Exploring the causal relationship between plasma lipids and varicose veins of lower extremity: A comprehensive two-sample Mendelian randomization study.

Varicose veins of the lower extremities (VVs) is a common chronic vascular disease, with high prevalence rates in some countries; however, their pathogenesis remains unclear. Some studies have identified associations between changes in specific plasma lipid molecules, such as phosphatidylethanolamine (PE), phosphatidylcholine (PC), and sphingomyelin (SM), and the onset of VVs, but due to confounders and reverse causality, the causal relationship remains unclear. Meanwhile, studies on the potential link between other plasma lipids beyond PE, PC, and SM and the risk of VVs in the lower extremities are lacking. This study aimed to explore the potential causal relationship between VVs and plasma lipid levels to provide theoretical insights into the interrelation of plasma lipids and VVs in their occurrence and progression. We conducted a two-sample Mendelian randomization (MR) analysis to assess the potential connection between genetically predicted levels of individual plasma lipids and the risk of developing VVs. We utilized data from a large-scale genome-wide association study involving 7174 Finnish individuals for 179 plasma lipidomes along with VVs genome-wide association study data from 408,455 UK individuals. MR analysis employed methods, such as inverse-variance weighting, weighted median, Bayesian Weighted Mendelian Randomization, and MR-Egger regression. The inverse-variance weighting method was primarily used to assess causality. The validity of the results was demonstrated through sensitivity analysis. In total, 12 lipids were found to have their plasma levels associated with an increased risk of VVs. This includes 3 types of PE, 7 types of PC, and 2 types of phosphatidylinositol. However, no significant causal relationship was found between the plasma levels of 11 types of SM and VVs. These results support the existence of a potential causal relationship between specific types of lipid levels and the risk of VVs, which can provide clues for further studies on biological mechanisms and the exploration of potential therapeutic targets.

Key Regulators of Angiogenesis and Inflammation Are Dysregulated in Patients with Varicose Veins.

Varicose veins (VVs) are the most common manifestation of chronic venous disease (CVD) and appear as abnormally enlarged and tortuous superficial veins. VVs result from functional abnormalities in the venous circulation of the lower extremities, such as venous hypertension, venous valve incompetence, and venous reflux. Previous studies indicate that enhanced angiogenesis and inflammation contribute to the progression and onset of VVs; however, dysregulations in signaling pathways associated with these processes in VVs patients are poorly understood. Therefore, in our study, we aimed to identify key regulators of angiogenesis and inflammation that are dysregulated in patients with VVs. Expression levels of 18 genes were analyzed in peripheral blood mononuclear cells (PBMC) using real-time PCR, as well as plasma levels of 6 proteins were investigated using ELISA. Higher levels of CCL5, PDGFA, VEGFC, TGF-alpha, TGF-beta 1, and VEGF-A, as well as lower levels of VEGFB and VEGF-C, were found to be statistically significant in the VV group compared to the control subjects without VVs. None of the analyzed factors was associated with the venous localization of the varicosities. The presented study identified dysregulations in key angiogenesis- and inflammation-related factors in PBMC and plasma from VVs patients, providing new insight into molecular mechanisms that could contribute to the development of VVs and point out promising candidates for circulatory biomarkers of this disease.

Clinical and Pathological Correlations in Chronic Venous Disease.

