Epidemiology and Genetics of Venous Thromboembolism and Chronic Venous Disease.

Venous disease is a term that broadly covers both venous thromboembolic disease and chronic venous disease. The basic pathophysiology of venous thromboembolism and chronic venous disease differ as venous thromboembolism results from an imbalance of hemostasis and thrombosis while chronic venous disease occurs in the setting of tissue damage because of prolonged venous hypertension. Both diseases are common and account for significant mortality and morbidity, respectively, and collectively make up a large health care burden. Despite both diseases having well-characterized environmental components, it has been known for decades that family history is an important risk factor, implicating a genetic element to a patient's risk. Our understanding of the pathogenesis of these diseases has greatly benefited from an expansion of population genetic studies from pioneering familial studies to large genome-wide association studies; we now have multiple risk loci for each venous disease. In this review, we will highlight the current state of knowledge on the epidemiology and genetics of venous thromboembolism and chronic venous disease and directions for future research.

Incentivizing physical activity through activity monitoring interventions in PAD - a pilot study.

Background: There is ample evidence to show that supervised exercise is efficacious and cost effective for improving claudication symptoms in patients with peripheral artery disease (PAD). Home based exercise therapy can be an effective alternative to supervised exercise however, the results of this is variable depending on the level of motivation and engagement of the patient. Patients and methods: We performed a pilot study in 41 patients to determine whether a home based exercise program with the use of an activity tracking device with personalized feedback and financial incentives can increase daily activity, improve walking and sustain engagement in the exercise regimen in patients with PAD. In this randomized pilot study, the patients in the study group were fitted with an activity monitoring device and given behavioral monitoring, motivational updates and feedback regarding their exercise program. This study group was further divided in to two groups. One half of these patients in the study group were also given financial incentives if they reached their set targets. The control group wore the device with no feedback or ability to see their number of steps walked. Results: Results showed that at the end of the 12 week period, patients in the study groups walked more compared to the controls and the financial incentive structure resulted in an additional 38-63% increase in average daily steps. Conclusions: This pilot study revealed that a home-based exercise program with activity monitoring, feedback and financial incentives resulted increased daily steps, 6-minute walking distance and overall compliance with the program in PAD patients with claudication.

Er:YAG laser vs. sharp debridement in management of chronic wounds: Effects on pain and bacterial load.

Chronic wounds affect roughly 6.5 million patients in the US annually. Current standard of therapy entails weekly sharp debridement. However, the sharp technique is associated with significant pain, while having minimal impact on the bioburden. Our study proposes the Er:YAG laser as an alternative method of debridement that may decrease procedural pain, reduce bioburden, and potentially improve overall healing. This pilot study was performed as a prospective, randomized, controlled, crossover clinical trial, containing two groups: (1) one group underwent single laser debridement session first, followed by single sharp debridement session one week later; and (2) the other group underwent single sharp debridement session first, followed by single laser debridement session one week later. Variables analyzed included pain during debridement, pre- and post-debridement wound sizes, pre- and post-debridement bacterial loads and patient preference. Twenty-two patients were enrolled (12 patients in Group 1, plus 10 patients in Group 2). The mean pain score for patients undergoing laser debridement was 3.0 ± 1.7 vs. 4.8 ± 2.6 for those undergoing sharp debridement (p = 0.003). The mean percent change in wound size 1-week post-laser debridement was -20.8% ± 80.1%, as compared with -36.7% ± 54.3% 1-week post-sharp debridement (p = 0.6). The percentage of patients who had a bacterial load in the low/negative category increased from 27.3% to 59.1% immediately after laser debridement (p = 0.04), vs. 54.5% to 68.2% immediately after sharp debridement (p = 0.38). Moreover, there was a sustained decrease in bacterial load 1-week post-laser debridement, as compared with no sustained decrease 1-week post-sharp debridement (p < 0.02). Overall, 52.9% of patients preferred laser debridement vs. 35.3% for sharp debridement. We believe that Er:YAG laser serves as a promising technology in chronic wounds, functioning as a potentially superior alternative to sharp debridement, the current standard of therapy.

Clinical and Genetic Determinants of Varicose Veins.

