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Background: The purpose of this study was to assess the feasibility and outcomes of recanalization and subsequent HeRO graft outflow component insertion across stent interstices in patients with an otherwise abandoned upper extremity.Methods: Over a 10-year period, 15 patients underwent central venous recanalization by interventional radiology across the interstices of one or more occluded stents for the purpose of subsequent HeRO graft creation. A tunneled central venous catheter was left across the stent and occlusions with tip in right atrium. On a later date, the catheter was used for rapid guidewire access for HeRO graft implantation in the OR by vascular surgery. Procedural and clinical outcomes were determined by retrospective review. Primary and secondary HeRO graft patency rates were estimated with the Kaplan-Meier technique.Results: The technical success rates of recanalization across stent interstices was 100% (15/15). Between one and four overlapping stent walls were traversed. The technical success of the patients who underwent attempted HeRO graft implantation with outflow component traversing across stent interstices was 91% (11/12). No major complications were encountered with either recanalization or HeRO graft implantation. The primary and secondary HeRO patency rates at 12 months were 64% and 80%, respectively.Conclusion: HeRO graft insertion across stent interstices is feasible and can provide effective permanent AV access; thus, the presence of stents across the subclavian and brachiocephalic veins should not be considered a contraindication.

Advances in standards of care have extended the life expectancy of patients with kidney failure. However, options for chronic vascular access for haemodialysis — an essential part of kidney replacement therapy — have remained unchanged for decades. The high morbidity and mortality associated with current vascular access complications highlights an unmet clinical need for novel techniques in vascular access and is driving innovation in vascular access care. The development of devices, biological approaches and novel access techniques has led to new approaches to controlling fistula geometry and manipulating the underlying cellular and molecular pathways of the vascular endothelium, and influencing fistula maturation and formation through the use of external mechanical methods. Innovations in arteriovenous graft materials range from small modifications to the graft lumen to the creation of completely novel bioengineered grafts. Steps have even been taken to create new devices for the treatment of patients with central vein stenosis. However, these emerging therapies face difficult hurdles, and truly creative approaches to vascular access need resources that include well-designed clinical trials, frequent interaction with regulators, interventionalist education and sufficient funding. In addition, the heterogeneity of patients with kidney failure suggests it is unlikely that a ‘one-size-fits-all’ approach for effective vascular access will be feasible in the current environment.

AbstractBackgroundPrevious studies have identified risk factors for femoral arterial thrombosis after paediatric cardiac catheterisation, but none of them have evaluated the clinical and economic significance of this complication at the population level. Therefore, we examined the national prevalence and economic impact of femoral arterial thrombosis after cardiac catheterisation in children.MethodsPatients⩽18 years of age who underwent cardiac catheterisation were identified in the 2003–2009 Kids’ Inpatient Database. Patients were stratified by age as follows: <1 year of age or 1–18 years of age. The primary outcome was arterial thrombosis of the lower extremity during the same hospitalisation as cardiac catheterisation. Propensity score matching was used to determine the impact of femoral arterial thrombosis on hospital length of stay, cost, and mortality.ResultsAmong the 11,497 paediatric cardiac catheterisations identified, 4558 catheterisations (39.6%) were performed in children <1 year of age. This age group experienced a higher prevalence of reported femoral arterial thrombosis, compared with children aged 1–18 years (1.3 versus 0.3%, p<0.001). After matching, femoral arterial thrombosis in children <1 year of age was associated with similar mortality (5.4 versus 1.8%, p=0.28), length of stay (8 versus 5 days, p=0.11), and total hospital cost ($27,135 versus $28,311, p=0.61), compared with absence of thrombosis.ConclusionsFemoral arterial thrombosis is especially prevalent in children <1 year of age undergoing cardiac catheterisation. Clinicians should be vigilant in monitoring femoral arterial patency in neonates and infants after cardiac catheterisation.

There is a need for bioengineered therapies to improve the overall health of the growing and aging world population. Patients with renal failure have a life-long requirement for a durable form of hemodialysis vascular access. In this article, we review the history of tissue engineering as it pertains to bioengineered grafts and vessels for hemodialysis access. Over the years, various strategies have been utilized to develop ideal, humanized vessels for vascular replacement such as fixation of animal or human vessels, cell seeding of synthetic materials, and the synthesis of completely autologous or allogeneic bioengineered vessels. Tissue engineering technologies from two companies have progressed to reach phase 2 and phase 3 clinical trials, but the prospect of newer strategies on the horizon may offer improved manufacturing efficiency, a greater variety of conduit size and length, and reduce the cost to produce.

