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Phlebectomy of large voluminous varicose veins comes with a risk of substantial blood loss. The purpose of the present study was to investigate the outcomes associated with the use of an adjunct tourniquet during varicose vein surgery of complex and large truncular varicosities.The prospectively collected registry data included anatomic and outcomes details for patients who presented with complex and large truncular varicosities with a CEAP clinical class of C2, or higher (indicating more serious venous disease) from December 2014 to December 2021. Of all patients, those treated with an adjunct tourniquet for large complex varicosities (largest diameter varicosity ≥1 cm by visual inspection) were selected for analysis. The venous clinical severity scores (VCSSs) and patient-reported outcomes (PROs) were obtained. Additional parameters, including operative time, tourniquet time, and blood loss, were obtained retrospectively via a review of the medical records. Univariate descriptive statistics of the demographic and procedural data were performed pre- and postoperatively, with comparisons performed using the Student two-tailed t test.The data from 19 patients (22 limbs; 7 women and 12 men) were analyzed. Of the 22 limbs, 11 (50%) had advanced venous disease of C4 or higher preoperatively. A review of the preoperative duplex ultrasound scans confirmed the presence of large varicosities (average, 1.0 ± 0.54 cm; n = 18). All the limbs were treated using radiofrequency ablation of axial reflux and phlebectomy (a combination of powered and stab) under tourniquet control (82%) or phlebectomy under tourniquet control alone (18%). The average tourniquet time was 40 ± 12 minutes, with a median blood loss of 50 mL (interquartile range, 30-100 mL). The average follow-up was 332 ± 422 days after 19 procedures for 16 patients (2 patients moved out of state during the immediate postoperative period and 1 patient was lost to follow-up). Of the patients who completed3 months of follow-up, 14 limbs experienced improvement in the CEAP class, 5 limbs had no change, and 3 were limbs of patients who moved or were lost to follow-up. The VCSSs significantly improved (8.8 ± 2.8 vs 3.9 ± 1.9; P .0001). The PROs also improved significantly (16.1 ± 5.0 vs 2.2 ± 2.3; P .0001).Tourniquet use in the treatment of varicosities has only been described in the setting of high ligation and stripping. Our data suggest that in the modern era of minimally invasive endovenous treatment of axial reflux and phlebectomy, adjunct tourniquet use during the treatment of large complex varicosities can result in significant improvements in the VCSSs and PROs, with minimal blood loss.

Background This study evaluated E-selectin inhibition with GMI-1271 (Uproleselan [GMI]) alone and in combination with the standard of care low-molecular-weight heparin (LMWH) to improve vein recanalization, decrease vein wall inflammation and protect against adverse bleeding in a primate model. We sought to examine this novel treatment of venous thrombosis. Methods Using a well-documented primate animal model, iliac vein thrombosis was induced by balloon occlusion of the iliac vein for 6 hours. Starting on day 2 after thrombosis, animals began treatment in two phases. In phase one, nontreated controls received no treatment (n = 5) vs animals treated with the E-selectin inhibitor GMI, 25 mg/kg, subcutaneous (SC), once daily (n = 4) for 21 days (previously published data). In phase two, animals were treated with GMI plus a combination of LMWH 1.5 mg/kg or 40 mg (GMI + LMWHc) SC once daily (n = 8) for 19 days; and animals treated with LMWH 1.5 mg/kg or 40 mg (LMWHc) SC once daily (n = 6) for 19 days. Animals were evaluated by magnetic resonance venography for vein recanalization and inflammation by gadolinium extravasation, duplex ultrasound, coagulation tests (thromboelastography, bleeding time, prothrombin time, activated partial thromboplastin time, fibrinogen) and complete blood count at baseline, days 2, 7, 14, and 21 at euthanasia. Statistical analysis included using unpaired t test with Welch's correction for direct comparisons and one-way analysis of variance for comparison between the groups. Results Percent vein recanalization by magnetic resonance venography was highest in the GMI alone group followed by GMI + LMWHc, both significantly different from control. On ultrasound examination, animals treated with GMI alone had no decrease in open vein lumen by day 21, whereas decreases were observed in groups GMI + LMWHc (–26%), LMWHc (–27%), and controls (–80%). Vein wall inflammation decreased significantly in all treated groups. Intimal fibrosis and intimal thickness was best preserved in the GMI alone group. An analysis of total vein wall collagen revealed a trend in all treatment groups of decreasing vein wall collagen. No clinically significant bleeding events were noted in any group. The LMWH groups trended to have prolonged coagulation test values, whereas E-selectin inhibition with GMI did not cause clinically significant changes in coagulation measures. Conclusions Treatment with E-selectin inhibition results in improved vein recanalization, a decrease in vein wall inflammation and vein wall intimal thickness and fibrosis, with no changes in markers of coagulation. E-selectin inhibition with GMI alone is superior to E-selectin inhibition combined with LMWH, LMWH alone, and no treatment in this deep vein thrombosis model of iliac vein thrombosis.

Coronavirus-associated coagulopathy (CAC) is a morbid and lethal sequela of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. CAC results from a perturbed balance between coagulation and fibrinolysis and occurs in conjunction with exaggerated activation of monocytes/macrophages (MO/Mφs), and the mechanisms that collectively govern this phenotype seen in CAC remain unclear. Here, using experimental models that use the murine betacoronavirus MHVA59, a well-established model of SARS-CoV-2 infection, we identify that the histone methyltransferase mixed lineage leukemia 1 (MLL1/KMT2A) is an important regulator of MO/Mφ expression of procoagulant and profibrinolytic factors such as tissue factor (F3; TF), urokinase (PLAU), and urokinase receptor (PLAUR) (herein, “coagulopathy-related factors”) in noninfected and infected cells. We show that MLL1 concurrently promotes the expression of the proinflammatory cytokines while suppressing the expression of interferon alfa (IFN-α), a well-known inducer of TF and PLAUR. Using in vitro models, we identify MLL1-dependent NF-κB/RelA–mediated transcription of these coagulation-related factors and identify a context-dependent, MLL1-independent role for RelA in the expression of these factors in vivo. As functional correlates for these findings, we demonstrate that the inflammatory, procoagulant, and profibrinolytic phenotypes seen in vivo after coronavirus infection were MLL1-dependent despite blunted Ifna induction in MO/Mφs. Finally, in an analysis of SARS-CoV-2 positive human samples, we identify differential upregulation of MLL1 and coagulopathy-related factor expression and activity in CD14+ MO/Mφs relative to noninfected and healthy controls. We also observed elevated plasma PLAU and TF activity in COVID-positive samples. Collectively, these findings highlight an important role for MO/Mφ MLL1 in promoting CAC and inflammation.

