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Objective: The 2010 Pacific Vascular Symposium 6 (PVS6) brought venous disease content experts together with a goal of addressing critical issues collated together in the next decade with concrete plans to achieve these goals. This mapping review aims to provide a broader representation of how progress in critical issues of chronic venous disease has been made by extrapolating scientific publications related to the PVS6 initiatives., Methods: We performed a mapping review identifying original or systematic review/meta-analysis articles related to PVS 6 initiatives (aims) that addressed one of the following key objectives: scales to measure chronic venous disease, effectiveness of interventional deep venous thrombus removal, development of a deep venous valve, and biomarkers related to venous disease. Searches were undertaken in PubMed, Ovid Medline, Cochrane Library, Embase (Elsevier), CINAHL (EBSCO), and Scopus. We extracted descriptive information about the studies and predefined variables for each specific aim, showing what and where research exists on the aims included., Results: A total of 2138 articles were screened from 3379 retrieved articles from six electronic databases. We mapped 186 included articles, finding that the total number of publications significantly increased after the 2010 PVS6 meeting. Aim results were visually summarized. The largest body of data addressed catheter-based thrombus removal strategies for acute iliofemoral deep venous thrombosis. Primary research on artificial venous valves and venous biomarkers remained limited. No new post-thrombotic syndrome (PTS) score has been developed., Conclusions: This mapping review identified and characterized the available evidence and gaps in our knowledge of chronic venous disease that exist visually, which may guide where more significant investments for the future should be targeted., Competing Interests: Disclosures None., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Balloon venoplasty is a commonly used clinical technique to treat deep vein stenosis and occlusion as a consequence of trauma, congenital anatomic abnormalities, acute deep vein thrombosis (DVT), or stenting. Chronic deep venous obstruction is histopathologically characterized by thrombosis, fibrosis, or both. Currently, no direct treatment is available to target these pathological processes. Therefore, a reliable in vivo animal model to test novel interventions is necessary. The rodent survival inferior vena cava (IVC) venoplasty balloon model (VBM) allows the study of balloon venoplasty in non-thrombotic and post-thrombotic conditions across multiple time points. The local and systemic effect of coated and uncoated venoplasty balloons can be quantified via tissue, thrombus, and blood assays such as real-time polymerase chain reaction (RT-PCR), western blot, enzyme-linked immunosorbent assay (ELISA), zymography, vein wall and thrombus cellular analysis, whole blood and plasma assays, and histological analysis. The VBM is reproducible, replicates surgical human interventions, can identify local vein wall-thrombi protein changes, and allows multiple analyses from the same sample, decreasing the number of animals required per group.

Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Iliac vein compression syndrome (IVCS) is present in over 20% of the population and is associated with left leg pain, swelling, and thrombosis. IVCS symptoms are thought to be induced by altered pelvic hemodynamics, however, there currently exists a knowledge gap on the hemodynamic differences between IVCS and healthy patients. To elucidate those differences, we carried out a patient-specific, computational modeling comparative study. Methods: Computed tomography and ultrasound velocity and area data were used to build and validate computational models for a cohort of IVCS (N = 4, Subject group) and control (N = 4, Control group) patients. Flow, cross-sectional area, and shear rate were compared between the right common iliac vein (RCIV) and left common iliac vein (LCIV) for each group and between the Subject and Control groups for the same vessel. Results: For the IVCS patients, LCIV mean shear rate was higher than RCIV mean shear rate (550 ± 103 s -1 vs. 113 ± 48 s -1 , p = 0.0009). Furthermore, LCIV mean shear rate was higher in the Subject group than in the Control group (550 ± 103 s -1 vs. 75 ± 37 s -1 , p = 0.0001). Lastly, the LCIV/RCIV shear rate ratio was 4.6 times greater in the Subject group than in the Control group (6.56 ± 0.9 vs. 1.43 ± 0.6, p = 0.00008). Discussion: Our analyses revealed that IVCS patients have elevated shear rates which may explain a higher thrombosis risk and suggest that their thrombus initiation process may share aspects of arterial thrombosis. We have identified hemodynamic metrics that revealed profound differences between IVCS patients and Controls, and between RCIV and LCIV in the IVCS patients. Based on these metrics, we propose that non-invasive measurement of shear rate may aid with stratification of patients with moderate compression in which treatment is highly variable. More investigation is needed to assess the prognostic value of shear rate and shear rate ratio as clinical metrics and to understand the mechanisms of thrombus formation in IVCS patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Assi, Lynch, Ricker, Ranjane, Williams, Wakefield, Obi and Figueroa.)

