Non-varicose Veins Research Articles

Current Diagnostic and Therapeutic Challenges in Superficial Venous Thrombosis.

Superficial venous thrombosis (SVT) is a fairly common disorder, characterized by the formation of thrombi inside superficial veins, with or without an associated inflammatory reaction. Its evolution is frequently self-limited. However, serious complications may change this clinical course with extension to deep vein thrombosis (DVT) and pulmonary embolism (PE). SVT shares similar risk factors with DVT and is frequently associated with the presence of varicose veins. However, the occurrence of non-varicose veins could conceal risk factors such as malignancies, thrombophilia, or Buerger's disease. While the clinical diagnosis is generally straightforward, additional diagnostic evaluations are often necessary. Duplex ultrasound (DUS) is an invaluable tool that provides the location of SVT, the proximity to the sapheno-femoral junction, and the clot length, all of which influence the decision for optimal management. The treatment of SVT should be symptomatic, pathogenic (limiting the extension of thrombosis), and prognostic (to prevent complications). There are several guidelines that provide recommendations, and despite the need for more consensus and for further studies, the treatment of SVT should be mainly medical, including anticoagulation in specific clinical situations and symptom relief, with invasive treatment in a minority of cases. Initiation, intensity, and length of anticoagulant treatment should be based on the eventual risk of progression to DVT or PE, which can be high, intermediate, or low, based on the location of SVT and the clot length. Our review summarizes the evaluation and proper management of SVT and highlights the importance of a shared decision within the heart team regarding this condition in order to prevent further complications.

Replication study identified EFEMP1 association with varicose vein predisposition among Indians

BackgroundVaricose vein is a chronic condition that affects the lower extremities of the human body. Several factors have been implicated in the development of this disease, viz age, gender, weight, height and prolonged standing. Recently, genome-wide studies have identified genetic biomarkers that are associated with varicose veins in different ethnic groups. Such genetic studies are lacking in South Asians specifically in Indians where the prevalence of varicose veins is high, and it is important to replicate these variants in the stated population. The study aimed to replicate the association of genetic variants associated with varicose veins in this target population, which were found to be associated with the other ethnic groups.MethodologyThe studied cohort is of the Indian population comprising unrelated 104 varicose veins cases and 448 non-varicose vein controls. The samples were genotyped using the Illumina Global Screening Array. Using the genomic data from UK BioBank and 23andMe studied cohorts; eight genetic variants were selected to replicate in our dataset. The allelic association was performed to identify the effective allele and risk was estimated using odds ratio and p-value as level of significance. Multifactor Dimensionality Reduction was used to estimate the cumulative effect of variants in Indians.ResultVariant rs3791679 of EFEMP1 was found to be associated with varicose veins in Indians. After observing the association of the EFEMP1 with varicose veins, we further ensued to identify all genetic variants within EFEMP1 to uncover the additional variants associated with this trait. Interestingly, we identified six new variants of EFEMP1 gene that have shown association. Moreover, the cumulative effect of all associated variations was estimated and the risk was 2.7 times higher in cases than controls whereas independently their effect ranges from 0.37–1.58.ConclusionThis study identifies EFEMP1 as a potential gene related to the risk of varicose veins in Indians. It also highlights that evaluating the maximum number of variants of a gene rather than focusing solely on replicating single variations offers a more comprehensive and nuanced understanding of the genetic factors contributing to a complex trait like varicose veins.

Epigenome-Wide Changes in the Cell Layers of the Vein Wall When Exposing the Venous Endothelium to Oscillatory Shear Stress.

Epigenomic changes in the venous cells exerted by oscillatory shear stress towards the endothelium may result in consolidation of gene expression alterations upon vein wall remodeling during varicose transformation. We aimed to reveal such epigenome-wide methylation changes. Primary culture cells were obtained from non-varicose vein segments left after surgery of 3 patients by growing the cells in selective media after magnetic immunosorting. Endothelial cells were either exposed to oscillatory shear stress or left at the static condition. Then, other cell types were treated with preconditioned media from the adjacent layer's cells. DNA isolated from the harvested cells was subjected to epigenome-wide study using Illumina microarrays followed by data analysis with GenomeStudio (Illumina), Excel (Microsoft), and Genome Enhancer (geneXplain) software packages. Differential (hypo-/hyper-) methylation was revealed for each cell layer's DNA. The most targetable master regulators controlling the activity of certain transcription factors regulating the genes near the differentially methylated sites appeared to be the following: (1) HGS, PDGFB, and AR for endothelial cells; (2) HGS, CDH2, SPRY2, SMAD2, ZFYVE9, and P2RY1 for smooth muscle cells; and (3) WWOX, F8, IGF2R, NFKB1, RELA, SOCS1, and FXN for fibroblasts. Some of the identified master regulators may serve as promising druggable targets for treating varicose veins in the future.

