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Venous thromboembolism (VTE) is a major preventable disease that affects hospitalized inpatients. Risk stratification and prophylactic measures have good evidence supporting their use, but multiple reasons exist that prevent full adoption, compliance, and efficacy that may underlie the persistence of VTE over the past several decades. This policy statement provides a focused review of VTE, risk scoring systems, prophylaxis, and tracking methods. From this summary, 5 major areas of policy guidance are presented that the American Heart Association believes will lead to better implementation, tracking, and prevention of VTE events. They include performing VTE risk assessment and reporting the level of VTE risk in all hospitalized patients, integrating preventable VTE as a benchmark for hospital comparison and pay-for-performance programs, supporting appropriations to improve public awareness of VTE, tracking VTE nationwide with the use of standardized definitions, and developing a centralized data steward for data tracking on VTE risk assessment, prophylaxis, and rates. [ABSTRACT FROM AUTHOR]

In the hope of accurately risk stratifying patients noninvasively (and perhaps reducing medicolegal exposure), stress testing will often be obtained by vascular surgeons before elective vascular surgery, even in the absence of formal cardiology consultation. Keywords: abdominal aortic aneurysm (AAA); endovascular therapy; risk stratification; vascular surgery EN abdominal aortic aneurysm (AAA) endovascular therapy risk stratification vascular surgery 476 477 2 10/12/22 20221001 NES 221001 Commentary on: Ponukumati AS, Columbo JA, Suckow BD, et al. [Extracted from the article]

Objective: To determine the predictors of periprocedural blood transfusion and the association of transfusion on outcomes in high risk patients undergoing endoluminal percutaneous vascular interventions (PVI) for peripheral arterial disease. Methods/Results: Between 2010–2014 at 47 hospitals participating in a statewide quality registry, 4.2% (n = 985) of 23,273 patients received a periprocedural blood transfusion. Transfusion rates varied from 0 to 15% amongst the hospitals in the registry. Using multiple logistic regression, factors associated with increased transfusion included female gender (OR = 1.9; 95% CI: 1.6–2.1), low creatinine clearance (1.3; 1.1–1.6), pre-procedural anemia (4.7; 3.9–5.7), family history of CAD (1.2; 1.1–1.5), CHF (1.4; 1.2–1.6), COPD (1.2; 1.1–1.4), CVD or TIA (1.2; 1.1–1.4), renal failure CRD (1.5; 1.2–1.9), pre-procedural heparin use (1.8; 1.4–2.3), warfarin use (1.2; 1.0–1.5), critical limb ischemia (1.7; 1.5–2.1), aorta-iliac procedure (1.9; 1.5–2.5), below knee procedure (1.3; 1.1–1.5), urgent procedure (1.7; 1.3–2.2), and emergent procedure (8.3; 5.6–12.4). Using inverse weighted propensity matching to adjust for confounders, transfusion was a significant risk factor for death (15.4; 7.5–31), MI (67; 29–150), TIA/stroke (24; 8–73) and ARF (19; 6.2–57). A focused QI program was associated with a 28% decrease in administration of blood transfusion (p = 0.001) over 4 years. Conclusion: In a large statewide PVI registry, post procedure transfusion was highly correlated with a specific set of clinical risk factors, and with in-hospital major morbidity and mortality. However, using a focused QI program, a significant reduction in transfusion is possible. [ABSTRACT FROM AUTHOR]

Abstract: Background: Patient positioning during surgeries for colorectal cancer may represent an unrecognized risk factor for deep venous thrombosis. Methods: Twelve healthy control patients were positioned supine with knee flexion at 90°. Duplex ultrasound examined common femoral vein (CFV) and proximal femoral vein diameter, peak systolic velocity, and volume flow with hip flexion at 0°, 30°, 60°, and 90°. Data were analyzed using the paired t test. Results: In the CFV, hip flexion to 90° was associated with a significant increase in mean volume flow when compared with hip flexion at 0° (.59 vs .36 L/min; P = .05) and 30° (.59 vs .35 L/min; P = .038). In both the CFV and proximal femoral vein, increased hip flexion was associated with significantly reduced vessel diameter and increased peak systolic velocity. Conclusions: Intraoperative positioning of the lower extremities represents a modifiable risk factor for deep venous thrombosis. When stirrups are used, hip flexion of 90° maximizes venous drainage from the legs. [Copyright &y& Elsevier]

Abstract: This overview delineates the current evidence and suggested practice protocols for three areas of vascular disease evaluation and treatment that have shown particular patient benefit. Presented as brief topical reviews are (1) preoperative cardiac evaluation and risk factor modification, (2) use of autologous tissue and graft surveillance for infrainguinal bypass, and (3) deep vein thrombosis risk stratification and prophylaxis. It is this author’s hope is that this overview will emphasize currently effective and underused therapies and stimulate further research into best practices for improving the quality of care for vascular surgery patients. [Copyright &y& Elsevier]

Background: There has been declining interest in surgery among medical students and one reason might be the third-year clerkship experience. The aim of this study was to clarify the perceptions and expectations of attendings, residents, and medical students on the clerkship experience. Study design: A survey was distributed to all general surgery attendings, the entire general surgery house staff, and an entire third year medical school class inclusive of the 2001–2002 academic year at a single institution. Statistic analysis consisted of chi-square and Kruskal-Wallis-ANOVA on ranks with Dunn’s test for multiple comparisons. A p < 0.05 was significant. Results: Responses were obtained from 59 attending surgeons (50%), 38 surgical residents (32%), and 107 medical students (66%). Of this student cohort, 35% were planning to choose a surgical specialty as a career. Agreement was high among faculty, students, and residents about factors considered important in evaluation, expectations of skills, and level of skills needed before the clerkship. Medical students desired more hours of instruction, believed they performed fewer procedures per week, and thought that feedback was poor compared with the opinions of faculty and residents (p < 0.002). Nearly 50% of medical students believed they were an inconvenience to the service; 30% of house officers and 27% of faculty (p < 0.001) believed this also. Almost all faculty and residents, however, wanted medical students on the service (> 95%). Faculty believed residents did a better job teaching than either the students or residents themselves did (p < 0.001), and students thought that residents were the primary source of education in patient care. Conclusions: Considerable differences exist between faculty, surgical resident, and medical student perceptions and expectations of medical student education. Structured direct faculty contact, definition of medical student roles on the surgical team, and more consistent feedback can be rapidly improved. [Copyright &y& Elsevier]

Evaluates outcome of treatment on patients with prosthetic vascular graft infections. Patients and methods utilized on the study; Alternative strategies that have emerged to circumvent vascular graft infection; Recovered organisms in patients used on the study.

