Publications by authors named "Thomas W Wakefield"

175 Publications

Antisense oligonucleotides and nucleic acids generate hypersensitive platelets.

Thromb Res 2021 Jan 18;200:64-71. Epub 2021 Jan 18.

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, Medical University of Vienna, Vienna, Austria. Electronic address:

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.
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http://dx.doi.org/10.1016/j.thromres.2021.01.006DOI Listing
January 2021

Low to Moderate Risk Non-Orthopedic Surgical Patients do not Benefit from VTE Chemoprophylaxis.

Ann Surg 2020 Nov 18. Epub 2020 Nov 18.

Section of Vascular Surgery.

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 post-surgical patients with and without VTE chemoprophylaxis between April 2013 - 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 UFH or LMWH compared to those not receiving chemoprophylaxis (1.22 vs. 1.13%, p = .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 = .092). Postoperative transfusion (8.28 vs. 7.50%, p = .057) and mortality (2.00% vs. 1.62%, p = .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 post-surgical care, VTE remains a significant occurrence, despite wide adoption of VTE risk assessment. While postoperative VTE chemoprophylaxis was broadly applied, after adjusting for confounders, no reduction in VTE was observed in at risk surgical patients.
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http://dx.doi.org/10.1097/SLA.0000000000004646DOI Listing
November 2020

Venous thrombosis epidemiology, pathophysiology, and anticoagulant therapies and trials in severe acute respiratory syndrome coronavirus 2 infection.

J Vasc Surg Venous Lymphat Disord 2021 01 8;9(1):23-35. Epub 2020 Sep 8.

Section of Vascular Surgery, Department of Surgery, Samuel and Jean Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Mich. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jvsv.2020.08.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834652PMC
January 2021

Effect of concomitant deep venous reflux on truncal endovenous ablation outcomes in the Vascular Quality Initiative.

J Vasc Surg Venous Lymphat Disord 2021 Mar 24;9(2):361-368.e3. Epub 2020 Jun 24.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Mich.

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, 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.
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http://dx.doi.org/10.1016/j.jvsv.2020.04.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768610PMC
March 2021

Outcomes after truncal ablation with or without concomitant phlebectomy for isolated symptomatic varicose veins (C2 disease).

J Vasc Surg Venous Lymphat Disord 2021 Mar 2;9(2):369-376. Epub 2020 Jun 2.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Mich.

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 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.
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http://dx.doi.org/10.1016/j.jvsv.2020.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788516PMC
March 2021

Comparison of unilateral vs bilateral and staged bilateral vs concurrent bilateral truncal endovenous ablation in the Vascular Quality Initiative.

J Vasc Surg Venous Lymphat Disord 2021 Jan 26;9(1):113-121.e3. Epub 2020 May 26.

Division of Vascular Surgery, Montefiore Medical Center, Bronx, NY.

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 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 vs 31.8 ± 7.6 kg/m; 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.
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http://dx.doi.org/10.1016/j.jvsv.2020.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768602PMC
January 2021

Closed plication is a safe and effective method for treating popliteal vein aneurysm.

J Vasc Surg Venous Lymphat Disord 2021 Jan 20;9(1):187-192. Epub 2020 May 20.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Mich. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jvsv.2020.04.026DOI Listing
January 2021

Practical diagnosis and treatment of suspected venous thromboembolism during COVID-19 pandemic.

J Vasc Surg Venous Lymphat Disord 2020 07 17;8(4):526-534. Epub 2020 Apr 17.

Department of Surgery, Section of Vascular Surgery, University of Michigan Health System, Ann Arbor, Mich. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jvsv.2020.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162794PMC
July 2020

Venous thromboembolism and transfusion after major abdominopelvic surgery.

Surgery 2020 06 3;167(6):1025. Epub 2020 Mar 3.

University of Michigan. Electronic address:

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http://dx.doi.org/10.1016/j.surg.2019.12.016DOI Listing
June 2020

Use of GMI-1271, an E-selectin antagonist, in healthy subjects and in 2 patients with calf vein thrombosis.