OBJECTIVE: Extremity venous aneurysms result in the risk of pulmonary embolism (PE) and chronic venous insufficiency. At present, owing to the rarity of these aneurysms, no consensus for their treatment has been established. The purpose of the present study was to review the presentation, natural history, and contemporary management of extremity venous aneurysms. METHODS: We performed a retrospective, multi-institutional review of all patients with extremity venous aneurysms treated from 2008 to 2018. A venous aneurysm was defined as saccular or fusiform with an aneurysm/vein ratio of >1.5. RESULTS: A total of 66 extremity aneurysms from 11 institutions were analyzed, 40 of which were in a popliteal location, 14 iliofemoral, and 12 in an upper extremity or a jugular location. The median follow-up was 27 months (range, 0–120 months). Of the 40 popliteal venous aneurysms, 8 (20%) had presented with deep vein thrombosis (DVT) or PE, 13 (33%) had presented with pain, and 19 had been discovered incidentally. The mean size of the popliteal venous aneurysms presenting with DVT or PE was larger than that of those presenting without thromboembolism (3.8 cm vs 2.5 cm; P = .003). Saccular aneurysm morphology in the lower extremity was associated with thromboembolism (30% vs 9%;P = .046) and fusiform aneurysm morphology with a thrombus burden >25% (45% vs 3%). Patients presenting with thromboembolism were more likely to have had a thrombus burden >25% in their lower extremity venous aneurysm compared with those who had presented without thromboembolism (70% vs 9%). Approximately half of all the patients underwent immediate intervention, and half were managed with observation or antithrombotic regimen. In the nonoperative cohort, three patients subsequently developed a DVT. Eight patients in the medically managed cohort went on to require surgical intervention. Of the 12 upper extremity venous aneurysms, none had presented with DVT or PE, and only 2 (17%) had presented with pain. Of the 66 patients in the entire cohort, 41 underwent surgical intervention. The most common indication was the absolute aneurysm size. Nine patients had undergone surgery because of a DVT or PE, and 11 for pain or extremity swelling. The most common surgery was aneurysmorrhaphy in 21 patients (53%), followed by excision and ligation in 14 patients (35%). Five patients (12%) had undergone interposition bypass grafting. A postoperative hematoma requiring reintervention was the most common complication, occurring in three popliteal vein repairs and one iliofemoral vein repair. None of the patients, treated either surgically or medically, had reported post-thrombotic complications during the follow-up period. CONCLUSIONS: Large lower extremity venous aneurysms and saccular aneurysms with thrombus >25% of the lumen are more likely to present with thromboembolic complications. Surgical intervention for lower extremity venous aneurysms is indicated to reduce the risk of venous thromboembolism (VTE) and the need for continued anticoagulation. Popliteal aneurysms >2.5 cm and all iliofemoral aneurysms should be considered for repair. Upper extremity aneurysms do not have a significant risk of VTE and warrant treatment primarily for symptoms other than VTE. (J Vasc Surg Venous Lymphat Disord 2022;10:1352–8.)

INTRODUCTION: Despite the great promise for therapies using antisense oligonucleotides (ASOs), their adverse effects, which include pro-inflammatory effects and thrombocytopenia, have limited their use. Previously, these effects have been linked to the phosphorothioate (PS) backbone necessary to prevent rapid ASO degradation in plasma. The main aim of this study was to assess the impact of the nucleic acid portion of an ASO-type drug on platelets and determine if it may contribute to thrombosis or thrombocytopenia. METHODS: Platelets were isolated from healthy donors and men with advanced prostate cancer. Effects of antisense oligonucleotides (ASO), oligonucleotides, gDNA, and microRNA on platelet activation and aggregation were evaluated. A mouse model of lung thrombosis was used to confirm the effects of PS-modified oligonucleotides in vivo. RESULTS: Platelet exposure to gDNA, miRNA, and oligonucleotides longer than 16-mer at a concentration above 8 mM resulted in the formation of hypersensitive platelets, characterized by an increased sensitivity to low-dose thrombin (0.1 nM) and increase in p-Selectin expression (6–8 fold greater than control; p < 0.001). The observed nucleic acid (NA) effects on platelets were toll-like receptor (TLR) -7 subfamily dependent. Injection of a p-Selectin inhibitor significantly (p = 0.02) reduced the formation of oligonucleotide-associated pulmonary microthrombosis in vivo. CONCLUSION: Our results suggest that platelet exposure to nucleic acids independent of the presence of a PS modification leads to a generation of hypersensitive platelets and requires TLR-7 subfamily receptors. ASO studies conducted in cancer patients may benefit from testing the ASO effects on platelets ex vivo before initiation of patient treatment.

Popliteal vein aneurysms are a rare vascular anomaly first reported in the 1980s. Degeneration of elastic fibers and smooth muscle cell reduction, possibly secondary to inflammation, are implicated as integral steps in the development of these aneurysms. Given the rarity of this clinical entity, significant controversy exists regarding ideal treatment strategies, including the role of observation, medical management with anticoagulation, and surgical intervention. Retrospective reviews have demonstrated a failure rate of40% with anticoagulation alone, with patients often presenting with pulmonary embolism. This has prompted our institutional preference for surgical management once the aneurysm is identified. Surgical management involves tangential repair with lateral venorrhaphy most commonly, followed in prevalence by aneurysm resection and end-to-end anastomosis either primarily or with vein interposition. Herein, we report our results with venous plications, through both closed and open techniques.We performed a retrospective review of prospectively collected data for 10 patients undergoing popliteal vein plication for treatment of popliteal vein aneurysms. Patient-level characteristics and operative details were examined from periprocedural and follow-up records.We identified 10 patients undergoing popliteal vein plication, including 9 closed plications and 1 open plication. The average aneurysm size at presentation was 2.35 ± 0.69 cm for closed plication and 4.74 cm for the one open plication. After treatment, the average popliteal vein size was significantly reduced to 1.12 ± 0.45 cm for the closed plications (P .001 from preprocedural size) and 1.13 cm for the open plication with 100% primary patency. Average follow-up for patients treated with closed plication was 35.0 ± 25.2 months, during which seven (78%) patients had a stable, normal popliteal vein size. One patient with recurrence was diagnosed with Klippel-Trénaunay syndrome. The other had degeneration of the popliteal vein cranial to the previous repair at 39 months after the original operation that required additional plication. The open plication patient experienced a hematoma requiring washout and resulting in a transient peroneal mononeuropathy. There was one case of cellulitis after closed plication but no hematomas within this group.Closed plication demonstrated favorable primary patency rates and low recurrence rates, avoiding technical issues or need for early institution of systemic anticoagulation associated with tangential repair and venorrhaphy or resection methods. Closed plication represents an attractive option in patients without luminal thrombus to limit the risk of these postoperative complications and obviates the need for bypass conduit and postoperative anticoagulation.

