Changes of the serum properties and its effect on the endothelial cells restoration in patients with chronic venous disease treated with sulodexide.

OBJECTIVE: Inflammation and endothelial dysfunction are important venous changes in patients with chronic venous disease (CVD). The use of the venoactive drugs remains an important treatment modality for patients with CVD, reducing the severity of the CVD-related symptoms and swelling but also reducing inflammation and protecting endothelial cells. In this research, the effects of the serum obtained from patients with CVD before and after sulodexide treatment were evaluated for in vivo and in vitro inflammatory markers and endothelial cell function. METHODS: Inflammatory markers (IL-6, matrix metalloproteinase-9 [MMP-9], vascular cell adhesion molecule-1 [VCAM-1], and von Willebrand factor [vWF]) from the incompetent great saphenous veins (GSVs) and from the systemic venous circulation were studied in 10 patients with CVD (C2s) before and after 2 months of sulodexide (2 × 500 lipasemic units/d) therapy. Serum obtained from the vein blood before and after sulodexide treatment was evaluated for in vitro cultured human umbilical vein endothelial cell function. RESULTS: The serum collected from lower leg incompetent GSVs had significantly elevated levels of VCAM-1 (+29%, P < .001) compared with the serum from the systemic circulation. Endothelial cells exposed to the serum from the incompetent lower leg veins of the untreated CVD patients demonstrated higher stimulated synthesis of MMP-9 (+17%, P < .01), as well as increased markers of senescence (prolongation of population doubling time, ß-galactosidase activity, and expression of p21 and p53 genes). CVD serum-induced senescent endothelial cells had a higher expression of genes regulating IL-6, MMP-9, VCAM-1, and vWF synthesis. The overall proinflammatory effect on endothelial cells by the serum collected from the incompetent GSVs was stronger as compared with the serum from the systemic circulation. Serum collected from the veins after sulodexide treatment caused lower levels of endothelial cell inflammatory markers as well as respective gene expression than serum obtained at the beginning of the study (before sulodexide treatment). Sulodexide application also reduced the inflammatory secretory activity of the senescent endothelial cells. Sulodexide treatment resulted in the decrease of the majority of the studied inflammatory parameters in both lower limb incompetent vein and systemic blood. CONCLUSIONS: In patients with CVD, there are significant differences between circulating inflammatory markers analyzed from the lower leg incompetent GSV segments compared with the systemic circulation, indicating a higher inflammatory condition in CVD. Treatment with sulodexide reduces the proinflammatory and endothelial cell activation properties of the serum from patients with CVD. CLINICAL RELEVANCE: The study documented the significant proinflammatory human vascular endothelial cell activation when exposed to the serum collected from the varicose veins as compared with the serum from the systemic circulation in patients with chronic venous disease (CVD). The inflammatory marker expression, endothelial dysfunction, and endothelial cell senescence transformation can be successfully controlled and downregulated by patients' exposure to the glycosaminoglycan (sulodexide) treatment. Further studies are needed to confirm if glycosaminoglycan application can prevent further CVD clinical progression due to potential CVD-related pathological processes' modulation and their downregulation.

Venous Thromboembolism Prophylaxis and Thrombotic Risk Stratification in the Varicose Veins Surgery-Prospective Observational Study.

