Elizabeth Andraska

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.

Endotoxaemia-augmented murine venous thrombosis is dependent on TLR-4 and ICAM-1, and potentiated by neutropenia

Venous thromboembolism is a major cause of death during and immediately post-sepsis. Venous thrombosis (VT) is mediated by cell adhesion molecules and leukocytes, including neutrophil extracellular traps (NETs). Sepsis, or experimentally, endotoxaemia, shares similar characteristics and is modulated via toll like receptor 4 (TLR4). This study was undertaken to determine if endotoxaemia potentiates early stasis thrombogenesis, and secondarily to determine the role of VT TLR4, ICAM-1 and neutrophils (PMNs). Wild-type (WT), ICAM-1-/- and TLR4-/- mice underwent treatment with saline or LPS (10 mg/kg i. p.) alone, or followed by inferior vena cava (IVC) ligation to generate stasis VT. In vivo microscopy of leukocyte trafficking was performed in non-thrombosed mice, and tissue and plasma were harvested during early VT formation. Pre-thrombosis, circulating ICAM-1 was elevated and increased leukocyte adhesion and rolling occurred on the IVC of LPS-treated mice. Post-thrombosis, endotoxaemic mice formed larger, platelet-poor thrombi. Endotoxaemic TLR4-/- mice did not have an augmented thrombotic response and exhibited significantly decreased circulating ICAM-1 compared to endotoxaemic WT controls. Endotoxaemic ICAM-1-/- mice had significantly smaller thrombi compared to controls. Hypothesising that PMNs localised to the inflamed endothelium were promoting thrombosis, PMN depletion using anti-Ly6G antibody was performed. Paradoxically, VT formed without PMNs was amplified, potentially related to endotoxaemia induced elevation of PAI-1 and circulating FXIII, and decreased uPA. Endotoxaemia enhanced early VT occurs in a TLR-4 and ICAM-1 dependent fashion, and is potentiated by neutropenia. ICAM-1 and/or TLR-4 inhibition may be a unique strategy to prevent sepsis-associated VT.

Extended Case Duration and Hypotension Are Associated With Higher-grade Postoperative Complications After Urinary Diversion for Non-oncological Disease

OBJECTIVE To report survival for patients who undergo urinary diversion for benign indications and to identify risk factors for morbidity at 90 days. METHODS This is a retrospective review of consecutive urinary diversions with or without cystectomy for non-oncological indications at a single institution. The indication for diversion was intractable incontinence, upper tract deterioration, urinary fistula, and unmanageable bladder pain. Patients were categorized according to their most severe complication within 90 days of surgery, using the Clavien-Dindo system. Multivariable analysis was performed to identify factors associated with high-grade complications. Survival analysis was performed. RESULTS Between 2007 and 2014, 141 patients underwent urinary diversion for non-oncological indications. The postoperative rate of high-grade adverse events (class III or greater) was 28%. Risk factors for class III or greater complications at 90 days included prolonged intraoperative mean arterial pressure below 75% of baseline, operative duration greater than 343 minutes, and postoperative vasopressor requirement. Kaplan-Meier survival analysis demonstrated a 1- and 5-year survival of 88.4% and 77.2%, respectively. The long-term survival of patients who experienced higher-grade complications was not statistically different from the survival of the rest of the group. The study was limited by a retrospective design and sample size in identifying additional variables associated with increased risk of long-term mortality. CONCLUSION Urinary diversion for non-oncological conditions has a good 5-year survival in this cohort. Extended case duration and hemodynamic instability during or immediately after urinary diversion are associated with a high-grade complication within 90 days of the procedure.

Plexiform schwannoma: an unusual clitoral mass

Acquired clitoral enlargement is a rare condition resulting from a variety of etiologies, including tumors and excess androgens. Few cases of nonmalignant schwannoma, a benign tumor of the peripheral nerve sheath, have been reported in the literature as causes of clitoral enlargement in patients without known neurofibromatosis. These painless, slow-growing tumors rarely recur once excised. We present the initial investigation of a patient with a large clitoral schwannoma and subsequent treatment with partial vulvectomy. The workup, including advanced pelvic imaging for diagnosis and surgical planning, as well as removal of the clitoral tumor with preservation of functional tissue and restoration of normal vulvar anatomy despite a large excision, is demonstrated.