Surgeon scientists are a vanishing group, a reason for which may be an initially frustrating experience in the laboratory. This essay proposes a specific plan to improve the first time researcher’s bench research experience. [Copyright &y& Elsevier]

Lower extremity peripheral artery and upper extremity artery disease are significant vascular conditions with distinct clinical presentations and diagnostic and therapeutic approaches. The lower extremity peripheral artery is associated with worse major adverse cardiovascular events compared with coronary artery disease, but often remains underdiagnosed and undertreated. Upper extremity artery disease encompasses a range of clinical presentations resulting from atherosclerosis and other obstructive lesions in arteries such as the subclavian artery and brachiocephalic trunk. While atherosclerosis is a common cause, non-atherosclerotic factors can also influence distal lesions. This review aims to synthesize existing knowledge on both conditions, encompassing risk factors, clinical manifestations, diagnostic modalities, and treatment options. Improved awareness and early intervention can mitigate complications and enhance patient outcomes for lower extremity peripheral artery and upper extremity artery disease. [ABSTRACT FROM AUTHOR]

Deep venous thrombosis and residual thrombus burden correlates with circulating IL-6 levels in humans. To investigate the cellular source and role of IL-6 in thrombus resolution, Wild type C57BL/6J (WT), and IL-6−/− mice underwent induction of VT via inferior vena cava (IVC) stenosis or stasis. Vein wall (VW) and thrombus were analyzed by western blot, immunohistochemistry, and flow cytometry. Adoptive transfer of WT bone marrow derived monocytes was performed into IL6-/- mice to assess for rescue. Cultured BMDMs from WT and IL-6−/− mice underwent quantitative real time PCR and immunoblotting for fibrinolytic factors and matrix metalloproteinase activity. No differences in baseline coagulation function or platelet function were found between WT and IL-6−/− mice. VW and thrombus IL-6 and IL-6 leukocyte-specific receptor CD126 were elevated in a time-dependent fashion in both VT models. Ly6Clo Mo/MØ were the predominant leukocyte source of IL-6. IL-6−/− mice demonstrated larger, non-resolving stasis thrombi with less neovascularization, despite a similar number of monocytes/macrophages (Mo/MØ). Adoptive transfer of WT BMDM into IL-6−/− mice undergoing stasis VT resulted in phenotype rescue. Human specimens of endophlebectomized tissue showed co-staining of Monocyte and IL-6 receptor. Thrombosis matrix analysis revealed significantly increased thrombus fibronectin and collagen in IL-6−/− mice. MMP9 activity in vitro depended on endogenous IL-6 expression in Mo/MØ, and IL-6−/− mice exhibited stunted matrix metalloproteinase activity. Lack of IL-6 signaling impairs thrombus resolution potentially via dysregulation of MMP-9 leading to impaired thrombus recanalization and resolution. Restoring or augmenting monocyte-mediated IL-6 signaling in IL-6 deficient or normal subjects, respectively, may represent a non-anticoagulant target to improve thrombus resolution. [ABSTRACT FROM AUTHOR]

Abstract: Chronic venous insufficiency resulting in post-thrombotic syndrome occurs commonly after acute deep vein thrombosis, and is a prevalent cause of vascular disease morbidity in the community. Therefore, a better understanding of the pathophysiologic mechanisms that promote the development of chronic venous insufficiency could lead to novel approaches to interrupt the natural history and prevent post-thrombotic syndrome. In this paper, we will review the evidence that venous thrombus resolution is an inflammatory process that is dependent on chemokines and leukocytes. [Copyright &y& Elsevier]

BACKGROUND: Therapeutic anticoagulation with either a vitamin K antagonist (VKA) or direct anticoagulant (DOAC) is often newly prescribed to patients undergoing lower extremity bypass (LEB) to aid in graft patency when risk factors for thrombosis are present or to treat postoperative venous thromboembolism or atrial fibrillation. There is a gap in knowledge as to how DOAC usage impacts postoperative outcomes compared with the standard-of-care VKAs. STUDY DESIGN: To determine temporal trends in DOAC prescription after infrainguinal LEB, impact on length of stay (LOS), and associated bleeding and thrombotic complications, patients undergoing elective LEB were identified from the Vascular Quality Initiative between January 2013 and May 2019. Postoperative bleeding, LOS, and graft occlusion for patients receiving VKA compared with DOAC were evaluated. RESULTS: A total of 24,459 LEBs were performed during the study period. Among 2,656 patients newly prescribed an anticoagulant, 78.0% (n = 2,072) received VKA and 22.0% (n = 584) received a DOAC, with DOAC use increasing throughout the study period. There was no significant difference in postoperative bleeding (VKA 2.3%, DOAC 1.7%, p = 0.413) or graft occlusion (VKA 1.2%, DOAC 1.4%, p = 0.762) between the anticoagulant classes. LOS was shorter in the DOAC group than in the VKA group (5.7 vs 6.8 days; p < 0.001). CONCLUSIONS: This analysis demonstrates that DOAC use is increasing with time in Vascular Quality Initiative centers. DOACs are a safe and comparable alternative to VKAs in the postoperative setting with similar rates of bleeding complications and early graft patency and are associated with a reduced postoperative LOS. [ABSTRACT FROM AUTHOR]

Despite anticoagulation therapy, up to one-half of patients with deep vein thrombosis (DVT) will develop the post-thrombotic syndrome (PTS). Improving the long-term outcome of DVT patients at risk for PTS will therefore require new approaches. Here we investigate the effects of statins—lipid-lowering agents with anti-thrombotic and anti-inflammatory properties—in decreasing thrombus burden and decreasing vein wall injury, mediators of PTS, in established murine stasis and non-stasis chemical-induced venous thrombosis (N = 282 mice). Treatment of mice with daily atorvastatin or rosuvastatin significantly reduced stasis venous thrombus burden by 25% without affecting lipid levels, blood coagulation parameters, or blood cell counts. Statin-driven reductions in VT burden (thrombus mass for stasis thrombi, intravital microscopy thrombus area for non-stasis thrombi) compared similarly to the therapeutic anticoagulant effects of low molecular weight heparin. Blood from statin-treated mice showed significant reductions in platelet aggregation and clot stability. Statins additionally reduced thrombus plasminogen activator inhibitor-1 (PAI-1), tissue factor, neutrophils, myeloperoxidase, neutrophil extracellular traps (NETs), and macrophages, and these effects were most notable in the earlier timepoints after DVT formation. In addition, statins reduced DVT-induced vein wall scarring by 50% durably up to day 21 in stasis VT, as shown by polarized light microscopy of picrosirius red-stained vein wall collagen. The overall results demonstrate that statins improve VT resolution via profibrinolytic, anticoagulant, antiplatelet, and anti-vein wall scarring effects. Statins may therefore offer a new pharmacotherapeutic approach to improve DVT resolution and to reduce the post-thrombotic syndrome, particularly in subjects who are ineligible for anticoagulation therapy. [ABSTRACT FROM AUTHOR]

Abstract: Background context: As research increasingly challenges the diagnostic accuracy of advanced imaging for lumbar spinal stenosis, the impression gleaned from the office evaluation becomes more important. Neurogenic claudication is a hallmark of lumbar spinal stenosis, but the reliability of clinical impression of claudication has not been studied. Purpose: To determine the reliability of the clinical examination for neurogenic claudication in an idealized setting. Study design: Prospective masked controlled trial. Patient sample: Persons aged 55 to 90 years were recruited to form three groups: those offered surgery for spinal stenosis by academic spine surgeons, those who had peripheral vascular symptoms and positive ankle-brachial index (ABI), and those who were asymptomatic. All were extensively screened against confounding diseases. Forty-three neurogenic, 12 vascular, and 35 asymptomatic recruits were tested. Outcome measures: Clinical impression of neurogenic claudication. Methods: A neurosurgeon and a vascular surgeon, masked to each other's findings, imaging, and recruitment status, performed a codified but unconstrained comprehensive spine and vascular history and physical examination for each subject. The surgeon's impression was recorded. Results: Masked surgeons strongly agreed with the recruitment diagnosis (neurosurgeon kappa 0.761, vascular surgeon kappa 0.803, both p<.001) and with each other (kappa 0.717, p<.001). However, disagreements did occur between examiners and recruitment diagnosis (neurosurgeon n=13 cases, vascular surgeon n=10) and between examiners (n=14 cases). Pain level and marginally some measures of disability related to the agreement, but specific aspects of the physical examination, showed poor interrater reliability and did not contribute to the agreement. Conclusions: The clinical impression of neurogenic claudication is a reliable construct. The history, but not the poorly reproduced physical examination, contributes to reliability. The level of disagreement between experts in this simplified, yet severely involved, population raises concern about the risk of misdiagnosis in individual cases. Thus, surgical and other consequential decisions about diagnosis may require ancillary tests such as electromyography or ABI. [Copyright &y& Elsevier]