BACKGROUND: An invasive phlebological treatment is still not free from complications such as thrombosis. As in other surgical populations, not only the treatment modality, but also patient condition-related venous thromboembolism (VTE) risk factors matter. The current protocols used in varicose vein surgery centers are based mostly on individual risk assessment as well as on an implementation and extrapolation of general surgery VTE prophylaxis guidelines. In the presented study, the efficacy of routine VTE pharmacological thromboprophylaxis in patients undergoing saphenous varicose vein surgery was prospectively evaluated. In the result assessment, VTE risk factor evaluation and Caprini score results were included; however, due to the limited size of the projected study group, as well as expected limited deep vein thrombosis (DVT) prevalence in this clinical scenario, it was not possible to perform the validation of the Caprini model efficacy in the projected study model. METHODS: In the study, 141 patients undergoing saphenous vein stripping and miniphlebectomy in spinal anesthesia were included. In all of the patients, VTE risk factors (including Caprini score evaluation) were assessed, and the routine thromboprophylaxis with enoxaparin 40 mg for 10 days was used. The venous ultrasounds were undertaken before the surgery and on the 10th and 30th day after surgery. The study endpoint was the presence of symptomatic or asymptomatic DVT confirmed in the imaging study. The study safety endpoint was major bleeding occurrence intraoperatively or within 30 days after surgery. RESULTS: The presence of a postoperative DVT was diagnosed in five cases (3.5%) In all of these cases, only distal DVT was confirmed. Despite extensive saphenous varicose vein surgery with stripping and miniphlebectomy performed in nontumescent but spinal anesthesia, no proximal lower leg episode was diagnosed. Three out of five DVT cases were diagnosed on day 10 postoperative control, while a further two were confirmed in the ultrasound examination performed 30 days after procedure. No clinically documented pulmonaly embolism (PE) as well as no bleeding episodes were noticed. Among the factors related to the statistically significant higher DVT occurrence, the results of the Caprini score were identified with odds ratio (OR) = 2.04 (95% CI = (0.998; 4.18)). Another factor that became statistically significant in terms of the higher postoperative DVT prevalence was the reported Venous Clinical Severity Score (VCSS) results (OR = 1.98; 95% CI (1.19; 3.26)). In the multiple logistic regression analysis, the patient age (OR = 0.86; 95% CI (0.75-0.99)), Caprini score evaluation results (OR = 4.04; 95% CI (1.26-12.9)) and VCSS results (OR = 2.4; 95% CI (1.23-4.7)) were of statistical significance as predictors for postoperative DVT occurrence, with a p value of 0.029 for age, and p = 0.017 and p = 0.009 for Caprini score results and VCSS results, respectively. Due to the confirmed limited number of the DVT events in our study cohort, as well as the descriptive and explorative nature of the achieved results, the final clinical potential and significance of the identified parameters, including Caprini score rate and VCSS rate, should be interpreted with caution and studied in the further trials in these clinical settings. CONCLUSION: All the patients undergoing varicose vein surgery should undergo VTE risk evaluation based on the individual assessment. In VTE risk evaluation, patient and surgical procedure characteristics based on the factors included into the Caprini score but also on specific chronic venous disease-related factors should be taken into consideration. Further studies are needed to propose an objective and validated VTE risk assessment model, as well as a validated antithrombotic prophylaxis protocol in this particular patient group.

The 2020 update of the CEAP classification system and reporting standards.

The CEAP (Clinical-Etiology-Anatomy-Pathophysiology) classification is an internationally accepted standard for describing patients with chronic venous disorders and it has been used for reporting clinical research findings in scientific journals. Developed in 1993, updated in 1996, and revised in 2004, CEAP is a classification system based on clinical manifestations of chronic venous disorders, on current understanding of the etiology, the involved anatomy, and the underlying venous pathology. As the evidence related to these aspects of venous disorders, and specifically of chronic venous diseases (CVD, C2-C6) continue to develop, the CEAP classification needs periodic analysis and revisions. In May of 2017, the American Venous Forum created a CEAP Task Force and charged it to critically analyze the current classification system and recommend revisions, where needed. Guided by four basic principles (preservation of the reproducibility of CEAP, compatibility with prior versions, evidence-based, and practical for clinical use), the Task Force has adopted the revised Delphi process and made several changes. These changes include adding Corona phlebectatica as the C4c clinical subclass, introducing the modifier "r" for recurrent varicose veins and recurrent venous ulcers, and replacing numeric descriptions of the venous segments by their common abbreviations. This report describes all these revisions and the rationale for making these changes.

Mechanical methods of venous thromboembolism prevention: from guidelines to clinical practice.

The paper discusses guidelines for the prevention of venous thromboembolism (VTE), with particular emphasis on the use of mechanical methods. Mechanical prophylaxis of VTE does not involve the risk of bleeding, which may be life­threatening. Mechanical methods are particularly recommended in patients at high risk of bleeding while on pharmacological thromboprophylaxis. Although antithrombotic prophylaxis is safe and cost­effective, there is evidence that the majority of preventive measures are applied too rarely in clinical practice, and that only a small proportion of patients receive complete and appropriate prophylaxis in the real­world clinical setting.

Heparins in cancer-associated venous thrombosis.