Objective: Elevated shear rates are known to play a role in arterial thrombosis; however, shear rates have not been thoroughly investigated in patients with iliac vein compression syndrome (IVCS) owing to imaging limitations and assumptions on the low shear nature of venous flows. This study was undertaken to develop a standardized protocol that quantifies IVCS shear rates and can aid in the diagnosis and treatment of patients with moderate yet symptomatic compression., Methods: Study patients with and without IVCS had their iliac vein hemodynamics measured via duplex ultrasound (US) at two of the following three vessel locations: infrarenal inferior vena cava (IVC), right common iliac vein, and left common iliac vein, in addition to acquiring data at the right and left external iliac veins. US velocity spectra were multiplied by a weighted cross-sectional area calculated from US and computed tomography (CT) data to create flow waveforms. Flow waveforms were then scaled to enforce conservation of flow across the IVC and common iliac veins. A three-dimensional (3D), patient-specific model of the iliac vein anatomy was constructed from CT and US examination. Flow waveforms and the 3D model were used as a basis to run a computational fluid dynamics (CFD) simulation. Owing to collateral vessel flow and discrepancies between CT and US area measurements, flows in internal iliac veins and cross-sectional areas of the common iliac veins were calibrated iteratively against target common iliac flow. Simulation results on mean velocity were validated against US data at measurement locations. Simulation results were postprocessed to derive spatial and temporal values of quantities such as velocity and shear rate., Results: Using our modeling protocol, we were able to build CFD models of the iliac veins that matched common iliac flow splits within 2% and measured US velocities within 10%. Proof-of-concept analyses (1 subject, 1 control) have revealed that patients with IVCS may experience elevated shear rates in the compressed left common iliac vein, more typical of the arterial rather than the venous circulation. These results encourage us to extend this protocol to a larger group of patients with IVCS and controls., Conclusions: We developed a protocol that obtains hemodynamic measurements of the IVC and iliac veins from US, creates patient-specific 3D reconstructions of the venous anatomy using CT and US examinations, and computes shear rates using calibrated CFD methods. Proof-of-concept results have indicated that patients with IVCS may experience elevated shear rates in the compressed left common iliac vein. Larger cohorts are needed to assess the relationship between venous compression and shear rates in patients with IVCS as compared with controls with noncompressed iliac veins. Further studies using this protocol may also give promising insights into whether or not to treat patients with moderate, yet symptomatic compression., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Patients with venous insufficiency can be treated with ablation or phlebectomy, or both. Patients undergoing superficial venous procedures have an elevated risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). At our institution, we initiated a standardized protocol in which patients with a Caprini score (2005 version) of ≥8 are treated with 1 week of prophylactic anticoagulation after the procedure. Duplex ultrasound was performed at 1 week and then within 90 days after the procedure. This aim of the present study was to determine the thrombotic and clinical outcomes after superficial vein procedures using a standardized protocol for DVT/PE risk assessment and prophylaxis., Methods: We performed a retrospective analysis of prospectively collected data of superficial vein procedures from 2015 to 2021 at a single center. The patient demographics, CEAP (Clinical-Etiology-Anatomy-Pathophysiology) clinical class, venous clinical severity score, patient-reported outcomes, treatment type, Caprini scores, pre- and postoperative anticoagulation use, and outcomes were collected. Descriptive statistics were used for the patient demographics, procedure details, and unadjusted surgical outcomes. Multivariable logistic regression was used to evaluate the relationship between procedure type and DVT and PE after adjusting for patient characteristics, disease severity, periprocedural anticoagulation, and Caprini score., Results: A total of 1738 limbs were treated with ablation (n = 820), phlebectomy (n = 181), or ablation and phlebectomy (n = 737). More patients were women (67.1%) and White (90.9%). The overall incidence of DVT/PE was 1.4%. Patients undergoing ablation with phlebectomy had higher rates of DVT/PE (2.7%) than those undergoing ablation (0.2%) or phlebectomy alone (1.7%; P < .01). However, only 30% of DVTs were above the knee. On multivariate analysis, only the procedure type predicted for DVT/PE. However, patients undergoing ablation and phlebectomy achieved better patient-reported outcomes (Caprini score, 5.9) compared with those undergoing ablation (Caprini score, 7.2) or phlebectomy (Caprini score, 7.9) alone (P < .01). The best improvement in the venous clinical severity score was seen with phlebectomy alone., Conclusions: The expected difference in the DVT/PE rates between high- and low-risk groups did not materialize in our patients, perhaps secondary to the additional chemoprophylaxis prescribed for the high-risk cohort (Caprini score, ≥8). These results call for a randomized trial to assess the efficacy of a standardized protocol in the reduction of DVT/PE after superficial vein procedures., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Superficial vein aneurysms (SVA) are rare vascular pathologies associated with trauma, chronic venous disease, and venous malformation., Method: We retrospectively reviewed cases of SVA treated from 1986 to 2022., Results: Out of 2463 venous procedures, 16 patients were found with 19 GSV and 1 SSV aneurysms, with 88% presenting with a palpable mass. Varicose veins were noted in 94% of patients, 81% had concomitant reflux, 15% had thrombus within the aneurysm sac, and 19% demonstrated multiple aneurysms. All patients underwent ligation and excision. Post-procedure, 55% of patients received anticoagulants, and 85% received compression. Mean follow-up was 19.4 months, with no aneurysm recurrence. We propose a modification to the current SVA classification., Conclusion: The prevalence of multiple aneurysms suggests the need for complete limb imaging in affected patients. Surgical management of SVA was effective in preventing SVA recurrence, while the proposed classification modification will aid in future SVA management.