Abstract: Background: Mentorship in academic surgery is reflected in part by senior surgeon support of younger individuals with their scholarly contributions to the literature. Scholarship is also reflected in the procurement of extramural funding. This study sought to quantify this process in recent years. Study design: All active American Surgical Association and Society of University Surgeons members in the following 2 eras were defined as being mentors (N = 559): 1993 to 1999 (I) and 2000 to 2006 (II). Mentees (N = 7,037) were defined as a primary author associated with the mentor. MEDLINE-cited papers of mentors and mentees were abstracted. Randomly selected mentees from era I and II were examined for academic productivity. The National Institutes of Health (NIH) Computer Retrieval of Information on Scientific Projects database was queried for federal research funding for the mentors and mentees. Continuous categoric and logistical regression was used as appropriate. Results: Combining both eras, mentors published a total of 23,558 articles, of which 3,854 were primary and 9,881 were senior authored. Mentor primary-authored papers were more common in era I than era II (mean = 8 vs 6 articles, P < .01), whereas the number of senior-authored papers was similar in both eras (mean = 18 vs 17 papers, P = .09). Fewer mentors had federal funding in era I compared with era II (42% vs 51%, P = .04). More mentees per mentor existed in era I compared with era II (15 ± 5 vs 9 ± 4, P < .001). Era I mentees examined in era II (n = 187) were primary and senior author of a mean of 2.5 and 5 articles, respectively. Of this group, 14 (7.5%) had federal funding. The number of primary- and senior-authored articles from the mentee but not their prior mentor correlated with federal funding (P < .05). Conclusions: The number of mentees per mentor has decreased in recent years as has primary-authored authors, whereas federal funding has increased for mentors. Overall NIH funding for mentees was low but is related to their productivity with the mentor. [Copyright &y& Elsevier]

The author examines the existing methods in managing varicose vein (VV) disease. Factors that play a role in the development of VV are cited including venous hypertension, valvular incompetence and genetic predisposition. Conservative management and compression are recommended for patients in the early stages of venous disease. Operative procedures for VV disease include endovenous ablation of the great saphenous vein, subfascial endoscopic perforator surgery and sclerotherapy.

The epidemiology of abdominal aortic aneurysm (AAA) disease has been well described over the preceding 50 years. This disease primarily affects elderly males with smoking, hypertension, and a positive family history contributing to an increased risk of aneurysm formation. The aging population as well as increased screening in high-risk populations has led some to suggest that the incidence of AAAs is increasing. The National Inpatient Sample (1993–2003), a national representative database, was used in this study to determine trends in mortality following AAA repair in the United States. In addition, the impact of the introduction of less invasive endovascular AAA repair was assessed. Overall rates of treated unruptured and ruptured AAAs remained stable (unruptured 12 to 15/100,000; ruptured 1 to 3/100,000). In 2003, 42.7% of unruptured and 8.8% of ruptured AAAs were repaired through an endovascular approach. Inhospital mortality following unruptured AAA repair continues to decline for open repair (5.3% to 4.7%, P= 0.007). Mortality after elective endovascular AAA repair also has statistically decreased (2.1% to 1.0%, P= 0.024) and remains lower than open repair. Mortality rates for ruptured AAAs following repair remain high (open: 46.5% to 40.7%, P= 0.01; endovascular: 40.0% to 35.3%, P= 0.823). These data suggest that the numbers of patients undergoing elective AAA repair have remained relatively stable despite the introduction of less invasive technology. A shift in the treatment paradigm is occurring with a higher percentage of patients subjected to elective endovascular AAA repair compared to open repair. This shift, at least in the short term, appears justified as the mortality in patients undergoing elective endovascular AAA repair is significantly reduced compared to patients undergoing open AAA repair. [ABSTRACT FROM AUTHOR]

Background: Cigarette smoking, hypertension, dyslipidemia, diabetes, and obesity are conventional risk factors (RFs) for coronary artery disease (CAD). Population trends for these RFs have varied in recent decades. Consequently, the risk factor profile for patients presenting with a new diagnosis of CAD in contemporary practice remains unknown. Objectives: To examine the prevalence of RFs and their temporal trends among patients without a history of myocardial infarction or revascularization who underwent their first percutaneous coronary intervention (PCI). Methods: We examined the prevalence and temporal trends of RFs among patients without a history of prior myocardial infarction, PCI, or coronary artery bypass graft surgery who underwent PCI at 47 non-federal hospitals in Michigan between 1/1/2010 and 3/31/2018. Results: Of 69,571 men and 38,930 women in the study cohort, 95.5% of patients had 1 or more RFs and nearly half (55.2% of women and 48.7% of men) had ≥3 RFs. The gap in the mean age at the time of presentation between men and women narrowed as the number of RFs increased with a gap of 6 years among those with 2 RFs to <1 year among those with 5 RFs. Compared with patients without a current/recent history of smoking, those with a current/recent history of smoking presented a decade earlier (age 56.8 versus 66.9 years; p <0.0001). Compared with patients without obesity, patients with obesity presented 4.0 years earlier (age 61.4 years versus 65.4 years; p <0.0001). Conclusions: Modifiable RFs are widely prevalent among patients undergoing their first PCI. Smoking and obesity are associated with an earlier age of presentation. Population-level interventions aimed at preventing obesity and smoking could significantly delay the onset of CAD and the need for PCI. [ABSTRACT FROM AUTHOR]

The authors reflect on the significance of the salicylate drug aspirin in the precluding of thrombosis. They discuss several research initiatives including Warfarin and Aspirin, and Aspirin to Prevent Recurrent Venous Thromboembolism (VTE), and explain the use of aspirin decreased bleeding. They recommend the oral Vitamin K antagonists or the New Oral Anticoagulant treatment for idiopathic VTE, and aspirin for low recurrence.