Objectives: Coronavirus associated coagulopathy (CAC) is postulated to be driven by systemic macrophage activation after SARS-CoV-2 infection and presents with elevated risk of thrombogenesis and hyperfibrinolysis. Previous work shows that the histone methyltransferase KMT2A/MLL1 is a key mediator of inflammatory signaling in monocytes and macrophages (Mo/Mϕs). In this study, we sought to identify the regulation of factors important in CAC by MLL1. Methods: Mice with myeloid specific knockout of MLL1 (Cre+) and littermate controls (Cre-) underwent intranasal inoculation of 2 x 10 5 pfu of the murine coronavirus MHVA59, an established model which phenocopies SARS-CoV-2 infection. Splenic Mϕs (surrogate for circulating Mo/Mϕs) were isolated and RNA and protein levels of urokinase (Plau; profibrinolytic), urokinase receptor (Plaur; profibrinolytic), and tissue factor (F3/TF; procoagulant) were analyzed using qRT-PCR and ELISA, respectively. Thromboelastography (TEG) on whole blood and urokinase activity assays from mouse plasma were performed. Urokinase and TF activity assays were performed on plasma from human samples. Results: RNA (top panel) and protein (bottom) levels of Plau, Plaur, and F3 were suppressed in the Splenic Mϕs harvested from sham (intranasal PBS) and infected Cre+ animals (white bars) compared to Splenic Mϕs harvested from Cre- animals (blue bars; Fig. 1A). Cre- mice displayed a shortened R-time (reaction time) as measured by TEG (Fig. 1B) and elevated plasma urokinase activity levels (not shown). Hospitalized COVID-positive patients (hCOV+) displayed elevated plasma urokinase and TF activity levels (Fig. 1C). Conclusions: We identify a role for MLL1 for basal expression and for coronavirus-mediated induction of factors important for fibrinolysis and coagulation in murine Mo/Mϕs and in driving coagulopathy. Our results suggest that MLL1 blockade may be an attractive strategy to combat coronavirus associated coagulopathy.

This retrospective cohort study analyzes venous thromboembolism (VTE) incidence, morbidity, and mortality amongst postsurgical patients with and without VTE chemoprophylaxis within a quality collaborative. Postoperative thromboprophylaxis was broadly applied, yet was associated with no decrease in VTE, without affecting transfusion or mortality. Predictors of breakthrough VTE development despite evidence-based thromboprophylaxis are identified.We hypothesized that a high rate of prescription of VTE chemoprophylaxis would be associated with decreased VTE incidence and mortality.Recommendations for VTE prevention in surgical patients include chemoprophylaxis based upon preoperative risk stratification.This retrospective cohort study analyzed VTE incidence, morbidity, and mortality amongst postsurgical patients with and without VTE chemoprophylaxis between April 2013 and September 2017 from 63 hospitals within the Michigan Surgical Quality Collaborative. A VTE risk assessment survey was distributed to providers. Bivariate and multivariate comparisons were made, as well as using propensity score matched cohorts to determine if VTE chemoprophylaxis was associated with decreased VTE events. Hospitals were compared using risk-reliability adjusted VTE prophylaxis and postoperative VTE event rates.Within the registry, 80% of practitioners reported performing formal VTE risk assessment. Amongst 32,856 operations, there were 480 (1.46%) postoperative VTE, and an overall mortality of 609 (1.85%) patients. Using a propensity matched cohort, we found that rates of VTE were similar in those receiving unfractionated heparin or low molecular weight heparin compared to those not receiving chemoprophylaxis (1.22 vs 1.13%, P = 0.57). When stratified further by VTE risk scoring, even the highest risk patients did not have an associated lower VTE rate (3.68 vs 4.22% P = 0.092). Postoperative transfusion (8.28 vs 7.50%, P = 0.057) and mortality (2.00% vs 1.62%, P = 0.064) rates were similar amongst those receiving and those not receiving chemoprophylaxis. No correlation was found between postoperative VTE chemoprophylaxis application and hospital specific risk adjusted postoperative VTE rates.In modern day postsurgical care, VTE remains a significant occurrence, despite wide adoption of VTE risk assessment. Although postoperative VTE chemoprophylaxis was broadly applied, after adjusting for confounders, no reduction in VTE was observed in at-risk surgical patients.

Post-thrombotic syndrome (PTS) is an end stage manifestation of deep vein thrombosis. This is an inherently inflammatory process, with consequent fibrosis. Multiple cellular types are involved, and are likely driven by leukocytes. Herein, we review the current gaps in therapy, and insights from rodent models of venous thrombosis that suggest possible targets to treat and prevent PTS.

Objective Venous thromboembolism (VTE) is a common disease with potentially devastating and long-term sequelae, such as pulmonary embolism and post-thrombotic syndrome (PTS). Given the mortality risk, prevalence of VTE, and limited access to diagnostic imaging, clinically relevant biomarkers for diagnosis and prognostication are needed. Therefore, this review aimed to summarize the data on clinically applicable biomarkers that best indicate acute VTE and chronic PTS. Methods We reviewed the medical and scientific literature from 2001 to 2019 for VTE biomarkers. Randomized controlled trials, meta-analyses, and review articles were included. Primary basic research papers with no clinical applicability, opinion papers, institutional guidelines, and case reports were excluded. Results We highlight the diagnostic value of D-dimer alongside other promising biomarkers, including cellular adhesion molecules, P-selectin, cytokines (interleukins 6 and 10), fibrin monomer complexes, and coagulation factors (factor VIII). Conclusions High-sensitivity D-dimer remains the most clinically established VTE biomarker. Current research endeavors are under way to identify more precise biomarkers of VTE and PTS.