BACKGROUND: Chronic Venous Disease (CVD) has a high prevalence in the western world. Varicose veins (VVs) are the main signs of this disease that is characterized by important pathological vessel wall changes. The aim of this study is to correlate the main histopathological abnormalities with related clinical issues of CVD. METHODS: A cohort of patients with VVs scheduled for open surgical treatment namely stab avulsion of VVs was recruited. Subsequently, venous tissue from stab avulsion was collected in order to evaluate the following biomarkers: Vascular-Endothelial Growth Factor (VEGF), Protein Gene Product 9.5 (PGP 9.5), Fibronectin (FN), and Matrix Metalloproteinase-9 (MMP-9). The Clinical-Etiology-Anatomy-Pathophysiology (CEAP) criteria were used to classify CVD. RESULTS: Fourteen tissue fragments were processed for histological and immunohistochemical studies. Of these, 43% were from CEAP C2 patients, 36% from CEAP C3 patients, and 21% from CEAP C4 patients. CEAP Class C2 had few to moderate structures positive to VEGF; occasional structures positive to Fibronectin, numerous structures positive to MMP9, few to moderate structures positive to PGP 9.5. CEAP Class C3 had moderate structures positive to VEGF; few to moderate structures positive to Fibronectin; many structures positive to MMP9; few to moderate structures positive to PGP 9.5. CEAP Class C4 had numerous structures positive to VEGF; numerous structures positive to Fibronectin; abundant structures positive to MMP-9; few structures positive to PGP 9.5. CONCLUSIONS: In this study, positive VEGF, FN, and MMP-9 structures were found with increasing trends in relation to the disease staging. VEGF and FN are associated with a progressive increase from C2 to C4. The MMP-9 marker has an important positivity even at early stage of the disease, being higher in CEAP C4 patients. PGP 9.5 decreases in CEAP C4 patients and this is concordant to decreased vein wall innervation.

Fatal hemorrhage from peripheral varicose vein rupture

Varix of the lower extremities is a common entity that eventually presents fatal outcome. Fatal massive bleeding due to rupture of a peripheral varicose vein is rare. The estimated incidence of these cases is 1/1000 autopsies. The case we present is unique among 26,054 autopsies performed in Milan from 1993 to 2020. It describes the investigations carried out in the suspicion of a non-natural event in an elderly woman. She was found dead at home with a large volume of blood near her feet that drained from the right leg. Pathological examination disclosed that the hemorrhage occurred by the rupture of a venous varix of the lower limb. Cases of fatal hemorrhage from peripheral variceal rupture are insidious and require proper characterization. The bloodstain pattern analysis, careful autopsy dissection by layers to demonstrate the rupture, and histologic examination of the lesion are the essential elements to find out the actual cause of death.

[ANALYSIS OF SERUM VEGF LEVEL IN PATIENTS WITH VARICOSE VEINS AFTER ENDOVENOUS LASER ABLATION].

The aim of the study was the analysis of serum VEGF level in patients with varicose veins before and after the endovenous laser ablation (EVLA) and to study the role of VEGF in recurrence of the disease. The research involved 216 persons. The study group included 136 patients with varicose veins. Control group included 80 healthy persons. All 136 persons were treated by endovenous laser ablation. To establish the presence of recurrent veins we conducted several observations of patients in period of 1/2-1-3-6-12 months after the treatment and then every 6 month during 3 years. Serum samples were collected from patients' before the operation and 3-6 month after the operation. Serum VEGF level were significantly higher in study group (86,63 pg/ml) comparing to control group 24.10 pg/ml (р 0,01). Mean level of VEGF before the operation were 86.83 pg/ml and in 3 month after the operation decreased to 24.98 pg/ml (р=0,01). In recurrent cases VEGF level were 3 times higher than in non-recurrent cases (р=0,01). There is a direct correlation of VEGF level and recurrence r=0,40, also direct correlation established between the СЕАР clinical class and VEGF level r=0,64.

Expression profile of tRNA­derived fragments and their potential roles in human varicose veins.