A close causal relationship between cancer and venous thrombosis gives rise to questions about the effect of treatment modalities, in particular of the administered drugs, in patients with cancer-related venous thrombosis. An increased risk of chemotherapy-associated venous thromboembolism (VTE) has been well documented, while the effect of heparins used in VTE treatment on the disease course and prognosis in cancer patients has not been fully elucidated. This paper discusses the outcomes of the studies conducted so far investigating the role of heparins, in particular, low-molecular-weight heparins (LMWHs), in the prevention of thrombosis in cancer patients. It also focuses on such aspects of the treatment for cancer-associated VTE as treatment duration and drugs used. The paper summarizes the often discrepant results of long-term therapies with various LMWH products, emphasising that in this specific case the class effect is rather unlikely. It also presents the possible effects of heparins administered as part of cancer treatment, and points to the effects of LMWHs on cancer that are not related to an antithrombotic effect. On the 100th anniversary of heparin discovery, it can be said that heparin is irreversibly connected with thrombosis in the course of cancer.

Sulodexide reduces the inflammatory reaction and senescence of endothelial cells in conditions involving chronic venous disease.

BACKGROUND: According to previous studies, sulodexide suppresses intravascular inflammation when used in patients with chronic venous disease (CVD). In the current study, we tested the effect of prolonged in vitro exposure of human venous endothelial cells to the serum from patients with CVD, examining the function of these cells and how it is modified when these cells are simultaneously exposed to sulodexide. METHODS: Human umbilical venous cells (HUVEC) were cultured in standard medium (control), in medium supplemented with 5% serum pooled from CVD patients (CVD-serum) or in medium from CVD patients who were treated with sulodexide (CVD-serum-SUL). The synthesis of interleukin-6 (IL-6), monocyte chemoattractant protein -1(MCP-1) and soluble intercellular adhesion molecule - 1 (s-ICAM-1) were studied at the beginning of incubation and were measured after 9 and 15 days of exposure to the studied media. The concentration of IL-6 after cell stimulation by interleukin -1 (IL-1) was also measured. In a subsequent part of the experiment, the effect of the studied sera on the in vitro replicative ageing of HUVEC was evaluated. A total of 15 passages of the cell culture were performed and both the PDT (population doubling time) and the cell hypertrophy were assessed. RESULTS: The concentrations of Il-6, MCP-1, and ICAM-1 gradually increased in the supernatants containing 5% CVD serum compared with the control medium. In the supernatants obtained after cell incubation with serum from sulodexide treated patients, the increase in concentrations of IL-6, MCP-1 and ICAM-1 was significantly less than the control. Release of IL-6 after stimulation with IL-1 (100 pg/mL) was the highest in the CVD-serum group: 3540±670 pg/105 cells vs. 1850±540 pg/105 cells in the control (P<0.01 vs. CVD-serum) and 2320 ±430 pg/105 cells in CVD-serum-SUL (P<0.02 vs. CVD-serum). PDT was significantly longer in the cells incubated with CVD serum compared with the control group, and PDT was reduced when serum from sulodexide treated patients was used. The cells became senescent in the presence of CVD serum, but the cells obtained from patients at the end of 8 weeks of treatment with sulodexide showed a much weaker inflammatory phenotype than the CVD group. CONCLUSIONS: Chronic in vitro exposure of HUVEC to medium supplemented with CVD patient serum induces an inflammatory phenotype. Sulodexide treatment significantly reduces that effect and slows HUVEC senescence in the milieu of CVD serum.

Superoxide dismutase 1 and glutathione peroxidase 1 are involved in the protective effect of sulodexide on vascular endothelial cells exposed to oxygen-glucose deprivation.