There is an inter-relationship between thrombosis and inflammation. Previously, we have shown the importance of P-selectin in thrombogenesis and thrombus resolution in many preclinical animal models. The role of E-selectin has been explored in rodent models and in a small pilot study of clinical calf vein deep venous thrombosis. The purpose of this study was to determine the role of E-selectin in thrombosis in a primate model of proximal iliac vein thrombosis, a model close to the human condition.Iliac vein thrombosis was induced with a well-characterized primate model. Through a transplant incision, the hypogastric vein and iliac vein branches were ligated. Thrombus was induced by balloon occlusion of the proximal and distal iliac vein for 6 hours. The balloons were then deflated, and the primates recovered. Starting on postocclusion day 2, animals were treated with the E-selectin inhibitor GMI-1271, 25 mg/kg subcutaneously, once daily until day 21 (n = 4). Nontreated control animals received no treatment (n = 5). All animals were evaluated by magnetic resonance venography (MRV); evaluation of vessel area by ultrasound, protein analysis, hematology (complete blood count), and coagulation tests (bleeding time, prothrombin time, activated partial thromboplastin time, fibrinogen, and thromboelastography) were performed at baseline, day 2, day 7, day 14, and day 21 with euthanasia. In addition, platelet function and CD44 expression on leukocytes were determined.E-selectin inhibition by GMI-1271 significantly increased vein recanalization by MRV vs control animals on day 14 (P .05) and day 21 (P .0001). GMI-1271 significantly decreased vein wall inflammation by MRV with gadolinium vein wall enhancement vs control also on day 14 (P .0001) and day 21 (P .0001). The thromboelastographic measure of clot strength (maximum amplitude) showed significant decreases in animals treated with GMI-1271 vs controls at day 2 (P .05) and day 7 (P .05). Animals treated with GMI-1271 had significant vessel area increase by day 21 vs controls (P .05) by ultrasound. Vein wall intimal thickening (P .001) and intimal fibrosis (P .05) scores were significantly decreased in GMI-1271-treated animals vs controls. Importantly, no significant differences in hematology or coagulation test results were noted between all groups, suggesting that E-selectin inhibition carries no bleeding potential. GMI-1271 did not affect platelet function or aggregation or CD44 expression on leukocytes. In addition, no episodes of bleeding were noted in either group.This study suggests that E-selectin modulates venous thrombus progression and that its inhibition will increase thrombus recanalization and decrease vein wall inflammation, without affecting coagulation. The use of an E-selectin inhibitor such as GMI-1271 could potentially change how we treat deep venous thrombosis.

Background There is an unmet need for antithrombotic treatments for venous thromboembolic disease that do not increase bleeding risk. Selectins are cell adhesion molecules that augment thrombosis by activating immune cells to initiate the coagulation cascade. GMI‐1271, a potent small‐molecule E‐selectin antagonist, has been shown in mouse models to decrease thrombus burden with a low risk of bleeding. Methods A first‐in‐human study of GMI‐1271 was conducted to assess its safety, tolerability, and pharmacokinetic (PK) profile. As a secondary end point, biomarkers of coagulation, cell adhesion, and leukocyte/platelet activation were evaluated. Aims 1 and 2 were performed in healthy volunteers and evaluated single and multiple doses of the study drug, respectively. Aim 3 included 2 patients with isolated calf‐level deep vein thrombosis (DVT). Results GMI‐1271 showed consistent PK parameters for doses ranging from 2 to 40 mg/kg. Plasma levels increased in a linear manner with respect to dose, while clearance, volume of distribution, and half‐life were not dose dependent. No accumulation was seen with multiple consecutive doses. No serious adverse events (grade 3 or 4) were reported. Biomarker analysis demonstrated a trend in reduction of soluble E‐selectin (sEsel) levels with GMI‐1271 exposure, while exposure did not impact laboratory testing of coagulation. Two patients with calf vein DVT were treated with GMI‐1271 and demonstrated rapid improvement of symptoms after 48 hours, with repeat ultrasound showing signs of clot resolution. Conclusions We demonstrate that GMI‐1271 is safe in healthy volunteers and provide proof of concept that an E‐selectin antagonist is a potential therapeutic approach to treat venous thrombosis.

Objective The growth of endovenous ablation in the United States over the last few years has raised concerns of overuse by many vascular societies and payers. Reasons for such growth are unclear (ie, increased awareness, less invasive procedure, or inappropriate overuse). The Medicare Provider Utilization and Payment database was analyzed to define metrics of current practice trends in Medicare patients by providers. Methods The Medicare Provider Utilization and Payment database was queried for endothermal ablation Current Procedural Terminology codes (36475, 36476, 36478, and 36479) from 2012 through 2015. These results were imported into a relational database program. Queries were designed to ascertain the practice trends of all providers, inclusive of all specialties, and the data were exported to a spreadsheet program for analysis. Analysis for ablations per patient was calculated by assessing the number of beneficiaries who underwent at least one ablation by a provider in relation to the total number of ablations performed by that provider. Results Most saphenous vein ablations were done by vascular surgeons (29%), cardiologists (21%), or general surgeons (14%). The remaining one-third was performed by 33 other provider specialties ranging from nuclear medicine specialists to ophthalmologists. Regional variation was significant with 51% of ablations being performed in the south (Florida, 15.7% and Texas, 11.4%). The Western region had the greatest percentage growth of 62% with the addition of 14,788 cases added between 2012 and 2015. Ablations per patient averaged 1.8 in the aggregate dataset. Over the 4-year period, there was a steady increase seen in the number of patients undergoing ablation, number of ablations performed, number of providers performing ablation, average amount of ablations being performed as well as the number and proportion of providers performing more than ablations per patient. The number of ablations per patient was higher than average in specialties without any formal vascular training. Conclusions Endovenous ablation is performed by a wide variety of subspecialists with different levels of formal training for the management of chronic venous disease. This data analysis can help to establish better guidelines and governance over the use of endovenous ablation, but care should be taken to realize this is only an average and many patients will require more than two ablations for appropriate care. As our health care system shifts from a fee-for-service to a value-based system, and taxpayer-funded resources in Medicare patients become less available, it is important that practice trends be scrutinized using data-driven initiatives so that the appropriate physician treats the appropriate patient for the appropriate reasons.

Background Deep venous thrombosis (DVT) in the pediatric population is rare, occurring in about 10 to 14 out of 10,000 pediatric admissions annually, but with serious consequences such as pulmonary embolism and/or post-thrombotic syndrome. There is a dearth of surgical literature regarding this entity, its pathophysiology, its treatment and its long-term sequelae. Methods An extensive search of available surgical and medical literature in Medline, PubMed was obtained by searching terms synonymous with pediatric DVT. Case reports and opinion articles were excluded. Ongoing clinical trials were culled from clinicaltrial.gov by searching for pediatric DVT studies. Institutional guidelines, where available, were included in this summary. Results We provide a clinically relevant summary with the aims of improving prevention, early identification and treatment of pediatric DVT. Conclusions Although rare and frequently with subtle presentations, pediatric DVT can be serious. Early identification and treatment can be instrumental in limiting sequelae and in improving outcomes for these patients.

Murine models are widely used valuable tools to study deep vein thrombosis. Leading experts in venous thrombosis research came together through the American Venous Forum to develop a consensus on maximizing the utility and application of available mouse models of venous thrombosis. In this work, we provide an algorithm for model selection, with discussion of the advantages, disadvantages, and applications of the main mouse models of venous thrombosis. Additionally, we provide a detailed surgical description of the models with guidelines to validate surgical technique.