Forearm and upper arm arteriovenous grafts perform similarly in terms of patency and complications. Primary patency at 1 year for forearm arteriovenous grafts versus upper arm grafts ranges from 22%-50% versus 22%-42%, and secondary patency at 1 year ranges from 78%-89% versus 52%-67%), respectively. Secondary patency at 2 years, ranges from 30%-64% versus 35%-60% for forearm and upper arteriovenous graft, respectively. Ample pre-operative planning is essential to improved clinical success and the decision to place a graft at one location versus the other should be based solely on previous access history, physical exam, appropriate venous imaging, and other factors that make up the clinical picture. Operative implant strategies and risk of complications are very similar between the two configurations. Postoperative ischemia due to steal syndrome is a potential complication that requires immediate attention. Utilization of the proximal radial or ulnar artery for inflow for the graft can minimize risk of clinically relevant steal syndrome.

Vascular graft infections are a particularly troublesome complication for dialysis patients, many of whom are in an already immunocompromised state. The objective of this review is to detail the risk factors, etiology, diagnosis, perioperative and operative management of vascular graft infections.

(s): Palliative treatment of Cyanotic congenital heart disease (CCHD) utilizes systemic-to-pulmonary conduits, often a modified Blalock-Taussig-Thomas shunt (mBTTs). Expanded polytetrafluoroethylene (ePTFE) mBTTs have associated risks for thrombosis and infection. The Human Acellular Vessel (HAV) (Humacyte Inc., Durham, NC) is a 6mm decellularized tissue engineered blood vessel currently in clinical trials in adults for vascular trauma, peripheral artery disease, and end-stage renal disease requiring hemodialysis. In addition to restoring blood flow, the engineered HAV demonstrates the capacity for host cellular remodeling into native-like vasculature. Here we report preclinical evaluation of a small diameter (3.5mm) HAV as a mBTTs in a non-human primate model.

For patients with end-stage renal disease who are not candidates for fistula, dialysis access grafts are the best option for chronic haemodialysis. However, polytetrafluoroethylene arteriovenous grafts are prone to thrombosis, infection, and intimal hyperplasia at the venous anastomosis. We developed and tested a bioengineered human acellular vessel as a potential solution to these limitations in dialysis access.

A lack of consensus on anticoagulant reversal during acute trauma is compounded by an aging population and the expanding spectrum of new anticoagulation agents. Developments in laboratory assays and transfusion medicine, including thromboelastography, recombinant factors, and factor concentrates, have revolutionized care for anticoagulated trauma patients. Accordingly, clinicians must be fully aware of drug mechanisms, assays to determine drug activity, and appropriate reversal strategies for patients on anticoagulants. Drugs include vitamin K antagonists, direct thrombin inhibitors, direct factor Xa inhibitors, low molecular weight heparin, and antiplatelet agents. This article discusses the appropriate assessment and management of trauma patients receiving these agents.

Purpose To explore the safety and efficacy of PRT-201.Methods Randomized, double-blind, placebo-controlled, single-dose escalation study of PRT-201 (0.0033 to 9 mg) applied after arteriovenous fistula (AVF) creation. Participants were followed for one year. The primary outcome measure was safety. Efficacy measures were the proportion with intra-operative increases in AVF outflow vein diameter or blood flow ≥25% (primary), changes in outflow vein diameter and blood flow, AVF maturation and lumen stenosis by ultrasound criteria and AVF patency.Results The adverse events in the PRT-201 group (n=45) were similar to those in the placebo group (n=21). There were no differences in the proportion with ≥25% increase in vein diameter or blood flow, successful maturation or lumen stenosis. There was no statistically significant difference in primary patency between the dose groups (placebo n=21, Low Dose n=16, Medium Dose n=17 and High Dose n=12). In a subgroup analysis that excluded three participants with early surgical failures, the hazard ratio (HR) for primary patency loss of Low Dose compared with placebo was 0.38 (95% CI 0.10-1.41, P=0.15). In a Cox model, Low Dose (HR 0.27, 95% CI 0.04-0.79, P=0.09), white race (HR 0.17, 95% CI 0.03-0.79, P=0.02), and age <65 years (HR 0.25, CI 0.05-1.15, P=0.08) were associated (P<0.10) with a decreased risk of primary patency loss.Conclusions PRT-201 was not different from placebo for safety or efficacy measures. There was a suggestion for improved AVF primary patency with Low Dose PRT-201 that is now being studied in a larger clinical trial.

