Biphasic Coagulopathies and Endotheliopathy in Burn Injured Patients: An Analysis of Mechanisms and Interplay
Abstract
Clinical studies previously conducted by our group (under previous ARO and Navy funding) of burn injured patients prospectively enrolled, sampled, and studied have demonstrated that contrary to conflicting (and scant) literature, bum patients experience changes in clotting status after injury. Extensive changes not identified by clinical laboratory measures (PT. INR) were seen following burn injury that may explain perturbed coagulation in these pa1icnts. Our data illustrate that burn patients exhibit hypercoagulable states and the timing and the severity of these hypercoagulablc states are patient specific and may not necessarily correspond with the severity of burn injury. Using viscoelastic assays, we have shown an increase in both clot kinetics and strength which indicate rapid fibrin formation and excessive platelet activity and a potential risk for thrombosis. Endothelial dysfunction may also play a role in clotting dynamics in response to burn injury in this patient population. Improved insight into burn-induced glycocalyx damage and its downstream effects is essential to understanding shock and refining resuscitation regimens in bum patients, especially in lhc acute time points after injury. In addition to introducing additional assays as described below, the presently proposed study will allow replication and expansion testing to be done on archived samples from all 135 individuals enrolled from the previous study, whereas much of the present data are based on subsamples and cohorts (generated as sample sets became available over the course of enrollment). This work expands the field by exploring quantification and temporality of damage to the glycocalyx following burn injury, which is critical to understanding the impact of endotheliopathy on clinical paradigms and patient outcomes. Delineating the effects of thermal injury on endotheliopathy, including the potential interplay of vascular permeability, inflammation and coagulation, will guide future therapeutic interventions to maintain vascular integrity in patients by moderating glycocalyx shedding. Further, this may help to elucidate the pathways that uncouple, resulting in the previously described development of hypercoagulable conditions in burn patients. The presently proposed study is in follow up to the initial studies of coagulopathies in burn patients described above and all described work will be completed on the existing sample (and data) archive. The study is aimed to (1) Further characterize and confirm the biphasic hypo-hypercoagulablc state shift phenomena measured in samples from previously enrolled patients and (2) Pursue endothelial dysfunction as unexplored player in burn-induced coagulopathy. Funding is not allocated to support this work at this time, therefore we are requesting to complete: 1. ELISA To detemine the extent of endothelial glycocalyx damage and build on previous data quantifying shed syndecan in a subset of patients, we will assay preserved plasma samples aliquoted and stored from every previously collected patient/timepoint for levels of shed glycocalyx components including syndecan I (CDl38) and endocan. 2. RT-PCR To enhance the dataset on circulating endothelial components. indicative of shedding, we will analyze RNA isolated from PAX gene-preserved blood for transcript-levels of syndecans, endocans, and other glycocalyx-relevant molecules. 3. PT/INR To further characterize the biphasic shift to a hypercoagulable state in these burn patients, all samples will be analyzed in the laboratory to repeat results from previously obtained clinical lab values. 4. TEG/ROTEM Similarly, we will assay preserved plasma samples aliquoted and stored from every previously collected patient/timepoint using TEO and ROTEM. Further analysis of existing clinical and previous assay data, integrated with the above described data generated, will yield a significantly robust assessment of coagulopathies in burn patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- May 07, 2018
- Source ID
- W911NF1710594
Entities
People
- Jeffrey Shupp
Organizations
- Army Contracting Command
- MedStar Health Research Institute
- Office of the Secretary of Defense