BACKGROUND: Varicose veins are a common problem with no approved medical therapies. Although it is believed that varicose vein pathogenesis is multifactorial, there is limited understanding of the genetic and environmental factors that contribute to their formation. Large-scale studies of risk factors for varicose veins may highlight important aspects of pathophysiology and identify groups at increased risk for disease. METHODS: We applied machine learning to agnostically search for risk factors of varicose veins in 493 519 individuals in the UK Biobank. Predictors were further studied with univariable and multivariable Cox regression analyses (2441 incident events). A genome-wide association study of varicose veins was also performed among 337 536 unrelated individuals (9577 cases) of white British descent, followed by expression quantitative loci and pathway analyses. Because height emerged as a new candidate risk factor, we performed mendelian randomization analyses to assess a potential causal role for height in varicose vein development. RESULTS: Machine learning confirmed several known (age, sex, obesity, pregnancy, history of deep vein thrombosis) and identified several new risk factors for varicose vein disease, including height. After adjustment for traditional risk factors in Cox regression, greater height remained independently associated with varicose veins (hazard ratio for upper versus lower quartile, 1.74; 95% CI, 1.51-2.01; P<0.0001). A genome-wide association study identified 30 new genome-wide significant loci, identifying pathways involved in vascular development and skeletal/limb biology. Mendelian randomization analysis provided evidence that increased height is causally related to varicose veins (inverse-variance weighted: odds ratio, 1.26; P=2.07×10-16). CONCLUSIONS: Using data from nearly a half-million individuals, we present a comprehensive genetic and epidemiological study of varicose veins. We identified novel clinical and genetic risk factors that provide pathophysiological insights and could help future improvements of treatment of varicose vein disease.

A systematic review on ablation techniques for larger saphenous veins in patients with symptomatic superficial venous disease.

OBJECTIVE: The aim of this study was to summarize the existing evidence for the treatment of saphenous veins >10 mm in diameter, to determine whether there were vein size limits for treatment modalities, and to determine if there are specific technical considerations for treatment of large veins. METHODS: We searched the literature for reports of treatment methods and outcomes for patients with large-diameter saphenous veins treated with various ablation methods between 1993 and 2023. These studies were evaluated for the size of the vein determined as "large diameter," type of ablation method, study type, outcomes, adverse events, and any technical considerations noted. A systematic review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. The COVIDENCE software was used for full-text screening and data extraction. Three reviewers reviewed the data, and the content expert served as the tiebreaker. RESULTS: Seventy-one records were identified, of which 24 studies were deemed appropriate for extraction. Most of the studies identified reported outcomes of endovenous thermal ablation modalities. There were fewer studies on non-thermal, non-tumescent techniques, and these studies reported an overall lower occlusion rate compared with endovenous thermal ablation techniques. CONCLUSIONS: Large head-to-head trials or randomized controlled that compare all the modalities over a long follow-up duration are yet to be performed. In the existing literature, there is considerable heterogeneity in terms of the study size, design, definition of large veins, site of vein measurement, and follow-up periods, making it challenging to make fair comparisons and draw firm conclusions. Currently available evidence supports the use of endothermal ablation techniques for the treatment of veins >10 mm in diameter as they have a more favorable efficacy and safety profile and have a larger body of evidence available compared with non-thermal, non-tumescent techniques or surgery.

A comparison of below-knee vs above-knee endovenous ablation of varicose veins.

OBJECTIVE: Varicose veins have a significant impact on quality of life and can commonly occur in the thigh and calves. However, there has been no large-scale investigation examining the relationship between anatomic distribution and outcomes after varicose vein treatment. This study sought to compare below-the-knee (BTK) and above-the-knee (ATK) varicose vein treatment outcomes. METHODS: Employing the Vascular Quality Initiative Varicose Vein Registry, 13,731 patients undergoing varicose vein ablation for either BTK or ATK lesions were identified. Outcomes were assessed using patient-reported outcomes (PROs) and the Venous Clinical Severity Score (VCSS). Continuous variables were compared using the t-test, and categorical variables were analyzed using the χ2 test. Multivariable logistic regression was used to estimate the odds of improvement after intervention. The multivariable model controlled for age, gender, race, preoperative VCSS composite score, and history of deep vein thrombosis. RESULTS: Patients who received below-knee treatment had a lower preoperative VCSS composite (7.0 ± 3.3 vs 7.7 ± 3.3; P < .001) and lower PROs composite scores (11.1 ± 6.4 vs 13.0 ± 6.6; P < .001) compared with those of patients receiving above-knee treatment. However, on follow-up, patients receiving below-knee intervention had a higher postoperative VCSS composite score (4.4 ± 3.3 vs 3.9 ± 3.5; P < .001) and PROs composite score (6.1 ± 4.4 vs 5.8 ± 4.5; P = .007), the latter approaching statistical significance. Patients receiving above-knee interventions also demonstrated more improvement in both composite VCSS (3.8 ± 4.0 vs 2.9 ± 3.7; P < .001) and PROs (7.1 ± 6.8 vs 4.8 ± 6.6; P < .001). Multivariable logistic regression analysis similarly revealed that patients receiving above-knee treatment had significantly higher odds of improvement in VCSS composite in both the unadjusted (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.28-1.65; P < .001 and adjusted (OR, 1.31; 95% CI, 1.14-1.50; P < .001) models. Patients receiving above-knee treatment also had a significantly higher odds of reporting improvement in PROs composite in both the unadjusted (OR, 1.85; 95% CI, 1.64-2.11; P < .001) and adjusted (OR, 1.65; 95% CI, 1.45-1.88; P < .001) models. CONCLUSIONS: Treatment region has a significant association with PROs and VCSS composite scores after varicose vein interventions. Preoperatively, there were significant differences in the composite scores of VCSS and PROs with patients receiving BTK treatment exhibiting less severe symptoms. Yet, the association appeared to reverse postoperatively, with those receiving BTK treatments exhibiting worse PROs, worse VCSS composites scores, and less improvement in VCSS composite scores. Therefore, BTK interventions pose a unique challenge compared with ATK interventions in ensuring commensurate clinical improvement after treatment.