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., (© 2023 by The American Society of Hematology.)

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., Objective: We hypothesized that a high rate of prescription of VTE chemoprophylaxis would be associated with decreased VTE incidence and mortality., Summary Background Data: Recommendations for VTE prevention in surgical patients include chemoprophylaxis based upon preoperative risk stratification., Methods: 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., Results: 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., Conclusions: 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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: 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., Methods: 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., Results: 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 completed >3 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)., Conclusions: 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., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the association between gender and long-term clinician-reported and patient-reported outcomes after endovenous ablation procedures., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

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 non-operative 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., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Venous thromboembolism is a very common and costly health problem worldwide. Anticoagulant treatment for VTE is imperfect: all have the potential for significant bleeding, and none prevent the development of post thrombotic syndrome after deep vein thrombosis or chronic thromboembolic pulmonary hypertension after pulmonary embolism. For these reasons, alternate forms of therapy with improved efficacy and decreased bleeding are needed. Selectins are a family (P-selectin, E-selectin, L-selectin) of glycoproteins that facilitate and augment thrombosis, modulating neutrophil, monocyte, and platelet activity. P- and E-selectin have been investigated as potential biomarkers for thrombosis. Inhibition of P-selectin and E-selectin decrease thrombosis and vein wall fibrosis, with no increase in bleeding. Selectin inhibition is a promising avenue of future study as either a stand-alone treatment for VTE or as an adjunct to standard anticoagulation therapies., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

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., (Copyright © 2021. Published by Elsevier Inc.)