Approach to: Venous Thromboembolism

Venous thromboembolisms can manifest as a spectrum of diseases and complications, such as deep vein thrombosis (DVT) and pulmonary embolism (PE), as a consequence of hypercoagulability, endothelial damage and/or venous stasis. DVT can present as localized pain or heaviness, unilateral edema, dilatation of superficial nonvaricose veins, a palpable cord or Homans’s sign. Symptoms of PE include acute or worsening shortness of breath and pleuritic chest pain while physical examination may be remarkable for tachycardia and tachypnea. However, given their non-specificity, using these signs and symptoms alone allows for poor differentiation between VTE and other entities. This review will focus on a multi-step diagnostic tree allowing for evidence-based interpretation of tests following a determined pre-test probability (PTP), as per Thrombosis Canada recommendations and ASH clinical guidelines. An introduction to VTE in Pediatrics and pregnancy will also be discussed.

Quantitative and structural characteristics of mitochondrial DNA in varicose veins

ObjectiveWe examined quantitative (in terms of mtDNA/nuclear DNA) and structural (in terms of common deletions in the MT-ND4 gene region) characteristics of mitochondrial DNA (mtDNA) in varicose veins (VVs) and venous wall layers by comparing mitochondrial genome parameters, as well as mitochondrial function (in terms of mitochondrial membrane potential (MtMP)), in varicose vein (VV) vs. non-varicose vein (NV) tissue samples. MethodsWe analyzed paired great saphenous vein samples (VV vs. NV segments from each patient left after venous surgery) harvested from patients with VVs. Relative mtDNA level and the proportion of no-deletion mtDNA were determined by a multiplex quantitative PCR (qPCR), confirming the latter with a more sensitive method – droplet digital PCR (ddPCR). Mitochondria's functional state in VVs was assessed using fluorescent (dependent on MtMP) live-staining of mitochondria in venous tissues. ResultsTotal mtDNA level was lower in VV than in NV samples (predominantly in the t. media layer). ddPCR analysis showed lower proportion of no-deletion mtDNA in VVs. Because of the decrease in relative MtMP in VVs, our results suggest a possible reduction of mitochondrial function in VVs. ConclusionQuantitative and structural changes (copy number and integrity) of mtDNA are plausibly involved in VV pathogenesis. Future clinical studies implementing the mitochondrial targeting may be eventually fostered after auxiliary mechanistic studies.

Superficial Vein Thrombosis

A large German registry on superficial vein thrombosis (SVT) documents that risk profiles, clinical presentation and treatment patterns are highly variable in patients with SVT, including a large variation in anticoagulation treatment modalities, intensities and durations. Inspite of a high percentage of initial anticoagulation there is a substantial risk of subsequent venous thromboembolism (VTE), recurrences or extension after three months. Inspite of current guideline recommendations, one third of the patients receives heparins, oral anticoagulants or no anticoagulation at all. At initial presentation about one quarter of the patients with SVT have a concomitant, frequently asymptomatic VTE. Risk factors for this complication include prior hospitalization, immobilization, prior VTE, autoimmune disorders, higher age, cancer and SVT occurring in a non-varicose veins or SVT-extension into the perforator veins. These risk factors are also associated with thromboembolic complications during follow-up. Based on a large placebo-controlled trial with clinical endpoints (The CALISTO-Study), guidelines recommend Fondaparinux 2.5 mg once daily administered over 4 to 6 weeks. Alternatively, an intermediate dose of low molecular weight heparin can be considered. In high-risk patients, rivaroxaban 10 mg once daily was noninferior compared to Fondaparinux. A rebound of VTE recurrences was observed in both study arms after treatment had been discontinued after 45 days. Further studies are required to determine whether treatment needs to be extended beyond 45 days in high-risk patients.

Signaling pathways associated with structural changes in varicose veins: a case-control study.

