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Objective: The Center for Medicare and Medicaid Services recently began assessing financial penalties to hospitals with high readmission rates for a narrow set of medical conditions. Because these penalties will be extended to surgical conditions in the near future, we sought to determine whether readmissions are a reliable predictor of hospital performance with vascular surgery. Methods: We examined 4 years of national Medicare claims data from 1576 hospitals on beneficiaries undergoing three common vascular procedures: open or endovascular abdominal aortic aneurysm repair (n = 81,520) or lower extremity arterial bypass (n = 57,190). First, we divided our population into two groups on the basis of operative date (2005-2006 and 2007-2008) and generated hospital risk- and reliability-adjusted readmission rates for each time period. We evaluated reliability through the use of the “test-retest” method; highly reliable measures will show little variation in rates over time. Specifically, we evaluated the year-to-year reliability of readmissions by calculating Spearman rank correlation and weighted κ tests for readmission rates between the two time periods. Results: The Spearman coefficient between 2005-2006 readmissions rankings and 2007-2008 readmissions rankings was 0.57 (P < .001) and weighted κ was 0.42 (P < .001), indicating a moderate correlation. However, only 32% of the variation in hospital readmission rates in 2007-2008 was explained by readmissions during the 2 prior years. There were major reclassifications of hospital rankings between years, with 63% of hospitals migrating among performance quintiles between 2005-2006 and 2007-2008. Conclusions: Risk-adjusted readmission rates for vascular surgery vary substantially year to year; this implies that much of the observed variation in readmission rates is either random or caused by unmeasured factors and not caused by changes in hospital quality that may be captured by administrative data. [Copyright &y& Elsevier]

Objective: Deep vein thrombosis (DVT) resolution instigates an inflammatory response, resulting in vessel wall damage and scarring. Urokinase-plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), are integral components of the fibrinolytic system, essential for venous thrombosis (VT) resolution. This study determined the vein wall response when exposed to increased and decreased plasmin activity. Methods: A mouse inferior vena cava (IVC) ligation model in uPA −/− or PAI-1 −/− and their genetic wild types (B6/SvEv and C57/BL6, respectively) was used to create stasis thrombi, with tissue harvest at either 8 or 21 days. Tissue analysis included gene expression of vascular smooth muscle cells (alpha smooth muscle actin [αSMA], SM22) and endothelial marker (CD31), by real-time polymerase chain reaction, enzyme-linked immunosorbent assay, matrix metalloproteinase (MMP)-2 and -9 activity by zymography, and vein wall collagen by picro-Sirius red histologic analysis. A P < .05 was considered significant. Results: Thrombi were significantly larger in both 8-day and 21-day uPA −/− as compared with wild type (WT) and were significantly smaller in both 8-day and 21-day PAI-1 −/− as compared with WT. Correspondingly, 8-day plasmin levels were reduced in half in uPA −/− and increased three-fold in PAI-1 −/− when compared with respective WT thrombi (P < .05; n = 5-6). The endothelial marker CD31 was elevated two-fold in PAI-1 −/− mice at 8 days, but reduced 2.5-fold at 21 days in uPA −/− as compared with WT (P = .02; n = 5-6), suggesting less endothelial preservation. Vein wall vascular smooth muscle cell (VSMC) gene expression showed that 8-day and 21-day PAI-1 −/− mice had 2.3- and 3.8-fold more SM22 and 1.8- and 2.3-fold more αSMA expression than respective WT (P < .05; n = 5-7), as well as 1.8-fold increased αSMA (+) cells (P ≤ .05; n = 3-5). No significant difference in MMP-2 or -9 activity was found in the PAI-1 −/− mice compared with WT, while 5.4-fold more MMP-9 was present in 21-day WT than 21-day uPA −/− (P = .03; n = 5). Lastly, collagen was ∼two-fold greater at 8 days in PAI-1 −/− IVC as compared with WT (P = .03; n = 6) with no differences observed in uPA −/− mice. Conclusions: In stasis DVT, plasmin activity is critical for thrombus resolution. Divergent vein wall responses occur with gain or loss of plasmin activity, and despite smaller VT, greater vein wall fibrosis was associated with lack of PAI-1. [Copyright &y& Elsevier]

Background: The anticoagulant treatment of acute deep venous thrombosis (DVT) has been historically directed toward the prevention of recurrent venous thromboembolism. However, such treatment imperfectly protects against late manifestations of the postthrombotic syndrome. By restoring venous patency and preserving valvular function, early thrombus removal strategies can potentially decrease postthrombotic morbidity. Objective: A committee of experts in venous disease was charged by the Society for Vascular Surgery and the American Venous Forum to develop evidence-based practice guidelines for early thrombus removal strategies, including catheter-directed pharmacologic thrombolysis, pharmacomechanical thrombolysis, and surgical thrombectomy. Methods: Evidence-based recommendations are based on a systematic review and meta-analysis of the relevant literature, supplemented when necessary by less rigorous data. Recommendations are made according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, incorporating the strength of the recommendation (strong: 1; weak: 2) and an evaluation of the level of the evidence (A to C). Results: On the basis of the best evidence currently available, we recommend against routine use of the term “proximal venous thrombosis” in favor of more precise characterization of thrombi as involving the iliofemoral or femoropopliteal venous segments (Grade 1A). We further suggest the use of early thrombus removal strategies in ambulatory patients with good functional capacity and a first episode of iliofemoral DVT of <14 days in duration (Grade 2C) and strongly recommend their use in patients with limb-threatening ischemia due to iliofemoral venous outflow obstruction (Grade 1A). We suggest pharmacomechanical strategies over catheter-directed pharmacologic thrombolysis alone if resources are available and that surgical thrombectomy be considered if thrombolytic therapy is contraindicated (Grade 2C). Conclusions: Most data regarding early thrombus removal strategies are of low quality but do suggest patient-important benefits with respect to reducing postthrombotic morbidity. We anticipate revision of these guidelines as additional evidence becomes available. [Copyright &y& Elsevier]