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

BACKGROUND Patients undergoing deep vein thrombosis (VT) have over 30% recurrence, directly increasing their risk of post-thrombotic syndrome. Current murine models of inferior vena cava (IVC) VT model host one thrombosis event. OBJECTIVE We aimed to develop a murine model to study IVC recurrent VT in mice. MATERIALS AND METHODS An initial VT was induced using the electrolytic IVC model (EIM) with constant blood flow. This approach takes advantage of the restored vein lumen 21 days after a single VT event in the EIM demonstrated by ultrasound. We then induced a second VT 21 days later, using either EIM or an IVC ligation model for comparison. The control groups were a sham surgery and, 21 days later, either EIM or IVC ligation. IVC wall and thrombus were harvested 2 days after the second insult and analysed for IVC and thrombus size, gene expression of fibrotic markers, histology for collagen and Western blot for citrullinated histone 3 (Cit-H3) and fibrin. RESULTS Ultrasound confirmed the first VT and its progressive resolution with an anatomical channel allowing room for the second thrombus by day 21. As compared with a primary VT, recurrent VT has heavier walls with significant up-regulation of transforming growth factor-β (TGF-β), elastin, interleukin (IL)-6, matrix metallopeptidase 9 (MMP9), MMP2 and a thrombus with high citrullinated histone-3 and fibrin content. CONCLUSION Experimental recurrent thrombi are structurally and compositionally different from the primary VT, with a greater pro-fibrotic remodelling vein wall profile. This work provides a VT recurrence IVC model that will help to improve the current understanding of the biological mechanisms and directed treatment of recurrent VT.

PC228. A Magnetic Cannulation Approach Reduces Time and Radiation Exposure During Simulated Fenestrated Endograft Repair

Bonemarrow-derived macrophages (BmDm) were isolated and cultured, and stimulated with LPS (100 mg/mc). LC-MS methods were used to quantify the metabolites. Results: We found that differentiated macrophages from control and DIO mice have alterations in the levels of many metabolites, with specific increases in the glycolytic and TCA cycle compounds. These baseline changes in metabolite levels were markedly amplified by stimulation with LPS, consistent with the hyperactivation state of macrophages from DIO mice. We have also found that SAM levels were significantly increased in DIO macrophages. To determine the source of increased SAM in DIO mice, we looked at the rate-limiting enzyme involved in the conversion of methionine to SAM, methionine adenosyl transferase (MAT2a). We found MAT2a was elevated in the DIO macrophages compared with controls (P < .05). Conclusions: Alterations in metabolites and particularly levels of SAM, which is induced by MAT2a, leads to phenotypic changes in the macrophages within the tissues.

Pathophysiology of varicose veins

BACKGROUND Varicose veins, a common problem with effects on quality of life, account for a significant cost burden on the health care system. Despite their prevalence, the pathophysiologic mechanism of varicose veins remains incompletely understood. The fundamental issue is whether venous hypertension and valvular incompetence precede and influence the development of vein wall changes or whether the reverse is true. METHODS We have reviewed the English-language literature to provide the most current understanding of the hemodynamic and cellular and molecular processes that underlie the development of varicose veins. RESULTS Data at this time remain inconclusive, with compelling arguments to be made for both sides. It is clear that valvular incompetence and hemodynamic factors play a significant role, despite heterogeneity in study findings and lack of clear data for a specific pattern of valvular incompetence as an inciting factor. Numerous factors influence the development of varices on the cellular level, including hypoxia, dysregulated apoptosis, and alterations in the extracellular matrix. CONCLUSIONS Based on currently available evidence, varicose veins are a complex disease with multifactorial pathogenesis; it is as yet not possible to state conclusively what inciting factor is responsible for the development of varicose veins, and their development may result from imbalance of any number of several factors.

Intravascular ultrasound imaging as a novel tool for the diagnosis of endofibrosis

Given the rise of high-intensity sport athletes and the paucity of literature on endofibrosis, we describe a novel adjunctive imaging technique to aid in diagnosis. A 41-year-old female triathlete presented with exercise-limiting claudication. Results of lower extremity magnetic resonance angiography, provocative Doppler, angiogram, and digital subtraction angiography with papaverine were nondiagnostic. Intravascular ultrasound imaging was able to delineate an abnormal segment of the proximal external iliac artery with intimal hypertrophy. We report intravascular ultrasound imaging as a superior imaging modality to definitively diagnose endofibrosis and assist proper planning and operative treatment of patients with endofibrosis.