Varicose veins (VVs) is a common disease presenting with chronic venous insufficiency. tRNA­derived fragments (tRFs) are associated with a variety of pathological conditions. However, the functions of tRFs in VVs have not been elucidated to date. The present study aimed to identify the key tRFs and investigate their potential roles in VVs. Small RNA sequencing (RNA­seq) was performed to investigate the expression of tRFs in tissues of patients with VVs and their matched adjacent normal veins tissues (ANVs). Reverse transcription­quantitative PCR (RT­qPCR) was used to confirm the differential expression of tRFs. A total of 13,789 tRFs were identified by small RNA­seq, including 45 differentially expressed tRFs (DETs), which comprised 14 upregulated and 31 downregulated tRFs in VV tissues compared with ANVs. In addition, DETs were mainly involved in the function of epidermal growth factor receptor and vascular endothelial growth factor receptor signaling pathways in VVs. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the target genes of DETs were predominantly involved in Wnt and mitogen­activated protein kinase (MAPK) signaling pathways, as well as calcium signaling. Additionally, two upregulated tRFs (tRF­36­F900BY4D84KRIME and tRF­23­87R8WP9IY) and one downregulated tRF (tRF­40­86J8WPMN1E8Y7Z2R) were further validated by RT­qPCR, and a signaling pathway regulation network of their target genes confirmed their involvement in the calcium, Wnt and MAPK signaling pathways. The results of the present study identified three DETs (tRF­36­F900BY4D84KRIME, tRF­23­87R8WP9IY and tRF­40­86J8WPMN1E8Y7Z2R), which may have crucial roles in the occurrence and progression of VVs by regulating Wnt and MAPK signaling, as well as calcium signaling. The present results may provide a basis for further investigation of the functional roles of tRFs in VVs.

Does the use of N-butyl-2 cyanoacrylate in the treatment of lower extremity superficial varicose veins cause acute systemic inflammation and allergic reactions?

INTRODUCTION: In this study we used N-butyl-2 cyanoacrylate (NBCA), including dimethyl sulfoxide (DMSO), via the endovenous route, for mechanochemical ablation in the treatment of superficial venous insufficiency, in an attempt to establish whether an early systemic inflammatory response and an allergic reaction occurred in the patients. METHODS: A total of 102 patients were treated with endovenous medical ablation in two centres between October 2015 and February 2016. This study was a two-centre, retrospective, non-randomised investigational study. Ablation treatment with endovenous NBCA was used in patients with C3 to C4b grade superficial venous insufficiency, according to the CEAP (clinical, aetiology, anatomy and pathophysiology) clinical classification, with sapheno-femoral junctional insufficiency and a reflux of 0.5 seconds and longer on duplex ultra-sonography. Pre-operative whole blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level and blood chemistry were studied in all patients on admission to the clinic, and repeated in the second hour post-intervention. RESULTS: All patients were treated successfully. Pre-operative white blood cell count (WBC) was 6.82 ± 1.67 × 109 cells/µl, and post intervention it was 6.57 ± 1.49 × 109 cells/µl; the difference was not statistically significant (p = 0.68). The neutrophil count before the intervention was 4.09 ± 1.33 × 109 cells/µl, while afterwards, it was 4.09 ± 1.33 × 109 cells/µl, with no statistically significant difference (p = 0.833). Pre-intervention eosinophil count was 0.64 ± 1.51 × 109 cells/µl, while it was 0.76 ± 1.65 × 109 cells/µl after the intervention, and the difference was statistically significant. Pre-intervention ESR and CRP values were 18.92 ± 9.77 mm/h and 1.71 ± 1.54 mg/dl, respectively. Postoperative ESR and CRP values were 19.78 ± 15.90 mm/h and 1.73 ± 1.59 mg/dl, respectively, but the differences were not statistically significant. When the parameters were analysed by gender, the differences between pre- and postoperative WBC and eosinophil count, ESR and CRP in women were not statistically significant. On the other hand, although the change in WBC count and CRP value were not statistically significant in males, the differences in eosinophil count and ESR were statistically significant. CONCLUSIONS: Cyanoacrylate has been used in the endovenous medical ablation of varicose veins and superficial venous insufficiency over the last few years without the use of thermal energy and tumescent anaesthesia, which represents the greatest advantage of this method. In addition, since it causes no systemic allergic or acute inflammatory reaction, it appears to be safe to use.