Variations and inconsistencies in venous ablation coverage policies between single-state and multistate carriers in the United States.

BACKGROUND: Vein ablation is a common and effective treatment for patients with chronic venous insufficiency. The overuse of vein ablation despite the existence of evidence-based guidelines has resulted in insurance companies developing restrictive policies for coverage that create barriers to appropriate care. This study compares the insurance coverage by single-state carriers (SSCs) and multistate carriers (MSCs), highlighting the variations and inconsistencies in the various policies. METHODS: The American Venous Forum Venous Policy Navigator was reviewed for the various policies available in the United States. The policies were divided into SSCs and MSCs. The characteristics of the policies, including the anatomic and hemodynamic criteria for specific veins, duration of conservative treatment, disease severity, symptoms, and types of procedures covered, were compared between the two groups. SAS, version 9.4 (SAS Institute Inc) was used for statistical analysis. RESULTS: A total of 122 policies were analyzed and divided between SSCs (n = 85; 69.7%) and MSCs (n = 37; 30.3%). A significant variation was found in the size requirement for great saphenous vein ablation. Although 48% of the policies did not specify a size criterion, the remaining policies indicated a minimal size, ranging from 3 to 5.5 mm. However, no significant differences were found between SSCs and MSCs. Similar findings were encountered for the small and anterior accessory saphenous veins. MSCs were more likely to define a saphenous reflux time >500 ms compared with SSCs (81.1% vs 58.8%; P = .04). A significant difference was found between the SSCs and MSCs in the criteria for perforator ablation in terms of size and reflux time. MSCs were significantly more likely to provide coverage for mechanochemical ablation than were SSCs (24.3% vs 8.2%; P = .03). SSCs were more likely to require ≥12 weeks of compression stocking therapy than were MSCs (76.5% vs 48.7%; P = .01). No significant differences were found in the clinical indications between the two groups; however, MSCs were more likely to mention major hemorrhage than were SSCs. CONCLUSIONS: The results of this study highlight the variations in policies for venous ablation, in particular, the striking inconsistencies in size criteria. MSCs were more likely to cover mechanochemical ablation and require a shorter duration of conservative therapy before intervention compared with SSCs. Evidence-based guidance is needed to develop more coherent policies for venous ablation coverage.

Serious Adverse Events with Cyanoacrylate Closure of Varicose Veins: An Initial Report from a Large-Scale National Survey in Japan.

Objective: Cyanoacrylate closure (CAC) is a minimally invasive technique for the treatment of varicose veins. A recent paper reported serious adverse events (AEs) associated with this use. This triggered an urgent survey to determine the incidence of AEs in Japan. Methods: The CAC-AE survey was sent to all 1,030 institutions authorized for CAC treatments. Cases performed between January 2020 and October 2023 were surveyed. Data on serious AEs and mortality were collected. Results: There were 623 surveys returned. There were 16 cases of proximal deep vein thrombosis, 3 cases of pulmonary embolism (PE), and 0 cases of stroke. Deep vein occlusion due to cyanoacrylate extension was observed in 1 case. Vein resection due to infection was observed in 4 cases. There were 299 cases of localized phlebitis and/or allergic reactions requiring steroid administration. Systemic allergic reactions requiring steroid administration were observed in 66 cases. There was no anaphylaxis associated with cyanoacrylate. There was one postoperative death from PE. Conclusion: This report's intent is to provide real world data on serious AEs following CAC from Japan given current concern over these events. An extensive report investigation of individual complications with analysis including causality will be provided following a full investigation separately.