Dialysis grafts have provided reliable access for millions of patients in need of renal replacement therapy. However, regardless of the material used for artificial dialysis grafts their mean patency remains generally poor and infection rates are greater than native arteriovenous fistulas. The need for superior alternatives to conventional synthetic materials used for vascular access has been an area of investigation for more than 25 years and recently there has been a great deal of progress in the field of tissue-engineered vascular grafts. Many of these technologies are either commercially available or are now entering early phases of clinical trials. This review briefly covers the history, potential advantages, and disadvantages of these technologies, which are likely to create an impact in the field of vascular access surgery.

This study investigated the augmentation of endothelial progenitor cell (EPC) thromboresistance by using gene therapy to overexpress thrombomodulin (TM), an endothelial cell membrane glycoprotein that has potent anti-coagulant properties. Late outgrowth EPCs were isolated from peripheral blood of patients with documented coronary artery disease and transfected with an adenoviral vector containing human TM. EPC transfection conditions for maximizing TM expression, transfection efficiency, and cell viability were employed. TM-overexpressing EPCs had a fivefold increase in the rate of activated protein C production over native EPCs and EPCs transfected with an adenoviral control vector expressing β-galactosidase (p<0.05). TM upregulation caused a significant threefold reduction in platelet adhesion compared to native EPCs, and a 12-fold reduction compared to collagen I-coated wells. Additionally, the clotting time of TM-transfected EPCs incubated with whole blood was significantly extended by 19% over native cells (p<0.05). These data indicate that TM-overexpression has the potential to improve the antithrombotic performance of patient-derived EPCs for endothelialization applications.

We report two cases in which patients on chronic hemodialysis presented with morbid unilateral edema of the upper extremity and chest on the side of a currently functioning arteriovenous access. Both patients were known to the vascular surgery service and had previously undergone multiple attempts to create and maintain vascular access. Both severe and disabling edema and the need to maintain dialysis access were of significant concern. These patients were taken to the operating room to address both issues. Upper extremity venography with central venous runoff revealed central vein stenosis and/or occlusion resistant to angioplasty and stenting. Ultimately, these two patients received the Hemodialysis Reliable Outflow vascular access device. The experiences in this study demonstrate the novel use of a relatively new vascular access device for salvage of a malfunctioning arteriovenous fistula or graft as well as treatment of symptoms and complications resulting from long standing vascular access.

Infected prosthetic arteriovenous grafts for hemodialysis present a profound risk to patient well being. Here we present five recent cases and describe our technique for total graft excision. We also review the literature and discuss the much debated role of partial, subtotal, and total graft excision.

Cyanotic congenital heart disease (CCHD) due to one or more structural abnormalities causes insufficient blood oxygenation. Approximately 2 out of every 1000 infants are born with CCHD and palliative treatment for many patients involves shunting blood from the systemic to the pulmonary circuits, often through a modified Blalock-Taussig-Thomas shunt (BTTs). Synthetic vascular grafts typically used for BTTs have associated risks for intimal hyperplasia, thrombosis, and infection. Humacyte, Inc. has developed a 6mm diameter tissue-engineered blood vessel, the Human Acellular Vessel (HAV), currently being studied in adults suffering from vascular trauma, peripheral arterial disease, and renal failure requiring hemodialysis. In addition to restoring blood flow and providing arteriovenous access in these patients, the HAV has demonstrated the capacity for host cellular remodeling that transformed it into a native-like living tissue. Here the HAV production platform was modified to generate small diameter (3.5mm) vessels for preclinical evaluation. BTTs were placed from the right subclavian artery to the pulmonary artery in juvenile rhesus macaques. Post-operative imaging from 1 week to 6 months using angiography and MRI was used to confirm HAV patency, structure, and quantify blood flow. At explantation, the HAV and surrounding tissues were collected and processed for histological analyses. Results confirmed the feasibility of using the HAV BTTs, but also showed that all macaques had some immunological reactivity to the HAV human extracellular matrix in this xenogeneic animal model. Nonetheless, the HAV BTTs remained patent and performed well for up to six months in animals that had only mild host reactivity. HAV repopulation by host cells expressing smooth muscle and endothelial markers as well as the formation of neoadventitial tissue was also observed. These findings may support use of the HAV as a BTTs in CCHD and potentially other pediatric indications.

The coagulopathy of trauma is a syndrome of non-surgical bleeding from mucosal lesions, serosal surfaces, and wound and vascular access sites associated with serious injury, hypothermia, acidosis, hemodilution, and occasionally with classic disseminated intravascular coagulation (DIC). It can be largely explained by the effects of cold on platelet function, the effect of pH on coagulation factor activity, and the dilutional effects of resuscitation fluids and conventional blood products. DIC occurs acutely after trauma when brain, fat, amniotic fluid, or other strong thromboplastins enter the circulation. It occurs subacutely when endothelial inflammation or failure reduces clearing of activated coagulation factors allowing microthrombi to cause secondary injury. The coagulopathy of trauma should be anticipated in massive transfusion situations. Early treatment with plasma can delay its onset. The underlying mechanisms should be confirmed with laboratory testing.