In varicose veins, blood pressure increases in the veins of the lower extremities due to mechanical stimulation and function remodeling. The aim of this study is assessment of Signaling pathways associated with structural changes in varicose veins. This pilot study was performed on patients with varicose veins, which had undergone surgery. The healthy tissues from trauma patients or vascular bypass without underlying diseases were used for control samples. Hematoxylin-eosin, trichrome, and elastin staining were used for histopathological examination. The levels of MDA (malondialdehyde), total thiol, SOD (Superoxide dismutase) and NO (nitric oxide) level were measured using Elisa kits to evaluate the oxidative stress level. Gene expression levels of MMP2, MMP9, FOXO3a, APOE and p53 genes were determined using Real-time PCR. This study showed, the vascular Vein wall changes are visible in vascular collagen staining. Although these changes are observed in the structure of vascular wall collagen fibers, the accumulation of collagen and elastin was increased in the walls of varicose veins compared to the control group. The amount of nitric oxide and thiol were increased in the varicose group (P < 0.0001). The expression of metalloproteinase2 gene associated with extracellular matrix change was increased in varicose veins. However, the amount of metalloproteinase 9 was decreased in this group compared to control group. FOXO3a, APOE Genes were down-regulated in the varicose veins compared to control group, while p53 gene expression was significantly increased in the varicose group (P < 0.0001). This study demonstrated changes in oxidative stress, morphological structure, and aging pathways in varicose when compared to non-varicose veins. The changes in oxidative stress may be associated with the variations in morphological structure and aging pathways which contribute to the pathogenesis of varicose veins.

Prevalence of cancer in patients with superficial vein thrombosis and its clinical importance

ObjectiveThe objective of the present study was to evaluate the prevalence of cancer in patients with superficial vein thrombosis (SVT) of the legs. Moreover, we evaluated the potential determinants of SVT complications by comparing a subgroup with isolated SVT and a subgroup of SVT complicated by concurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) with respect to the presence of cancer and other clinical and laboratory characteristics. MethodsThe present single-center, retrospective study of prospectively collected data was conducted in a tertiary care setting. We included patients who had been treated in the thrombosis clinic from 2006 to 2018 for symptomatic SVT of the legs, either isolated SVT or SVT complicated by concurrent DVT/PE. We evaluated the prevalence and type of malignancy (diagnosed ≤12 months before SVT and/or ongoing therapy), demographics, and clinical and laboratory characteristics of the patients. For statistical evaluation, we used the Student t test, Kruskal-Wallis test, Fisher exact two-sided test, and logistic regression. ResultsOf 276 patients with SVT (mean age, 58.9 ± 14.7 years; 60.9% women), 191 had had isolated SVT and 85 had had SVT complicated by concurrent DVT/PE. The prevalence of malignancy was 8.7% in the whole group (mainly breast and urinary tract cancer), including 4.2% of those with isolated SVT and 18.8% of those with SVT and concurrent DVT/PE (P < .001). Between the two subgroups, no significant differences were present in the duration of leg symptoms, family or personal history of SVT and/or DVT, SVT location, and smoking. In logistic regression, several factors were significantly associated with the concurrent presence of DVT/PE: age (odds ratio [OR], 1.024; 95% confidence interval [CI], 1.004-1.044), female gender (OR, 0.545; 95% CI, 0.309-0.960), varicose vein SVT (OR, 0.42; 95% CI, 0.194-0.902), thrombophilia (OR, 1.939; 95% CI, 1.089-3.454), and cancer (OR, 4.727; 95% CI, 1.814-12.316). ConclusionsThe prevalence of malignancy in the patients with SVT was 8.7%. Age, thrombophilia, male gender, nonvaricose vein SVT, and cancer were significantly associated with the presence of concurrent DVT/PE. Cancer was the strongest determinant of concurrent DVT/PE.

A Novel View to Varicose Veins Pathogenesis: Proteomic Analysis

Introduction - The advent of proteomics techniques allows large-scale studies of gene expression at protein level. Although morphological and anatomical studies indicate that venous wall weakening and subendothelial fibrosis characterize varicose veins, the pathogenesis of varicose veins remains poorly understood. The aim this study is to obtain protein expression profiles in patients with varicose veins. Finally, the identification of possible biomarkers may open possibilities for pharmacological inhibition of disease progression. Methods - Varicose saphenous veins removed during phlebectomy and normal saphenous veins obtained during vascular surgery were collected for proteomics analysis. The same layers of venous wall from varicose and non-varicose veins were incubated, and the proteins released were analyzed by ion mobility spectrometry (IMS-MS) with Synapt G2.All differentially expressed proteins and their pathways, coexpression and physical interactions were analyzed in GeneMANIA and AmiGO databases. Results - Proteomic analysis of the human vein revealed totally 1387 proteins. 200 proteins demonstrated significant differences in their quantity (more than 1.5 fold) between the two types of venous tissue (p<0.05). Among the most differentially expressed proteins 10 were found significantly decreased in the varicose vein tissue, and only two- increased. CXXC-type zinc finger protein was more permanent (38- fold down regulated). This protein is known as receptor for vascular endothelial growth factor. Most prominent proteins were proved with Western Blotting analysis. Conclusion - This study provides novel insights into the biochemical mechanisms of this disease and a basis for further studies. Our proteomics discovery approach suggests that extracellular matrix degradation play a pivotal role in the pathogenesis of venous varicose. The identified proteins suggest that the varicose venous wall responds to a stressful condition and that proteolytic degradation of the cytoskeleton, inflammation and apoptosis of smooth muscle cells may be part of the response. Larger studies are required to confirm the potential and clinical role of the identified proteins.