Sulodexide (SDX) is widely used in the treatment of both arterial and venous thrombotic disorders. In addition to its recognized antithrombotic action, SDX has endothelial protective potential, which is independent of the coagulation/fibrinolysis system. However, the detailed molecular mechanisms of the endothelioprotective action of the drug are still unresolved. The aim of the present study was to determine whether treatment with SDX at concentrations of 0.125-0.5 lipase releasing unit (LRU)/ml have on the expression and activity of antioxidant enzymes in ischemic endothelial cells and how these effects might be related to the antiapoptotic properties of SDX. In the present study, human umbilical vein endothelial cells (HUVECs) were subjected to ischemia-simulating conditions (combined oxygen and glucose deprivation, OGD) for 6h to determine the protective effects of SDX. SDX (0.25 and 0.5LRU/ml) in OGD significantly increased the cell viability and prevented mitochondrial depolarization in the HUVECs. Moreover, SDX protected the HUVECs against OGD-induced apoptosis. At concentrations of 0.25 and 0.5LRU/ml, the drug increased both superoxide dismutase 1 (SOD1) and glutathione peroxidase 1 (GPx1) mRNA/protein expression together with a significant attenuation of oxidative stress in ischemic HUVECs. Our findings also demonstrate that an increase in both SOD and GPx activity is involved in the protective effect of SDX on ischemic endothelial cells. Altogether, these results suggest that SDX has a positive effect on ischemia-induced endothelial damage because of its antioxidant and antiapoptotic properties.

Effects of Intermittent Pneumatic Compression on Reduction of Postoperative Lower Extremity Edema and Normalization of Foot Microcirculation Flow in Patients Undergoing Arterial Revascularization.

BACKGROUND In patients with chronic leg ischemia, the beneficial effect of arterial revascularization can be significantly decreased due to postoperative leg swelling. The aim of this study was to assess the effects of intermittent pneumatic compression (IPC) on skin flow normalization in patients undergoing revascularization procedures due to chronic leg ischemia. MATERIAL AND METHODS We evaluated 116 patients with chronic leg ischemia. The patients were divided into groups according to the performed treatment (endovascular or surgical) and implementation of IPC postoperatively. The leg edema assessment and microcirculation flow assessment were performed pre- and postoperatively, using percutaneous O2 pressure (TcpO2), cutaneous blood perfusion (CBP) measurements, and skin flow motion assessment. RESULTS In patients who did not receive IPC, a decrease in CBP value was observed in the 1st postoperative assessment. Among patients receiving IPC, the CBD value increased at the 1st and 2nd postoperative measurements, especially in the surgical group. The lowest TcpO2 values were observed in by-pass surgery group without IPC postoperatively. CONCLUSIONS The benefits of the by-pass procedure in patients with leg ischemia can be significantly reduced by postoperative edema. Among patients with postoperative leg edema, local tissue blood perfusion can be improved by the use of IPC, which can result in decreased local leg swelling, as well as improved skin blood perfusion and TcpO2.

Effect of Micronized Purified Flavonoid Fraction Therapy on Endothelin-1 and TNF-α Levels in Relation to Antioxidant Enzyme Balance in the Peripheral Blood of Women with Varicose Veins.

OBJECTIVE: The aetiology of varicose veins involves various factors and pathomechanisms including endothelial cell activation or dysfunction, venous hypertension, vein wall hypoxia, shear stress disturbances, inflammatory reaction activation or free radical production. To improve our understanding of the mechanisms of potential pharmacological interventions for chronic venous disease, we evaluated the influence of micronized purified flavonoid fraction (MPFF) on the relationship between antioxidant enzyme balance, endothelin-1 (ET-1) and tumour necrosis factor-α (TNF-α) levels. MATERIAL AND METHODS: Blood samples were obtained from 89 women with primary varicose veins; 34 were treated with MPFF and 55 did not receive any phlebotropic drug treatment. For the evaluation of the blood antioxidant enzyme balance, catalase (CAT) and superoxide dismutase (SOD) activity was assessed and the CAT/SOD ratio was calculated. RESULTS: Patients taking MPFF had significantly lower ET-1 levels than those not taking MPFF [median (25-75th quartile): 24.2 (22.30-27.87) vs 37.62 (24.9-44.58) pg.ml-1; p <0.05]. In those taking MPFF, a higher CAT/SOD ratio [39.8 (24.7-72.6) vs 28.8 (16.3-57.7); p<0.05] and a lower TNF-α concentration [6.82 (4.42-13.39) vs 12.94 (6.01-27.33) pg.ml-1; p<0.05] was also observed. In women not taking MPFF, ET-1 levels increased with the CAT/SOD ratio. In those taking MPFF, the ET-1 level was stable at approximately 25.0 pg.ml-1¬ up to a CAT/SOD ratio of 100. TNF-α level increased continuously with an increasing CAT/SOD ratio; however, the highest levels of TNF-α were observed in women not taking MPFF. CONCLUSION: We demonstrate the ability of MPFF to effectively lower the levels of ET-1 and TNF-α in patients with chronic venous disease. Further investigations are needed to define the therapeutic potential of MPFF including the potential effect on chronic subclinical inflammation, antioxidant imbalance and vascular dysfunction during the development of chronic venous disease.

