The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair.

Macrophage plasticity is critical for normal tissue repair to ensure transition from the inflammatory to the proliferative phase of healing. We examined macrophages isolated from wounds of patients afflicted with diabetes and of healthy controls and found differential expression of the methyltransferase Setdb2. Myeloid-specific deletion of Setdb2 impaired the transition of macrophages from an inflammatory phenotype to a reparative one in normal wound healing. Mechanistically, Setdb2 trimethylated histone 3 at NF-κB binding sites on inflammatory cytokine gene promoters to suppress transcription. Setdb2 expression in wound macrophages was regulated by interferon (IFN) ß, and under diabetic conditions, this IFNß-Setdb2 axis was impaired, leading to a persistent inflammatory macrophage phenotype in diabetic wounds. Setdb2 regulated the expression of xanthine oxidase and thereby the uric acid (UA) pathway of purine catabolism in macrophages, and pharmacologic targeting of Setdb2 or the UA pathway improved healing. Thus, Setdb2 regulates macrophage plasticity during normal and pathologic wound repair and is a target for therapeutic manipulation.

The oxylipin analog CS585 prevents platelet activation and thrombosis through activation of the prostacyclin receptor.

Cardiovascular disease remains the primary cause of morbidity and mortality globally. Platelet activation is critical for maintaining hemostasis and preventing the leakage of blood cells from the vessel. There has been a paucity in the development of new drugs to target platelet reactivity. Recently, the oxylipin 12(S)-hydroxy-eicosatrienoic acid (12-HETrE), which is produced in platelets, was shown to limit platelet reactivity by activating the prostacyclin receptor. Here, we demonstrated the synthesis of a novel analog of 12-HETrE, known as CS585. Human blood and mouse models of hemostasis and thrombosis were assessed for the ability of CS585 to attenuate platelet activation and thrombosis without increasing the risk of bleeding. Human platelet activation was assessed using aggregometry, flow cytometry, western blot analysis, total thrombus formation analysis system, microfluidic perfusion chamber, and thromboelastography. Hemostasis, thrombosis, and bleeding assays were performed in mice. CS585 was shown to potently target the prostacyclin receptor on the human platelet, resulting in a highly selective and effective mechanism for the prevention of platelet activation. Furthermore, CS585 was shown to inhibit platelet function in human whole blood ex vivo, prevent thrombosis in both small and large vessels in mouse models, and exhibit long-lasting prevention of clot formation. Finally, CS585 was not observed to perturb coagulation or increase the risk of bleeding in the mouse model. Hence, CS585 represents a new validated target for the treatment of thrombotic diseases without the risk of bleeding or off-target activation observed with other prostaglandin receptor agonists.

The histone methyltransferase MLL1/KMT2A in monocytes drives coronavirus-associated coagulopathy and inflammation.

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

IL-4-STAT6 axis amplifies histamine-induced vascular endothelial dysfunction and hypovolemic shock.

BACKGROUND: Mast cell-derived mediators induce vasodilatation and fluid extravasation, leading to cardiovascular failure in severe anaphylaxis. We previously revealed a synergistic interaction between the cytokine IL-4 and the mast cell-derived mediator histamine in modulating vascular endothelial (VE) dysfunction and severe anaphylaxis. The mechanism by which IL-4 exacerbates histamine-induced VE dysfunction and severe anaphylaxis is unknown. OBJECTIVE: We sought to identify the IL-4-induced molecular processes regulating the amplification of histamine-induced VE barrier dysfunction and the severity of IgE-mediated anaphylactic reactions. METHODS: RNA sequencing, Western blot, Ca2+ imaging, and barrier functional analyses were performed on the VE cell line (EA.hy926). Pharmacologic degraders (selective proteolysis-targeting chimera) and genetic (lentiviral short hairpin RNA) inhibitors were used to determine the roles of signal transducer and activator of transcription 3 (STAT3) and STAT6 in conjunction with in vivo model systems of histamine-induced hypovolemic shock. RESULTS: IL-4 enhancement of histamine-induced VE barrier dysfunction was associated with increased VE-cadherin degradation, intracellular calcium flux, and phosphorylated Src levels and required transcription and de novo protein synthesis. RNA sequencing analyses of IL-4-stimulated VE cells identified dysregulation of genes involved in cell proliferation, cell development, and cell growth, and transcription factor motif analyses revealed a significant enrichment of differential expressed genes with putative STAT3 and STAT6 motif. IL-4 stimulation in EA.hy926 cells induced both serine residue 727 and tyrosine residue 705 phosphorylation of STAT3. Genetic and pharmacologic ablation of VE STAT3 activity revealed a role for STAT3 in basal VE barrier function; however, IL-4 enhancement and histamine-induced VE barrier dysfunction was predominantly STAT3 independent. In contrast, IL-4 enhancement and histamine-induced VE barrier dysfunction was STAT6 dependent. Consistent with this finding, pharmacologic knockdown of STAT6 abrogated IL-4-mediated amplification of histamine-induced hypovolemia. CONCLUSIONS: These studies unveil a novel role of the IL-4/STAT6 signaling axis in the priming of VE cells predisposing to exacerbation of histamine-induced anaphylaxis.