Background: Up to 50% of patients with proximal deep vein thrombosis (DVT) will develop the postthrombotic syndrome characterized by limb swelling and discomfort, hyperpigmentation, skin ulcers, and impaired quality of life. Although catheter-based interventions enabling the restoration of blood flow (RBF) have demonstrated little benefit on postthrombotic syndrome, the impact on the acuity of the thrombus and mechanisms underlying this finding remain obscure. In experimental and clinical studies, we examined whether RBF has a restricted time window for improving DVT resolution.Methods: First, experimental stasis DVT was generated in C57/BL6 mice (n=291) by inferior vena cava ligation. To promote RBF, mice underwent mechanical deligation with or without intravenous recombinant tissue plasminogen activator administered 2 days after deligation. RBF was assessed over time by ultrasonography and intravital microscopy. Resected thrombosed inferior vena cava specimens underwent thrombus and vein wall histological and gene expression assays. Next, in a clinical study, we conducted a post hoc analysis of the ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) pharmacomechanical catheter-directed thrombolysis (PCDT) trial (NCT00790335) to assess the effects of PCDT on Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores for specific symptom-onset-to-randomization timeframes.Results: Mice that developed RBF by day 4, but not later, exhibited reduced day 8 thrombus burden parameters and reduced day 8 vein wall fibrosis and inflammation, compared with controls. In mice without RBF, recombinant tissue plasminogen activator administered at day 4, but not later, reduced day 8 thrombus burden and vein wall fibrosis. It is notable that, in mice already exhibiting RBF by day 4, recombinant tissue plasminogen activator administration did not further reduce thrombus burden or vein wall fibrosis. In the ATTRACT trial, patients receiving PCDT in an intermediate symptom-onset-to-randomization timeframe of 4 to 8 days demonstrated maximal benefits in Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores (between-group difference=8.41 and 1.68, respectively, P<0.001 versus patients not receiving PCDT). PCDT did not improve postthrombotic syndrome scores for patients having a symptom-onset-to-randomization time of <4 days or >8 days.Conclusions: Taken together, these data illustrate that, within a restricted therapeutic window, RBF improves DVT resolution, and PCDT may improve clinical outcomes. Further studies are warranted to examine the value of time-restricted RBF strategies to reduce postthrombotic syndrome in patients with DVT. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is a pathology encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with high morbidity and mortality. Because patients often present after a thrombus has already formed, the mechanisms that drive DVT resolution are being investigated in search of treatment. Herein, we review the current literature, including the molecular mechanisms of fibrinolysis and collagenolysis, as well as the critical cellular roles of macrophages, neutrophils, and endothelial cells. We propose two general models for the operation of the immune system in the context of venous thrombosis. In early thrombus resolution, neutrophil influx stabilizes the tissue through NETosis. Meanwhile, macrophages and intact neutrophils recognize the extracellular DNA by the TLR9 receptor and induce fibrosis, a complimentary stabilization method. At later stages of resolution, pro-inflammatory macrophages police the thrombus for pathogens, a role supported by both T-cells and mast cells. Once they verify sterility, these macrophages transform into their pro-resolving phenotype. Endothelial cells both coat the stabilized thrombus, a necessary early step, and can undergo an endothelial-mesenchymal transition, which impedes DVT resolution. Several of these interactions hold promise for future therapy. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Venous thromboembolism is a major cause of morbidity and mortality. The impact of the US Surgeon General's The Surgeon General's Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism in 2008 has been lower than expected given the public health impact of this disease. This scientific statement highlights future research priorities in venous thromboembolism, developed by experts and a crowdsourcing survey across 16 scientific organizations. At the fundamental research level (T0), researchers need to identify pathobiological causative mechanisms for the 50% of patients with unprovoked venous thromboembolism and to better understand mechanisms that differentiate hemostasis from thrombosis. At the human level (T1), new methods for diagnosing, treating, and preventing venous thromboembolism will allow tailoring of diagnostic and therapeutic approaches to individuals. At the patient level (T2), research efforts are required to understand how foundational evidence impacts care of patients (eg, biomarkers). New treatments, such as catheter-based therapies, require further testing to identify which patients are most likely to experience benefit. At the practice level (T3), translating evidence into practice remains challenging. Areas of overuse and underuse will require evidence-based tools to improve care delivery. At the community and population level (T4), public awareness campaigns need thorough impact assessment. Large population-based cohort studies can elucidate the biological and environmental underpinnings of venous thromboembolism and its complications. To achieve these goals, funding agencies and training programs must support a new generation of scientists and clinicians who work in multidisciplinary teams to solve the pressing public health problem of venous thromboembolism. [ABSTRACT FROM AUTHOR]

Macrophages are critical for the initiation and resolution of the inflammatory phase of wound healing. In diabetes, macrophages display a prolonged inflammatory phenotype preventing tissue repair. TLRs, particularly TLR4, have been shown to regulate myeloid-mediated inflammation in wounds. We examined macrophages isolated from wounds of patients afflicted with diabetes and healthy controls as well as a murine diabetic model demonstrating dynamic expression of TLR4 results in altered metabolic pathways in diabetic macrophages. Further, using a myeloid-specific mixed-lineage leukemia 1 (MLL1) knockout (Mll1f/fLyz2Cre+), we determined that MLL1 drives Tlr4 expression in diabetic macrophages by regulating levels of histone H3 lysine 4 trimethylation on the Tlr4 promoter. Mechanistically, MLL1-mediated epigenetic alterations influence diabetic macrophage responsiveness to TLR4 stimulation and inhibit tissue repair. Pharmacological inhibition of the TLR4 pathway using a small molecule inhibitor (TAK-242) as well as genetic depletion of either Tlr4 (Tlr4-/-) or myeloid-specific Tlr4 (Tlr4f/fLyz2Cre+) resulted in improved diabetic wound healing. These results define an important role for MLL1-mediated epigenetic regulation of TLR4 in pathologic diabetic wound repair and suggest a target for therapeutic manipulation. [ABSTRACT FROM AUTHOR]

Although New York's Medicaid expansion increased coverage in 2001, little is known regarding changes in surgical care utilization among patients with vascular disease. We sought to measure the impact of expansion on the rates of both vascular procedures and amputations. A retrospective analysis was performed using the State Inpatient Databases of New York and Arizona, 1998-2006. Patients aged 18-64 who underwent lower extremity vascular surgery procedures or amputations between 1998 and 2006 were included. Outcomes included rates of total vascular, open vascular, and endovascular procedures, in addition to rates of amputation. A difference-in-difference analysis measured changes in the rates of procedure types, while adjusting for temporal trends in both states. In this cohort (n = 112,624), Medicaid expansion was not associated with a change in mortality (odds ratio 0.92, P = 0.5). Expansion was associated with a lower incidence of total vascular procedures (incidence rate ratio [IRR] 0.65, P < 0.001) and open vascular procedures (IRR 0.92, P = 0.002), but a higher incidence of endovascular procedures (IRR 1.13, P < 0.001). There was no change in the rate of amputations (IRR 1.02, P = 0.58). In patients with chronic limb-threatening ischemia (n = 12,668), expansion was associated with a lower incidence of total procedures (IRR 0.59, P < 0.001) and endovascular procedures (IRR 0.59, P < 0.001) but a higher incidence of amputations (IRR 1.43, P = 0.001) and higher odds of mortality (odds ratio 2.21, P = 0.032). After Medicaid expansion, the rates of total vascular procedures decreased, with no impact on amputations rates. Furthermore, the utilization of limb-saving procedures in patients with chronic limb-threatening ischemia did not increase. [ABSTRACT FROM AUTHOR]

Myeloid cells are critical for orchestrating regulated inflammation during wound healing. TLRs, particularly TLR4, and its downstream-signaling MyD88 pathway play an important role in regulating myeloid-mediated inflammation. Because an initial inflammatory phase is vital for tissue repair, we investigated the role of TLR4-regulated, myeloid-mediated inflammation in wound healing. In a cutaneous tissue injury murine model, we found that TLR4 expression is dynamic in wound myeloid cells during the course of normal wound healing. We identified that changes in myeloid TLR4 during tissue repair correlated with increased expression of the histone methyltransferase, mixed-lineage leukemia 1 (MLL1), which specifically trimethylates the histone 3 lysine 4 (H3K4me3) position of the TLR4 promoter. Furthermore, we used a myeloid-specific Mll1 knockout (Mll1f/fLyz2Cre+) to determine MLL1 drives Tlr4 expression during wound healing. To understand the critical role of myeloid-specific TLR4 signaling, we used mice deficient in Tlr4 (Tlr4-/-), Myd88 (Myd88-/-), and myeloid-specific Tlr4 (Tlr4f/fLyz2Cre+) to demonstrate delayed wound healing at early time points postinjury. Furthermore, in vivo wound myeloid cells isolated from Tlr4-/- and Myd88-/- wounds demonstrated decreased inflammatory cytokine production. Importantly, adoptive transfer of monocyte/macrophages from wildtype mice trafficked to wounds with restoration of normal healing and myeloid cell function in Tlr4-deficient mice. These results define a role for myeloid-specific, MyD88-dependent TLR4 signaling in the inflammatory response following cutaneous tissue injury and suggest that MLL1 regulates TLR4 expression in wound myeloid cells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Macrophages are critical for the initiation and resolution of the inflammatory phase of wound repair. In diabetes, macrophages display a prolonged inflammatory phenotype in late wound healing. Mixed-lineage leukemia-1 (MLL1) has been shown to direct gene expression by regulating nuclear factor-κB (NF-κB)-mediated inflammatory gene transcription. Thus, we hypothesized that MLL1 influences macrophage-mediated inflammation in wound repair. We used a myeloid-specific Mll1 knockout (Mll1f/fLyz2Cre+ ) to determine the function of MLL1 in wound healing. Mll1f/fLyz2Cre+ mice display delayed wound healing and decreased wound macrophage inflammatory cytokine production compared with control animals. Furthermore, wound macrophages from Mll1f/fLyz2Cre+ mice demonstrated decreased histone H3 lysine 4 trimethylation (H3K4me3) (activation mark) at NF-κB binding sites on inflammatory gene promoters. Of note, early wound macrophages from prediabetic mice displayed similarly decreased MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines compared with controls. Late wound macrophages from prediabetic mice demonstrated an increase in MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines. Prediabetic macrophages treated with an MLL1 inhibitor demonstrated reduced inflammation. Finally, monocytes from patients with type 2 diabetes had increased Mll1 compared with control subjects without diabetes. These results define an important role for MLL1 in regulating macrophage-mediated inflammation in wound repair and identify a potential target for the treatment of chronic inflammation in diabetic wounds. [ABSTRACT FROM AUTHOR]

