Simulated Thrombin Generation in the Presence of Surface-Bound Heparin and Circulating Tissue Factor

An expanded computational model of surface induced thrombin generation was developed that includes hemodynamic effects, 22 biochemical reactions and 44 distinct chemical species. Surface binding of factors V, VIII, IX, and X was included in order to more accurately simulate the formation of the surface complexes tenase and prothrombinase. In order to model these reactions, the non-activated, activated and inactivated forms were all considered. This model was used to investigate the impact of surface bound heparin on thrombin generation with and without the additive effects of thrombomodulin (TM). In total, 104 heparin/TM pairings were evaluated (52 under venous conditions, 52 under arterial conditions), the results demonstrating the synergistic ability of heparin and TM to reduce thrombin generation. Additionally, the role of circulating tissue factor (TF[subscript p]) was investigated and compared to that of surface-bound tissue factor (TF[subscript s]). The numerical results suggest that circulating TF has the power to amplify thrombin generation once the coagulation cascade is already initiated by surface-bound TF. TF[subscript p] concentrations as low as 0.01 nM were found to have a significant impact on total thrombin generation.National Institutes of Health (U.S.) (Grants HL106018 and HL56819

Cell behavior on a CCN1 functionalized elastin-mimetic protein polymer

a b s t r a c t We report the design of an elastin-mimetic triblock copolymer with the ability to guide endothelial cell adhesion, spreading, and migration while maintaining the elastomeric properties of the protein polymer. The V2 ligand sequence from matricellular protein CCN1 (cysteine-rich 61, CYR61) was multimerized and cloned into elastin polymer LysB10, creating LysB10.V2. Cell adhesion studies demonstrated that a LysB10.V2 surface density of at least 40 pmol/cm 2 was required to elicit cell attachment. Peptide blocking studies confirmed V2 specific engagement with integrin receptor a v b 3 (P < 0.05) and we observed the formation of actin stress fiber networks and vinculin clustering, characteristic of focal adhesion assembly. Haptotatic migration assays demonstrated the ability of LysB10.V2 surfaces to stimulate migration of endothelial cells (P < 0.05). Significantly, we illustrated the ability of LysB10.V2 to support a quiescent endothelium. The CCN1 molecule functions to support many key biological processes necessary for tissue repair and thus presents a promising target for bioengineering applications. Collectively, our results demonstrate the potential to harness CCN1 specific function in the design of new scaffold materials for applications in regenerative medicine

Scanning Electron Microscopy Analysis of Polyethylene Oxide Hydrogels for Blood Contact

Hydrogels are a class of synthetic material, composed of a polymer-water matrix and have been proposed as tissue substitutes and drug delivery vehicles. Polyethylene oxide (PEO) hydrogels were synthesized and used to produce coated wires and conduits for baboon blood compatibility studies. Blood-material interactions were studied both by Scanning Electron Microscopy (SEM) and 111In labeled platelet deposition. SEM processing modifications were first evaluated in order to reduce shrinkage and surface distortion incurred during sample preparation of these high water content materials. Pretreatment with 1% tannic acid reduced bulk shrinkage associated with critical point drying by 10-20%. This effect is small, nevertheless, it prevented major sample disruption. Coated guidewires were exposed to baboon blood for one hour in the inferior vena cava and conduits were placed for either 30 or 60 minutes in an ex vivo femoral arteriovenous shunt. Reference materials included Gore-tex®, polyethylene and silica-free polydimethyl siloxane (PDMS). In the guidewire studies, 111In labeled platelet levels were highest on Gore-tex® (6568.97 platelets/ 1000 μm2) and large thrombotic deposits were well visualized by SEM. Formulations containing PEO had low levels of platelet deposition and little evidence of platelet activation was noted by SEM. Shunt studies demonstrated that materials of high PEO content and molecular weight had the lowest levels of platelet deposition. After 60 minutes of blood flow, mean platelet deposition on PDMS and Gore-tex® was 50 and 1000 fold higher than on a network composed of 65% PEO 20,000 (p \u3c 0.05). SEM confirmed these findings

Fenofibrate in the management of AbdoMinal aortic anEurysm (FAME): Study protocol for a randomised controlled trial

Background: Abdominal aortic aneurysm (AAA) is a slowly progressive destructive process of the main abdominal artery. Experimental studies indicate that fibrates exert beneficial effects on AAAs by mechanisms involving both serum lipid modification and favourable changes to the AAA wall. Methods/design: Fenofibrate in the management of AbdoMinal aortic anEurysm (FAME) is a multicentre, randomised, double-blind, placebo-controlled clinical trial to assess the effect of orally administered therapy with fenofibrate on key pathological markers of AAA in patients undergoing open AAA repair. A total of 42 participants scheduled for an elective open AAA repair will be randomly assigned to either 145 mg of fenofibrate per day or identical placebo for a minimum period of 2 weeks prior to surgery. Primary outcome measures will be macrophage number and osteopontin (OPN) concentration within the AAA wall as well as serum concentrations of OPN. Secondary outcome measures will include levels of matrix metalloproteinases and proinflammatory cytokines within the AAA wall, periaortic fat and intramural thrombus and circulating concentrations of AAA biomarkers. Discussion: At present, there is no recognised medical therapy to limit AAA progression. The FAME trial aims to assess the ability of fenofibrate to alter tissue markers of AAA pathology. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12612001226897. Registered on 20 November 2012. © 2017 The Author(s)

ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery)

These guidelines represent an update to those published in 2002 and are intended for physicians and nonphysician caregivers who are involved in the preoperative, operative, and postoperative care of patients undergoing noncardiac surgery. They provide a framework for considering cardiac risk of noncardiac surgery in a variety of patient and surgical situations. The writing committee that prepared these guidelines strove to incorporate what is currently known about perioperative risk and how this knowledge can be used in the individual patient

ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery)

"These guidelines are intended for physicians and nonphysician caregivers who are involved in the preoperative, operative, and postoperative care of patients undergoing noncardiac surgery. They provide a framework for considering cardiac risk of noncardiac surgery in a variety of patient and surgical situations. The writing committee that prepared these guidelines strove to incorporate what is currently known about perioperative risk and how this knowledge can be used in the individual patient. The tables and algorithms provide quick references for decision making. The overriding theme of this document is that intervention is rarely necessary to simply lower the risk of surgery unless such intervention is indicated irrespective of the preoperative context. The purpose of preoperative evaluation is not to give medical clearance but rather to perform an evaluation of the patient's current medical status; make recommendations concerning the evaluation, management, and risk of cardiac problems over the entire perioperative period; and provide a clinical risk profile that the patient, primary physician, and nonphysician caregivers, anesthesiologist, and surgeon can use in making treatment decisions that may influence short- and long-term cardiac outcomes. No test should be performed unless it is likely to influence patient treatment. The goal of the consultation is the optimal care of the patient.