A variant of the castor zinc finger 1 (CASZ1) gene is differentially associated with the clinical classification of chronic venous disease

Recent reports have suggested a reproducible association between the rs11121615 SNP, located within an intron of the castor zinc finger 1 (CASZ1) gene, and varicose veins. This study aimed to determine if this variant is also differentially associated with the various clinical classifications of chronic venous disease (CVD). The rs11121615 SNP was genotyped in two independent cohorts from New Zealand (n = 1876 controls /1606 CVD cases) and the Netherlands (n = 1626/2966). Participants were clinically assessed using well-established CVD criteria. The association between the rs11121615 C-allele and varicose veins was validated in both cohorts. This was strongest in those with higher clinical severity classes and was not significant in those with non-varicose vein CVD. Functional analysis of the rs11121615 variant demonstrated that the risk allele was associated with increased enhancer activity. This study demonstrates that the CASZ1 gene associated C-allele of rs11121615 has a significant, reproducible, association with CVD (CEAP C ≥ 2 meta-odds ratio 1.31, 95% CI 1.27–1.34, P = 1 × 10−98, PHet = 0.25), but not with non-varicose vein (CEAP C1, telangiectasia or reticular veins) forms of venous disease. The effect size of this association therefore appears to be susceptible to influence by phenotypic heterogeneity, particularly if a cohort includes a large number of cases with lower severity CVD.

Rac1 Pharmacological Inhibition Rescues Human Endothelial Dysfunction.

BackgroundEndothelial dysfunction contributes significantly to the development of vascular diseases. However, a therapy able to reduce this derangement still needs to be identified. We evaluated the effects of pharmacological inhibition of Rac1, a small GTPase protein promoting oxidative stress, in human endothelial dysfunction.Methods and ResultsWe performed vascular reactivity studies to test the effects of NSC23766, a Rac1 inhibitor, on endothelium‐dependent vasorelaxation of saphenous vein segments collected from 85 subjects who had undergone surgery for venous insufficiency and from 11 patients who had undergone peripheral vascular surgery. The endothelium‐dependent vasorelaxation of the varicose segments of saphenous veins collected from patients with venous insufficiency was markedly impaired and was also significantly lower than that observed in control nonvaricose vein tracts from the same veins. Rac1 activity, reactive oxygen species levels, and reduced nicotine adenine dinucleotide phosphate (NADPH) oxidase activity were significantly increased in varicose veins, and NSC23766 was able to significantly improve endothelium‐dependent vasorelaxation of dysfunctional saphenous vein portions in a nitric oxide–dependent manner. These effects were paralleled by a significant reduction of NADPH oxidase activity and activation of endothelial nitric oxide synthase. Finally, we further corroborated this data by demonstrating that Rac1 inhibition significantly improves venous endothelial function and reduces NADPH oxidase activity in saphenous vein grafts harvested from patients with vascular diseases undergoing peripheral bypass surgery.ConclusionsRac1 pharmacological inhibition rescues endothelial function and reduces oxidative stress in dysfunctional veins. Rac1 inhibition may represent a potential therapeutic intervention to reduce human endothelial dysfunction and subsequently vascular diseases in various clinical settings.

Prevention of thromboembolic complications in patients with superficial-vein thrombosis given rivaroxaban or fondaparinux: the open-label, randomised, non-inferiority SURPRISE phase 3b trial