Comparative evaluation of transcutaneous oxygen tension and ankle-brachial index as predictors of reoperation following below-knee amputation.

OBJECTIVE: Decision-making regarding level of lower extremity amputation is sometimes challenging. Selecting an appropriate anatomic level for major amputation requires consideration of tradeoffs between postoperative function and risk of wound complications that may require additional operations, including debridement and/or conversion to above-knee amputation (AKA). We evaluated the utility of common, non-invasive diagnostic tests used in clinical practice to predict the need for reoperations among patients undergoing primary, elective, below knee-amputations (BKAs) by vascular surgeons. METHODS: Patients undergoing elective BKA over a 5-year period were identified using Current Procedural Terminology codes. Medical records were reviewed to characterize demographics, pre-amputation testing transcutaneous oxygen tension (TcPO2), and ankle-brachial index (ABI). The need for ipsilateral post-BKA reoperation (including BKA revision and/or conversion to AKA) regardless of indication was the primary outcome. Associations were evaluated using univariable and multivariable logistic regression models. Cutpoints for TcPO2 values associated with amputation reoperation were evaluated using receiver operating characteristic curves. RESULTS: We identified 175 BKAs, of which 46 (26.3%) required ipsilateral reoperation (18.9% BKA revisions and 14.3% conversions to AKA). The mean age was 63.3 ± 14.8 years. Most patients were male (65.1%) and White (72.0%). Mean pre-amputation calf TcPO2 was 40.0 ± 20.5 mmHg, and mean ABI was 0.64 ± 0.45. In univariable models, post-BKA reoperation was associated with calf TcPO2 (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.94-0.99; P = .013) but not ABI (OR, 0.53; 95% CI, 0.19-1.46; P = .217). Univariable associations with reoperation were also identified for age (OR, 0.97; 95% CI, 0.94-0.990; P = .003) and diabetes (OR, 0.43; 95% CI, 0.21-0.87; P = .019). No associations with amputation revision were identified for gender, race, end-stage renal disease, or preoperative antibiotics. Calf TcPO2 remained associated with post-BKA reoperation in a multivariable model (OR, 0.97; 95% CI, 0.94-0.99; P = .022) adjusted for age (OR, 0.98; 95% CI, 0.94-1.01; P = .222) and diabetes (OR, 0.98; 95% CI, 0.94-1.01; P = .559). Receiver operating characteristic analysis suggested a TcPO2 ≥38 mmHg as an appropriate cut-point for assessing risk for BKA revision (area under the curve = 0.682; negative predictive value, 0.91). CONCLUSIONS: Reoperation after BKA is common, and reoperation risk was associated with pre-amputation TcPO2. For patients undergoing elective BKA, higher risk of reoperation should be discussed with patients with an ipsilateral TcPO2 <38 mmHg.

Low to Moderate Risk Non-orthopedic Surgical Patients Do Not Benefit From VTE Chemoprophylaxis.

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

Optimal Medical Therapy Following Deep Venous Interventions: Proceedings from the Society of Interventional Radiology Foundation Research Consensus Panel.