Evaluation of Plasma Growth Factors (VEGF, PDGF, EGF, ANG1, and ANG2) in Patients with Varicose Veins Before and After Treatment with Endovenous Laser Ablation.

OBJECTIVE: To measure pre- and postoperative plasma concentrations of growth factors (VEGF, PDGF, EGF, ANG1, and ANG2) in patients with primary lower limb varicose veins (VVs) treated with endovenous laser ablation (EVLA). BACKGROUND: Many studies have explored the potential relationship between primary VVs and growth factors. No previous studies were done for patients treated with EVLA. MATERIALS AND METHODS: Blood samples were obtained from 30 patients with primary VVs undergoing treatment with EVLA before and 1 week after treatment. Similar samples were obtained from 20 healthy matched adults as a control. Plasma concentrations of growth factor derivatives (VEGF, PDGF, EGF, ANG1, and ANG2) were measured through commercially available enzyme-linked immunosorbent assay. RESULTS: There was statistically significant reduction in median plasma growth factor (VEGF, PDGF, EGF, and ANG1) levels in the preoperative group (p = 0.001) when compared with the control group except for ANG2, which showed increased plasma level (p = 0.001). However, values of plasma concentration of those growth factors after treatment with EVLA were nearly equal to the control group, especially in EGF and VEGF (p = 0.564, 0.515, respectively). CONCLUSIONS: The altered plasma concentrations of growth factors VEGF, PDGF, EGF, ANG1, and ANG2 among patients with VVs normalized 1 week after treatment with EVLA compared with the control group. This may support the role of these factors in the pathogenesis of the disease. Future studies may evaluate if these changes can play a prognostic and/or predictive value regarding the adequacy of treatment and the possibility of recurrence.

Antioxidative mechanism in the course of varicose veins.

Objective Our objective was to evaluate the state of oxidative stress in the great saphenous varicose vein wall and blood of varicose vein patients taken from the antecubital vein. Methods The superoxide dismutase, reduced glutathione (GSH) and total antioxidant status were measured with commercially available colorimetric kits in erythrocytes, plasma and varicose vein wall of 65 patients (second degree of clinical state classification, etiology, anatomy and pathophysiology) aged 22-70 (49 women, 16 men) in comparison to normal great saphenous vein walls collected from 10 patients who underwent coronary artery bypass graft and blood collected from 20 healthy individuals. Results A statistically significant decrease (p < 0.001) in superoxide dismutase activity in erythrocytes and the increase (p < 0.05) in superoxide dismutase activity in varicose vein has been observed. There have been no significant changes in the concentration of GSH in plasma and in varicose vein. The decreased concentration of total antioxidant status in plasma (p < 0.001) and in varicose vein wall (p < 0.05) in comparison to the control has been noticed. Conclusion The varicose vein patients are affected by oxidative stress. Our results indicate impaired antioxidant defense mechanism in the blood of varicose vein patients. In contrast to the blood, an increased process of antioxidant defense in the varicose vein wall was noticed.

Erythrocytes properties in varicose veins patients.