Superficial-vein thrombosis can lead to deep-vein thrombosis and pulmonary embolism. Rivaroxaban, an oral factor Xa inhibitor, might simplify treatment compared with fondaparinux because it does not require daily subcutaneous injection and is cheaper. We compared efficacy outcomes in patients with superficial-vein thrombosis and additional risk factors given either rivaroxaban or fondaparinux to assess whether rivaroxaban is non-inferior to fondaparinux in the prevention of thromboembolic complications. In this open-label, masked endpoint, randomised, non-inferiority phase 3b trial, we recruited patients aged 18 years or older with symptomatic superficial-vein thrombosis from 27 sites (academic, community hospitals, and specialist practices) in Germany. We randomly assigned patients (1:1) to receive 10 mg oral rivaroxaban or 2·5 mg subcutaneous fondaparinux once a day for 45 days. Patients were eligible if they had symptomatic thrombosis (at least 5 cm in a supragenual superficial-vein segment) and at least one additional risk factor (older than 65 years, male sex, previous venous thromboembolism, cancer, autoimmune disease, thrombosis of non-varicose veins). Main exclusion criteria were: symptoms for longer than 3 weeks, thrombus within 3 cm of the sapheno-femoral junction, indication for full-dose anticoagulation therapy, and substantial hepatic or renal impairment. Randomisation was done with a central block randomisation process. The primary efficacy outcome was a composite of symptomatic deep-vein thrombosis or pulmonary embolism, progression or recurrence of superficial vein-thrombosis, and all-cause mortality at 45 days in the per-protocol population (all randomly assigned patients without major protocol violations). We used a non-inferiority margin of 4·5% (absolute difference between rivaroxaban and fondaparinux). The main safety outcome was major bleeding. This study is registered with ClinicalTrials.gov, number NCT01499953. Between April 25, 2012, and Feb 18, 2016, 485 patients were enrolled in the study and 472 were randomly assigned to the rivaroxaban group (n=236) or the fondaparinux group (n=236). In the 435 patients included in the per-protocol analysis set, the primary efficacy outcome occurred in seven (3%) of 211 patients (95% CI 1·6-6·7) in the rivaroxaban group and in four (2%) of 224 patients (0·7-4·5) in the fondaparinux group (hazard ratio [HR] 1·9, 95% CI 0·6-6·4; p=0·0025 for non-inferiority) at day 45. There were no major bleeds in either group. There was one death in the rivaroxaban group; this patient died from cardiogenic shock on day 50 after a type A aortic dissection, not related to treatment. Rivaroxaban was non-inferior to fondaparinux for treatment of superficial-vein thrombosis in terms of symptomatic deep-vein thrombosis or pulmonary embolism, progression or recurrence of superficial vein-thrombosis, and all-cause mortality, and was not associated with more major bleeding. Therefore, rivaroxaban could offer patients with symptomatic superficial-vein thrombosis a less burdensome and less expensive oral treatment option instead of a more expensive subcutaneous injection. GWT-TUD and Bayer Vital.

Superficial vein thrombosis in non-varicose veins of the lower limbs and thrombophilia.

Objectives Superficial vein thrombosis in non-varicose veins of the lower limbs is rather frequent and may be underestimated. This study aims to evaluate the prevalence of inherited or acquired thrombophilia in a sample of outpatients with the disease. Method An observational study was conducted on 73 consecutive superficial vein thrombosis patients tested for inherited or acquired thrombophilia. Results Sixty of 73 patients with superficial vein thrombosis completed the testing protocol, while 13 dropped out; 46 of 60 patients were found to have a thrombophilia (76.6%). The types detected were: factor V Leiden (31/60, i.e. 51.6%), prothrombin mutation (2/60, i.e. 3.3%), MTHFR mutation (23/60, i.e. 38.3%), antiphospholipid antibodies (5/60, i.e. 8.3%), protein C deficit (1/60, i.e. 1.6%), protein S deficit (1/60, i.e. 1.6%), and antithrombin deficit (0/60, i.e. 0%). Conclusions Among patients with superficial vein thrombosis in non-varicose veins, testing demonstrated a high prevalence of thrombophilia. The most common form proved to be factor V Leiden. As thrombophilia was found to be a major cause of superficial vein thrombosis in non-varicose veins, the authors recommend that patients with superficial vein thrombosis in non-varicose veins be investigated for thrombophilia.

Rivaroxaban Versus Fondaparinux in the Treatment of Superficial Vein Thrombosis - the Surprise Trial

