Augmentation of Hemostasis in Pediatric Cardiopulmonary Bypass

描述（由申请人提供）：体外循环（CPB）后出血是心脏手术的严重并发症，与大量发病率和死亡率相关；新生儿尤其容易发生cpb后出血。在这些患者中，cpb后输血是必要的。输血的血液制品主要由血小板和纤维蛋白原（以低温沉淀的形式）组成。虽然常规向儿科患者输注成人血液制品以控制失血，但已证明减少输注血液制品的使用与改善患者预后相关。不幸的是，几乎没有其他选择，这突出了需要更好的方法来控制出血。止血包括形成嵌在纤维蛋白网中的血小板塞。然而，新生儿的凝块形成受损，部分原因是缺乏维生素d

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.