Background: Hyperlipidemia increases the level of blood plasminogen activator inhibitor-1 (PAI-1) that is responsible for regulating fibrinolysis by inhibiting both urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA). While this fibrinolytic pathway is well known, the role of PAI-1 in venous thrombosis (VT) under hyperlipidemic conditions has not been fully established. We sought to determine the effects of PAI-1 in an in vivo hyperlipidemic model of VT. Methods: C57BL/6 wild-type (WT) mice, apolipoprotein E gene-deleted mice (ApoE-/-) having hyperlipidemia, and PAI-1 gene-deleted (PAI-1-/-) mice were used in this study. Inferior vena cava (IVC) ligation below the level of the renal veins was performed to create a stasis VT. Endpoints included measuring acute thrombosis (day 2) and chronic thrombosis (days 6 and 14). At euthanasia, blood samples were collected for plasmin and PAI-1 activity. In addition, the IVC and its thrombus were evaluated for thrombus weight (TW), u-PA activity, and differential leukocyte count while the vein wall only was analyzed for monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase (MMP) 2, and MMP-9. Results: Compared to WT at day 2, ApoE-/-mice demonstrated a statistically significant 14% increase in TW (P < .05) and a significant 41% increase in circulating PAI-1 activity (P < .05), while showing a trend of decreased plasmin activity. In addition, TW in ApoE-/-mice was 45% higher than PAI-1-/-mice at day 2 (P < .05), 33% at day 6 (P < .01), and 41% at day 14 (P < .01). ApoE-/-mice exhibited undetectable levels of u-PA in both vein wall and thrombus, compared to WT, at all time points. Also, vein wall MMP-2 was significantly decreased by 64% at day 6 (P < .01) and 58% at day 14 (P < .05). MMP-9 was significantly decreased by 71% at day 2 (P < .01) and 48% at day 6 (P < .01), in ApoE-/-mice compared to WT mice. In addition, in ApoE-/-mice, MCP-1 was significantly decreased by 38% at day 2 (P < .01) and 67% at day 6 (P < .01) vs WT mice. As expected in ApoE mice, following a decrease in MCP-1, monocyte recruitment was significantly decreased at days 6 (P < .01) and 14 (P < .05). Conclusions: A significant increase of circulating PAI-1 levels in hyperlipidemic mice correlated with an early increase in TW due to impaired fibrinolysis. The undetectable levels of u-PA in ApoE-/-mice correlated to a decrease in vein wall MMP-2, MMP-9, MCP-1, and a decrease in monocyte recruitment diminishing thrombus resolution. [Copyright &y& Elsevier]

Background: Postthrombotic syndrome is characterized by a fibrotic vein injury following deep vein thrombosis (DVT). We sought to quantify the change in vein wall thickness in patients who fail to resolve DVT by 6 months and whether there were differences in blood or plasma levels of inflammatory proteins associated with venous remodeling. Methods: Patients presenting with confirmed lower extremity DVT were prospectively recruited for this study. Duplex imaging of the lower extremity venous system was performed, and blood was collected at entrance and repeat evaluation with blood draw and ultrasound imaging at 1 and 6 months. DVT resolution and thickness of the vein wall was quantified by ultrasound imaging in each segment affected by thrombus, and a contralateral, unaffected vein wall served as a control. Gene and protein expression of inflammatory markers were examined from leukocytes and serum, respectively. Analysis of variance or Student t-tests were used, and a P < .05 was significant. N = 10 to 12 for all analyses. Results: Thirty-two patients (12 patients with DVT resolution at 6 months, 10 patients with persistent thrombus at 6 months, and 10 healthy controls) were compared. Both resolving and nonresolving DVT were associated with a 1.5- to 1.8-fold increased vein wall thickness at 6 months (P = .008) as compared with nonaffected vein wall segments. However, the thickness of the affected segments was 1.4-fold greater in patients who had total resolution of the DVT by 6 months than in patients who had persistent chronic thrombus 6 months after presentation (P = .01). There was a four- to five-fold increased level of matrix metalloproteinase-9 (MMP-9) antigen in thrombosed patients compared with nonthrombosed patient controls (P < .05), while Toll-like receptor-9 (TLR-9) gene expression was three-fold less than controls (P < .05) at enrollment. D-dimer and P-selectin were higher in thrombosed as compared to controls at diagnosis but not at 6 months. Both TLR-4 (marker of inflammation) and P-selectin gene expression were higher in leukocytes from patients with chronic DVT compared with those who resolved at 1 month after diagnosis (P < .05). Conclusions: This preliminary study suggests ongoing vein wall remodeling after DVT, measurable by ultrasound and associated with certain biomarkers. At 6 months, the vein wall is markedly thickened and directly correlates with resolution. This suggests that the vein wall response is initiated early following thrombus formation and persists even in the presence of total resolution. [Copyright &y& Elsevier]