▪BackgroundThe current standard of therapy in superficial vein thrombosis (SVT) comprises subcutaneous injections of the indirect factorXainhibitorfondaparinuxfor up to 45 days, which was highlyeffectivecompared to placebo in the CALISTO trial. However,fondaparinuxis expensive, requires daily injections and cost-effectiveness in SVT therapy has been questioned. Rivaroxaban is a direct oral factorXainhibitor which has been shown to be effective in the prevention and treatment of venous thromboembolism (VTE). We hypothesizedthat SVT patientsat high risk for VTE complications may be treated as efficacious and safe with rivaroxaban as withfondaparinux.MethodsThe SURPRISE trial, a randomized, open-label blinded outcome event adjudication trial, compared rivaroxaban 10 mg once daily withfondaparinux2.5 mg once daily in patients with SVT at high risk of VTE complications (defined assupragenualSVT + age > 65 years, male sex, previous VTE, cancer, autoimmune disease or SVT of non-varicose veins). Treatment duration for both treatments was 45+5 days with an observational period until day 90+10. The primary efficacy outcome was a composite endpoint of deep vein thrombosis, pulmonary embolism, SVT progression towards thesaphenofemoraljunction, SVT recurrence or all cause death in the per-protocol analysis at day 45. A predefined sensitivity analysis was performed in all randomized patients (full analysis set). The primary safety outcome was the rate of ISTH major bleeding during treatment. Further outcome measures included the composite efficacy outcome up to day 90, each component of the primary efficacy outcome, rates of surgical treatment of SVT and rates of major VTE (composite of symptomatic PE or symptomatic proximal DVT or VTE-related death) at days 45 and 90. The trial was designed to test for non-inferiority of rivaroxaban compared tofondaparinuxwith respect to the primary efficacy outcome and to the rates of ISTH major bleeding.ResultsA total of 472 patients were randomized (mean age 60.3 years; 60.4% female) and treated with rivaroxaban (n=236) orfondaparinux(n=236). Mean treatment duration was 44.0 days for rivaroxaban and 44.8 days forfondaparinux. Until day 45+5, the primary efficacy outcome (n=435 in per-protocol analysis set) occurred in 3.3% (95%-CI 0.90; 5.73) of patients treated with rivaroxaban and 1.8% (95%-CI 0.05; 3.52) of patients receivingfondaparinux(absolute difference between rivaroxaban andfondaparinuxwas 1.53%; one-sided upper CI limit 4.03%; p-value for non-inferiority 0.025; table 1 and figure 1). Until day 90+10, the respective rates were 7.1% for rivaroxaban and 6.7% forfondaparinux(absolute difference 0.41;one-sided upper CI limit 4.41%;p-value for non-inferiority 0.047). Non-inferiority of rivaroxaban vs.fondaparinuxwas preserved in the full analysis set.No major bleeding occurred and rates of non-major, clinically relevant bleeding were 2.5 vs. 0.4% for day 45+5 and 2.5 vs. 0.9% for day 90+10 in safety set for rivaroxaban andfondaparinux, respectively (table 1).Mean±SDadherence (pill/syringe count at day 45) was 98.9±13.4% for rivaroxaban and 99.3±6.2% forfondaparinux(full analysis set).ConclusionsIn high-risk SVT patients, rivaroxaban was non-inferior tofondaparinuxin preventing thromboembolic complications with comparable safety. VTE events were predominantly SVT recurrence. Few cases of DVT and PE occurred, which indicates that a 45 days course of rivaroxaban 10 mg orfondaparinux2.5 mg is sufficient to prevent serious complications in this specific subset of SVT patients. As to whether oral rivaroxaban offers a better quality of life compared to 45 days of injections, this has to be investigated in future studies.We found higher SVT complications rates in both treatment arms compared to thefondaparinuxarm in the CALISTO trial. Therefore, patients at higher VTE risk can be identified by use of a simple risk factor assessment, which may help to improve cost-effectiveness of SVT therapy. However, the concept of SVT risk stratification needs to be further investigated, since patients without additional risk factors may not need anticoagulant therapy at all.(Funded by Bayer Vital GmbH, Germany, ClinicalTrials.gov NCT01499953)In response to a pre-submission enquiry, the New England Journal of Medicine indicated potential interest in the study results and a simultaneous publication/presentation is targeted. [Display omitted] [Display omitted] DisclosuresBeyer-Westendorf:Daichii Sankyo: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; LEO: Consultancy, Honoraria, Research Funding. Schellong:Bayer: Honoraria; Pfizer: Honoraria; Boehringer-Ingelheim: Honoraria; Daichii Sankyo: Honoraria; LeoPharma: Honoraria. Gerlach:ASPEN: Honoraria; Bayer: Honoraria; Boehringer-Ingelheim: Honoraria; LeoPharma.: Honoraria. Rabe:Bayer: Honoraria; Boehringer Ingelheim: Honoraria; Daichii-Sankyo: Honoraria; LeoPharma: Honoraria; Pfizer: Honoraria. Bauersachs:Bayer: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; BristolMyers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; ASPEN: Honoraria, Research Funding.

Benefit of anticoagulation for the treatment of lower extremity superficial venous thrombosis.

Superficial venous thrombosis (SVT) of the lower extremity is an acute disorder characterized by thrombosis and inflammation of superficial veins. This most commonly affects varicose veins but can also occur in patients with nonvaricose veins, who may have an underlying condition such as a malignant disease or thrombophilia. It is important to be aware that SVT confers a significant risk for the development of the more serious and debilitating condition of deep venous thrombosis and the potentially life-threatening condition of pulmonary embolism. Recognition of SVT, determination of appropriateness of therapy, and institution of timely therapy are paramount to prevention of deep venous thrombosis and pulmonary embolism in properly selected patients. The objective of this evidence-based summary was to provide clinically applicable information from the current literature and guidelines regarding the best treatment options for SVT. There are no randomized trials that compare the efficacy and outcomes of newer therapies, such as the novel oral anticoagulants and endovenous ablation, with traditional therapies, such as traditional anticoagulant and surgery exclusion, in the treatment of SVT.