Varicose veins (VV) are enlarged veins of the subcutaneous tissue, usually caused by faulty or damaged venous valves leading to impaired blood flow. Blood stasis, excessive clotting disorder and alterations in the vein walls are symptoms of Virchow's triad which may affect the morphotic elements of blood, including erythrocytes. The aim of this study was to investigate alterations in the properties of the erythrocytes taken from varicose veins in comparison to those from antecubital vein of patients with chronic venous disease. The investigation was conducted on whole erythrocytes using spin labeling method in EPR spectroscopy and flow cytometry. The internal viscosity of cells was determined by Tempamine. The conformation state of internal proteins, mainly hemoglobin and membrane proteins was determined by maleimide spin label (MSL, 4-maleimido-2,2,6,6-tetramethylpiperidine-1-oxyl). The plasma membrane fluidity was measured using two spin labeled fatty acids (5- and 16-doxylstearic acid), while conformational state of membrane protein was measured using two covalently bound spin labels MSL and ISL [4-(2-iodoacetamido)-2,2,6,6-tetramethylpiperidine-1-oxyl]. The osmotic fragility and the shape and size of the erythrocytes were also determined. A decrease in internal viscosity of the erythrocytes from varicose vein was observed. A significant decrease in lipid membrane fluidity indicated by 5-DS, which is located at the polar region of lipid layer was found in the erythrocytes from varicose vein in comparison to normal vein. A significant decrease in the motion of MSL and ISL attached to erythrocyte membrane proteins from varicose vein was found. Changes in the plasma membrane of the erythrocytes from varicose vein were also confirmed by measuring osmotic fragility. These cells were more sensitive to hemolysis than red blood cells from the peripheral blood vein. Meanwhile, no significant differences in size and shape were observed between the erythrocytes taken from varicose veins and those from peripheral veins. In conclusion, the erythrocytes from varicose veins exhibited decreased intracellular viscosity and decreased plasma membrane fluidity. At the same time, conformational changes of membrane proteins and higher osmotic fragility of these cells were found in comparison to the erythrocytes obtained from peripheral veins in the same patients with chronic venous disease. Our findings strongly suggest that presented abnormalities in the erythrocyte plasma membrane may have significant pathophysiological implications, including shortened cell survival and alterations in the hemorheology of the varicose vein blood.

[Concentration of matrix metalloproteinases and magnesium ions in patients with varicose veins of lower limbs]. / Kontsentratsiya matriksnykh metalloproteinaz i ionov magniya pri varikoznoi bolezni ven nizhnikh konechnostei.

The study was aimed at investigating alterations in the concentration of matrix metalloproteinases (MMP-1, MMP-9) and the tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as the level of magnesium ions (Mg2+) as an indicator of connective tissue dysplasia (CTD) in patients presenting with lower limb varicose veins. The study included a total of 110 people. Of these, the Study Group comprised 90 patients with lower limb varicose veins of clinical class C2-C6 (according to the CEAP classification) and the Control Group was composed of 20 apparently healthy volunteers. Samples of peripheral blood were examined. The content of MMP-9, MMP-1 and TIMP-1 in blood serum was determined by means of the quantitative solid-phase immunoenzymatic assay. The concentration of Mg2+ was determined by the colorimetric method. We revealed a statistically significant interrelationship between the concentrations of matrix metalloproteinases and severity of varicose transformation of lower-limb veins, with the highest level of matrix metalloproteinases being observed in patients with cutaneous alterations and trophic ulcers. Determination of the level of matrix metalloproteinases and magnesium ions, characterizing connective tissue dysplasia, makes it possible to predict the development of lower limb chronic venous insufficiency and to evaluate the degree of its severity.

Serum from Varicose Patients Induces Senescence-Related Dysfunction of Vascular Endothelium Generating Local and Systemic Proinflammatory Conditions.

Although the role of endothelium in varicose vein development is indisputable, the effect of the pathology on biological properties of endothelial cells remains unclear. Here we examined if the presence of varicose veins affects senescence of endothelial cells (HUVECs) and, if so, what will be the local and systemic outcome of this effect. Experiments showed that HUVECs subjected to serum from varicose patients display improved proliferation, increased expression of senescence marker, SA-ß-Gal, and increased generation of reactive oxygen species (ROS), as compared with serum from healthy donors. Both increased SA-ß-Gal activity and ROS release were mediated by TGF-ß1, the concentration of which in varicose serum was elevated and the activity of which in vitro was prevented using specific neutralizing antibody. Senescent HUVECs exposed to varicose serum generated increased amounts of ICAM-1, VCAM-1, P-selectin, uPA, PAI-1, and ET-1. Direct comparison of sera from varicose and healthy donors showed that pathological serum contained increased level of ICAM-1, VCAM-1, P-selectin, uPA, and ET-1. Calendar age of healthy subjects correlated positively with serum uPA and negatively with P-selectin. Age of varicose patients correlated positively with ICAM-1, VCAM-1, and ET-1. Collectively, our findings indicate that the presence of varicose veins causes a senescence-related dysfunction of vascular endothelium, which leads to the development of local and systemic proinflammatory environment.