Res Pract Thromb Haemost 2020 Feb 11;4(2):193-204. Epub 2020 Feb 11.

Department of Internal Medicine Division of Hematology/Oncology University of Michigan Ann Arbor MI USA.

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.
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http://dx.doi.org/10.1002/rth2.12279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040550PMC
February 2020

Inflammatory biomarkers in deep venous thrombosis organization, resolution, and post-thrombotic syndrome.

J Vasc Surg Venous Lymphat Disord 2020 03;8(2):299-305

Section of Vascular Surgery, Department of Surgery, Michigan Medicine, University of Michigan, Ann Arbor, Mich. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jvsv.2019.09.008DOI Listing
March 2020

Clinical response to combination therapy in the treatment of varicose veins.

J Vasc Surg Venous Lymphat Disord 2020 03 14;8(2):216-223. Epub 2019 Dec 14.

Division of Vascular Surgery, University of Maryland School of Medicine, Baltimore, Md. Electronic address:

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 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.
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http://dx.doi.org/10.1016/j.jvsv.2019.10.015DOI Listing
March 2020

Choosing a mouse model of venous thrombosis: a consensus assessment of utility and application.

J Thromb Haemost 2019 Apr 30;17(4):699-707. Epub 2019 Mar 30.

University of Maryland.

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.
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http://dx.doi.org/10.1111/jth.14413DOI Listing
April 2019

Pediatric deep venous thrombosis.

J Vasc Surg Venous Lymphat Disord 2019 May 8;7(3):452-462. Epub 2019 Mar 8.

Section of Vascular Surgery, Department of Surgery, Michigan Medicine, University of Michigan, Ann Arbor, Mich. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jvsv.2018.12.012DOI Listing
May 2019

Tuning the Thromboinflammatory Response to Venous Flow Interruption by the Ectonucleotidase CD39.

Arterioscler Thromb Vasc Biol 2019 04;39(4):e118-e129

From the Department of Molecular and Integrative Physiology (A.C.A., D.J.P.), University of Michigan Medical Center, Ann Arbor.

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.
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http://dx.doi.org/10.1161/ATVBAHA.119.312407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467508PMC
April 2019

Zika and Chikungunya Virus and Risk for Venous Thromboembolism.

Clin Appl Thromb Hemost 2019 Jan-Dec;25:1076029618821184

7 Loyola University Medical Center, Maywood, IL, USA.

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.
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http://dx.doi.org/10.1177/1076029618821184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714924PMC
June 2019

Choosing a Mouse Model of Venous Thrombosis.

Arterioscler Thromb Vasc Biol 2019 03;39(3):311-318

Department of Surgery, University of Maryland, College Park (B.K.L.).

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.
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http://dx.doi.org/10.1161/ATVBAHA.118.311818DOI Listing
March 2019

Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients.

J Vasc Surg Venous Lymphat Disord 2019 05 23;7(3):317-324. Epub 2018 Nov 23.

Acute Care Surgery, Department of Surgery, University of Michigan, Ann Arbor, Mich. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jvsv.2018.08.010DOI Listing
May 2019

Venous Thrombosis and Post-Thrombotic Syndrome: From Novel Biomarkers to Biology.

Methodist Debakey Cardiovasc J 2018 Jul-Sep;14(3):173-181

UNIVERSITY OF MICHIGAN, ANN ARBOR, MICHIGAN.

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.
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http://dx.doi.org/10.14797/mdcj-14-3-173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217569PMC
January 2019

Invited commentary.

J Vasc Surg Venous Lymphat Disord 2018 07;6(4):448-449

Ann Arbor, Mich.

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http://dx.doi.org/10.1016/j.jvsv.2018.01.009DOI Listing
July 2018

Clinical outcomes after varicose vein procedures in octogenarians within the Vascular Quality Initiative Varicose Vein Registry.

J Vasc Surg Venous Lymphat Disord 2018 07 8;6(4):464-470. Epub 2018 May 8.

Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Mich.