The optimal medical management of patients following endovascular deep venous interventions remains ill-defined. As such, the Society of Interventional Radiology Foundation (SIRF) convened a multidisciplinary group of experts in a virtual Research Consensus Panel (RCP) to develop a prioritized research agenda regarding antithrombotic therapy following deep venous interventions. The panelists presented the gaps in knowledge followed by discussion and ranking of research priorities based on clinical relevance, overall impact, and technical feasibility. The following research topics were identified as high priority: 1) characterization of biological processes leading to in-stent stenosis/rethrombosis; 2) identification and validation of methods to assess venous flow dynamics and their effect on stent failure; 3) elucidation of the role of inflammation and anti-inflammatory therapies; and 4) clinical studies to compare antithrombotic strategies and improve venous outcome assessment. Collaborative, multicenter research is necessary to answer these questions and thereby enhance the care of patients with venous disease.

Epigenetic Regulation of TLR4 in Diabetic Macrophages Modulates Immunometabolism and Wound Repair.

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.

Accessing the academic influence of vascular surgeons within the National Institutes of Health iCite database.

OBJECTIVE: A diverse array of measures are used to evaluate academic physicians. One critical factor is the scholarly influence an author has on the research discourse within a field. The National Institutes of Health recently developed the Relative Citation Ratio (RCR) as a method to quantify the influence of published research. The aim of this study was to examine the academic influence of vascular surgeons using RCR within common vascular disease research fields. METHODS: Using the PubMed and National Institutes of Health iCite databases, scientific fields of abdominal and thoracic aortic aneurysm, peripheral artery disease (PAD), cerebral vascular occlusive disease, deep venous thrombosis (DVT), and venous insufficiency were queried for the highest rated RCR articles in each category (2007-2012). To calculate the RCR, article citation rates are divided by an expected citation rate derived from performance of articles in the same field, with the resulting RCR being level and field independent. Article categories were divided into basic science, health services, and clinical research on the basis of two independent reviews. For articles, academic backgrounds of the first, second, and last authors ("influential authors") were collected analyzing procedural specialty: surgery, medicine subspecialty (cardiology, neurology, nephrology), radiology/engineering, and other (anesthesia and pediatrics). Statistical significance between scientific fields and academic background was determined using Student t-test or analysis of variance followed by Newman-Keuls post hoc test. RESULTS: The academic influence of vascular surgeons varied substantially by the scientific field. Vascular surgeons compared with medical specialists were found to have the highest academic influence in abdominal aortic aneurysm research, composing 51% of the influential authors on the highest rated RCR studies (5.9 ± 0.8 vs 5.6 ± 0.8; P = .6). In contrast, vascular surgeons composed only 13% of influential authors compared with medical specialists in DVT (RCR, 2.6 ± 0.3 vs 15.7 ± 1.7; P < .003) and 18% in PAD (RCR, 1.9 ± 0.5 vs 2.1 ± 0.2; P = .78) research fields. Grouping all vascular fields of study together, no difference in RCR was found between vascular surgery and radiology/engineering. However, the mean RCR was significantly lower for vascular surgeons compared with medical subspecialties (4.5 ± 0.4 vs 6.8 ± 0.5; P < .05). CONCLUSIONS: Vascular surgeons exhibit a moderate academic influence in the field of aneurysmal disease but lag behind medical subspecialists in high-impact scientific contributions to the fields of PAD and DVT. Innovative strategies and collaborations are likely needed to increase the influence of vascular surgeons on the academic discourse of several vascular disease research fields.

Bleeding and thrombotic outcomes associated with postoperative use of direct oral anticoagulants after open peripheral artery bypass procedures.