Generation of two iPSC lines from vascular Ehlers-Danlos Syndrome (vEDS) patients carrying a missense mutation in COL3A1 gene.

Vascular Ehlers-Danlos Syndrome (vEDS) is an inherited connective tissue disorder caused by COL3A1 gene, mutations that encodes type III collagen, a crucial component of blood vessels. vEDS can be life-threatening as these patients can have severe internal bleeding due to arterial rupture. Here, we generated induced pluripotent stem cell (iPSC) lines from two vEDS patients carrying a missense mutation in the COL3A1 (c.226A > G, p.Asn76Asp) gene. These lines exhibited typical iPSC characteristics including morphology, expression of pluripotency markers, and could differentiate to all three germ layer. These iPSC lines can serve as valuable tools for elucidating the pathophysiology underlying vEDS.

Generation of induced pluripotent stem cell line from a patient suffering from arterial calcification due to deficiency of CD73 (ACDC).

Arterial calcification due to deficiency of CD73 (ACDC) is an adult onset, rare genetic vascular disorder signified by calcium deposition in lower extremity arteries and joints of hands and feet. Mutations in NT5E gene has been shown to be responsible for the inactivation of enzyme CD73 causing calcium buildup. Here, we report a iPSC line generated from a patient showing signs of ACDC and carrying a missense mutation in NT5E (c.1126A→G,p.T376A) gene. This iPSC line shows normal morphology, pluripotency, karyotype, and capability to differentiate into three germ layers, making it useful for disease modeling and investigating pathological mechanisms of ACDC.

Factors associated with lack of clinical improvement after vein ablation in the vascular quality initiative.

BACKGROUND: Insurance companies have adopted variable and inconsistent approval criteria for chronic venous disease (CVD) treatment. Although vein ablation (VA) is accepted as the standard of care for venous ulcers, the treatment criteria for patients with milder forms of CVD remain controversial. This study aims to identify factors associated with a lack of clinical improvement (LCI) in patients with less severe CVD without ulceration undergoing VA to improve patient selection for treatment. METHODS: We performed a retrospective analysis of patients undergoing VA for CEAP C2 to C4 disease in the Vascular Quality Initiative varicose veins database from 2014 to 2023. Patients who required intervention in multiple veins, had undergone prior interventions, or presented with CEAP C5 to C6 disease were excluded. The difference (Δ) in venous clinical severity score (VCSS; VCSS before minus after the procedure) was used to categorize the patients. Patients with a ΔVCSS of ≤0 were defined as having LCI after VA, and patients with ≥1 point decrease in the VCSS after VA (ΔVCSS ≥1) as having some benefit from the procedure and, therefore, "clinical improvement." The characteristics of both groups were compared, and multivariable regression analysis was performed to identify factors independently associated with LCI. A second analysis was performed based on the VVSymQ instrument, which measures patient-reported outcomes using five specific symptoms (ie, heaviness, achiness, swelling, throbbing pain, and itching). Patients with LCI showed no improvement in any of the five symptoms, and those with clinical improvement had a decrease in severity of at least one symptom. RESULTS: A total of 3544 patients underwent initial treatment of CVD with a single VA. Of the 3544 patients, 2607 had VCSSs available before and after VA, and 420 (16.1%) had LCI based on the ΔVCSS. Patients with LCI were more likely to be significantly older and African American and have CEAP C2 disease compared with patients with clinical improvement. Patients with clinical improvement were more likely to have reported using compression stockings before treatment. The vein diameters were not different between the two groups. The incidence of complications was overall low, with minor differences between the two groups. However, the patients with LCI were significantly more likely to have symptoms after intervention than those with improvement. Patients with LCI were more likely to have technical failure, defined as vein recanalization. On multivariable regression, age (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00-1.02) and obesity (OR, 1.47; 95% CI, 1.09-2.00) were independently associated with LCI, as was treatment of less severe disease (CEAP C2; OR, 1.82; 95% CI, 1.30-2.56) compared with more advanced disease (C4). The lack of compression therapy before intervention was also associated with LCI (OR, 6.05; 95% CI, 4.30-8.56). The analysis based on the VVSymQ showed similar results. CONCLUSIONS: LCI after VA is associated with treating patients with a lower CEAP class (C2 vs C4) and a lack of compression therapy before intervention. Importantly, no significant association between vein size and clinical improvement was observed.

The 2023 Society for Vascular Surgery, American Venous Forum, and American Vein and Lymphatic Society clinical practice guidelines for the management of varicose veins of the lower extremities. Part II: Endorsed by the Society of Interventional Radiology and the Society for Vascular Medicine.