Summary Guideline 1.1: Compression after thermal ablation or stripping of the saphenous veins. When possible, we suggest compression (elastic stockings or wraps) should be used after surgical or thermal procedures to eliminate varicose veins. [GRADE - 2; LEVEL OF EVIDENCE - C] Guideline 1.2: Dose of compression after thermal ablation or stripping of the varicose veins. If compression dressings are to be used postprocedurally in patients undergoing ablation or surgical procedures on the saphenous veins, those providing pressures >20 mm Hg together with eccentric pads placed directly over the vein ablated or operated on provide the greatest reduction in postoperative pain. [GRADE - 2; LEVEL OF EVIDENCE - B] Guideline 2.1: Duration of compression therapy after thermal ablation or stripping of the saphenous veins. In the absence of convincing evidence, we recommend best clinical judgment to determine the duration of compression therapy after treatment. [BEST PRACTICE] Guideline 3.1: Compression therapy after sclerotherapy. We suggest compression therapy immediately after treatment of superficial veins with sclerotherapy to improve outcomes of sclerotherapy. [GRADE - 2; LEVEL OF EVIDENCE - C] Guideline 3.2: Duration of compression therapy after sclerotherapy. In the absence of convincing evidence, we recommend best clinical judgment to determine the duration of compression therapy after sclerotherapy. [BEST PRACTICE] Guideline 4.1: Compression after superficial vein treatment in patients with a venous leg ulcer. In a patient with a venous leg ulcer, we recommend compression therapy over no compression therapy to increase venous leg ulcer healing rate and to decrease the risk of ulcer recurrence. [GRADE - 1; LEVEL OF EVIDENCE - B] Guideline 4.2: Compression after superficial vein treatment in patients with a mixed arterial and venous leg ulcer. In a patient with a venous leg ulcer and underlying arterial disease, we suggest limiting the use of compression to patients with ankle-brachial index exceeding 0.5 or if absolute ankle pressure is >60 mm Hg. [GRADE - 2; LEVEL OF EVIDENCE - C]

To evaluate the association between gender and long-term clinician-reported and patient-reported outcomes after endovenous ablation procedures.This retrospective cohort study of prospectively collected data from the Vascular Quality Initiative's Varicose Vein Registry included patients undergoing endovenous ablation procedures on truncal veins with or without treatment of perforating veins between 2015 and 2019. A univariate analysis included comparisons of preprocedural, postprocedural, and periprocedural change in Venous Clinical Severity Score (VCSS) and total symptom score by gender. Rates of complications including deep vein thrombosis, endovenous heat-induced thrombosis, leg pigmentation, blistering, paresthesia, incisional infection, and any postprocedural complications were reported by gender. Multivariable analysis leveraged linear regression to examine how gender affected the relationships between patient characteristics, complication rates, and periprocedural change in VCSS score and total symptom score.Of 9743 patients who met the inclusion criteria, 3090 (31.7%) were men and 6653 (68.2%) were women. The perioperative change in VCSS score was greater for men than women (average -4.46 for men vs -4.13 for women; P .0001). Perioperative change in total symptom score was greater for women than for men (average -10.64 for women vs -9.64 for men; P .0001). Women had lower incidence of any leg complication (6.1% vs 8.6%; P = .001) endovenous heat-induced thrombosis (1.1% vs 2.2%; P = .002), and infection (0.4% vs 0.7%; P = .001). In multivariable analysis, among patients with a body mass index of more than 40, presence of deep reflux, and preoperative Clinical, Etiologic, Anatomic, and Physiologic classification of 2, women had a greater periprocedural change in VCSS score than men.Women benefited from endovenous ablation similarly as men, with a lower incidence of postprocedural complications. Gender may be useful for patient selection and counseling for endovenous ablation, with particular usefulness among patients with a high body mass index, presence of deep reflux, and preoperative Clinical, Etiologic, Anatomic, and Physiologic classification of 2.

Objective Chronic venous disease (CVD) describes a spectrum of conditions associated with venous hypertension. The association between various CVD etiologies and the subsequent risk of venous thromboembolism (VTE), such as deep vein thrombosis or pulmonary embolism, is a topic of considerable clinical interest. The aims of the present review were to characterize the risk of VTE according to the CVD etiology and to determine the optimal anticoagulation strategy for the treatment or prevention of VTE in patients with CVD. Methods An extensive search of the available surgical and medical data was conducted in PubMed and Google Scholar. We searched for the following terms and other related terms to identify relevant studies: CVD, chronic venous insufficiency, varicose veins, post-thrombotic syndrome (PTS), anticoagulation, venous thromboembolism, and venous disease scoring systems (eg, CEAP [clinical, etiology, anatomic, pathophysiology], Villalta, Ginsberg, venous clinical severity score). The identified studies included randomized control trials, retrospective and prospective observational studies, narrative and systematic reviews, case reports, and case series that contributed to the proposed aims. The ClinicalTrials.gov database was also queried to identify any relevant ongoing clinical trials. Results Congenital CVD carries a heightened risk of VTE, although few higher level studies are available to inform on this topic or on the appropriate anticoagulation strategies for these patients. Noncongenital CVD seems to carry a heightened risk of VTE, although few studies have adequately differentiated between primary and secondary etiologies. Varicose veins are a risk factor for primary VTE but might not be associated with an increased risk of recurrent VTE. In the hospital setting, patients with varicosities should be provided thromboprophylaxis. In the setting of varicose vein intervention, high-risk patients should be identified using risk assessment models and receive thromboprophylaxis. The risk of recurrent VTE in the setting of PTS is unclear but indefinite anticoagulation is not currently indicated. For patients with PTS, residual vein thrombosis might be an indicator of when anticoagulation can be safely stopped, although practical limitations to its application exist. Conclusions CVD is associated with an increased risk of VTE. Few studies have differentiated between classes of CVD using a standardized method and have assessed the efficacy of anticoagulation prophylaxis against or treatment of VTE. Additional studies are needed to determine the optimal therapy for preventing and treating VTE in patients with active concurrent CVD.

A markedly increased demand for vascular ultrasound laboratory and other imaging studies in COVID-19-positive patients has occurred, due to most of these patients having a markedly elevated D-dimer and a presumed prothrombotic state in many of the very ill patients. In the present report, we have summarized a broad institutional consensus focusing on evaluation and recommended empirical therapy for COVID-19-positive patients. We recommend following the algorithms with the idea that as more data becomes available these algorithms may well change.

