Augmentation of Hemostasis in Pediatric Cardiopulmonary Bypass

小儿心肺转流术中的强化止血

基本信息

批准号：
8770359
负责人：
Thomas Harrison Barker
金额：
$ 25.22万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8770359
关键词：
Adult Affinity Age Animals Antibodies Binding Biocompatible Materials Biodistribution Biological Assay Biophysics Birth Bleeding time procedure Blood Blood Circulation Blood Coagulation Disorders Blood Coagulation Factor Blood Platelets Blood specimen Cardiac Surgery procedures Cardiopulmonary Bypass Childhood Coagulation Process Complex Complication Contracts Coupled Data Development Engineering Fiber Fibrin Fibrinogen Gel Goals Half-Life Hemorrhage Hemostatic Agents Hemostatic function Hydrogels In Vitro Injury Maps Methods Microfluidic Microchips Microscopic Mission Modeling Molecular Monitor Morbidity - disease rate Nature Neonatal Outcome Patients Pediatric Surgical Procedures Plasma Polymers Prothrombin Research Rodent Rodent Model Sampling Scientist Site Specificity Surgical sutures Techniques Technology Thrombelastography Transfusion Whole Blood Work Wound Healing base blood product cardiac repair crosslink design improved in vivo innovation mortality multidisciplinary neonate novel particle poly-N-isopropylacrylamide public health relevance skills treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Bleeding after cardiopulmonary bypass (CPB) is a serious complication of cardiac surgery and is associated with substantial morbidity and mortality; neonates in particular are vulnerable to post-CPB bleeding. In these patients, transfusion post-CPB is a necessity. Transfused blood products consist primarily of platelets and fibrinogen (in the form of cryoprecipitate) prepared from adult blood. Although the transfusion of adult blood products to pediatric patients is performed routinely to control blood loss, reduction in the usage of transfused blood products has been shown to correlate with better patient outcomes. Unfortunately, few alternatives exist, highlighting the need for better methods to control bleeding. Hemostasis involves the formation of a platelet plug embedded within a fibrin mesh. However, clot formation is impaired in neonates, in part, due to deficiencies in several coagulation factors at birth and platelet hyporeactivity. CPB further impairs these already compromised platelets. Thus, the overarching design goal of this project is to create a biomaterial that recapitulates key hemostatic functions of platelets to augment clotting in neonatal CPB patients. To achieve this objective, we utilize platelet-like particles (PLPs), recently designed in our lab, that mimic numerous features of natural platelets by interacting with fibrin with high affinity and, more importantly, specificity at the sites of injury to augment clotting in plasma samples obtained from neonates undergoing CPB. To achieve this objective, the proposal is divided into two specific aims: 1. Characterization of platelet function and clottig in neonatal CPB plasma samples in the a) absence and b) presence of PLPs and 2. Characterization of augmentation of clotting in vivo in a rodent model of platelet hyporeactivity. In Aim 1, we will analyze neonatal platelet function in blood samples collected prior to CPB (baseline), post-CPB and post-transfusion from neonates undergoing elective cardiac surgery, through thromboelastography/platelet mapping assays and dynamic clotting assays utilizing a novel endothelialized microfluidic device developed in our labs. We will then perform identical analyses with post-CPB samples in the presences of PLPs. Because neonatal patients are known to have hyporeactive platelets, in Aim 2, we will model this condition and evaluate the efficacy of PLPs in vivo in a small animal platelet deficiency model by monitoring bleeding times. Furthermore, the biodistribution and circulation half-life of PLPs will be evaluated. The proposed research is innovative because it combines unique microgels with fibrin specific binding motifs to create PLPs that interact extensively with fibrin networks. These features result in particles that are capable of recapitulating more features of nature platelets than previously achieved by other platelet-mimicking materials. The significance of the proposed research is that this work will enable better treatment options for coagulopathy in neonatal CPB patients.

描述（由申请人提供）：心肺旁路（CPB）后出血是心脏手术的严重并发症，并且与大量的发病率和死亡率有关；特别是新生儿很容易受到CPB后出血的影响。在这些患者中，CPB后输血是必要的。输血的血液产物主要由成人血液制备的血小板和纤维蛋白原（以冻干的形式）组成。尽管经常进行成人血液产品向小儿患者的输血以控制失血，但已证明输血血液产品的使用量减少与更好的患者结局相关。不幸的是，很少有替代方案，强调需要更好地控制出血的方法。止血涉及形成纤维蛋白网中的血小板塞。但是，新生儿中的凝块形成受损，部分原因是由于缺陷在出生时的几个凝结因子和血小板低血压。 CPB进一步损害了这些已经受损的血小板。因此，该项目的总体设计目标是创建一种生物材料，该生物材料概括了血小板的关键止血功能，以增强新生儿CPB患者的凝结。为了实现这一目标，我们利用了最近在实验室设计的血小板状颗粒（PLP）（PLP），通过与具有高亲和力的纤维蛋白相互作用，模仿天然血小板的众多特征，更重要的是，在损伤部位的特异性以增强的特异性从接受CPB的新生儿获得的血浆样品中凝结。为了实现这一目标，该提案分为两个具体目的：1。在a）不存在和b）存在PLP和2的情况下在新生儿CPB血浆样品中表征血小板功能和clottig。在AIM 1中，我们将分析在CPB（基线），CPB之前收集的血液样本中的新生儿血小板功能，以及通过血栓层学/血小板映射测定法和动态凝结测定的新生儿的新生儿的转移，并利用一种新型的内皮化微荧光设备开发了我们的Labs in Il Labs。然后，我们将在PLP的存在中使用CPB后样品进行相同的分析。由于已知新生儿患者的血小板异常，因此在AIM 2中，我们将通过监测出血时间来对这种情况进行建模并评估PLP在体内的疗效。此外，将评估PLP的生物分布和循环半衰期。拟议的研究具有创新性，因为它将独特的微凝胶与纤维蛋白特异性结合基序相结合，以创建与纤维蛋白网络广泛相互作用的PLP。这些特征导致颗粒能够概括自然血小板比其他模仿材料所获得的颗粒。拟议的研究的意义在于，这项工作将使新生儿CPB患者的凝血病更好地治疗选择。