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., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Few studies have investigated outcomes after truncal endovenous ablation in patients with combined deep and superficial reflux and no studies have evaluated patient-reported outcomes., Methods: We investigated the short- and long-term clinical and patient-reported outcomes among patients with and without deep venous reflux undergoing truncal endovenous ablation from 2015 to 2019 in the Vascular Quality Initiative. Preprocedural and postprocedural comparisons were performed using the t-test, χ 2 , or their nonparametric counterpart when appropriate. Multivariable logistic regression models were used to assess for confounding., Results: A total of 4881 patients were included, of which 2254 (46.2%) had combined deep and superficial reflux. The median follow-up was 336.5 days. Patients with deep reflux were less likely to be female (65.9% vs 69.9%; P = .003), more likely to be Caucasian (90.2% vs 86.5%; P = .003) and had no difference in BMI (30.6 ± 7.5 vs 30.6 ± 7.2; P = .904). Additionally, no difference was seen in rates of prior varicose vein treatments, number of pregnancies, or history of deep venous thrombosis; however, patients without deep reflux were more likely to be on anticoagulation at the time of the procedure (10.9% vs 8.1%; P < .001). Patients without deep reflux had slightly higher median preprocedural Venous Clinical Severity Score (VCSS) scores (8 [interquartile range (IQR), 6-10]) vs 7 [IQR, 6-10]; P = .005) as well as postprocedural VCSS scores (5 [IQR, 3-7] vs 4 [IQR, 2-6]; P < .001). The median change in VCSS from before to after the procedure was lower for patients without deep reflux (3 [IQR, 1.0-5.5] vs 3.5 [IQR, 1-6]; P = .006). Total symptom score was higher for patients without deep reflux both before (median, 14 [IQR, 10-19] vs median, 13.5 [IQR, 9.5-18]; P = .005) and postprocedurally (median, 4 [IQR, 1-9] vs median, 3.25 [IQR, 1-7]; P < .001), but no difference was seen in change in symptom score (median, 8 [IQR, 4-13] vs median, 9 [IQR, 4-13]; P = .172). Patients with deep reflux had substantially higher rates of complications (10.4% vs 3.0%; P < .001), with a particular increase in proximal thrombus extension (3.1% vs 1.1%; P < .001). After controlling for confounding, this estimate of effect size for any complication increased (odds ratio, 5.72; 95% confidence interval, 2.21-14.81; P < .001)., Conclusions: No significant difference is seen in total symptom improvement when patients undergo truncal endovenous ablation with concomitant deep venous reflux, although a greater improvement was seen in VCSS score in these patients. Patients with deep venous reflux had a significantly increased rate of complications, independent of confounding variables, and should be counseled appropriately before the decision for treatment., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus confers a risk of significant coagulopathy, with the resulting development of venous thromboembolism (VTE), potentially contributing to the morbidity and mortality. The purpose of the present review was to evaluate the potential mechanisms that contribute to this increased risk of coagulopathy and the role of anticoagulants in treatment., Methods: A literature review of coronavirus disease 2019 (COVID-19) and/or SARS-CoV-2 and cell-mediated inflammation, clinical coagulation abnormalities, hypercoagulability, pulmonary intravascular coagulopathy, and anticoagulation was performed. The National Clinical Trials database was queried for ongoing studies of anticoagulation and/or antithrombotic treatment or the incidence or prevalence of thrombotic events in patients with SARS-CoV-2 infection., Results: The reported rate of VTE among critically ill patients infected with SARS-CoV-2 has been 21% to 69%. The phenomenon of breakthrough VTE, or the acute development of VTE despite adequate chemoprophylaxis or treatment dose anticoagulation, has been shown to occur with severe infection. The pathophysiology of overt hypercoagulability and the development of VTE is likely multifactorial, with evidence supporting the role of significant cell-mediated responses, including neutrophils and monocytes/macrophages, endothelialitis, cytokine release syndrome, and dysregulation of fibrinolysis. Collectively, this inflammatory process contributes to the severe pulmonary pathology experienced by patients with COVID-19. As the infection worsens, extreme D-dimer elevations, significant thrombocytopenia, decreasing fibrinogen, and prolongation of prothrombin time and partial thromboplastin time occur, often associated with deep vein thrombosis, in situ pulmonary thrombi, and/or pulmonary embolism. A new phenomenon, termed pulmonary intravascular coagulopathy, has been associated with morbidity in patients with severe infection. Heparin, both unfractionated heparin and low-molecular-weight heparin, have emerged as agents that can address the viral infection, inflammation, and thrombosis in this syndrome., Conclusions: The overwhelming inflammatory response in patients with SARS-CoV-2 infection can lead to a hypercoagulable state, microthrombosis, large vessel thrombosis, and, ultimately, death. Early VTE prophylaxis should be provided to all admitted patients. Therapeutic anticoagulation therapy might be beneficial for critically ill patients and is the focus of 39 ongoing trials. Close monitoring for thrombotic complications is imperative, and, if confirmed, early transition from prophylactic to therapeutic anticoagulation should be instituted. The interplay between inflammation and thrombosis has been shown to be a hallmark of the SARS-CoV-2 viral infection., (Copyright © 2020 Society for Vascular Surgery. All rights reserved.)

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., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: 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 of >40% 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., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 Society for Vascular Surgery. All rights reserved.)