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 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.
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http://dx.doi.org/10.1016/j.jvsv.2018.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005729PMC
July 2018

Pre-Clinical Model to Study Recurrent Venous Thrombosis in the Inferior Vena Cava.

Thromb Haemost 2018 06 25;118(6):1048-1057. Epub 2018 Apr 25.

Department of Surgery, Section of Vascular Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States.

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.
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http://dx.doi.org/10.1055/s-0038-1645855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527429PMC
June 2018

Deep Vein Thrombosis Exhibits Characteristic Serum and Vein Wall Metabolic Phenotypes in the Inferior Vena Cava Ligation Mouse Model.

Eur J Vasc Endovasc Surg 2018 05 8;55(5):703-713. Epub 2018 Mar 8.

Academic Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejvs.2018.01.027DOI Listing
May 2018

A pilot study of venous duplex ultrasound parameters in healthy children.

J Vasc Surg Venous Lymphat Disord 2018 05 29;6(3):347-350. Epub 2017 Dec 29.

Department of Surgery, University of Michigan, Ann Arbor, Mich. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jvsv.2017.09.009DOI Listing
May 2018

Invited commentary.

J Vasc Surg 2018 01;67(1):299

Ann Arbor, Mich.

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http://dx.doi.org/10.1016/j.jvs.2016.12.089DOI Listing
January 2018

Age is not a barrier to good outcomes after varicose vein procedures.

J Vasc Surg Venous Lymphat Disord 2017 09;5(5):647-657.e1

Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Mich.

Background: The Vascular Quality Initiative (VQI) Varicose Vein Registry (VVR) represents a patient-centered database launched in January 2015. Previous work describing overall trends and outcomes of varicose vein procedures across the United States demonstrates a benefit from these procedures. The existing gaps in evidence to support current and future Medicare coverage of varicose vein procedures necessitate further description of clinical outcomes in patients ≥65 years old compared with the population <65 years old.

Methods: This study analyzed prospectively captured anatomic, procedural, and outcome data for all patients in a national cohort of all VQI VVR-participating centers. The VQI VVR database was queried for all patients undergoing varicose vein procedures between January 2015 and July 2016. Preprocedural and postprocedural Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) classification, Venous Clinical Severity Score (VCSS), and patient-reported outcomes (PROs) were compared between patients <65 years and ≥65 years old. Univariate descriptive statistics of demographic and procedural data were performed. Student t-tests were then performed on change in CEAP classification, VCSS score, and PROs (heaviness, achiness, throbbing, swelling, itching, appearance, and impact on work) for each group.

Results: There were 4841 varicose vein procedures performed from January 2015 to May 2016. There were 3441 procedures performed in 2691 patients (3631 limbs) in the group <65 years old and 1400 procedures performed in 1068 patients (1467 limbs) in the group ≥65 years old. Truncal veins alone were the most common veins treated in both groups. The majority of patients were white and female in both groups. Most of the demographic characteristics were clinically similar (although statistically different) in both groups with the exception of a higher body mass index in the group <65 years old and a history of bilateral varicose vein treatment, and anticoagulation was more common among patients ≥65 years old. Patients in both groups experienced statistically significant improvement in VCSS, PROs, and CEAP class. There was no difference in overall complications between age groups.

Conclusions: All patients demonstrated an associated improvement in both clinical outcomes (CEAP class, VCSS) and PROs. There was no significant difference in the improvement in CEAP class and VCSS between patients younger and older than 65 years, although the younger population reported greater improvement in PROs. Given these findings, patients older than 65 years appear to benefit from varicose vein procedures and should not be denied interventions on their varicose veins and venous insufficiency on the basis of their age only.
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http://dx.doi.org/10.1016/j.jvsv.2017.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584572PMC
September 2017

Pathophysiology of varicose veins.

J Vasc Surg Venous Lymphat Disord 2017 05;5(3):460-467

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Mich.