The Society for Vascular Surgery, the American Venous Forum, and the American Vein and Lymphatic Society recently published Part I of the 2022 clinical practice guidelines on varicose veins. Recommendations were based on the latest scientific evidence researched following an independent systematic review and meta-analysis of five critical issues affecting the management of patients with lower extremity varicose veins, using the patients, interventions, comparators, and outcome system to answer critical questions. Part I discussed the role of duplex ultrasound scanning in the evaluation of varicose veins and treatment of superficial truncal reflux. Part II focuses on evidence supporting the prevention and management of varicose vein patients with compression, on treatment with drugs and nutritional supplements, on evaluation and treatment of varicose tributaries, on superficial venous aneurysms, and on the management of complications of varicose veins and their treatment. All guidelines were based on systematic reviews, and they were graded according to the level of evidence and the strength of recommendations, using the GRADE method. All ungraded Consensus Statements were supported by an extensive literature review and the unanimous agreement of an expert, multidisciplinary panel. Ungraded Good Practice Statements are recommendations that are supported only by indirect evidence. The topic, however, is usually noncontroversial and agreed upon by most stakeholders. The Implementation Remarks contain technical information that supports the implementation of specific recommendations. This comprehensive document includes a list of all recommendations (Parts I-II), ungraded consensus statements, implementation remarks, and best practice statements to aid practitioners with appropriate, up-to-date management of patients with lower extremity varicose veins.

Approach to diagnosing lower extremity ulcers.

Chronic leg ulcers (as differentiated from wound of the foot) are most often due to venous disease, arterial insufficiency (peripheral arterial disease), or a combination of both. Treatment modalities vary depending on the etiology of the ulcer, so it is important to make an appropriate diagnosis of the wound. Like for most medical illnesses, the determination of the etiology of these wounds is based on history, physical examination, and testing.

Varicose Veins: Approach, Assessment, and Management to the Patient with Chronic Venous Disease.

Varicose veins are tortuous and dilated veins commonly seen in chronic venous disease. This article will review chronic venous disease, including its differential diagnosis, workup, and treatment.

Characteristics of venous leg ulcer patients at a tertiary wound care center.

OBJECTIVE: The objective of this study was to assess patient, wound, care, and reflux characteristics of venous leg ulcers (VLUs) to update and improve knowledge of disease etiology, identify barriers to healing, and improve treatment. METHODS: Patients diagnosed with VLUs treated at the Stanford Advanced Wound Care Center between 2018 and 2019 were identified from the Healogics iHeal database. We identified 327 VLU entries, of which 133 were patients who had multiple or recurring wounds. An additional 27 patients were labeled as misdiagnosis, resulting in a final patient sample of 167. Patient demographics, wound, care, and ultrasound data for these patients were extracted from the Stanford electronic medical records regarding characteristics. The initial data analysis suggested possible differences in VLU characteristics depending on patient age and body mass index (BMI), which was then further analyzed. RESULTS: Of the 167 VLU patients assessed, 53.9% were male and 46.1% were female. The mean age was 74.7 years, and the average BMI was 30.2 kg/m2, including 41.1% of patients with a BMI over 30 kg/m2. Approximately 50% of wounds were presented in multiples, had cellulitis, or were recurring, and 39.5% were caused by trauma. Most common venous reflux patterns on duplex ultrasound examination were below-knee great saphenous vein reflux and calf perforator reflux, which was identified in 37.7% and 29.3% of the patients, respectively. Axial great saphenous vein reflux was detected in 14.4% of patients. When looking at the patient sample under 60 years of age, 67.7% were male, 61.3% presented with venous skin changes, and 51.6% had diabetes. In the patients older than 60, only 51.9% were male, 37.6% presented with venous skin changes, and 31.6% had diabetes. BMI was greater in the patients under age 60, with an average of 39.2 kg/m2, compared with 28.2 kg/m2 in those above 60. Of the patients with a BMI ≥30 kg/m2, 64.3% had multiple wounds, 61.4% had recurring wounds, and 56.5% had venous skin changes. In contrast, in patients with BMI <30 kg/m2, 47.4% had multiple wounds, 39.2% had recurring wounds, and 32.0% had venous skin changes. CONCLUSIONS: VLU pathology appears to differ depending on patient demographics and characteristics. Different drivers may influence disease cause, progression, and prognosis, making a standard approach to VLUs difficult. Our findings suggest that identifying different subtypes of VLUs and adapting an algorithm of care with a personalized treatment may help optimize management of these patients.