OBJECTIVE: Many insurance payers are hesitating to cover interventional treatments in patients with isolated symptomatic varicose veins. In this study, we sought to determine the outcomes of patients with varicose veins who were treated with venous ablation alone or ablation plus phlebectomy using the Vascular Quality Initiative Varicose Vein Registry. METHODS: Using data from the Varicose Vein Registry between January 2015 and March 2019, we investigated immediate postoperative as well as long-term clinical and patient-reported outcomes among patients with documented symptomatic C2 disease undergoing truncal endovenous ablations alone and combined ablation and phlebectomy. Preprocedural and postprocedural comparisons were performed using t-test, χ(2) test, or nonparametric tests when appropriate. Multivariable ordinal logistic regression was performed on ordinal outcome variables. RESULTS: Among 3375 patients with symptomatic C2 disease, 40.1% of patients (1376) underwent isolated truncal ablation and 59.9% (1999) underwent ablation and phlebectomy. Complications overall were low (8.6%) and varied between 8.4% and 8.7% in patients undergoing ablation alone and ablation plus phlebectomy, respectively (P = .820). The most common complication noted was paresthesia, 3.4% overall, which occurred more commonly after ablation and phlebectomy (4.5%) than after ablation alone (1.3%; P < .001). An improvement in Venous Clinical Severity Score (VCSS) was experienced by 87.4% of patients; median change in VCSS was 4 points (interquartile range [IQR], 2–5 points), with an improvement of 3 points among patients undergoing ablation alone (IQR, 1–5 points) and 5 points among patients undergoing ablation and phlebectomy (IQR, 3–5 points; P < .001). An improvement in overall symptoms was experienced by 94.4% of patients (median improvement, 11 points; (maximum, 30 points), with more significant decreases among patients undergoing ablation and phlebectomy (median, 12 points; IQR, 8–17 points) compared with ablation alone (median, 9 points; IQR, 5–13 points; P < .001). CONCLUSIONS: Among patients with isolated symptomatic varicose veins (C2 disease), ablation and ablation with phlebectomy are safe and effective in improving both patient-reported outcomes and clinical severity (VCSS). Given these data, payers should continue to cover these treatments.

OBJECTIVE: Venous insufficiency is commonly bilateral, and patients often prefer single-episode care compared with staged procedures. Few studies have investigated clinical outcomes after unilateral vs bilateral venous ablation procedures or between staged and concurrent bilateral procedures. Here, we report data from the Vascular Quality Initiative regarding truncal venous ablation for chronic venous insufficiency. METHODS: Using data from the Vascular Quality Initiative, we investigated immediate postoperative as well as long-term clinical and patient-reported outcomes of patients undergoing unilateral vs bilateral truncal endovenous ablation from 2015 to 2019. We further investigated outcomes between staged bilateral and concurrent bilateral ablations. Preprocedural and postprocedural comparisons were performed using t-test, χ(2) test, or their nonparametric counterpart when appropriate. Multivariable ordinal logistic regression was performed on ordinal outcome variables. RESULTS: A total of 5029 patients were included, of whom 3782 (75.2%) underwent unilateral procedures. Median follow-up was 227 days (interquartile range [IQR], 55–788 days). Unilateral patients were less likely to be female (67.0% vs 70.3%; P = .031) and white (86.3% vs 91.2%; P < .001) and had lower body mass index (30.3 ± 7.3 kg/m(2) vs 31.8 ± 7.6 kg/m(2); P < .001) compared with patients undergoing bilateral procedures. In addition, unilateral patients had fewer prior varicose vein treatments (23.0% vs 15.7%; P < .001) and had higher median preprocedural Venous Clinical Severity Score (VCSS; 8 [IQR, 6–10] vs 7 [IQR, 5.5–9]; P < .001). No difference was seen in complications (6.9% vs 8.2%; P = .292), and systemic complications were rare in both groups. No difference was seen in VCSS improvement after treatment (median, 3 [IQR, 1–6] for unilateral; median, 3 [IQR 1–5] for bilateral; P = .055). In comparing staged with concurrent bilateral procedures, there was no difference in overall complications (7.5% vs 12.2%; P = .144). Staged bilateral patients were older (56.9 ± 13.3 years vs 54.2 ± 12.9 years; P = .002), less likely to have had prior varicose vein treatment (14.3% vs 19.8%; P = .020), and more likely to be therapeutically anticoagulated (10.8% vs 6.5%; P = .028) compared with concurrent bilateral patients. Staged patients also have higher preprocedural VCSS compared with concurrent patients (median, 8 [IQR, 6–10] vs 7 [IQR, 5.5–9]; P < .001). In multivariable analysis, there was no difference in the likelihood of VCSS improvement for concurrent compared with staged procedures (odds ratio, 0.70; 95% confidence interval, 0.40–1.24; P = .226). CONCLUSIONS: Concurrent bilateral truncal endovenous ablation can be performed safely without increased morbidity compared with staged bilateral or unilateral ablations.

BACKGROUND: While Chronic Venous Insufficiency (CVI) and Varicose Veins (VVs) are a universally recognized problem, they are frequently under-appreciated as major contributors to long-term morbidity in the elderly despite the increasing prevalence with age. Prior studies have demonstrated that CVI and VV treatments in patients ≥ 65 yield an overall benefit, however, there has been little data if octogenarians are undergoing these procedures and with what success. As such, our objectives were to (1) investigate the procedures selected, (2) examine clinical outcomes following VV procedures in elderly patients ≥ 80 years old and (3) explore complication rates (both systemic and leg specific) following VV procedures in patients ≥ 80 years old. METHODS: We performed a retrospective review using the Vascular Quality Initiative Varicose Vein Registry (VQI VVR) of all VV procedures performed for ≥ C2 disease from January 2015 – February 2017. We divided all procedures into three age groups: patients < 65, patients ≥ 65 – 79, and patients ≥ 80 years of age. Statistical testing included Chi squared test for categorical variables and student t test for continuous variables. Two comparisons were performed. First comparing patients < 65 to ≥ 65 – 79 and second, comparing patients ≥ 65 – 79 to ≥ 80. RESULTS: There were a total of 12,262 procedures performed with 8,608 procedures in the < 65 group, 3,226 in the 65-79 group, and 428 procedures in patients ≥ 80 years old. A total of 22,050 veins were treated during the 12,262 procedures. Almost half of procedures (46.51%, N=5,703) had only one vein treated during a single procedure. Between age groups, the percentage of one vein treated increased as patient age increased, ranging from 45.39% (N=3,875) for patients < 65, 48.55% (N=1,555) for patients between 65-79, to 64.08% (N=273) for patients ≥ 80. Patients in the ≥ 80 group had an overall lower average BMI, were more likely to be on anticoagulation and undergo truncal procedures alone compared to the other groups. The ≥ 80 group had a significant improvement in both venous clinical severity scores (VCSS) (4.37 ± 4.16, p < .001) and patient reported outcomes (PROs) (8.79 ± 7.27, p < .001) from pre to post procedure. Overall complications were low in all age groups. The octogenarians had no higher risk of systemic complications. CONCLUSIONS: Vascular specialists are performing VV procedures in octogenarians and are more likely to perform truncal only therapy. Additionally, octogenarians have statistically significant improvement of VCSS and PROs with a low risk of complications despite more advanced venous disease at presentation.