Are Inflammatory Biomarkers Increased in Varicose Vein Blood?

OBJECTIVES: To test for the presence of inflammatory biomarkers in blood taken from varicose veins versus antecubital blood of the same patient and compare this to levels in healthy controls. METHODS: Using a multiplex biochip array method (Randox, United Kingdom), the interleukins (ILs) IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, and IL-10; vascular endothelial growth factor; interferon γ, tumor necrosis factor α ; monocyte chemotactic protein 1 (MCP-1); and epidermal growth factor were measured in citrated plasma samples drawn from the arms and legs of 24 patients with varicose veins and 24 controls. RESULTS: Expressed as median (interquartile range) in pg/mL, leg samples from patients with varicose veins had significantly higher levels of IL-8 and MCP-1 compared to their own arm samples (IL-8: local 2.3 [1.71-3.3] vs systemic 2.3 [1.62-2.98], P = .023; MCP-1: local 114.42 [84.29-139.05] vs systemic 103.56 [79.75-126.42], P < .0005). This was not observed in the control group. Leg samples from both patients with varicose vein and controls had higher levels of IL-6 compared to their own arm samples (patients: local 1.67 [0.82-4.48] vs systemic 1.24 [0.58-3.26], P = .002; controls: local 1.23 [0.83-1.7] vs systemic 1.03 [1.7-1.52], P = .005). No significant differences were detected with the other biomarkers. CONCLUSIONS: Blood drawn from the site of varicose veins appears to have significantly increased concentrations of IL-6, IL-8, and MCP-1 when compared to the same patient's arm blood. This supports the hypothesis that inflammation is activated from the tissues drained by the varicose veins.

Endogenous pro-thrombotic biomarkers from the arm and leg may not have the same value.

OBJECTIVE: Assessments of endogenous pro-thrombotic biomarkers are performed invariably on arm blood. However, the commonest site for thrombosis is in the leg. A leg blood sample may reflect local pro-thrombotic processes more accurately than systemic arm blood. The aim was to determine whether pro-thrombotic biomarkers from standard venous arm samples differed significantly from leg samples. METHOD: Concurrent blood samples were taken from an ankle/lower calf varicose vein and an ante-cubital vein in 24 patients awaiting laser treatment as well as age approximated and sex matched healthy controls without venous disease. The following assays were performed: thrombin-antithrombin (ng/ml), antithrombin (%) activity, microparticles (nM), fibrinogen (mg/dl), prothrombin fragment 1.2 (F1.2) (pM) and P-selectin (ng/ml). RESULTS: Expressed as median (inter-quartile range). Significant arm/leg differences were observed in thrombin-antithrombin, antithrombin, prothrombin fragment 1.2 and P-selectin. The legs of patients had significantly reduced antithrombin activity and P-selectin concentrations compared to their arms (leg: 101 (90-108) versus arm: 112 (99-126), P = 0.001 and leg: 42 (26-52) versus 45 (27-52), P = 0.044, respectively). Control leg samples had significantly increased thrombin-antithrombin and P-selectin compared to control arm samples (leg: 2.1 (0.9-3.2) versus arm: 0.8 (0.5-1.7), P = 0.015 and leg: 36 (24-50) versus arm: 30 (23-41), P = 0.007, respectively). However, the control legs had significantly reduced F1.2 (leg: 265 (230-333) versus arm: 299 (236-361), P = 0.028). No significant arm/leg differences were detected in the microparticle or fibrinogen levels. CONCLUSIONS: These findings indicate that venous arm blood is significantly different from venous leg blood in four out of six biomarkers studied. Recognition of local venous leg sampling as a site for investigation may unravel why the leg has a greater predisposition to thrombosis and lead the way towards an arm/leg differential test.