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., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Varicose vein ablation procedures are being performed with increasing frequency; however, there is a lack of consensus on the relative efficacy of combined treatment of saphenous incompetence and symptomatic varicosities vs a staged approach. In this study, we examined the impact on symptom severity when a procedure to eliminate varicosities was added to standard endovenous saphenous ablation., Methods: The Varicose Vein Module of the American Venous Registry was established by the American Venous Forum in 2010 and collected data from 48 physicians during a 5-year period. We analyzed patients with Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) C2 disease severity and without prior treatment. Combination therapy (CT) was defined as the use of a procedure directly addressing visible varicosities (stab phlebectomy or injection of sclerosant into varicosity) combined with endovenous saphenous vein ablation. Unimodal therapy (UT) was defined as endovenous saphenous vein ablation alone (radiofrequency or laser). Change in symptom severity was assessed by the pretreatment and 1-month follow-up Venous Clinical Severity Score (VCSS). Univariate statistics compared the CT and UT groups, with P values obtained using the Student t-test or Pearson χ 2 test as appropriate. A multivariable linear regression model assessed the association of CT with the change in VCSS., Results: There were 526 patients included for analysis (UT, 97; CT, 429). UT patients were more likely to be white (85.6% vs 62.7%; P < .001), had a higher initial VCSS (6.71 vs 5.07; P < .001), and were assessed at an earlier follow-up visit (28.9 days postoperatively vs 33.3 days; P < .001). Compared with UT, CT was associated with an additional half-point reduction in VCSS on univariate analysis (-3.71 points for UT vs -4.20 for CT; P = .13). After treatment, CT was associated with significantly lower scores on the pain and varicose vein components of the VCSS (pain: 0.31 for UT vs 0.07 for CT [P = .0008]; varicose veins: 0.47 for UT vs 0.03 for CT [P < .001]). On the multivariable model, after adjustment for white race, day of follow-up, age group, and initial VCSS, CT was associated with an additional reduction in VCSS of 1.52 points compared with UT (P = .002)., Conclusions: Invasive treatment of C2 chronic venous insufficiency improves symptom severity. Whereas treatment of venous reflux is essential to address venous symptoms, our results suggest that patients further benefit from additional direct treatment of varicosities. For selected patients, CT may present a more effective treatment strategy than saphenous ablation alone., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: 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., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

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., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.)

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., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: An association between increased venous thromboembolism (VTE) events and influenza A H1N1 (H1N1) was noted in the first 10 patients with severe acute respiratory distress syndrome (ARDS). An empirical systemic anticoagulation protocol (heparin intravenous infusion) was initiated when autopsy of patients with severe hypoxemia confirmed multiple primary pulmonary thrombi and emboli. The purpose of this study was to examine the relationship between H1N1 and VTE events and to assess the efficacy of empirical systemic heparin anticoagulation in preventing VTE and death in H1N1 severe ARDS patients., Methods: An observational cohort study of critically ill severe ARDS patients with possible H1N1 viral pneumonia was performed in a surgical intensive care unit in a single 990-bed academic tertiary care center. Early empirical systemic heparin anticoagulation for all severe ARDS patients with possible H1N1 viral pneumonia was initiated as a VTE preventive strategy., Results: Univariate comparisons and multivariate logistic regression were used to identify risk factors for VTE. Independent risk factors for VTE included H1N1, culture-positive bacterial pneumonia, and vasopressor requirement. Independent risk factors for pulmonary embolism included H1N1, culture-positive bacterial pneumonia, and male sex. H1N1 ARDS patients had 23.3-fold higher risk for pulmonary embolism and 17.9-fold increased risk for VTE. Kaplan-Meier analysis and log-rank test confirmed that empirical systemic heparin anticoagulation provided significant protection from thrombotic events in the H1N1-positive but not in the H1N1-negative critically ill ARDs patients. In multivariate analysis, adjusting for H1N1 status, patients without empirical systemic anticoagulation were 33 times more likely to have any VTE compared with those treated with empirical systemic heparin anticoagulation (P = .01)., Conclusions: Critically ill patients with H1N1 ARDS have increased risk of venous thrombotic complications, particularly pulmonary thromboembolism. Empirical systemic heparin anticoagulation in this cohort of patients significantly reduced VTE incidence without increased hemorrhagic complications., (Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

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 (VT). Leading experts in VT research came together through the American Venous Forum to develop a consensus on maximizing the utility and application of available mouse models of VT. In this work, we provide an algorithm for model selection, with discussion of the advantages, disadvantages, and applications of the main mouse models of VT. Additionally, we provide a detailed surgical description of the models with guidelines to validate surgical technique., (© 2019 International Society on Thrombosis and Haemostasis.)

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.