Differential Metabolic Phenotype of Human Varicose Veins Tissue and Their Utility in Understanding Disease Pathogenesis and Identifying Potential Prognostic Biomarkers.

Human metabolic phenotype reflects the genetic and environmental perturbations, both of which predispose to the development of varicose veins (VV). It is considered core to understanding disease pathogenesis, and identification of biomarkers and targets for preventative and therapeutic strategies. This study aims to investigate the key metabolic differences between human varicose and non-varicose veins (non-VV).

Diagnosis and treatment of superficial vein thrombosis

Superficial vein thrombosis (SVT) is a common disease, characterized by an inflammatory-thrombotic process in a superficial vein. Typical clinical findings are pain and a warm, tender, reddish cord along the vein. Until recently, no reliable epidemiological data were available. The incidence is estimated to be higher than that of deep-vein thrombosis (DVT) (1/1000). SVT shares many risk factors with DVT, but affects twice as many women than men and frequently occurs in varicose veins. Clinically, SVT extension is commonly underestimated, and patients may have asymptomatic DVT. Therefore, ultrasound assessment and exclusion of DVT is essential. Risk factors for concomitant DVT are recent hospitalization, immobilization, autoimmune disorders, age > 75 years, prior VTE, cancer and SVT in non-varicose veins. Even though most patients with isolated SVT (without concomitant DVT or PE) are commonly treated with anticoagulation for a median of 15 days, about 8% experience symptomatic thromboembolic complications within three months. Risk factors for occurrence of complications are male gender, history of VTE, cancer, SVT in a non-varicose vein or SVT involving the sapheno-femoral junction (SFJ). As evidence supporting treatment of isolated SVT was sparse and of poor quality, the large, randomized, double-blind, placebo-controlled CALISTO trial was initiated assessing the effect of fondaparinux on symptomatic outcomes in isolated SVT. This study showed that, compared with placebo, 2.5 mg fondaparinux given for 45 days reduced the risk of symptomatic thromboembolic complications by 85% without increasing bleeding. Based on CALISTO and other observational studies, evidence-based recommendations can be made for the majority of SVT patients. Further studies can now be performed in higher risk patients to address unresolved issues.

Measurements of Calf Muscle Oxygenation during Standing and Exercise in Patients with Chronic Venous Insufficiency

Background: Varicose vein tissues have been shown to have differential metabolic profiles as compared with non-varicose veins, suggesting a metabolic component of the disease. Vein wall stretch has been suggested as a potential etiological factor in the development of varicose veins. However, the relation between vein wall stretch and the metabolic profile of the vein wall is unclear. The aim of the study was to determine whether vein wall stretch alters the metabolic profile of the vein wall. Methods: Segments of male rat inferior vena cava (IVC) were suspended in tissue bath under 0.5 g basal tension for 1 hour, and a control contraction to phenylephrine (PHE, 10 5 M) and KCl (96 mM) was elicited. The veins were then exposed to normal 0.5 g or high 2 g tension for short 4 or prolonged 18 hours (five vein segments in each group). The veins were frozen, then hydrophilic and organic metabolites were extracted using a bilayer extraction method. Aqueous and organic extracts obtained from stretched (2 g tension) and non-stretched (0.5 g basal tension) IVC segments were run on 1-dimensional H Nuclear Magnetic Resonance (NMR) spectroscopy (800 MHz) and liquid-chromatography coupled to Mass Spectrometry (LC-MS) LCT QTOF premier (Waters Corporation, Milford, MA), respectively. Spectra acquired from NMR and chromatograms from LC-MS were mathematically modelled and statistically analysed using multivariate statistical models including MATLAB (Mathworks ) and SIMPCA-P + 12.0 (UMETRICS Sweden). 2-Dimensional NMR and tandem MS experiments were performed on selected samples for structural elucidation of molecules. Results: H NMR spectra of aqueous extracts of stretched and nonstretched veins for 4 hrs revealed the presence of several metabolites including leucine, isoleucine, valine, creatine, myo-inositol, choline, glucose, and aspartate. There was no significant difference in aqueous or lipid metabolic profiles of non-stretched and stretched IVC segments for 4 hours. Univariate analysis revealed increased concentrations of leucine, isoleucine, and valine metabolites in IVC segments stretched as compared with nonstretched for 18 hours (P value range, 0.01-0.004). Orthogonal partial least square-discriminatory (OPLS-DA) identified triglycerides moieties as a differentiating markers and were present in higher concentrations in stretched segments as compared with non-stretched vein segments for 18 hours (P value range, 0.01-0.003). Conclusions: We have shown, for the first time, a complete metabolic profile of aqueous and organic extracts from rat veins subjected to normal (0.5 g) and high (2 g) mechanical stretch. Elucidation of cellular pathways linked to these differential metabolites may disclose cellular mechanisms affected by stretch and may improve our understanding about varicose vein disease.