[Duplex Doppler ultrasound examination of extremities arteries: guidelines of the Polish Society for Vascular Surgery]. / Zalecenia dotyczace wykonywania badan USG dupleks dopler tetnic konczyn Polskiego Towarzystwa Chirurgii Naczyniowej.

The duplex Doppler examination of extremities arteries is the primary diagnostic method in detecting disorders leading to lower and upper extremities blood supply disturbances. In many cases the Doppler ultrasound plays a major role in the process of qualification to the reconstructive procedures or conservative treatment, especially to the endovascular procedures. Regardless of the widespread availability and high sensitivity and specificity of this method it's burdened with serious drawbacks. The most important of them are evaluation subjectivity and variety of methods determining the haemodynamic stenosis consequences. They often cause difficulties in comparing the test results carried out in different centres and to find correlations with other imaging methods results. In order to overcome these drawbacks, Polish Society for Vascular Surgery has attempted to develop recommendations for uniform methodology of extremities arteries Doppler examination. Legal terms, the manner of examination and its interpretation were presented. Proposing the way of highlights results and messages conclusion to enable the recommendations implementation of endovascular and surgical qualifications relating to surgical treatment. We hope that these recommendations will help to standardise examination techniques.

Tension-free vaginal tape, transobturator tape, and own modification of transobturator tape in the treatment of female stress urinary incontinence: comparative analysis.

INTRODUCTION: This study is a comparative evaluation of the TVT, TOT, and our own modification of TOT (mTOT) in the treatment of female stress urinary incontinence from a single center experience. MATERIAL AND METHODS: The study was conducted on 527 patients with SUI diagnosed on the basis of urodynamic studies. They were divided into three groups--TVT: n=142, (TOT): n=129, and mTOT: n=256. All of the patients underwent evaluation at 1, 3, and 6 months after surgery. Results were statistically analysed and compared. RESULTS: Objective and subjective effectiveness after the surgery were not significantly different in the study groups and ranged from 90.1% to 96.4%. Mean surgery time was 32.3, 28.2, and 26.4 in the TVT, TOT, and mTOT, respectively. Mean hospitalization time was 2.51 days. Mean catheter maintenance time was significantly higher in the TVT than in other groups. In the TVT group total incidence of complications was 13.4%, and it was significantly higher than that in TOT and mTOT (9.3% and 8.6%, resp.). CONCLUSIONS: TVT, TOT, and mTOT are highly effective and safe methods in the treatment of SUI. There are no differences in the efficacy between the methods with a little higher percentage of complications in the TVT group.

Duplex Doppler ultrasound examination of carotid and vertebral arteries: guidelines of the Polish Society for Vascular Surgery.

The duplex Doppler examination of carotid and vertebral arteries is the primary diagnostic method in detecting disorders leading to the brain blood supply disturbances. In many cases, in patients with carotid artery stenosis, the Doppler ultrasound plays a major role in the process of qualification to the reconstructive procedures. Regardless of the widespread availability and high sensitivity and specificity of this method it's burdened with serious drawbacks. The most important of them are evaluation subjectivity and variety of methods to assess stenosis degree and the nature of atherosclerotic plaques. They often cause difficulties in comparing the test results carried out in different centers and to find correlations with other imaging methods results. In order to overcome these drawbacks, Polish Society for Vascular Surgery has attempted to develop recommendations for uniform methodology of carotid and vertebral arteries Doppler examination. Legal terms, the manner of examination and its interpretation were presented. Proposing the way of highlights results and messages conclusion to enable the recommendationsimplementation of endovascular and surgical qualifications relating to surgical treatment. We hope that these recommendations will help to standardize examination techniques.

[Polish guidelines for the prevention and treatment of venous thromboembolism. 2012 update]. / Polskie wytyczne profilaktyki i leczenia zylnej choroby zakrzepowo-zatorowej. Aktualizacja 2012.