Background: The national burden of venous disease and use of ultrasound (US) in the outpatient and emergency department (ED) settings has not been well described. The objective of this study is to describe venous disease in the outpatient and ED settings nationally as well as to characterize the use of US for diagnosis of venous disease, including phlebitis. Methods: Data from the 1997 to 2006 National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) were compiled, and complex sampling methods were used to describe the number of outpatient and ED visits for adults given a diagnosis of venous disease or phlebitis by ICD-9 coding. Logistic regression analysis with calculated odds ratios are used to examined patient visit characteristics and use of US. Results: During the 10 years studied, an office or ED visit for venous disease occurred over 46 million times, for an average of 4.6 million visits per year, with this rate increasing from 4.03 million to 5.71 million per year (odds ratio [OR] 1.01, confidence interval [CI] 1.00-1.01). The majority of these patients were seen by specialists, such as surgeons or cardiologists, but a significant number were also seen by primary care providers (PCP). There were 2 million office visits (PCP and specialists) on average per year with no significant increase. There were approximately 236,000 ED visits for deep vein thrombosis (DVT) on average per year, which showed a small increase (OR 1.01, CI 1.00-1.01). Visits for DVT and phlebitis were as likely to be seen by PCPs as ED physicians. Non-DVT venous disease is much more likely to be seen by a surgeon (OR 4.88, CI 3.53-6.74) than a PCP. DVT is much less likely to be diagnosed by a specialist (OR 0.27, CI 0.18-0.29) than a PCP. Insurance status and geographic region were not associated with DVT or non-DVT venous disease diagnosis. Conclusions: Nationally, a significant and growing number of patients with venous disease are being seen in the outpatient setting by PCPs and specialists. A significant number of patients with DVT are being seen in the outpatient setting, but without a trend away from care in the ED over the 10-year study period. Additionally, the majority of patients with DVT diagnosis do not seem to be getting ultrasounds at the same visit. Many of these patients are being seen by PCPs who may require additional training and infrastructure for appropriate patient care. [Copyright &y& Elsevier]

Deep venous thrombosis and pulmonary embolism, together called venous thromboembolism, remain a serious national health problem. Estimates suggest that over 900,000 cases occur in the United States per year, with 300,000 deaths per year. Because of the significant and serious nature of this problem, a workshop was held in May of 2006, which resulted in the Acting U.S. Public Health Service Surgeon General''s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. On September 15, 2008, Acting Surgeon General, Rear Admiral Steven K. Galson, MD, MPH, and Elizabeth Nabel, MD, Director National Heart, Lung, and Blood Institute, announced the Call to Action. The Call to Action highlights public awareness about the risk factors, triggering events, and symptoms of venous thrombosis and pulmonary embolism, and encourages the development of evidence based practices for screening, prevention, diagnosis, and treatment of venous thrombosis and pulmonary embolism. It is designed to encourage new scientific investigation in an effort to obtain needed evidence to fill in the gaps of knowledge about venous thrombosis and pulmonary embolism. This knowledge should be quickly and easily disseminated to the public and put into practice by health professionals. The Surgeon General''s Call to Action represents one of the most important advances in the field of venous thromboembolism and sets the stage for multidisciplinary efforts to combat this serious national health problem. [Copyright &y& Elsevier]

Objective: We hypothesize that endovenous laser ablation (EVA) therapy is equally successful in improving venous insufficiency symptoms in patients with or without deep venous insufficiency (DVI). Methods: From January 2005 through August 2007, EVA of the great saphenous vein (GSV) was attempted in 364 patients (460 limbs) with symptomatic GSV reflux. The GSV was successfully cannulated and obliterated in all but 17 limbs. EVA was performed alone in 308 limbs (69.5%) and with phlebectomy or perforator ligation (EVAP) in 135 limbs (30.5%). Venous clinical severity scores (VCSS) were recorded preoperatively and at 30, 90, 180, and 360 days postoperatively. Patients were classified as those with or without DVI based on duplex imaging valve closure times at the common femoral vein (CFV) and popliteal vein (PV). In a subset of 181 patients undergoing EVA therapy in the operating room, perioperative thrombosis prophylaxis was administered based on a risk-stratification protocol. Patients were assessed with direct end points (VCSS) and indirect end points (vein occlusion rates). Results: Successful performance of EVA led to complete saphenous vein ablation in 99.8% at 1 month and 95.9% at 1 year. Median VCSS preoperatively was 6 (interquartile range, 5-8), generally decreasing over all time points to 4 (interquartile range, 2-5) beyond 360 days (P < .001). Male gender was independently associated with greater improvement in scores with time (P = .019). Changes in VCSS and duration of vessel occlusion were equivalent regardless of DVI for both isolated EVA and EVAP. For EVAP, the true deep venous thrombosis (DVT) rate was 2.2%, whereas for isolated EVA, the rate was 0% (P = .028); the rate of saphenofemoral thrombus extension was 5.9% for EVAP vs 7.8% for isolated EVA (P = .554). The use of risk-adjusted heparin prophylaxis in patients undergoing EVAP did not have a significant effect on thrombotic complications. There were no differences in true DVT, thrombus extension, or superficial thrombophlebitis between patients with or without DVI. Performance of concomitant phlebectomy, DVI, gender, and age had no effect on the duration of vessel occlusion. Conclusion: EVA produces successful ablation and is associated with sustained improvement in VCSS. These outcomes are independent of the presence of DVI. Finally, the use of a risk-adjusted thrombosis prevention protocol had no effect on the rate of superficial thrombus extension from EVA or EVAP in patients undergoing general anesthesia. [Copyright &y& Elsevier]