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.
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http://dx.doi.org/10.1016/j.jvsv.2016.12.014DOI Listing
May 2017

Report of the Society for Vascular Surgery and the American Venous Forum on the July 20, 2016 meeting of the Medicare Evidence Development and Coverage Advisory Committee panel on lower extremity chronic venous disease.

J Vasc Surg Venous Lymphat Disord 2017 May;5(3):378-398

Section of Vascular Surgery, University of Michigan, Ann Arbor, Mich.

On July 20, 2016, a Medicare Evidence Development and Coverage Advisory Committee panel assessed the benefits and risks of currently used lower extremity chronic venous disease (CVD) treatments and their effects on health outcome of the American adult population. The main purpose of the meeting was to advise the Centers for Medicare & Medicaid Services on coverage determination for interventions used for treatment of CVD. A systematic review of the Agency for Healthcare Research and Quality was presented, followed by lectures of invited experts and a public hearing of representatives of professional societies and the industry. After discussing critical issues, the panel voted for key questions. This report summarizes the presented evidence to support recommendations of the Society for Vascular Surgery/American Venous Forum coalition and the presentations on selected discussion topics. These included important venous disease evidence gaps that have not been sufficiently addressed, venous disease treatment disparities and how they may affect the health outcomes of Medicare beneficiaries, and mechanisms that might be supported by the Centers for Medicare & Medicaid Services to improve the evidence base to optimize the care of patients with lower extremity CVD.
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http://dx.doi.org/10.1016/j.jvsv.2017.02.001DOI Listing
May 2017

First 10-month results of the Vascular Quality Initiative Varicose Vein Registry.

J Vasc Surg Venous Lymphat Disord 2017 05;5(3):312-320.e2

Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Mich. Electronic address:

Objective: The Vascular Quality Initiative Varicose Vein Registry (VQI VVR) represents a new Patient Safety Organization database launched in January 2015 as a collaborative effort between the American Venous Forum and the Society for Vascular Surgery. This study was undertaken to identify real-world trends among treatment choices and outcomes of varicose vein patients.

Methods: Registry data prospectively captured anatomic, procedural, and outcome data for patients with C2 or more severe disease undergoing intervention for venous varicosities from January to November 2015. Univariate descriptive statistics of demographic and procedural data was performed. Preprocedural and postprocedural comparisons were performed with t-test or χ analysis as appropriate.

Results: In total, 2661 veins in 1803 limbs of 1406 patients were treated for varicose vein disease. The majority of patients were female (71.5%) and white (78.3%). Previous varicose vein treatment had been undertaken by 31.2%. The most common site of reflux was the great saphenous vein in 74.4%, with 31% of patients having coexisting deep venous reflux. The right and left extremities were affected equally. Endovenous treatment of axial reflux was the preferred treatment in 89.1%, divided largely between radiofrequency ablation (55.2%) and endovenous laser ablation (33.9%). Clusters were often treated concomitantly with truncal reflux (n = 488 [76%]). The majority of cluster treatments were performed in an office-based setting (78.1%). The majority of clusters were located at the calf (89.7%) and treated with stab phlebectomy (84.8%). For all patients undergoing intervention for varicose veins, Venous Clinical Severity Score (VCSS) improved on average 4.68 ± 3.35 (n = 719; P < .001) postoperatively from a mean preoperative VCSS of 9.39 ± 3.87 to a mean postoperative VCSS of 4.71 ± 3.83. Improvements were seen in patient-reported outcomes (PROs) of heaviness, achiness, throbbing, swelling, itching, appearance, and work impact (total score change, 10.75 ± 6.94; n = 607; P < .001) from a mean preoperative PRO score of 16.48 ± 6.23 to a mean postoperative PRO score of 5.73 ± 5.80.

Conclusions: The VQI VVR provides detailed assessment of varicose vein interventions and is useful for monitoring of changes after treatment. Modern-day varicose vein surgery is characterized by predominantly endovenous treatment of axial vein reflux, phlebectomy of clusters, and substantial improvements in both VCSS and PROs.
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http://dx.doi.org/10.1016/j.jvsv.2016.12.007DOI Listing
May 2017