Background Patients undergoing deep vein thrombosis (VT) have over 30% recurrence, directly increasing their risk of post-thrombotic syndrome. Current murine models of inferior vena cava (IVC) VT model host one thrombosis event. Objective We aimed to develop a murine model to study IVC recurrent VT in mice. Materials and Methods An initial VT was induced using the electrolytic IVC model (EIM) with constant blood flow. This approach takes advantage of the restored vein lumen 21 days after a single VT event in the EIM demonstrated by ultrasound. We then induced a second VT 21 days later, using either EIM or an IVC ligation model for comparison. The control groups were a sham surgery and, 21 days later, either EIM or IVC ligation. IVC wall and thrombus were harvested 2 days after the second insult and analysed for IVC and thrombus size, gene expression of fibrotic markers, histology for collagen and Western blot for citrullinated histone 3 (Cit-H3) and fibrin. Results Ultrasound confirmed the first VT and its progressive resolution with an anatomical channel allowing room for the second thrombus by day 21. As compared with a primary VT, recurrent VT has heavier walls with significant up-regulation of transforming growth factor-β (TGF-β), elastin, interleukin (IL)-6, matrix metallopeptidase 9 (MMP9), MMP2 and a thrombus with high citrullinated histone-3 and fibrin content. Conclusion Experimental recurrent thrombi are structurally and compositionally different from the primary VT, with a greater pro-fibrotic remodelling vein wall profile. This work provides a VT recurrence IVC model that will help to improve the current understanding of the biological mechanisms and directed treatment of recurrent VT.

Anticoagulation pharmacy has been dramatically altered with US Food and Drug Administration (FDA) approval of 5 direct oral anticoagulants, 1 novel reversal agent and, a second designated for fast-track approval. Trial data surrounding current trends in anticoagulant choice for VTE, reversal, and bridging are constantly redefining practice. Extended therapy for unprovoked VTE has expanded to include low-dose direct oral anticoagulants, aspirin, and the use of the HERDOO2 system to identify women who can stop anticoagulant therapy without increased risk of recurrent VTE. Trends in thromboprophylaxis include extended duration low-dose direct oral anticoagulants to prevent VTE in high-risk patients.

The calf muscle pump is a major determinate of venous return in the legs but has not been studied as a risk factor for venous thromboembolism (VTE). A population-based cohort study of Olmsted County, Minnesota residents was performed using calf pump function (CPF) measurements from venous plethysmography studies from 1998 to 2015. Patients with a history of VTE were excluded. Nursing validated VTE outcomes from the Rochester Epidemiology Project were identified after the index study date, and patients with reduced CPF (rCPF) were compared with patients with normal CPF. A total of 1532 patients with recorded CPF (28% air and 72% strain gauge plethysmography) were included; 591 (38.5%) had normal CPF, 353 (23.0%) had unilateral rCPF, and 588 (38.3%) had bilateral rCPF. Any VTE occurred in 87 patients (5.7%) after a median follow-up of 11.7 years (range, 0-22.0 years). Comparing patients with bilateral reduced to bilateral normal CPF, the unadjusted hazard ratio (HR) for incident VTE was 2.0 (95% confidence interval [CI], 1.2-3.4) and after adjusting for age, BMI, and Charlson Comorbidity Index, the HR was 1.68 (95% CI, 0.98-2.89). The adjusted HR for ipsilateral deep vein thrombosis was evaluated in 3064 legs comparing legs with reduced to normal CPF and was 1.71 (95% CI, 1.03-2.84). Mortality was significantly higher in both the bilateral (P < .001) and unilateral (P < .001) rCPF groups compared with normal CPF. Our results demonstrate that CPF is a risk factor for VTE in an otherwise low-risk ambulatory population and might be a useful component in risk stratification models.

Background Varicose veins, a common problem with effects on quality of life, account for a significant cost burden on the health care system. Despite their prevalence, the pathophysiologic mechanism of varicose veins remains incompletely understood. The fundamental issue is whether venous hypertension and valvular incompetence precede and influence the development of vein wall changes or whether the reverse is true. Methods We have reviewed the English-language literature to provide the most current understanding of the hemodynamic and cellular and molecular processes that underlie the development of varicose veins. Results Data at this time remain inconclusive, with compelling arguments to be made for both sides. It is clear that valvular incompetence and hemodynamic factors play a significant role, despite heterogeneity in study findings and lack of clear data for a specific pattern of valvular incompetence as an inciting factor. Numerous factors influence the development of varices on the cellular level, including hypoxia, dysregulated apoptosis, and alterations in the extracellular matrix. Conclusions Based on currently available evidence, varicose veins are a complex disease with multifactorial pathogenesis; it is as yet not possible to state conclusively what inciting factor is responsible for the development of varicose veins, and their development may result from imbalance of any number of several factors.

Symptoms suggestive of deep vein thrombosis (DVT) are extremely common in clinical practice, but unfortunately nonspecific. In both ambulatory and inpatient settings, clinicians are often tasked with evaluating these concerns. Here, we review the most recent advances in biomarkers and imaging to diagnose lower extremity DVT.The modified Wells score remains the most supported clinical decision rule for risk stratifying patients. In uncomplicated patients, the D-dimer can be utilized with risk stratification to reasonably exclude lower extremity DVT in some patients. Although numerous biomarkers have been explored, soluble P-selectin has the most promise as a novel marker for DVT. Imaging will be required for many patients and ultrasound is the primary modality. Nuclear medicine techniques are under development, and computed tomography (CT) and magnetic resonance venography are reasonable alternatives in select patients.D-dimer is the only clinically applied biomarker for DVT diagnosis, with soluble P-selectin a promising novel biomarker. Recent studies have identified several other potential biomarkers. Ultrasound remains the imaging modality of choice, but CT, MRI, or nuclear medicine tests can be considered in select scenarios.