Objective: To evaluate the results of the expanded National Venous Screening Program (NVSP) as administered by the American Venous Forum. Methods: Eighty-three physicians across 40 states participated in screening Americans for venous disease. The NVSP instrument included demographics, venous thromboembolism (VTE) risk assessment, quality-of-life (QOL) assessment, duplex ultrasound scan for reflux and obstruction, and clinical inspection. Participants received educational materials and a report card to give their physician. Results: A total of 2234 individuals underwent screening (mean, 26 people/site; range, 4-42). Demographic data observed included mean age of 60 years (range, 17-93 years); 77% female; 80% Caucasian; mean BMI of 29 (range, 11-68); 40% current or previous smoker; and 24% taking antiplatelet therapy and 4% taking warfarin. If placed in a situation conducive for VTE, 40% of participants were low risk, 22% were moderate risk, 21% were high risk, and 17% were very high risk. On a venous QOL assessment, 17% had a combined total score for all 11 questions of “very limited” or “impossible to do.” Reflux or obstruction was noted in 37% and 5% of participants, respectively. CEAP class 0 to 6 was 29%, 29%, 23%, 10%, 9%, 1.5%, 0.5%, respectively. Discussion: Despite a dramatic expansion in the second annual NSVP (from 17 to 83 centers), the presence of venous disease observed in a larger screened population continues to be high. The NVSP represents one pathway to increasing public awareness about venous disease. [Copyright &y& Elsevier]

Objective: Vein wall endothelial turnover after stasis deep vein thrombosis (DVT) has not been well characterized. The purpose of this study was to quantify re-endothelialization after DVT and determine if low-molecular-weight heparin (LMWH) therapy affects this process. Methods: Stasis DVT was generated in the rat by inferior vena cava ligation, with harvest at 1, 4, and 14 days. Immunohistologic quantification of vascular smooth muscle cells and luminal endothelialization was estimated by positive staining for α-smooth muscle actin and von Willebrand factor, respectively. In separate experiments, rats were treated either before or after DVT with subcutaneous LMWH (3 mg/kg daily) until harvesting at 4 and 14 days. The inferior vena cava was processed for histologic analysis or was processed for organ culture after the thrombus was gently removed. The vein wall was stimulated in vitro with interleukin-1β (1 ng/mL), and the supernatant was processed at 48 hours for nitric oxide. Cells were processed by real-time polymerase chain reaction for endothelial nitric oxide synthase, inducible nitric oxide synthase, cyclooxygenase-1 and -2, and thrombomodulin at 4 and 14 days, and collagen I and III at 14 days. Comparisons were done with analysis of variance or t test. A P < .05 was significant. Results: Thrombus size peaked at 4 days, whereas luminal re-endothelialization increased over time (1 day, 11% ± 2%; 4 days, 23% ± 4%; 14 days, 64% ± 7% (+) von Willebrand factor staining; P < .01, n = 3 to 4, compared with non-DVT control). Similarly, vascular smooth muscle cell staining was lowest at day 1 and gradually returned to baseline by 14 days. Both before and after DVT, LMWH significantly increased luminal re-endothelialization, without a difference in thrombus size at 4 days, but no significant difference was noted at 14 days despite smaller thrombi with LMWH treatment. Pretreatment with LMWH was associated with increased vascular smooth muscle cell area and recovery of certain inducible endothelial specific genes. No significant difference in nitric oxide levels in the supernatant was found at 4 days. At 14 days, type III collagen was significantly elevated with LMWH treatment. Conclusions: Venous re-endothelialization occurs progressively as the DVT resolves and can be accelerated with LMWH treatment, although this effect appears limited to the early time frame. These findings may have clinical relevance for LMWH timing and treatment compared with mechanical forms of therapy. [Copyright &y& Elsevier]

Background: Iliac vein compression syndrome (IVCS) results from compression of the left iliac vein by the overlying right iliac artery against the pelvic brim. In many cases, patients are symptomatic. In symptomatic cases, management consists of angioplasty and stenting. Although therapy is often initially successful, factors associated with long-term outcome have been poorly defined. The purpose of this study was to identify factors associated with stent patency. Methods: The medical records of all patients who underwent iliac vein percutaneous transluminal angioplasty and stenting from January 1996 to December 2006 for symptomatic IVCS were reviewed retrospectively. There were 50 women and 8 men, with a mean age of 42 years (median, 39 years; range, 17-71 years). Primary, assisted primary, and secondary patency rates were determined. Patient characteristics and clinical variables were evaluated by univariate and multivariate analysis to determine association with vein patency. Results: Symptoms consisted of lower extremity swelling (81%) and lower extremity pain (67%). Iliac vein obstruction was treated with pharmacologic thrombolysis (31% of patients) and mechanical thrombus fragmentation (17% of patients). The primary, assisted primary, and secondary patency rates of angioplasty/stenting were 74.1%, 79.7%, and 85.8% at 1 year and 38.1%, 62.8%, and 73.8% at 5 years, respectively. Using a Cox proportional risk model, male sex (hazard ratio, 6.5; P = .001), recent trauma (hazard ratio, 5.3; P = .001), and age younger than 40 years (hazard ratio, 3.8; P = .015) were associated with decreased primary patency. In the absence of any risk factors, primary patency was 94.4% at 1 year and 63.0% at 5 years, decreasing to 28.6% and 0% for two or more risk factors. Conclusions: Patency rates for iliac vein percutaneous transluminal angioplasty and stenting in patients with IVCS can potentially be predicted on the basis of a multivariate model. Assessing risk factors allows for patient stratification and appropriate clinical decision making. Prospective validation of these variables is necessary. [Copyright &y& Elsevier]