Background: The incidence, risk factors, and outcomes associated with Contrast-induced nephropathy (CIN) after Percutaneous Vascular Intervention (PVI) in contemporary medical practice are largely unknown.Methods: A total of 13 126 patients undergoing PVI were included in the analysis. CIN was defined as an increase in serum creatinine from pre-PVI baseline to post-PVI peak Cr of ≥0.5 mg/dL.Results: CIN occurred in 3% (400 patients) of the cohort, and 26 patients (6.5%) required dialysis. Independent predictors of CIN were high and low body weight, diabetes, heart failure, anemia, baseline renal dysfunction, critical limb ischemia, and a higher acuity of the PVI procedure and a contrast dose that was greater than three times the calculated creatinine clearance (CCC) (adjusted OR 1.4, 95% CI: 1.1-1.8, P = 0.003). CIN was strongly associated with adverse outcome including in-hospital death (adjusted OR 18.1, CI 10.7-30.6, P < 0.001), myocardial infarction (adjusted OR 16.2, CI 8.9-29.5, P < 0.001), transient ischemic attack/stroke (adjusted OR 5.5, CI 3.2-14.9, P = 0.001), vascular access complications (adjusted OR 3.4, CI 2.3-5, P < 0.001), and transfusion (adjusted OR 7, CI 5.4-9, P < 0.001). Hospital stay was longer in patients who developed CIN versus those who did not.Conclusions: CIN is not an uncommon complication associated with PVI, can be reliably predicted from pre-procedural variables, including a contrast dose of greater than three times the CCC and is strongly associated with the risk of in-hospital death, MI, stroke, transfusion, and increased hospital length of stay. [ABSTRACT FROM AUTHOR]

Objective Antiphospholipid syndrome (APS) is a leading acquired cause of thrombotic events. Although antiphospholipid antibodies have been shown to promote thrombosis in mice, the role of neutrophils has not been explicitly studied. The aim of this study was to characterize neutrophils in the context of a new model of antiphospholipid antibody-mediated venous thrombosis. Methods Mice were administered fractions of IgG obtained from patients with APS. At the same time, blood flow through the inferior vena cava was reduced by induction of stenosis. Resulting thrombi were characterized for size and neutrophil content. Circulating factors and the vessel wall were also assessed. Results As measured by both thrombus weight and thrombosis frequency, mice treated with IgG from patients with APS (APS IgG) demonstrated exaggerated thrombosis as compared with control IgG-treated mice. Thrombi in mice treated with APS IgG were enriched for citrullinated histone H3 (a marker of neutrophil extracellular traps [NETs]). APS IgG-treated mice also demonstrated elevated levels of circulating cell-free DNA and human IgG bound to the neutrophil surface. In contrast, circulating neutrophil numbers and markers of vessel wall activation were not appreciably different between APS IgG-treated mice and control mice. Treatment with either DNase (which dissolves NETs) or a neutrophil-depleting antibody reduced thrombosis in APS IgG-treated mice to the level in control mice. Conclusion These data support a mechanism whereby circulating neutrophils are primed by antiphospholipid antibodies to accelerate thrombosis. This line of investigation suggests new, immunomodulatory approaches for the treatment of APS. [ABSTRACT FROM AUTHOR]

Background/Aims: Pneumonia is a significant risk factor for the development of venous thrombosis (VT). Cell-adhesion molecules (CAMs) are linked to the pathogenesis of both pneumonia and VT. We hypothesized that remote infection would confer a prothrombogenic milieu via systemic elevation of CAMs. Methods: Lung injury was induced in wild-type (C57BL/6) mice by lung contusion or intratracheal inoculation with Klebsiella pneumoniae or saline controls. K. pneumoniae-treated mice and controls additionally underwent inferior vena cava (IVC) ligation to generate VT. Results: Lung-contusion mice demonstrated no increase in E-selectin or P-selectin whereas mice infected with K. pneumoniae demonstrated increased circulating P-selectin, ICAM-1, VCAM-1 and thrombin-antithrombin (TAT) complexes. Mice with pneumonia formed VT 3 times larger than controls, demonstrated significantly more upregulation of vein-wall and systemic CAMs, and formed erythrocyte-rich thrombi. Conclusion: Elevated CAM expression was identified in mice with pneumonia, but not lung contusion, indicating that the type of inflammatory stimulus and the presence of infection drive the vein-wall response. Elevation of CAMs was associated with amplified VT and may represent an alternate mechanism by which to target the prevention of VT. [ABSTRACT FROM AUTHOR]

We evaluated the impact of the prescription of evidence-based medical therapy (EBMT) including aspirin (ASA), beta-blockers (BB), ACE-inhibitors or angiotensin receptor blockade (ACE/ARB), and statins prior to discharge after peripheral vascular intervention (PVI) on long-term medication utilization in a large multi-specialty, multicenter quality improvement collaborative. Among patients undergoing coronary revascularization, use of the component medications of EBMT at hospital discharge is a major predictor of long-term utilization. Predictors of EBMT use after PVI are largely unknown. A total of 10,169 patients undergoing PVI between 1 January 2008 and 31 December 2011 were included. Post-PVI discharge and 6-month medication utilization in patients without contra-indications to ASA, BB, ACE/ARB, and statins were compared. ASA was prescribed at discharge to 9345 (92%) patients, BB to 7012 (69%), ACE/ARB to 6424 (63%), and statins to 8342 (82%), and all four component drugs of EBMT in 3953 (39%). Compared with patients not discharged on the appropriate medications, post-procedural use was associated (all p<0.001) with reported 6-month use: ASA (84.5% vs 39.2%), BB (82.5% vs 11.1%), ACE/ARB (78.2% vs 11.8%), statins (84.6% vs 21.8%). Multivariable analysis revealed that prescription of EBMT at the time of discharge remained strongly associated with use at 6 months for each of the individual component drugs as well as for the combination of all four EBMT medications. In conclusion, prescription of the component medications of EBMT at the time of PVI is associated with excellent utilization at 6 months, while failure to prescribe EBMT at discharge is associated with low use of these medications 6 months later. These data suggest that the time of a PVI is a therapeutic window in which to prescribe EBMT in this high-risk cohort and represents an opportunity for quality improvement. [ABSTRACT FROM AUTHOR]