OBJECTIVE: Widespread adoption of direct oral anticoagulants (DOACs) for atrial fibrillation and venous thromboembolism treatment has resulted in peripheral bypass patients receiving therapeutic anticoagulation with DOACs postoperatively. This study was undertaken to evaluate patient outcomes after open peripheral bypass based on anticoagulation treatment. METHODS: Postoperative treatment and outcomes of patients undergoing peripheral bypass operations between January 2012 and December 2017 from a statewide multicenter quality improvement registry were examined. Surgeons participating in the registry were surveyed on practice patterns regarding DOACs in bypass patients. Multivariate logistic regression was performed for 30-day transfusion outcomes, and multiple linear regression was performed for length of stay. RESULTS: Among 9682 patients, 7685 patients received no anticoagulation, whereas 1379 received a vitamin K antagonist (VKA) and 618 received a DOAC postoperatively. Patients receiving anticoagulation compared with no anticoagulation had a higher body mass index and were more likely to have preoperative anemia, congestive heart failure, and atrial fibrillation (all P < .001). Compared with patients receiving VKAs, patients receiving DOACs were less likely to have chronic kidney disease (P = .002) and more likely to have atrial fibrillation (P < .001). The shortest length of stay was among patients receiving no anticoagulation (median, 5 days; interquartile range, 3-9 days; P < .001), followed by DOACs (median, 6 days; interquartile range 3-11 days; P < .001) and VKAs (median, 8 days; interquartile range, 5-13 days; P < .001). Compared with patients receiving VKAs postoperatively, there was no difference in readmission for anticoagulation complications, bypass thrombectomy or thrombolysis, major amputation, or graft patency at 1 year among patients receiving DOACs. On multivariate logistic regression, patients receiving a DOAC (odds ratio, 0.743; confidence interval, 0.59-0.94; P = .011) or no anticoagulation (odds ratio, 0.792; confidence interval, 0.69-0.91; P = .001) were less likely to require transfusion within 30 days than patients taking VKAs. Approximately 70% of the surveyed surgeons reported that they "sometimes" or "always" use DOACs instead of VKAs for protection of a high-risk bypass. CONCLUSIONS: Among patients undergoing lower extremity surgical bypass, those receiving a DOAC postoperatively had a shorter length of stay and were less likely to receive a transfusion in 30 days without compromising graft patency and readmission for anticoagulation complications, thrombectomy, or thrombolysis or affecting amputation rate compared with those receiving a VKA. A majority of surgeons within the quality collaborative have adopted the use of DOACs after peripheral bypass, suggesting the need for a prospective trial evaluating DOAC safety and efficacy in patients requiring anticoagulation for high-risk bypass grafts.

Sepsis Induces Prolonged Epigenetic Modifications in Bone Marrow and Peripheral Macrophages Impairing Inflammation and Wound Healing.

OBJECTIVE: Sepsis represents an acute life-threatening disorder resulting from a dysregulated host response. For patients who survive sepsis, there remains long-term consequences, including impaired inflammation, as a result of profound immunosuppression. The mechanisms involved in this long-lasting deficient immune response are poorly defined. Approach and Results: Sepsis was induced using the murine model of cecal ligation and puncture. Following a full recovery period from sepsis physiology, mice were subjected to our wound healing model and wound macrophages (CD11b+, CD3-, CD19-, Ly6G-) were sorted. Post-sepsis mice demonstrated impaired wound healing and decreased reepithelization in comparison to controls. Further, post-sepsis bone marrow-derived macrophages and wound macrophages exhibited decreased expression of inflammatory cytokines vital for wound repair (IL [interleukin]-1ß, IL-12, and IL-23). To evaluate if decreased inflammatory gene expression was secondary to epigenetic modification, we conducted chromatin immunoprecipitation on post-sepsis bone marrow-derived macrophages and wound macrophages. This demonstrated decreased expression of Mll1, an epigenetic enzyme, and impaired histone 3 lysine 4 trimethylation (activation mark) at NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells)-binding sites on inflammatory gene promoters in bone marrow-derived macrophages and wound macrophages from postcecal ligation and puncture mice. Bone marrow transplantation studies demonstrated epigenetic modifications initiate in bone marrow progenitor/stem cells following sepsis resulting in lasting impairment in peripheral macrophage function. Importantly, human peripheral blood leukocytes from post-septic patients demonstrate a significant reduction in MLL1 compared with nonseptic controls. CONCLUSIONS: These data demonstrate that severe sepsis induces stable mixed-lineage leukemia 1-mediated epigenetic modifications in the bone marrow, which are passed to peripheral macrophages resulting in impaired macrophage function and deficient wound healing persisting long after sepsis recovery.

Murine macrophage chemokine receptor CCR2 plays a crucial role in macrophage recruitment and regulated inflammation in wound healing.