Objective: Although the treatment for acute deep vein thrombosis (DVT) is uniform, the circumstances under which it develops vary widely and may impact outcomes. This study compared clinical features and outcomes in patients who developed a primary DVT associated with a defined risk to those without any proximate risk factor. Methods: Consecutive patients with a primary DVT and no past venous thromboembolism history from 2000 to 2002 were abstracted for demographics, risk factors, DVT anatomical characteristics, treatment, and outcomes of death and new pulmonary embolism. Comparison between patients with a proximate risk event within 30 days of DVT (Inpt) and those presenting with DVT with no defined proximate event (Outpt) was done by univariable and multivariable statistics. A validated survey was mailed to all living patients to assess long-term sequela. Results: A total of 293 patients with a mean age of 55 years and 49% men had confirmed DVT by objective means (92% duplex) with a mean follow-up of 25 ± 21 months. Inpts were more likely to have recent surgery or blunt trauma, bilateral DVT, less use of low molecular weight heparin (LMWH), and new pulmonary emboli (all P <.05). Outpts with DVT were more likely to have a history of malignancy, tibial-popliteal DVT compared with iliofemoral DVT, higher use of LMWH, and coumadin. However, there was no difference in mortality. From the patient survey (21% response), Outpts were more likely than Inpts to develop later varicosities and have daily frustration related to their legs (P < .05), but no difference in edema or ulceration. Considering the entire group, independent factors associated with freedom from PE included ambulation (odds ratio [OR] = 2.3; 95% confidence interval [CI] = 1.1-5.0; P = .04) while bilateral DVT (OR = .26; 95% CI = .09-.76; P = .013) or subcutaneous heparin (OR = 22; 95% CI = .05-.98; P = .047) were associated with greater risk. Independent factors associated with survival included ambulation (OR = 3.0; 95% CI = 1.3-7.2; P = .02), Coumadin use (OR = 2.7; 95% CI = 1.2-6.1; P = .015), and tibiopopliteal DVT (OR = 2.4; 95% = 1.1-5.5; P = .03), while malignancy (OR = 0.1; 95% CI = .05-.24; P < .01) and myocardial infarction (OR = 0.12; 95% CI = .01-.92; P = .04) were associated with lower survival. Conclusion: Patients who develop DVT related to a defined proximate risk event (Inpt) generally have more extensive DVT, an increased risk of PE, but less long-term functional morbidity and no difference in long-term mortality compared to those with no proximate risk. [Copyright &y& Elsevier]

Background: Although common risk factors for venous thromboembolism (VTE) are well known, little data exist concerning the clinical impact of VTE in postoperative patients outside of controlled studies. This study evaluated prospective perioperative demographic and clinical variables associated with occurrence of postoperative symptomatic VTE. Methods: Demographic and clinical data were collected on surgical patients undergoing nine common general, vascular, and orthopedic operations presenting to the Veterans Health Administration Hospitals between 1996 and 2001 as part of the National Surgical Quality Improvement Program (NSQIP). The association between covariates and the incidence of postoperative symptomatic VTE (includes deep venous thrombosis and pulmonary embolism) was assessed using bivariable and multivariable regression. Results: Complete demographic and clinical information for analysis were available for 75,771 patients. The mean patient age was 65 years, and 96.6% were men. Major comorbidities included diabetes mellitus (DM), 25%; chronic obstructive pulmonary disease (COPD), 18.3%; and congestive heart failure (CHF), 3.9%. Symptomatic VTE was diagnosed in 805 patients (0.68%), varied significantly with procedure (0.14% for carotid endarterectomy vs 1.34% for total hip arthroplasty), and was associated with increased 30-day mortality (16.9% vs 4.4%, P < .0001). The incidence of VTE did not decline substantially between 1996 and 2001 (0.72% vs 0.68%). Preoperative factors associated with symptomatic VTE were older age, male gender, corticosteroid use, COPD, recent weight loss, disseminated cancer, low albumin, and low hematocrit (all P < .01) but not DM. Postoperative factors associated with VTE were myocardial infarction (MI), blood transfusion (>4 units), coma, pneumonia, and urinary tract infection (UTI), whereas those with hemodialysis-dependent renal failure were less likely to experience VTE (all P < .01). In multivariable analysis, adjusting for age and the variables significant by bivariable analysis, the strongest positive predictors of symptomatic VTE included UTI (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.3 to 2.5), acute renal insufficiency (OR, 1.9; 95% CI, 1.1 to 3.2), postoperative transfusion (OR, 2.3; 95% CI, 1.4 to 3.7), perioperative MI (OR, 2.4; 95% CI, 1.5 to 3.9), and pneumonia (OR, 2.7; 95% CI, 2.1 to 3.5). In contrast, hemodialysis (OR, 0.3; 95% CI, 0.07 to 0.71), DM (OR, 0.75; 95% CI, 0.61 to 0.93), and higher preoperative albumin levels (OR, 0.8; 95% CI, 0.74 to 0.96, per mg/dL change) were protective from symptomatic VTE. Conclusions: Although the overall incidence of symptomatic VTE is low in surgical patients, it is associated with significantly increased 30-day mortality. In addition to previously recognized risk factors, patients who have postoperative complications of an infectious nature, bleeding, or MI are at particular risk. [Copyright &y& Elsevier]