Prolonged Mechanical Stretch Alters the Metabolic Profile in Rat Inferior Vena Cava

Varicose vein tissues have been shown to have differential metabolic profiles as compared with non-varicose veins, suggesting a metabolic component of the disease. Vein wall stretch has been suggested as a potential etiological factor in the development of varicose veins. However, the relation between vein wall stretch and the metabolic profile of the vein wall is unclear. The aim of the study was to determine whether vein wall stretch alters the metabolic profile of the vein wall.

Impact of Anatomical Location of Lower Limb Venous Thrombus On the Risk of Subsequent Cancer

AbstractAbstract 630 Background:Cancer constitutes a strong risk factor for proximal deep-vein thrombosis (DVT). After a proximal DVT, the risk of being diagnosed a previously undiagnosed cancer in the following years is high. This has justified a cancer screening in this situation, the optimal modalities of which (extensive vs. limited screening) are currently under evaluation. However, little is known on the risk of subsequent cancer in case of symptomatic isolated distal DVT (e.g. infra-popliteal DVT without PE) and symptomatic isolated superficial vein thrombosis (SVT) (e.g. without concomitant DVT and PE). The value of cancer screening is therefore debated in these situations. Yet, each of those two other clinical expressions of venous thromboembolic disease (VTE) in the lower limbs is at least as frequent as proximal DVT. Objective:As compared with patients with a first episode of symptomatic isolated proximal DVT (e.g. without PE), we aim assessing the risk of subsequent cancer in patients with a first isolated distal DVT or with a first isolated SVT. A secondary objective was to assess the influence of anatomical characteristics of distal DVT and SVT (deep calf DVT vs. muscular DVT and SVT on varicose vein vs. SVT on non-varicose vein) on the risk of subsequent cancer. Methods:We analysed the data from the OPTIMEV prospective, observational, multicenter study of consecutive in and outpatients recruited after an objectively confirmed symptomatic VTE and followed up three years. All VTE events were diagnosed via a standardized bilateral whole leg compression ultrasonographic protocol screening the entire deep and superficial venous networks. Results:327 patients with a proximal DVT, 536 with a distal DVT, and 329 with an SVT fulfilled our study’s inclusion criteria. 2.9% (n=35) of patients were lost to follow-up before 3 years. At 3 years cumulative rates of cancer were similar whatever the kind of VTE considered (Figure 1). Incidence of subsequent cancer was respectively of 3.9% [2.2 – 6.1] in case of proximal DVT, 4.1% (95% CI [2.7 – 6.1]) in case of distal DVT and 3.1% [1.7 – 5.7] in case of isolated SVT.Neither anatomical characteristics of distal DVT (cumulative rates of subsequent cancer 4.2% [2.3 – 7.4] in case of muscular DVT, 3.7% [1.6 – 8.6] in case of deep calf DVT and 4.3% [1.8 – 9.9] in case of combined muscular and deep calf DVT, p=0.98) nor anatomical characteristics of SVT (cumulative rates of subsequent cancer 1.9% [0.5 – 7.2] in case of SVT on non-varicose vein and 3.4% [1.9 – 7.4] in case of SVT on varicose vein, p=0.4) significantly influenced the risk of subsequent cancer. Main strengths/limitations:This is the largest prospective observational cohort of in and out patients with an objectively confirmed isolated SVT or isolated distal DVT, managed in routine practice, and with a long-term follow-up. Our results only apply to first episodes of isolated SVT or distal DVT. As compared with previous reports on the risk of subsequent cancer in case of VTE, our population of DVT/SVT patients was at low risk of cancer a priori. Indeed, we only included first episodes of VTE, most of which were diagnosed and managed in an outpatient setting and/or were associated with a transient risk factor. Therefore the number of newly diagnosed cancer was limited and we may have lacked statistical power for some sub-group analyses. However our rate of subsequent cancer in proximal DVT patients was in the range of that from recent studies and significantly higher than the expected rate of cancer in the French general population of the same age. Conclusion:In patients managed in routine practice without previous history of cancer or VTE, every clinical expression of lower limb VTE (proximal DVT, distal DVT and SVT) is associated with a similar risk of subsequent cancer. Anatomical characteristics of distal DVT and SVT do not seem to have a strong impact on this risk. These results suggest that cancer screening should not be modulated according to the deep-proximal, deep-distal or superficial location of lower limb thrombosis. [Display omitted] Cumulative rates of subsequent cancer according to the proximal, distal or superficial location of VTE were estimated with the Kaplan-Meier method and compared with logrank test. Disclosures:No relevant conflicts of interest to declare.