Do blood constituents in varicose veins differ from the systemic blood constituents?

OBJECTIVE: Varicose veins represent one of the most frequent vascular diseases and are in most cases benign. However, advanced disease is frequently associated with complications such as chronic venous insufficiency and superficial vein thrombosis. The pathogenic mechanisms are not well understood. Besides increased venous pressure, it is suggested that local blood constituents trigger various mechanisms responsible for the progression of the disease and its complications. DESIGN: The aim of this study was to investigate the changes in the blood in varicose veins and to compare them with the systemic markers of inflammation and endothelial damage. MATERIALS AND METHODS: Forty patients with primary varicose veins were included in the study. Most patients were class C2. Blood samples were taken from the leg from the tortuous and dilated varicose tributaries of the great saphenous vein and from the cubital vein. RESULTS: The values of basic hematologic tests were comparable between blood samples (varicose vs. systemic). In varicose veins, the following parameters were significantly increased in comparison with systemic blood: hsCRP (3.12 ± 2.18 mg/L vs. 2.04 ± 2.21 mg/L, p = .04), IL-6 (3.54 ± 2.59 pg/mL vs. 2.25 ± 1.27 pg/mL, p = .008), vWF (118.4  ±  27% vs. 83.2  ±  22%, p < .05). D-dimer, in samples taken from the leg varicose veins, was also significantly higher than in the systemic blood (104.3 ± 9.3 ng/mL vs. 89.5 ± 8.3 ng/mL, p = .039). CONCLUSIONS: Some inflammatory markers and indicators of endothelial dysfunction are increased in varicose vein blood. This is most probably the consequence of deteriorated blood flow in dilated and tortuous superficial veins, and increased venous pressure. Damage to the venous wall, which causes a chronic inflammatory response, together with the procoagulant properties of local blood may promote further progression of the disease and thrombotic complications.

Serum estradiol/free testosterone ratio can be important predictor for varicose vein recurrence in men.

AIM: Recurrent varicose veins are a frustration for both the patient and the surgeon. More investigation of the exact diagnosis, proper practice, and causes for the recurrence of varicose veins is needed. METHODS: We investigated a total number of 187 patients in a five year period with an estradiol-2/free testosterone (E2/fT) ratio relationship on recurrent varicose veins in men between the ages of 20-50. Fifity years was the maximum age due to the age dependent sex steroid hormone regression that occurs after this age, which may interefere with the assessment. Fifty three men with an elevated E2/fT ratio (group A), and 143 men with no endocrinologic problems (group B) were enrolled in the study and had surgery for varicose veins. After 5 years follow up (mean 3 years), Group A (N.=29) and group B (N.=43) had recurrent varicose veins by clinical and radiologic findings. Venous blood samples were driven from all patients of both groups in the morning to detect the levels of serum E2 and fT levels. Patient history of surgery for varicose veins, physical examination, color duplex ultrasound of both limbs, and classification of CEAP were performed in both groups. RESULTS: The serum E2/fT ratio was significantly higher in Group A (5.21 ± 0.56) compared to group B (2.54±0.27) in the recurrent varicose vein groups (p ≤ 0.05). Moreover, there was a high correlation between serum E2/fT ratio and the CEAP clinical classification in group A (5) compared to group B (2) (P≤0.05). Also, recurrence rate was higher in group A (54%) compared to group B (32%)(P≤0.05). CONCLUSION: Elevated serum E2/fT ratio is a precipitating factor for recurrent varicose veins in male patients.

Biomarkers of low-grade inflammation in primary varicose veins of the lower limbs.