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]., (Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

A variety of viral infections are associated with hypercoagulable states and may be linked to the development of deep venous thrombosis and pulmonary embolism. The Zika and Chikungunya viral infections spread through the South and Central American continents, moving to North America in 2016, with severe cases of polyarthralgia, fever, and Guillain-Barré syndrome leading eventually to death. A decreased trend for both infections was reported in the first quarter of 2017. In this article, we report the possible association of venous thromboembolic events associated with Zika infection. After 2 cases of deep venous thrombosis in patients with acute Zika infections, D-dimer levels were measured in 172 consecutive patients who presented to the emergency department of a university hospital in an endemic region of Brazil with either Zika or Chikungunya infections confirmed by polymerase chain reaction tests. D-dimer levels were increased in 19.4% of 31 patients with Zika and in 63.8% of 141 patients with Chikungunya infections. The mechanisms behind this association are yet to be elucidated as well as the potential for venous thromboembolism prevention strategies for in-hospital patients affected by Zika and Chikungunya infections.

Background: Whereas chronic venous insufficiency and varicose veins (VVs) are a universally recognized problem, they are frequently underappreciated as major contributors to long-term morbidity in the elderly despite the increasing prevalence with age. Previous studies have demonstrated that chronic venous insufficiency and VV treatments in patients ≥65 years old yield an overall benefit; however, there have been few data as to whether octogenarians are undergoing these procedures and with what success. As such, our objectives were to investigate the procedures selected, to examine clinical outcomes after VV procedures in elderly patients ≥80 years old, and to explore complication rates (both systemic and leg specific) after VV procedures in patients ≥80 years old., Methods: We performed a retrospective review using the Vascular Quality Initiative Varicose Vein Registry of all VV procedures performed for ≥C2 disease from January 2015 to February 2017. We divided all procedures into three age groups: patients <65 years, patients ≥65 to 79 years, and patients ≥80 years. Statistical testing included χ 2 test for categorical variables and Student t-test for continuous variables. Two comparisons were performed: first, comparing patients <65 years old with patients ≥65 to 79 years old; and second, comparing patients ≥65 to 79 years old with patients ≥80 years old., Results: There were a total of 12,262 procedures performed, with 8608 procedures in the patients <65 years, 3226 in patients 65 to 79 years, and 428 procedures in patients ≥80 years. A total of 22,050 veins were treated during the 12,262 procedures. Almost half of procedures (46.51%; n = 5703) had only one vein treated during a single procedure. Between age groups, the percentage of one vein treated increased as the patient's age increased, ranging from 45.39% (n = 3875) for patients <65 years to 48.55% (n = 1555) for patients between 65 and 79 years and 64.08% (n = 273) for patients ≥80 years. Patients in the group ≥80 years had an overall lower average body mass index and were more likely to be receiving anticoagulation and to undergo truncal procedures alone compared with the other groups. The group ≥80 years had a significant improvement in both Venous Clinical Severity Score (4.37 ± 4.16; P < .001) and patient-reported outcomes (8.79 ± 7.27; P < .001) from before to after the 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. In addition, octogenarians have statistically significant improvement of Venous Clinical Severity Score and patient-reported outcomes with a low risk of complications despite more advanced venous disease at presentation., (Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Deep vein thrombosis (DVT) is a common disease that carries serious ramifications for patients, including pulmonary embolism and post-thrombotic syndrome (PTS). Although standard treatment for DVT is anticoagulation, this carries an added risk of bleeding and increased medication monitoring. Identifying those at risk for DVT and PTS can be difficult, and current research with murine models is helping to illuminate the biologic changes associated with these two disorders. Potential novel biomarkers for improving the diagnosis of DVT and PTS include ICAM-1, P-selectin, and cell-free DNA. Inhibition of factor XI, P- and E-selectin, and neutrophil extracellular traps holds promise for novel clinical treatment of DVT. Experimental research on PTS suggests potential cellular and mediator therapy targets of TLR9, MMP-2 and-9, PAI-1, and IL-6. Although many important concepts and mechanisms have been elucidated through research on DVT and PTS, more work must be done to translate experimental findings to the clinical arena. This review examines the currently used murine models of DVT, biomarkers involved in the pathophysiology and diagnosis of DVT and PTS, and potential pharmacologic targets for PTS treatment., Competing Interests: Conflict of Interest Disclosure: The authors have completed and submitted the Methodist DeBakey Cardiovascular Journal Conflict of Interest Statement and none were reported.