Classically activated (M1) macrophages are known to play a role in the development of chronic inflammation associated with impaired wound healing in type 2 diabetes (T2D); however, the mechanism responsible for the dominant proinflammatory (M1) macrophage phenotype in T2D wounds is unknown. Since epigenetic enzymes can direct macrophage phenotypes, we assessed the role of histone methylation in bone marrow (BM) stem/progenitor cells in the programming of macrophages toward a proinflammatory phenotype. We have found that a repressive histone methylation mark, H3K27me3, is decreased at the promoter of the IL-12 gene in BM progenitors and this epigenetic signature is passed down to wound macrophages in a murine model of glucose intolerance (diet-induced obese). These epigenetically "preprogrammed" macrophages result in poised macrophages in peripheral tissue and negatively impact wound repair. We found that in diabetic conditions the H3K27 demethylase Jmjd3 drives IL- 12 production in macrophages and that IL-12 production can be modulated by inhibiting Jmjd3. Using human T2D tissue and murine models, we have identified a previously unrecognized mechanism by which macrophages are programmed toward a proinflammatory phenotype, establishing a pattern of unrestrained inflammation associated with nonhealing wounds. Hence, histone demethylase inhibitor-based therapy may represent a novel treatment option for diabetic wounds. [ABSTRACT FROM AUTHOR]

BACKGROUND: Sequential compression devices (SCDs) reduce deep venous thrombosis in postsurgical patients, but the use is hindered by poor compliance. METHODS: General and orthopedic surgery patients (n = 67) were randomized to standard- or battery-powered SCDs. Compliance was documented hourly. Nurses and patients were issued a survey to assess barriers to compliance and device satisfaction. RESULTS: Compliance with standard SCDs was 47% compared with 85% with battery-powered SCDs (P < .001). The most common barriers identified by nurses and patients were ambulation and transfers, which were mitigated with the battery-powered device. A majority (79%) of those issued a battery-powered device reported no major problems compared with only 14% of patients issued a standard device (P < .005). CONCLUSIONS: The dual venous thromboembolism prevention strategies of early mobilization and SCD utilization can be met with the appropriate equipment. [ABSTRACT FROM AUTHOR]

Galectin-3-binding protein (gal3bp) and its receptor/ligand, galectin-3 (gal3), are secreted proteins that initiate signaling cascades in several diseases, and recent human proteomic data suggest they may play a role in venous thrombosis (VT). We hypothesized that gal3bp and gal3 may promote VT. Using a mouse stasis model of VT, we found that gal3bp and gal3 were localized on vein wall, red blood cells, platelets, and microparticles, whereas leukocytes expressed gal3 only. Gal3 was dramatically increased during early VT and gal3bp:gal3 colocalized in the leukocyte/endothelial cell interface, where leukocytes were partially attached to the vein wall. Thrombus size correlated with elevated gal3 and interleukin-6 (IL-6) vein wall levels. Recombinant gal3 promoted VT and increased vein wall IL-6 mRNA. Although recombinant gal3 restored the VT size in gal3-/- mice, it had no effect on IL6-/- mice, suggesting that gal3:gal3bp promotes VT through IL-6. Moreover, significantly fewer activated neutrophils were present in the gal3-/- vein walls. In a group of human patients, elevated circulating gal3bp correlated with acute VT. In conclusion, gal3bp:gal3 play a critical role in VT, likely via IL-6 and PMN-mediated thrombotic mechanisms, and may be a potential biomarker in human VT. [ABSTRACT FROM AUTHOR]

Given the very ill nature of patients with critical limb ischemia (CLI), the use of percutaneous vascular interventions (PVIs) for limb salvage may or may not be efficacious; in particular, for those with polyvascular arterial disease. Herein, we reviewed large, multi-institutional outcomes of PVI in polyvascular and peripheral arterial disease (PAD) patients with CLI. An 18-hospital consortium collected prospective data on patients undergoing endovascular interventions for PAD with 6-month follow-up from January 2008 to December 2011. The patient cohort included 4459 patients with CLI; of those, 3141 patients had polyvascular (coronary artery disease, cerebrovascular disease and PAD) disease, whereas 1318 patients suffered from only PAD. All patients were elderly and with significant comorbidities. The mean ankle–brachial index (ABI) was 0.44 and was not different between those with and without polyvascular disease. Polyvascular patients had more femoropopliteal and infra-inguinal interventions and less aortoiliac interventions than PAD patients. Pre- and post-procedural cardioprotective medication use was less in the PAD patients as compared with polyvascular patients. Vascular complications requiring surgery were higher in PAD patients whereas other access complications were similar between groups. At 6-month follow-up, death was more common in the polyvascular group (6.7% vs 4.1%, p<0.001) as was repeat PVI, but no difference was found in the amputation rate. Considering the group as a whole at the 6-month follow-up, predictors of amputation/death included age (HR=1.01; 95% CI=1.002–1.02), anemia (HR=2.6; 95% CI=2.1–3.2), diabetes mellitus (HR=1.6; 95% CI=1.3–1.9), congestive heart failure (HR=1.6; 95% CI=1.4–1.9), and end-stage renal failure (HR=1.9; 95% CI=1.5–2.3), while female sex was protective (HR=0.7; 95% CI=0.6–0.8). In conclusion, from examination of this large, multicenter, multi-specialist practice registry, patients with polyvascular disease had higher 6-month mortality than PAD patients, but this was not a factor in 6-month limb amputation outcomes. This study also underscores that PAD patients still lag in cardioprotective medication use as compared with polyvascular patients. [ABSTRACT FROM AUTHOR]

Background: Accurate detection of recurrent same-site deep vein thrombosis (DVT) is a challenging clinical problem. Because DVT formation and resolution are associated with a preponderance of inflammatory cells, we investigated whether noninvasive (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging could identify inflamed, recently formed thrombi and thereby improve the diagnosis of recurrent DVT.Methods and Results: We established a stasis-induced DVT model in murine jugular veins and also a novel model of recurrent stasis DVT in mice. C57BL/6 mice (n=35) underwent ligation of the jugular vein to induce stasis DVT. FDG-PET/computed tomography (CT) was performed at DVT time points of day 2, 4, 7, 14, or 2+16 (same-site recurrent DVT at day 2 overlying a primary DVT at day 16). Antibody-based neutrophil depletion was performed in a subset of mice before DVT formation and FDG-PET/CT. In a clinical study, 38 patients with lower extremity DVT or controls undergoing FDG-PET were analyzed. Stasis DVT demonstrated that the highest FDG signal occurred at day 2, followed by a time-dependent decrease (P<0.05). Histological analyses demonstrated that thrombus neutrophils (P<0.01), but not macrophages, correlated with thrombus PET signal intensity. Neutrophil depletion decreased FDG signals in day 2 DVT in comparison with controls (P=0.03). Recurrent DVT demonstrated significantly higher FDG uptake than organized day 14 DVT (P=0.03). The FDG DVT signal in patients also exhibited a time-dependent decrease (P<0.01).Conclusions: Noninvasive FDG-PET/CT identifies neutrophil-dependent thrombus inflammation in murine DVT, and demonstrates a time-dependent signal decrease in both murine and clinical DVT. FDG-PET/CT may offer a molecular imaging strategy to accurately diagnose recurrent DVT. [ABSTRACT FROM AUTHOR]

