 5 years with no differences between nonthrombotic and post-thrombotic obstructions, limbs with severe vs moderate reflux, and limbs with axial and segmental reflux; venous stenting did not result in a deterioration of reflux parameters; and deep venous reflux can be initially ignored if it is combined with iliac vein obstruction. The authors of the current study have been leaders in the area of iliac venous obstruction treatment, and they have the largest world experience using venoplasty and stenting. They used large caliber stents (14-18 mm), covered all lesions without skip areas, extended stents into the inferior vena cava (IVC) 3 to 5 cm, and extended stents below the inguinal ligament as necessary. The patients exhibited advanced chronic venous disease with all having deep venous reflux, 59% demonstrating severe global reflux, 42% showing deep axial reflux, and 65% having superficial venous reflux in addition. By intravascular ultrasound (IVUS) scan, the percent stenosis was 74%, and despite this only 43% demonstrated collaterals on venography suggesting that this venographic sign leaves much to be desired. Only a small percentage of patients required open valve reconstructions by the authors, a group that has written extensively on these vein valve procedures in the past. It is surprising that the results were so good in which only the obstructive component of the disease was treated. The authors have suggested that nonthrombotic iliac vein lesions (NIVL) play a pivotal “permissive” role in the development of chronic venous insufficiency, and the current study supports this suggestion. How can this study be put into context? As the authors suggest, “a stepwise correction of pathology may be applied using initially minimally invasive techniques.” One cannot comment on saphenous vein ablation related to iliac vein stenting from the current study as limbs with concurrent saphenous ablation performed along with stenting were excluded, as were limbs with reflux confined only to the superficial venous system. However, the current study suggests that if iliac venous obstruction is part of the pathophysiology of CVI, iliac venous stenting should be performed as first-line therapy. Unexpected major role for venous stenting in deep reflux diseaseJournal of Vascular SurgeryVol. 51Issue 2PreviewTreatment of chronic venous insufficiency (CVI) has largely focused on reflux. Minimally-invasive techniques to address superficial and perforator reflux have evolved, but correction of deep reflux continues to be challenging. The advent of intravascular ultrasound (IVUS) scan and minimally invasive venous stent technology have renewed interest in the obstructive component in CVI pathophysiology. The aim of this study is to assess stent-related and clinical outcomes following treatment by iliac venous stenting alone in limbs with a combination of iliac vein obstruction and deep venous reflux. Full-Text PDF Open Archive

Thrombus resolution and vein wall injury: dependence on chemokines and leukocytes

Chronic venous insufficiency resulting in post-thrombotic syndrome occurs commonly after acute deep vein thrombosis, and is a prevalent cause of vascular disease morbidity in the community. Therefore, a better understanding of the pathophysiologic mechanisms that promote the development of chronic venous insufficiency could lead to novel approaches to interrupt the natural history and prevent post-thrombotic syndrome. In this paper, we will review the evidence that venous thrombus resolution is an inflammatory process that is dependent on chemokines and leukocytes.