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., Competing Interests: J.A.D. is on the Board of Directors of the American Venous Forum, as a Research Council Chair and Member of the ISTH-SSC Board. All the other authors report no conflict of interest., (Schattauer GmbH Stuttgart.)

Objective: The spectrum of chronic venous disease (CVD) in adults is well documented, whereas there is a paucity of data published commenting on pediatric CVD. We previously identified that there is often venous reflux present in cases of pediatric lower extremity edema despite an alternative confirmed diagnosis. To further assess the clinical significance of this venous reflux, this study aimed to elicit venous parameters in healthy pediatric controls., Methods: Healthy pediatric volunteers aged 5 to 17 years were recruited for venous reflux study. A comprehensive venous reflux study was performed with the patient standing. Vein diameter, patterns of valvular reflux, and accessory venous anatomy were examined in the deep and superficial venous systems., Results: Eighteen children including 10 boys and 8 girls were studied. Five volunteers were aged 5 to 8 years, six volunteers were aged 9 to 12 years, and seven volunteers were aged 13 to 17 years. Great saphenous vein (GSV) diameter at the saphenofemoral junction significantly increased with age. Deep vein valve closure time (VCT) did not differ significantly between groups, whereas GSV VCT was significantly higher in the 9- to 12-year age group. Incidental venous insufficiency was identified in 60% of children aged 5 to 8 years (n = 3), 50% of children aged 9 to 12 years (n = 3), and 57% of children aged 13 to 17 years (n = 4). All superficial venous reflux was confined to the GSV; there were no cases of isolated deep venous reflux. Reflux was identified at multiple GSV stations in 60% of children. There was no significant difference in incompetent GSV VCT in comparing children with and without deep venous reflux. Accessory superficial veins were identified in 20% of children aged 5 to 8 years (n = 1), 50% of children aged 9 to 12 years (n = 3), and 43% of children aged 13 to 17 years (n = 3). The presence of an accessory saphenous vein was not associated with deep venous reflux in any patient, and only 29% of those with accessory saphenous venous anatomy had evidence of superficial venous (GSV) reflux., Conclusions: The GSV continues to grow in diameter through the teenage years. Incidental valvular incompetence and GSV reflux are common. The presence of accessory saphenous veins is similarly common and not associated with venous reflux. The clinical significance and natural history of this incidental venous reflux remain unclear. Future research should determine whether these changes seen in the pediatric age group lead to CVD during later years of life., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: Deep vein thrombosis (DVT) is a major health problem, responsible for significant morbidity and mortality. The identification of a simple and effective diagnostic biomarker of DVT remains a challenge. Metabolomics have recently emerged as a new powerful scientific tool to characterise metabolic phenotypes of complex diseases and investigate small molecules in biofluids. The aim of the study was to identify the blood and vein wall metabolomic signature of DVT in a murine experimental model., Methods: An established inferior vena cava ligation mouse model of DVT (n=10) was used and compared with sham surgery controls (n=10). Comprehensive untargeted metabolic profiling of serum and vein wall extracts was undertaken using liquid chromatography coupled mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy., Results: Multivariate and univariate statistical analysis demonstrated a differential metabolic profile when comparing DVT mice and control animals. Serum from DVT mice was characterised by differential concentrations of adenosine (decreased in DVT mice 9.6 fold), adenine (decreased 10.6 fold), and tricyclic acid cycle (TCA) intermediates, including citrate, succinate, and fumarate (1.5, 2.3, and 2.8 fold decreases, respectively). l-carnitine was found to be of greater abundance in the serum of DVT animals (67.0 fold change). A number of lipid moiety classes, including sphingomyelins, phosphatidylcholines, and triglycerides, were differentially abundant. Several metabolites were found in vein wall, including acetylcarnitine (increased in DVT mice 1.9 fold), adenosine (increased 2.2 fold), and ceramide (increased 2.7 fold). Correlation analysis illustrated the biochemical relationships between assigned metabolites, with the discriminatory molecules being highly correlated with each other, in both serum and vein wall., Conclusions: The present findings demonstrate that metabolic dysregulations in DVT centre on energy metabolism, sphingolipid, and adenosine metabolism, representing a DVT specific metabolite signature in a murine experimental model., (Copyright © 2018 European Society for Vascular Surgery. All rights reserved.)