Objective: This report describes the pilot of a free comprehensive national screening program for venous disease. Methods: The screening process consisted of a venous thromboembolism (VTE) risk assessment, abbreviated duplex examination for venous obstruction and reflux, inspection for signs of chronic venous insufficiency (CVI), and an exit interview. Physicians coordinating the screenings were members of the American Venous Forum. Results: Seventeen institutions screened 476 people (mean, 28 per site; range, 6 to 71). Mean age was 60 years (range, 40 to 91 years), with 78% women and 68% with a body mass index of ≥25. If placed in a situation conducive for VTE, 22 participants (5%) were low risk, 87 (18%) were moderate risk, 186 (39%) were high risk, and 179 (38%) were at very high risk. In 26 people (6%), one or more segments had venous obstruction, and 190 (40%) had one or more segments of venous reflux in the lower extremities. Varicose veins were present in 32%, edema without skin changes in 11%, skin changes attributable to venous disease in 8%, and healed or active venous stasis ulcer in 1.3% (CEAP classification 2, 3, 4, 5, and 6, respectively). Increasing age and increasing deep venous thrombosis risk score significantly correlated with increasing clinical classification, r = 0.09, P = .04, and r = 0.16, P = .0004, respectively. Those participants with reflux in one or more segments were significantly more likely to have a higher clinical classification compared with those with no reflux (P = .0001). Conclusion: The first comprehensive national screening for venous disease was performed. Participants were informed of their risk for VTE if placed in a situation conducive to VTE, screened for evidence of obstruction, reflux, and CVI, and empowered to share their results with their primary care provider. [Copyright &y& Elsevier]

Background: Vein wall injury after thrombosis is multifactorial but seems dependent on thrombus and local thrombotic and inflammatory mechanisms. We hypothesized that inhibition of vein wall injury through reduction of thrombotic and inflammatory events with P-selectin inhibition and/or low-molecular-weight heparin (LMWH) occurs independently of thrombus resolution in a rat model of venous thrombosis. Methods: Male rats underwent inferior vena cava (IVC) stenosis (94.4% ± 0.5% reduction in IVC diameter) to induce thrombosis. Rats were treated from 2 days after thrombosis until they were killed 7 days later. Groups consisted of (1) PSI-697, a P-selectin inhibitor (30 mg/kg; oral gavage daily); (2) LMWH-Lovenox (LOV; enoxaparin) 3 mg/kg subcutaneously daily; (3) PSI-697 (30 mg/kg; oral gavage daily) plus LOV 3 mg/kg subcutaneously daily (PSI + LOV); (4) and untreated controls. Evaluations included thrombus mass, vein wall tensiometry (stiffness [inverse of compliance]), intimal thickness scoring by light microscopy, vein wall inflammatory mediators by enzyme-linked immunosorbent assay, and vein wall inflammatory cells by histologic evaluation. Results: Thrombus mass was not reduced by any treatment. Animals treated with PSI-697 alone, LOV alone, or PSI + LOV demonstrated significant decreases in vein wall stiffness when compared with controls. The vein wall stiffness of the PSI-697–treated groups was also significantly lower than in the LOV-only group. Animals treated with PSI-697 showed a significantly decreased intimal thickness score when compared with vehicle control IVCs. Vein wall intimal thickening was also significantly decreased in animals treated with PSI-697 vs LOV. The PSI-697 and PSI + LOV groups manifested significant decreases in the immunoregulatory and inflammatory cytokine interleukin 13 as compared with controls and LOV. Vein wall monocyte chemotactic protein 1 levels were also significantly reduced in the PSI-697 and PSI + LOV groups vs control. Only PSI-697 significantly decreased vein wall levels of platelet-derived growth factor ββ. Both the LOV and PSI + LOV groups had significant increases in vein wall monocytes and total inflammatory cells vs controls. Conclusions: These data suggest that both LMWH and PSI-697 inhibit vein wall injury independently of thrombus mass. P-selectin inhibition seemed superior to LMWH in measured parameters of injury and mediator inhibition. [Copyright &y& Elsevier]