OBJECTIVE: To analyze serum biomarkers of CVD in selected patients with primary axial reflux of great saphenous vein in one or both lower limbs. PATIENTS AND METHODS: Ninety-six patients affected by uncomplicated varicose veins, were enrolled in the study. A unilateral, primary axial reflux in great saphenous veins was detected in 54 patients (U-CVD group) and a bilateral one in 42 (B-CVD group). Sixty-five age and sex-matched subjects without venous reflux were enrolled as controls. Mean venous pressure of both lower limbs at the distal great saphenous vein (mGSVP) and venous reflux were measured by continuous-wave Doppler ultrasound and echoduplex scanning, respectively. Reactive Oxygen Species (ROS), tissue Plasminogen Activator (t-PA) and its Inhibitor 1 (PAI-1) activities, Hematocrit (HTC), White Blood Cells (WBC), Neutrophyls (NEU), Platelets (PLT), Fibrinogen (FIB) and Blood Viscosity (BV) were assessed in blood samples drawn from the antecubital vein. RESULTS: B-CVD group showed higher fibrinogen values (p < 0.005) and higher mean venous pressure (0 < 0.0001) in comparison to controls, while U-CVD did not. No difference was found between both groups and controls for all the other parameters. CONCLUSIONS: Increased fibrinogen levels in patients with bilateral varicose veins may represent an early warning signal, as it could be associated to the long-term progression of chronic venous disease.

d-Dimer Levels are Significantly Increased in Blood Taken From Varicose Veins Compared With Antecubital Blood From the Same Patient.

d-Dimer is a prothrombotic biomarker and a very sensitive measure of endogenous fibrinolysis. It is used as a screening test for suspected deep vein thrombosis. This study investigated whether d-dimer levels were increased in the varicose veins of patients in comparison to their own arm samples. Patients, n = 24, 17 male, age 45 (25-91), C2-6, awaiting saphenous laser ablation were compared to matched controls, n = 24, 17 male, age 42 (24-89). Concurrent venous blood samples were taken from the arm and a lower calf/ankle (varicose) vein. The median (interquartile range) d-dimer (ng/mL) level was significantly greater in the ankle than in the arm blood of the same patient at 319 (164-631) versus 281 (167-562), P = .003, Wilcoxon. This did not occur in the controls at 269 (80-564) versus 262 (106-526), P = .361, Wilcoxon. The results indicate increased endogenous fibrinolysis in varicose veins compared with arm blood. This suggests there is more thrombotic activity or dissolution of formed subclinical fibrin thrombus which may explain the association of varicose veins with superficial vein thrombosis. This contrasts with earlier studies reporting a local reduction in fibrinolysis in venous disease.

Protein C deficiency related obscure gastrointestinal bleeding treated by enteroscopy and anticoagulant therapy.

Obscure gastrointestinal bleeding is an uncommonly encountered and difficult-to-treat clinical problem in gastroenterology, but advancements in endoscopic and radiologic imaging modalities allow for greater accuracy in diagnosing obscure gastrointestinal bleeding. Ectopic varices account for less than 5% of all variceal bleeding cases, and jejunal variceal bleeding due to extrahepatic portal hypertension is rare. We present a 47-year-old man suffering from obscure gastrointestinal bleeding. Computed tomography of the abdomen revealed multiple vascular tufts around the proximal jejunum but no evidence of cirrhosis, and a visible hypodense filling defect suggestive of thrombus was visible in the superior mesenteric vein. Enteroscopy revealed several serpiginous varices in the proximal jejunum. Serologic data disclosed protein C deficiency (33.6%). The patient was successfully treated by therapeutic balloon-assisted enteroscopy and long-term anticoagulant therapy, which is normally contraindicated in patients with gastrointestinal bleeding. Diagnostic modalities for obscure gastrointestinal bleeding, such as capsule endoscopy, computed tomography enterography, magnetic resonance enterography, and enteroscopy, were also reviewed in this article.