Background--Accurate detection of recurrent same-site deep vein thrombosis (DVT) is a challenging clinical problem. Because DVT formation and resolution are associated with a preponderance of inflammatory cells, we investigated whether noninvasive 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging could identify inflamed, recently formed thrombi and thereby improve the diagnosis of recurrent DVT. Methods and Results--We established a stasis-induced DVT model in murine jugular veins and also a novel model of recurrent stasis DVT in mice. C57BL/6 mice (n=35) underwent ligation of the jugular vein to induce stasis DVT. FDG-PET/computed tomography (CT) was performed at DVT time points of day 2, 4, 7, 14, or 2+16 (same-site recurrent DVT at day 2 overlying a primary DVT at day 16). Antibody-based neutrophil depletion was performed in a subset of mice before DVT formation and FDG-PET/CT. In a clinical study, 38 patients with lower extremity DVT or controls undergoing FDG-PET were analyzed. Stasis DVT demonstrated that the highest FDG signal occurred at day 2, followed by a time-dependent decrease (P<0.05). Histological analyses demonstrated that thrombus neutrophils (P<0.01), but not macrophages, correlated with thrombus PET signal intensity. Neutrophil depletion decreased FDG signals in day 2 DVT in comparison with controls (P=0.03). Recurrent DVT demonstrated significantly higher FDG uptake than organized day 14 DVT (P=0.03). The FDG DVT signal in patients also exhibited a time-dependent decrease (P<0.01). Conclusions--Noninvasive FDG-PET/CT identifies neutrophil-dependent thrombus inflammation in murine DVT, and demonstrates a time-dependent signal decrease in both murine and clinical DVT. FDG-PET/CT may offer a molecular imaging strategy to accurately diagnose recurrent DVT. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to examine sex-related differences in outcomes related to peripheral vascular intervention (PVI) procedures. Background: Percutaneous PVI is frequently performed for the treatment of peripheral arterial disease (PAD). However, little is known about sex-related differences related to PVI procedures. Methods: We assessed the impact of sex among 12,379 patients (41% female) who underwent lower extremity (LE)-PVI from 2004 to 2009 at 16 hospitals participating in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium PVI registry. Multivariate propensity-matched analyses were performed to adjust for differences in baseline characteristics, procedural indications, and comorbidities on the basis of sex. Results: Compared with men, women were older and have multilevel disease and critical limb ischemia. In a propensity-matched analysis, female sex was associated with a higher rate of vascular complications, transfusions, and embolism. No differences were observed for in-hospital death, myocardial infarction, or stroke or transient ischemic attack. Technical success was more commonly achieved in women (91.2% vs. 89.1%, p = 0.014), but because of a higher complication rate, the overall procedural success rates were similar in men and women (79.7% vs. 81.6%, p = 0.08). Conclusions: Women represent a significant proportion of patients undergoing LE-PVI, have a more severe and complex disease process, and are at increased risk for adverse outcomes. Despite higher complications rates, women had similar procedural success compared with men, making PVI an effective treatment strategy among women with LE-PAD. [Copyright &y& Elsevier]

Background: Surgical intensive care unit (SICU) patients are known to be at high risk for venous thromboembolism (VTE). The 2005 Caprini Risk Assessment Model (RAM) predicts VTE risk in surgical patients. However, a physician's ability to accurately complete this RAM and the effect that inaccurate RAM completion might have on VTE risk remain unknown. Study Design: Between 2009 and 2012, physicians completed a 2005 Caprini score for all SICU admissions at our institution. For comparison, we used a previously validated, computer-generated score. Regression-based techniques examined the effect of inadequate risk stratification on inpatient VTE risk, when controlling for other confounders. Results: Among 3,338 consecutive SICU admissions, 55.2% had computer-generated scores that were higher than the physician-reported score, and 20.6% of scores were equal. Computer-generated scores were higher than physician-reported scores for both median (6 vs 5) and interquartile range (5 to 8 vs 3 to 7). Inter-rater reliability between the 2 scores was poor (kappa = 0.238). Risk score underestimation by ≥2 points was significantly associated with inpatient VTE (7.67% vs 4.59%, p = 0.002). Regression analysis demonstrated that each additional day's delay in chemoprophylaxis (odds ratio [OR] 1.05, 95% CI 1.01 to 1.08, p = 0.011) and under-risk stratification by ≥2 points (OR 2.46, 95% CI 1.53 to 3.96, p < 0.001) were independent predictors of inpatient VTE, as were higher admission APACHE score, personal history of VTE, recent pneumonia, and younger age. Conclusions: Physicians under-risk stratify SICU patients when using the 2005 Caprini RAM. As hospitals incorporate electronic medical records into daily practice, computer-calculated Caprini scores may result in more accurate VTE risk stratification. Inadequate VTE risk assessment and delay to chemoprophylaxis carry independent and significant increased risk for VTE. [Copyright &y& Elsevier]

The article reports that venous thromboembolism (VTE) is linked to 100,000 annual deaths of surgical patients (SP) in the U.S. Topics discussed include the identification of high- and low-risk patients using regression models, the use of a dataset to validate the risk index (RI) and the favorable response of selected SP to chemoprophylaxis. Also mentioned is the incorporation of risk factors to the weighted RI during the 90-day monitoring for VTE after surgery.

Abstract: Introduction: Post thrombotic syndrome therapy is primarily palliative, and the associated vein wall inflammatory mechanisms are unclear. Vein wall fibrotic injury following deep venous thrombosis (VT) is associated with elevated matrix metalloproteinases (MMPs). Whether and by what mechanism MMP9 directly contributes to vein wall remodeling after VT is unknown. Methods: WT and MMP9 -/- mice underwent stasis VT by ligation of the inferior vena cava (IVC) and tissue was harvested at 2, 8, and 21days. Assessment of thrombus size, and gene, protein and structural vein wall determinations were done. Results: VT resolution was increased in MMP9-/- mice as compared with controls at 21d only. The primary phenotypic fibrotic vein wall differences occurred at 8d post VT, with significantly less vein wall collagen content as assessed by Picosirius red staining in MMP9 -/- mice as compared with WT. Increased monocytic vein wall influx with less IL-1b and TGFb was found in MMP9 -/- vein walls as compared with WT. Corresponding levels of PAI-1 were increased in MMP9 -/- compared with WT, and no difference in FSP-1+cells as compared with controls. Conclusions: In stasis VT, MMP9 modulates midterm vein wall collagen content, with an altered local inflammatory and profibrotic environment, likely directed by monocytes. Thus, MMP9 plays a role in both vein wall responses as well as late thrombus resolution. [Copyright &y& Elsevier]

Abstract: Background: The objective of this study was to test a novel model of inducing abdominal aortic aneurysms (AAAs) in different mouse strains and genders. Materials and methods: Male and female C57BL/6 and B6129 mice (n = 5 per group) underwent periaortic dissection and porcine pancreatic elastase (30 μL) or inactivated elastase application (5 min) to the aorta. Aortic measurements were taken on days 0 and 14. Aortic samples were analyzed for histology and zymography for matrix metalloproteinase (MMP) activity. Comparison statistics were performed using unpaired t-test. Results: AAA phenotype (50% aortic increase) occurred in external elastase–treated males (100%) and females (90%). No control animals developed AAAs. The aortic diameter was larger in C57BL/6 and B6129 elastase-treated versus control males (P = 0.0028 and P < 0.0001, respectively) and females (P < 0.0001 and P = 0.0458, respectively). Histology verified phenotype via disrupted internal elastic laminae. Macrophage counts in elastase-treated animals were >6-fold higher than in controls (all groups significant). MMP9 activity was greater in elastase-treated males and females in C57BL/6 (P = 0.0031, P = 0.0004) and B6129 (P = 0.025, P = 0.2) mice; MMP2 activity was greater in C57BL/6 versus B6129 male elastase-treated mice. Conclusions: This rodent model produced AAAs in both genders and strains of mice. This model is simple, has little variability, and occurs in the infrarenal aorta, substantiating the external elastase model for future studies. [Copyright &y& Elsevier]