Background: Pulmonary embolism (PE) is a life-threatening condition that is associated with the long-term sequelae of chronic pulmonary hypertension. Prior experimental work has suggested that post-PE inflammation is accompanied by pulmonary artery intimal hyperplasia. This study evaluated the effect of the thrombus and tested the hypothesis that thrombolytic, antiplatelet, and anticoagulant agents would decrease pulmonary injury. Methods: Male Sprague-Dawley rats (n = 267) underwent laparotomy and temporary clip occlusion of the infrarenal inferior vena cava for the formation of endogenous thrombus or placement of an inert silicone “thrombus.” Two days later, repeat laparotomy was performed, the clip removed, and the thrombus or silicone plug was embolized to the lungs. The endogenous thrombus group received normal saline, low-molecular-weight heparin (LMWH), tissue plasminogen activator (tPA), or a gIIB/IIIA antagonist (abciximab). Lung tissue was harvested at various times over 21 days and assayed for total collagen, monocyte chemoattractant protein-1 (MCP-1), interleukin-13 (IL-13), and transforming growth factor-β (TGF-β). Fixed sections were stained with trichrome for intimal hyperplasia determination and ED-1 monocytes and α-actin-positive staining. Results: The overall survival for rats undergoing PE was 90%, was not affected by treatment, and 84% of all PE localized to the right pulmonary artery. The PE significantly reduced Pao 2 in all groups. Compared with controls, the silicone emboli group had an increased level of IL-13 on day 1, an increased level of MCP-1 on day 4, and an increase in the levels of all inflammatory mediators on day 14 (P < .05). Accompanying these differences were greater pulmonary artery intimal hyperplasia at days 4 and 21 in the silicone group compared with controls (P < .05). LMWH treatment in the thrombus of PE rats significantly decreased IL-13 levels at all time points, whereas treatment with abciximab or tPA significantly increased IL-13 levels compared with controls. TGF-β levels were significantly increased by LMWH at day 4 and 14, and abciximab was associated with lower TGF-β at day 14. Only LMWH was associated with less pulmonary artery intimal hyperplasia at day 14 compared with controls and the other treatment groups. Conclusions: Persistent pulmonary artery distention by an inert material is sufficient to invoke significant inflammation and intimal hyperplasia independent of the thrombus itself. Compared with nontreated PE, LMWH is the only therapy associated with a significant reduction in late intimal hyperplasia and, with the exception of TGF-β, lower profibrotic growth-factor production. [Copyright &y& Elsevier]

Background: P-selectin inhibition with protein therapeutics such as antibodies or soluble ligands given intravenously can decrease thrombosis in a mouse ligation model of venous thrombosis. In this study, we hypothesized that oral inhibition of P selectin with a novel oral nonprotein inhibitor (PSI-697) would decrease thrombosis and circulating microparticle populations. This study evaluated the effects on thrombosis and circulating microparticle populations in this murine venous thrombosis model. Methods: Mice underwent inferior vena cava ligation to induce thrombosis. Mice with high circulating level of P selectin, Delta Cytoplasmic Tail (^CT), mice gene-deleted for both E- and P-selectin knockout (EPKO), and wild-type C57BL/6 mice (WT) were studied without and with administration of PSI-697 in food (100 mg/kg daily) from 2 days before thrombosis until the end of the study. Animals were killed 2 and 6 days later. Evaluations included thrombus weight (TW), vein wall morphometrics, microparticle quantification by using fluorescence-activated cell sorter analysis, and vein wall enzyme-linked immunosorbent assays for interleukin (IL)-10, P selectin, and monocyte chemotactic protein 1. Results: PSI-697 significantly decreased TW in WT and ^CT mice, with a treated vs nontreated TW of 132 ± 24 vs 228 ± 29 × 10−4 g (P = .014) and 166 ± 19 vs 281 ± 16 × 10−4 g (P = .001), respectively. At day 6, the effect was significant only in the ^CT group (P < .05). Drug therapy at day 2 significantly increased vein wall monocytes in WT mice and increased monocytes and total inflammatory cells in ^CT animals. A significant decrease in neutrophils and total inflammatory cells was seen in EPKO mice at day 2 with therapy. Therapy significantly increased platelet-derived microparticles and total microparticles in ^CT mice on day 2. Changes in treated WT and treated EPKO animals were not significant compared with respective vehicle treatments at day 2. On day 6, therapy significantly decreased total microparticles in EPKO animals. Vein wall expression of IL-10 increased in all groups with therapy at day 2 (n = 18) and was significantly increased in WT (2687.5 ± 903 pg/mL vs 636 ± 108 pg/mL total protein; P = .038) and ^CT (2078 ± 295 pg/mL vs 432 ± 62 pg/mL total protein; P = .001) mice. Therapy significantly decreased vein wall P selectin, monocyte chemotactic protein 1, and IL-10 levels at day 6. Conclusions: PSI-697 decreased thrombosis. P-selectin inhibition allowed vein wall inflammatory cell extravasation in this model of complete ligation. Circulating microparticles (platelet-derived microparticles and total microparticles) increased with P-selectin inhibition, possibly because of decreased consumption into the thrombus. In summary, the oral administration of an inhibitor to P selectin provides significant TW reduction. Clinical Relevance: Deep venous thrombosis is a significant national health problem in the general population. The average annual incidence of deep venous thrombosis is approximately 250,000 cases per year. The selectin family of adhesion molecules is thought to be largely responsible for the initial attachment and rolling of leukocytes on stimulated vascular endothelium. Recent studies have explored the possible therapeutic implications of P-selectin inhibition to modulate venous thrombosis. For example, prophylactic dosing of a recombinant P-selectin ligand decreases venous thrombosis in a dose-dependent fashion in both feline and nonhuman primate animal models. Additionally, treatment of 2-day iliac thrombi with a recombinant protein, P-selectin inhibitor, significantly improves vein reopening in nonhuman primates. It is interesting to note that P-selectin inhibition decreases thrombosis without adverse anticoagulation. On the basis of the results from these previous studies, the use of P-selectin antagonism is a logical therapeutic approach to treat venous thrombosis. All inhibitors developed to date are either proteins or small molecules with low oral bioavailability that require intravenous or subcutaneous injection. This study evaluates, for the first time, a novel orally bioavailable inhibitor of P-selectin (PSI-697). [Copyright &y& Elsevier]