Objective— Warfarin is the current standard for oral anticoagulation therapy in patients with mechanical heart valves, yet optimal therapy to maximize anticoagulation and minimize bleeding complications requires routine coagulation monitoring, possible dietary restrictions, and drug interaction monitoring. As alternatives to warfarin, oral direct acting factor Xa inhibitors are currently approved for the prophylaxis and treatment of venous thromboembolism and reduction of stroke and systemic embolization. However, no in vivo preclinical or clinical studies have been performed directly comparing oral factor Xa inhibitors such as apixaban to warfarin, the current standard of therapy. Approach and Results— A well-documented heterotopic aortic valve porcine model was used to test the hypothesis that apixaban has comparable efficacy to warfarin for thromboprophylaxis of mechanical heart valves. Sixteen swine were implanted with a bileaflet mechanical aortic valve that bypassed the ligated descending thoracic aorta. Animals were randomized to 4 groups: control (no anticoagulation; n=4), apixaban oral 1 mg/kg twice a day (n=5), warfarin oral 0.04 to 0.08 mg/kg daily (international normalized ratio 2–3; n=3), and apixaban infusion (n=4). Postmortem valve thrombus was measured 30 days post-surgery for control-oral groups and 14 days post-surgery for the apixaban infusion group. Control thrombus weight (mean) was significantly different (1422.9 mg) compared with apixaban oral (357.5 mg), warfarin (247.1 mg), and apixiban 14-day infusion (61.1 mg; P Conclusions— Apixaban is a promising candidate and may be a useful alternative to warfarin for thromboprophylaxis of mechanical heart valves. Unlike warfarin, no adverse bleeding events were observed in any apixaban groups.

SummaryVenous thromboembolism is a major cause of death during and immediately post-sepsis. Venous thrombosis (VT) is mediated by cell adhesion molecules and leukocytes, including neutrophil extracellular traps (NETs). Sepsis, or experimentally, endotoxaemia, shares similar characteristics and is modulated via toll like receptor 4 (TLR4). This study was undertaken to determine if endotoxaemia potentiates early stasis thrombogenesis, and secondarily to determine the role of VT TLR4, ICAM-1 and neutrophils (PMNs). Wild-type (WT), ICAM-1-/- and TLR4-/- mice underwent treatment with saline or LPS (10 mg/kg i.p.) alone, or followed by inferior vena cava (IVC) ligation to generate stasis VT. In vivo microscopy of leukocyte trafficking was performed in non-thrombosed mice, and tissue and plasma were harvested during early VT formation. Pre-thrombosis, circulating ICAM-1 was elevated and increased leukocyte adhesion and rolling occurred on the IVC of LPS-treated mice. Post-thrombosis, endotoxaemic mice formed larger, platelet-poor thrombi. Endotoxaemic TLR4-/- mice did not have an augmented thrombotic response and exhibited significantly decreased circulating ICAM-1 compared to endotoxaemic WT controls. Endotoxaemic ICAM-1-/- mice had significantly smaller thrombi compared to controls. Hypothesising that PMNs localised to the inflamed endothelium were promoting thrombosis, PMN depletion using anti-Ly6G antibody was performed. Paradoxically, VT formed without PMNs was amplified, potentially related to endotoxaemia induced elevation of PAI-1 and circulating FXIII, and decreased uPA. Endotoxaemia enhanced early VT occurs in a TLR-4 and ICAM-1 dependent fashion, and is potentiated by neutropenia. ICAM-1 and/or TLR-4 inhibition may be a unique strategy to prevent sepsis-associated VT.Supplementary Material to this article is available online at www.thrombosis-online.com.

Background Stimulated by published reports of potentially inappropriate application of venous procedures, the American Venous Forum and its Ethics Task Force in collaboration with multiple other professional societies including the Society for Vascular Surgery (SVS), American Vein and Lymphatic Society (AVLS), and the Society of Interventional Radiology (SIR) developed the appropriate use criteria (AUC) for chronic lower extremity venous disease to provide clarity to the application of venous procedures, duplex ultrasound imaging, timing, and reimbursements. Methods The AUC were developed using the RAND/UCLA Appropriateness Method, a validated method of developing appropriateness criteria in health care. By conducting a modified Delphi exercise and incorporating best available evidence and expert opinion, AUC were developed and scored. Results There were 119 scenarios rated on a scale of 1 to 9 by an expert panel, with 1 being never appropriate and 9 being appropriate. The majority of scenarios consisted of symptomatic indications were deemed appropriate for venous intervention. For scenarios with anatomically short segments of reflux and/or no symptoms, the indications were rated less appropriate. For the indication of edema, a wide dispersion of ratings was observed especially for short segments of saphenous reflux or stenting for iliac/ inferior vena cava disease, noting that there are multifactorial causes of edema, some of which could coexist with venous disease and possibly impact effectiveness of treatment. Several scenarios were considered never appropriate, including treatment of saphenous veins with no reflux, iliac vein or inferior vena cava stenting for iliac vein compression as an incidental finding by imaging with minimal or no symptoms or signs, and incentivizing sonographers to find reflux. Conclusions The AUC statements are intended to serve as a guide to patient care, particularly in areas where high-quality evidence is lacking to aid clinicians in making day-to-day decisions for common venous interventions. This may also prove useful when applied on a population level, such as practice patterns, and not necessarily to dictate decision making for individual cases. As a product of a collaborative effort, it is hoped that this could be utilized by physicians and multiple stakeholders committed toward improving patient care and to identify and stimulate future research priorities.

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

Objective— Leukocyte flux contributes to thrombus formation in deep veins under pathological conditions, but mechanisms that inhibit venous thrombosis are incompletely understood. Ectonucleotide di(tri)phosphohydrolase 1 ( ENTPD1 or Cd39 ), an ectoenzyme that catabolizes extracellular adenine nucleotides, is embedded on the surface of endothelial cells and leukocytes. We hypothesized that under venous stasis conditions, CD39 regulates inflammation at the vein:blood interface in a murine model of deep vein thrombosis. Approach and Results— CD39-null mice developed significantly larger venous thrombi under venous stasis, with more leukocyte recruitment compared with wild-type mice. Gene expression profiling of wild-type and Cd39 -null mice revealed 76 differentially expressed inflammatory genes that were significantly upregulated in Cd39 -deleted mice after venous thrombosis, and validation experiments confirmed high expression of several key inflammatory mediators. P-selectin, known to have proximal involvement in venous inflammatory and thrombotic events, was upregulated in Cd39 -null mice. Inferior vena caval ligation resulted in thrombosis and a corresponding increase in both P-selectin and VWF (von Willebrand Factor) levels which were strikingly higher in mice lacking the Cd39 gene. These mice also manifest an increase in circulating platelet-leukocyte heteroaggregates suggesting heterotypic crosstalk between coagulation and inflammatory systems, which is amplified in the absence of CD39. Conclusions— These data suggest that CD39 mitigates the venous thromboinflammatory response to flow interruption.

Murine models are widely used valuable tools to study deep vein thrombosis. Leading experts in venous thrombosis research came together through the American Venous Forum to develop a consensus on maximizing the utility and application of available mouse models of venous thrombosis. In this work, we provide an algorithm for model selection, with discussion of the advantages, disadvantages, and applications of the main mouse models of venous thrombosis. Additionally, we provide a detailed surgical description of the models with guidelines to validate surgical technique.