Macrophages play a critical role in the establishment of a regulated inflammatory response following tissue injury. Following injury, CCR2+ monocytes are recruited from peripheral blood to wound tissue, and direct the initiation and resolution of inflammation that is essential for tissue repair. In pathologic states where chronic inflammation prevents healing, macrophages fail to transition to a reparative phenotype. Using a murine model of cutaneous wound healing, we found that CCR2-deficient mice (CCR2-/- ) demonstrate significantly impaired wound healing at all time points postinjury. Flow cytometry analysis of wounds from CCR2-/- and WT mice revealed a significant decrease in inflammatory, Ly6CHi recruited monocyte/macrophages in CCR2-/- wounds. We further show that wound macrophage inflammatory cytokine production is decreased in CCR2-/- wounds. Adoptive transfer of mT/mG monocyte/macrophages into CCR2+/+ and CCR2-/- mice demonstrated that labeled cells on days 2 and 4 traveled to wounds in both CCR2+/+ and CCR2-/- mice. Further, adoptive transfer of monocyte/macrophages from WT mice restored normal healing, likely through a restored inflammatory response in the CCR2-deficient mice. Taken together, these data suggest that CCR2 plays a critical role in the recruitment and inflammatory response following injury, and that wound repair may be therapeutically manipulated through modulation of CCR2.

Aggressive Phenotype of Intravascular Lymphoma Relative to Other Malignant Intraabdominal Tumors Requiring Vascular Reconstruction.

BACKGROUND: Safe resection of intraabdominal and retroperitoneal malignancies with a goal of negative margins may require vascular surgical assistance with grafting of the aorta and/or vena cava. The current report reviews malignancies associated with major vascular reconstructions at a single tertiary referral center. METHODS: Adults with abdominal or retroperitoneal tumors involving the aorta, vena cava, or iliac arteries that underwent reconstruction with vascular grafts at the University of Michigan from 2010 to 2016 were reviewed retrospectively. The initial presentation, surgical management, and outcomes were analyzed. RESULTS: Twelve patients with tumors involving the abdominal aorta, vena cava, or iliac arteries underwent major vascular reconstruction in this seven-year study period. Tumor pathology included solid tumors (leiomyosarcoma [n = 7], germ cell tumor [n = 3], and intravascular lymphoma [n = 2]). Surgical treatment included grafting of the vena cava (n = 6), aorta (n = 3), iliac artery (n = 4), or both the aorta and vena cava (n = 1). Patients with intravascular lymphoma were identified incidentally during treatment of abdominal aortic aneurysm or on pathological analysis of thromboembolism from an aortic source. Other patients had planned resection. Follow-up ranged from 9 to 86 months (median: 28.9). There were no graft occlusions. Tumor metastasized or recurred in patients with sarcoma (n = 2; 28.6%), germ cell tumor (n = 1; 33.3%), and intravascular lymphoma (n = 2; 100%). Both patients with lymphoma had multiple anastomotic or tumor-embolic pseudoaneurysms for <14 months after vascular reconstruction. Both lymphoma patients died during follow-up. CONCLUSIONS: This single-center review suggests that sarcoma and germ cell tumors may be safely resected in conjunction with major vascular reconstruction in carefully selected patients. In comparison, intravascular lymphoma identified incidentally at the time of aortic reconstruction resulted in a more malignant course with pseudoaneurysm formation of anastomoses or native vessels, cancer recurrence, and 100% mortality. Aneurysm contents and emboli should be carefully reviewed perioperatively by pathologists.

The association of venous thromboembolism chemoprophylaxis timing on venous thromboembolism after major vascular surgery.