Cardiovascular disease is the leading cause of morbidity and mortality in Western society. More than 1 million arterial bypass procedures are performed annually in the United States, where either autologous veins or synthetic grafts are used to replace arteries in the coronary or peripheral circulation. Tissue engineering of blood vessels from autologous cells has the potential to produce biological grafts for use in bypass surgery. Ex vivo development of vascular grafts also provides an ideal target of site-specific gene therapy to optimize the physiology of the developing conduit, and for the possible delivery of other therapeutic genes to a vascular bed of interest. In this article, we demonstrate that by using a novel retroviral gene delivery system, a target gene of interest can be specifically delivered to the endothelial cells of a developing engineered vessel. Further, we demonstrate that this technique results in stable incorporation of the delivered gene into the target endothelial cells for more than 30 days. These data demonstrate the utility of the retroviral gene delivery approach for optimizing the biologic phenotype of engineered vessels. This also provides the framework for testing an array of genes that may improve the function of engineered blood vessels after surgical implantation.

Dendritic cells (DC) are potent antigen-presenting cells that govern the effector cell responses of the immune system. DC are thought to continuously develop from circulating progenitors in a process that is accelerated by inflammatory stimuli. However, the physiological signals that regulate the development of DC from precursor cells have not been well defined. Here we show that a serine protease acting viaprotease-activated receptor-2 (PAR-2) stimulates the development of DC from bone marrow progenitor cells cultured in granulocyte-macrophage colony-stimulating factor and IL-4. DC fail to develop in bone marrow cultures treated with soy bean trypsin inhibitor, a serine protease inhibitor, but this inhibition is overcome by a PAR-2 agonist peptide. DC do not spontaneously develop from the bone marrow of PAR-2-deficient mice, but can be stimulated to do so by inflammatory mediators. These results suggest that endogenous serine proteases stimulate DC development in vitro. Thus, serine proteases may help trigger adaptive immune responses in vivo.

Profound coagulopathy has been proposed as a barrier to xenotransplantation. Disseminated intravascular coagulation (DIC) has been observed with the rejection of renal and bone marrow xenografts but has not yet been described in pulmonary xenografts.

Bovine thrombin is used as an aid to hemostasis in medical and surgical procedures. At least 500,000 Americans are exposed to this therapeutic annually and reports suggest that exposure is associated with the development of autoreactive antibodies. To determine whether bovine thrombin can induce pathological autoimmunity we exposed nonautoimmune-prone galactose-α1-3-galactose-deficient mice to the two bovine thrombin preparations currently approved for use in the United States. We found that, like humans exposed to bovine thrombin, mice developed an immune response against the therapeutic and the xenogeneic carbohydrate galactose-α1-3-galactose, and some mice developed autoantibodies against clotting factors. Further, unexpectedly, a single exposure to this therapeutic also induced autoimmunity with features characteristic of systemic lupus erythematosus including antibodies against nuclear antigens, native DNA, double-stranded DNA, and cardiolipin. High levels of these autoantibodies correlated with glomerulonephritis in all mice evaluated. This autoimmune syndrome was detected in mice 15 weeks after a secondary exposure to bovine thrombin and female mice were found to develop the syndrome at a significantly greater frequency than males. Thus, these studies indicate that exposure to bovine thrombin preparations can induce a pathological systemic autoimmune syndrome with lupus-like serology.

PURPOSE: To determine whether fibrin sealant injected into the tract created by liver biopsy can be used to decrease postprocedural bleeding. An innovative delivery system was used to deploy the fibrin sealant. MATERIALS AND METHODS: Fibrin sealant is a hemostatic agent consisting of a suspension of fibrinogen and thrombin. A delivery system was devised whereby fibrin sealant could be injected into the tract created by liver biopsy. Thirty swine were randomized into three groups: control (n = 10), heparin (n = 10), and warfarin (n = 10). Each swine underwent laparotomy and was randomized to undergo three to five open liver biopsies with either a 14-gauge cutting needle in conjunction with the fibrin sealant device or a standard 14-gauge cutting needle alone. Forty-seven biopsy procedures were performed with the device; 64 biopsy procedures were performed without the device. Immediate blood loss per biopsy (mL) was estimated based on the size of the blood stain on a sponge. Specimens were assessed for sample size. RESULTS: Immediate blood loss with and without the device, respectively, was: control, 0.1 mL, 5.4 mL; heparin, 0 mL, 7 mL; warfarin, 0.1 mL, 9.3 mL. These differences were significant (P< .01) for each group of swine. In 43 of 47 biopsies (91%), the device functioned without difficulty. There was no difference in sample size when the device was used. CONCLUSION: The fibrin sealant device is effective in reducing bleeding after open liver biopsy in anticoagulated and nonanticoagulated swine. The promising results suggest that a trial of percutaneous liver biopsy in swine should be considered.