Hypothesis: Deep venous thrombosis (DVT) confers vein wall injury associated with fibrosis and extracellular matrix (ECM) turnover, likely mediated by matrix proteases. This study investigated the expression of proteases and collagen involved in early vein wall remodeling. Methods: In the mouse, DVT was produced by ligation of the infrarenal inferior vena cava (IVC) or sham operation, and tissue was harvested at 4, 8, and 12 days. The vein wall tissue was processed for real-time reverse transcriptase-polymerase chain reaction (6 to 8 per time point), Western immunoblotting (5 per time point), and gelatin zymography (5 per time point). Analysis of variance was used for multiple comparisons, and a P < .05 was significant. Results: Thrombus resolution was documented by a 38% decrease in the thrombosed IVC weight from day 4 to day 12 (P = .007). Total vein wall collagen increased over time, with a corresponding increase in procollagen I and III, and expression peaked at 12 days (24-fold and 6.1-fold, respectively, P < .02). Matrix metalloproteinase-2 (MMP-2) gene expression was 23-fold greater at 12 days after thrombus formation compared with sham or 4 days after thrombosis (P < .05). Total MMP-2 activity was also significantly elevated at 12 days compared with sham (P < .05). MMP-9 expression was 19-fold and 27-fold higher at days 4 and 8, respectively, relative to sham (P < .05), with no difference in activity. MMP-14 expression was twofold to 3.6-fold greater at day 12 compared with earlier time points and shams (P < .001), but no differences in protein levels were found. Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) protein levels were not significantly different from sham over time; however, the ratio of uPA to PAI-1 was decreased through 8 days. Conclusions: Vein wall remodeling after DVT is similar to wound healing and is associated with increased procollagen gene expression and total collagen. It is also associated with increased early MMP-9 expression, followed by MMP-2 expression and activity after DVT resolution. Clinical Relevance: Deep vein thrombosis is an often neglected problem that long term is associated with the postphlebitic syndrome of limb swelling, pain, and often ulceration. The basic mechanisms of the vein wall damage that results have not been delineated. The following study describes the vein wall matrix metalloproteinase gene and activity response induced over time in the vein wall after DVT. Additionally, the corresponding collagen upregulation and proximate plasmin system mediators are determined. With this knowledge, potential therapies to reduce vein wall injury directly might be possible. [Copyright &y& Elsevier]

Intentional interruption of the inferior vena cava with caval ligation and a Mobin-Uddin filter was once commonly used to prevent recurrent pulmonary emboli and was associated with significant mortality and morbidity, including a high incidence of post-thrombotic syndrome. Recanalization of an intentionally interrupted inferior vena cava has been rarely described in literature and is commonly considered futile. We describe two patients with post-thrombotic syndrome as a late complication of caval ligation and a thrombosed Mobin-Uddin filter, with significant and sustained improvement after endovascular recanalization. [ABSTRACT FROM AUTHOR]

Background: Vein wall fibrotic injury following deep venous thrombosis (VT) is associated with elevated matrix metalloproteinases (MMPs). Whether and by what mechanism MMP2 contributes to vein wall remodeling after VT is unknown. Methods: Stasis VT was produced by ligation of the inferior vena cava and tissue was harvested at 2, 8, and 21 days in MMP2 -/- and genetic wild type (WT) mice. Tissue analysis by immunohistochemistry, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and zymography was performed. Results: Thrombus resolution was less at 8 days in MMP2 -/- compared with WT, evidenced by a 51% increase in VT size (P < .01), and threefold fewer von Willebrand's factor positive channels (P < .05). In MMP2 -/- mice, the main phenotypic fibrotic differences occurred at 8 days post-VT, with significantly less vein wall collagen content (P = .013), fourfold lower procollagen III gene expression (P < .01), but no difference in procollagen I compared with WT. Decreased inflammation in MMP2 -/- vein walls was suggested by ∼ threefold reduced TNFα and IL-1β at 2 days and 8 days post-VT (P < .05). A fourfold increase in vein wall monocytes (P = .03) with threefold decreased apoptosis (P < .05), but no difference in cellular proliferation at 8 days was found in MMP2 -/- compared with WT. As increased compensatory MMP9 activity was observed in the MMP2 -/-mice, MMP2/9 double null mice had thrombus induced with VT harvest at 8 days. Consistently, twofold larger VT, a threefold decrease in vein wall collagen, and a threefold increase in monocytes were found (all P < .05). Similar findings were observed in MMP9 -/- mice administered an exogenous MMP2 inhibitor. Conclusions: In stasis VT, deletion of MMP2 was associated with less midterm vein wall fibrosis and inflammation, despite an increase in monocytes. Consideration that VT resolution was impaired with MMP2 (and MMP2/9) deletion suggests direct inhibition will likely also require anticoagulant therapy. [Copyright &y& Elsevier]