The overall objective of the Polish guidelines for the prevention and treatment of venous thromboembolism is to increase patient benefit and safety by appropriate prevention and treatment of deep vein thrombosis and pulmonary embolism as well as proper management of the complications associated with antithrombotic and thrombolytic therapy. These guidelines apply to adult trauma, cancer, surgical, and medical patients as well as those at increased risk of venous thromboembolism. Specific recommendations have been formulated for pregnant women, patients requiring surgery while receiving long-term oral anticoagulant treatment, and patients undergoing regional anesthesia and/or analgesia. We chose to update the existing Polish guidelines with the use of the most recent high-quality international guidelines that we identified and adjusted the final product to Polish cultural and organizational setting. We based our recommendations primarily on the 9th edition of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis, the European Society of Cardiology Guidelines on the Diagnosis and Management of Acute Pulmonary Embolism, the 3rd edition of the American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines on Regional Anesthesia in the Patient Receiving Antithrombotic or Thrombolytic Therapy, the ACOG practice bulletin on thromboembolism in pregnancy (Number 123), and Guidance from the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis on the Duration of Anticoagulant Therapy after a First Episode of Unprovoked Pulmonary Embolus or Deep Vein Thrombosis, as well as two other Polish practice guidelines on the prophylaxis and treatment of venous thromboembolism and the management of patients treated with oral direct inhibitors of factor X or factor II. To make recommendations regarding specific management issues that had not been addressed in other guidelines, or whenever the panel members felt they needed additional information to reach the decision, we also consulted the authors of guidelines developed by other professional societies and organizations as well as additional sources of evidence. For each adapted recommendation, we explicitly assessed its relevance and applicability in the context of the healthcare system in Poland. When necessary, we explicitly stated the rationale for modification of the previously published recommendations and judgements about the values and preferences we assumed. The information regarding reimbursement of drugs mentioned in the recommendations was added in chapters 6-9 and 13 and approved by the National Health Fund. The final version of the practice guidelines was officially approved by the scientific societies and institutions listed at the beginning of the document.  

[Venous thromboembolism prophylaxis in hernia surgery]. / Profilaktyka przeciwzakrzepowa w chirurgii przepuklin.

In the paper, the data concerning VTE incidence and currently used methods of thromboprophylaxis in hernia surgery were presented. The role of individual trhomboembolic risk assessment in each case of open or laparoscopic surgical hernia repair were emphasized. The VTE risk stratification methods in surgical patients as well as the current guidelines (ACCP, International Consensus Statement, SAGES) concerning this kind of surgery were presented and discussed, taking into account the way of surgery performance (open vs laparoscopic), as well as the type of anaesthesia and duration of perioperative immoblisation. In each case of the patient undergoing surgical hernia repair the actual risk of VTE should be evaluated.

Sapheno-femoral junction pathology: molecular mechanism of saphenous vein incompetence.

A molecular mechanism responsible for varicose vein occurrence was investigated. The role of potential cell cycle regulator p21 and programmed cell death in the pathology leading to the proximal long saphenous vein (LSV) incompetence was investigated. Proximal LSV specimens were obtained from 40 patients with primary varicose veins who had undergone crossectomy. The expression of the p21, p53, and fas encoding genes was investigated by the means of real-time RT-QPCR. Immunostaining for gene product presence, proliferating cell nuclear antigen (PCNA), and apoptotic cells (TUNEL assay) was carried out. The results were compared to the control healthy vein specimens and correlated with pathologic examination findings (of the valve and vein structure). A significant increase in p21, p53, and fas mRNA expression were reported in the proximal incompetent veins. The expression of p21 correlated with expression of p53 (r = 0.658; p<0.05) and negative correlation between media apoptotic index and p21 mRNA expression was found (r = -0.493; p<0.05). Decrease in the muscular component within the media and disturbances of the local structure in the incompetent LSVs were reported. Fas overexpression did not correlate with p53 expression level and did not correlate with apoptotic cell number in the respective vein layers. PCNA-positive cells were present more frequently in the media of the control veins, especially in young subjects. Apoptosis downregulation, cell cycle inhibition and smooth muscle cell hypertrophy are important factors influencing vein wall disturbances related to sapheno-femoral junction incompetence.