Abstract: Background: From the legacy of Shukri Khuri, we have successfully implemented a regional quality collaborative in Michigan, the Michigan Surgical Quality Collaborative (MSQC). Methods: The MSQC represents a partnership between the American College of Surgeons (ACS), 34 Michigan hospitals, and a large private payer. It is based on a “pay for participation” rather than a “pay for performance” model. Although based on the ACS National Surgical Quality Improvement Program (NSQIP) platform, this collaborative has a unique infrastructure for information technology, collaboration, and ad hoc quality improvement (QI) initiatives. Results: Specific initiatives have been implemented with colectomy, myocardial ischemia, and surgical site infection (SSI). Based on these initiatives, best practices have been implemented. Adherence to these best practices is modest, but despite this, there has been significant QI. Conclusions: The improved quality was likely the result of diverse process measures, many not yet recognized in the literature, which came together effectively in specific hospitals. [Copyright &y& Elsevier]

Abstract: Venous thromboembolism (VTE) accounts for an estimated 900,000 cases of deep venous thrombosis (DVT) and pulmonary embolism (PE) yearly, resulting in approximately 300,000 deaths [1]. For the past 150 years, Virchow''s triad has encompassed the elements of venous thrombogenesis, including stasis, changes in the vessel wall, and thrombogenic changes in the blood. However, in the early 1970s, through the work of Gwendylen Stewart, a relationship between thrombosis and inflammation was suggested. In this review, we will address the role of selectins and fibrinolysis in the process of venous thrombogenesis. [Copyright &y& Elsevier]

Background: In humans, there is a 4:1 male:female ratio in the incidence of abdominal aortic aneurysms (AAAs). c-Jun-N-terminal kinase (JNK) is an important upstream regulator of several enzymes involved in AAA formation, including the matrix metalloproteinases (MMPs). The purpose of this study was to determine if there is a gender difference between males and females in JNK during AAA formation. Materials and Methods: Male and female C57/B6 mice underwent aortic perfusion with elastase or heat inactivated elastase with aortas harvested at d 3 and 14 for phenotype determination, RT-PCR, Western blot, and zymography. Additionally, in vitro experiments using siRNA were conducted to define JNK regulation of matrix metalloproteinases (MMPs). A t-test was used to compare between groups. Results: Males formed larger AAAs at d 14 compared with females (P < 0.001), with significantly higher levels of JNK1 protein, proMMP9, proMMP2, and active MMP2. At d 3, males had more JNK1 mRNA, protein, and MMP activity. Knockdown of JNK 1 or 2 in vitro decreased MMP activity, while knockdown of JNK 1 and 2 together blocked all MMP activity. Conclusion: Alterations in JNK between genders is partially responsible for the differential rates of experimental AAA formation, likely through differential regulation of MMPs. [ABSTRACT FROM AUTHOR]

The serine proteases, along with their inhibitor plasmin activator inhibitor- 1 (PAI-1), have been shown to play a role in abdominal aortic aneurysm (AAA) formation. The aim of this study is to determine if PAI-1 may be a protective factor for AAA formation and partially responsible for the gender difference observed in AAAs. Male and female wild-type (WT) C57BL/6 and PAI-1–/– mice 8–12 wk of age underwent aortic perfusion with porcine pancreatic elastase. Animals were harvested 14 days following perfusion and analyzed for phenotype, PAI-1 protein levels, and matrix metalloproteinase (MMP)-9 and -2 activity. WT males had an average increase in aortic diameter of 80%, whereas females only increased 32% (P < 0.001). PAI-1–/– males increased 204% and females 161%, significantly more than their WT counterparts (P < 0.001). Western blot revealed 61% higher PAI-1 protein levels in the WT females compared with the WT males (P = 0.01). Zymography revealed higher levels of pro-MMP-2 and active MMP-2 in the PAI-1–/– males and females compared with their WT counterparts. PAI-1–/– females had significantly higher serum plasmin levels compared with WT females (P = 0.003). In conclusion, WT female mice are protected from aneurysm formation and have higher levels of PAI-1 compared with males during experimental aneurysm formation. Additionally, both male and female PAI-1–/– animals develop significantly larger aneurysms than WT animals, correlating with higher pro- and active MMP-2 levels. These findings suggest that PAI-1 is protective for aneurysm formation in the elastase model of AAA and plays a role in the gender differences seen in AAA formation. [ABSTRACT FROM AUTHOR]

Background: The present experiments were conducted to explore the role of mitogen-activated protein kinase (MAPK) pathways, potential upstream regulators of MMPs, in abdominal aortic aneurysms (AAAs). Methods: Rat aortic smooth muscle cells (RASMCs) from males and females were treated with media containing interleukin (IL)-1β (2 ng/mL), a concentration known to be present in AAAs. Levels of both total and phosphorylated (activated) extracellular signal-regulated kinase (ERK), c-Jun amino terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38 were examined by Western blotting at various time intervals up to 60 min. Similar experiments were conducted following exposure of RASMCs to elastase (6 U/mL), a concentration known to induce AAA formation in rodents. Finally, media was assayed for MMP activity by zymography. Results: Total ERK (t-ERK) was consistently no different in females compared with males prior to or following IL-1β exposure. In contrast, levels of phosphorylated ERK (p-ERK) were significantly higher in males than females throughout the postexposure period (P < 0.0001). Levels of t-p38, p-p38, and t-JNK were not altered in a gender-dependent manner. The lack of p-JNK levels detected in both male and female RASMCs did not allow for conclusions to be drawn regarding gender disparities in this pathway. Results were similar following RASMC elastase exposure, although t-ERK levels were consistently higher in females than males (P < 0.0001). Pro-MMP2 levels were significantly higher (P = 0.0035) in males than females at each time point following elastase exposure. Conclusions: These data provide evidence implicating alterations in p-ERK signaling via the up-regulation of MMPs as a potential explanation for gender-related discrepancies in AAA formation. [Copyright &y& Elsevier]

Abstract: Introduction: To evaluate the effects of aging on venous thrombosis. Material and Methods: Anesthetized male mice (C57BL/6, n=125) underwent complete inferior vena cava occlusion to produce venous thrombosis. Experimental groups included 11-month-old mice (OLD), 2-month-old mice (YOUNG), and age-matched non-thrombosed controls. Mice were euthanized and the following parameters were evaluated two days post-thrombosis: thrombus mass (grams/cm), vein wall inflammatory cells (cells per 5 high powered fields), active plasma plasminogen activator inhibitor-1 (PAI-1, ng/mL), vein wall P-selectin protein determination by ELISA (pg/mL), circulating plasma microparticles (MPs, MPs/200µL), MP tissue factor (TF) activity (pM), and in vivo MP re-injection experiments. Results: Thrombosed OLD mice had greater thrombus mass than YOUNG mice (389±18 vs. 336±14 g×10−4/cm, P<.05). OLD mice had decreased vein wall monocyte, lymphocyte, and total inflammatory cell populations versus YOUNG mice (P<.05). Vein wall P-selectin levels were greater in OLD thrombosed mice versus YOUNG (7306±938 vs. 3805±745pg/mL, P<.05). Active plasma PAI-1 concentrations were increased in OLD mice versus YOUNG thrombosed animals (20±4 vs. 8±2ng/mL, P<.05). OLD mice had significantly higher circulating leukocyte-derived MPs versus YOUNG mice (5817±850 vs. 2563±283 MPs/200μL PPP, P<.01). OLD mice had plasma MPs with increased TF activity versus YOUNG animals post-thrombosis (34±4 vs. 24±2 pM, P<.05). Finally, YOUNG recipient animals, whether re-injected with OLD or YOUNG donor MPs, had a significant increase in thrombus mass versus OLD recipient animals (P<.01). Conclusion: Aging influenced several circulating and vein wall factors that decreased thrombus resolution in older animals compared to younger ones in our mouse thrombosis model. [Copyright &y& Elsevier]