OBJECTIVE: Venous thromboembolism (VTE) is reported to occur in up to 33% of patients undergoing major vascular surgery. Despite this high incidence, patients inconsistently receive timely VTE chemoprophylaxis. The true incidence of VTE among patients receiving delayed VTE chemoprophylaxis is unknown. We sought to identify the association of VTE chemoprophylaxis timing on VTE risk, postoperative transfusion rates, and 30-day mortality and morbidity in patients undergoing major open vascular surgery. METHODS: Patients undergoing major open vascular surgery (open abdominal aortic aneurysm [oAAA] repair, aortofemoral bypass, and lower extremity infrainguinal bypass [LEB]) were identified using the Michigan Surgical Quality Collaborative (MSQC) between July 2012 and June 2015. The VTE rate was compared between patients receiving early versus delayed VTE chemoprophylaxis. VTE chemoprophylaxis delay was defined as therapy initiation more than 24 hours after surgery. The risk-adjusted association of the chemoprophylaxis timing and VTE development was determined using multivariable logistic regression. Blood transfusion rates, 30-day mortality, and postoperative complications were compared across groups. RESULTS: A total of 2421 patients underwent major open vascular surgery, including 196 oAAA repair, 259 aortofemoral bypass, and 1966 LEB. The overall incidence of 30-day VTE was 1.40%, ranging from 1.12% for LEB to 3.57% for oAAA repair. Among patients receiving early VTE chemoprophylaxis, the rate of VTE was 0.78% versus 2.26% among those with a delay in VTE chemoprophylaxis (P = .002). When accounting for the preoperative risk of VTE, delayed chemoprophylaxis was associated with a significantly higher risk of VTE (odds ratio, 2.38; 95% confidence interval, 1.12-5.06; P = .024). The early VTE chemoprophylaxis group was associated with a significantly decreased risk of bleeding compared with those with a delay (14.31% vs 18.90%; P = .002). Overall 30-day mortality and postoperative complications were similar with the exception of an associated higher rate of infectious complications in the delayed VTE chemoprophylaxis group, including superficial surgical site infection (6.00% vs 4.06%; P = .028), pneumonia (3.25% vs 1.85%; P = .028), urinary tract infection (2.95% vs 1.57%; P = .020), and severe sepsis (3.05% vs 1.71%; P = .029). CONCLUSIONS: Although patients undergoing major open vascular surgery have a low risk of VTE at baseline, there is a significantly greater risk of developing VTE among patients who have a delay in the administration of VTE chemoprophylaxis. Postoperative transfusion rates were significantly lower among patients receiving early chemoprophylaxis. There were no differences in the 30-day mortality and postoperative complications, except for infectious complications. Given these findings, surgeons should consider early chemoprophylaxis in the postoperative setting after major open vascular surgery without contraindication.

Risk Factors Associated with Perioperative Myocardial Infarction in Major Open Vascular Surgery.

BACKGROUND: Among patients undergoing noncardiac surgery, major vascular surgery is associated with a high risk of perioperative myocardial infarction (MI). Currently, there are no perioperative MI risk calculators accounting for intraoperative and postoperative risk factors in vascular surgery patients. We aimed to investigate specific risk factors for perioperative MI after major open vascular surgery to determine which patients are at highest risk of MI and the association of perioperative MI with perioperative transfusion. METHODS: This statewide, retrospective cohort study analyzed risk factors for perioperative MI in major open vascular surgery between July 2012 and December 2015 using the Michigan Surgical Quality Collaborative, a multicenter quality collaborative. Patients were identified using current procedure terminology codes including open abdominal aortic aneurysm repairs (oAAA), aortobifemoral bypasses (AFB), and lower extremity bypasses (LEB). Rates of myocardial infarction were described for each procedure. A priori, preoperative, intraoperative, and postoperative variables were evaluated using univariate and multivariable statistics after adjusting for intraoperative factors including anesthesia type, intraoperative blood loss, intraoperative transfusion, and intraoperative vasopressor medications. RESULTS: A total of 3,689 patients underwent major open vascular surgery, including 375 oAAA, 392 AFB, and 2,922 LEB procedures. The overall incidence of MI was 2.4%, varying from 1.8% for aortobifemoral bypass, 2.4% for lower extremity bypass, and 3.7% for open abdominal aortic aneurysm repair. Although preoperative risk factors for myocardial infarction included age, American Society of Anesthesiologists score, diabetes, coronary artery disease, congestive heart failure, use of beta blocker, lower preoperative hematocrit, and surgical priority (urgent/emergent cases), after adjusting for intraoperative risk factors, all preoperative risk factors were not significant with the exception of surgical priority. After adjusting for intraoperative factors, only surgical priority (odds ratio [OR] = 1.70, 95% confidence interval [CI] [1.01-2.85], P < 0.001) and postoperative transfusion (OR = 2.65, 95% CI [1.59-4.44], P < 0.001) was associated with myocardial infarction, and higher nadir hematocrit was inversely associated with myocardial infarction (OR = 0.89, 95% CI [0.85-0.94], P < 0.001). CONCLUSIONS: Among vascular surgery patients undergoing major open vascular surgery, surgical priority was the only preoperative risk factors independently associated with MI, and only postoperative variables such as nadir hematocrit and postoperative transfusion were associated with MI. This suggests minimizing intraoperative blood loss and prioritizing early intraoperative transfusion may be the potential targets for process improvement.

Gram-Negative Pneumonia Alters Large-Vein Cell-Adhesion Molecule Profile and Potentiates Experimental Stasis Venous Thrombosis.

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.