Purpose The purpose of this study is to report a case of Hemodialysis Reliable Outflow (HeRO) device malfunction in the subclavian position secondary to costoclavicular impingement.Methods and Results The electronic medical record was reviewed for the patient in question and pertinent imaging was collected and photographs were taken with the patient's consent. The patient presented with signs of outflow obstruction after a period of HeRO venous outflow component function. The outflow component was found to be crushed between the first rib and the clavicle at the costoclavicular junction.Conclusions This case suggests that costoclavicular impingement should be considered as a mode of outflow failure with the HeRO outflow component in the subclavian position. Other central venous access points should be considered first, and the central veins accessed through the lower extremities are possible alternatives if this failure mode was to arise. First rib resection would also be a viable strategy to relieve impingement at this site.

A 68-year-old man, following mitral valve replacement, presented with a low-grade chronic consumptive coagulopathy. Laboratory analysis showed mild fibrinolysis, minimal effect of Coumadin therapy, and a prolonged thrombin time (>150 seconds using bovine IIa). When purified human IIa was used the thrombin time normalized to within 17 seconds of controls, suggesting a possible inhibitor of bovine IIa. An anti-IIa antibody was isolated by protein A-Sepharose (Sigma, St Louis, MO) chromatography followed by affinity chromatography using a bovine IIa-Sepharose column. The effects of this purified anti-IIa antibody on both bovine and human IIa procoagulant and anticoagulant functions were studied. The isolated immunoglobulin G (IgG) was observed to inhibit bovine IIa in all assays tested. This IgG was also able to slightly prolong fibrinogen clotting by human IIa. Using an enzyme-linked immunosorbent assay it was observed that the IgG bound to bovine IIa, bovine II, human IIa, but not to human II. Further, binding was detectable at approximately 50-fold lower concentrations to bovine IIa (1 nmol/L IgG concentration) than to human Ha (50 nmol/L IgG concentration). The effect of the antibody on the reaction between IIa and AT III/heparin was investigated. Human IIa was found to be protected from AT III/heparin neutralization in the presence of this antibody. These results suggest that this patient developed an antibody that strongly binds to and inhibits the bovine IIa in all assays tested. However, the antibody only significantly affects human IIa neutralization by AT III/heparin, and has little effect on the human IIa procoagulant activity. These data suggest that the decreased effect of AT III/heparin on this patient's IIa may have been a contributing factor in his coagulopathy. The exact cause of this antibody development is unclear, but the role of bovine topical thrombin used during cardiac valve replacement surgery is suspect.

Background: One major barrier to successful xenotransplantation is acute vascular rejection, a process pathologically characterized by microvascular thrombosis and diffuse fibrin deposition in transplant blood vessels. This pathologic picture may result from a disturbance in the coagulant or fibrinolytic pathways that regulate normal vascular patency. This study evaluated the regulation of fibrinolytic activity defined by tissue plasminogen activator and plasminogen activator inhibitor-1 as it may exist in the setting of acute vascular rejection. Materials and Methods, Results: Serial biopsies from cardiac xenotransplants evaluated by immunofluorescence microscopy demonstrated progressive decreases in tissue plasminogen activator and increases in plasminogen activator inhibitor-1. In vitro studies measuring fibrinolytic activity of cell culture medium from porcine aortic endothelial cells stimulated with human serum or autologous porcine serum revealed that human serum triggered as much as 93% increase in antifibrinolytic activity. Conclusions: These findings demonstrate that porcine vascular endothelial cells change toward an antifibrinolytic state following stimulation with human xenoreactive antibodies and complement. The shift is at least partly explained by an increased ratio of plasminogen activator inhibitor-1 to tissue plasminogen activator, and is at least in part mediated by the activation of complement. This increased antifibrinolytic activity may contribute to the thrombotic diathesis seen in acute vascular rejection in pig-to-primate xenografts.

Bioengineered human acellular vessels repopulate with host cells and evolve into self-sustaining living blood vessels in hemodialysis patients.