Novel Dried Cryoprecipitate-Based Intervention to Improve Outcomes from Trauma and Hemorrhagic Shock: Applicability for Multidomain Operations
Abstract
When people suffer trauma that causes massive bleeding (hemorrhage), they may go into hemorrhagic shock (HS). HS is the leading cause of early deaths on the battlefield and in civilian trauma. Recent data has shown that when HS patients are resuscitated (given fluids to improve blood pressure) with plasma, the liquid part of blood, organ damage and deaths are reduced. This may be because plasma slows or reverses the damage HS causes to blood vessels. The early use of plasma after HS has led to its inclusion in the Joint Trauma System guidelines. However, plasma is not available in the battlefield where it would be of the most benefit as it requires refrigeration and thaw time. As future areas of operation will require prolonged field care (pFC), delays in being able to use plasma will place injured Soldiers who survive HS at risk for poor outcomes. As treatment of HS on the battlefield will be unique to pFC, new ways to treat this condition that are possible on the battlefield are urgently needed. We propose the use of two novel cryoprecipitate products. Cryoprecipitate is prepared from plasma and contains fibrinogen and other clotting factors to assist in hemostasis (stop bleeding) and, as we will show, reduce organ injury. Similar to plasma, logistic challenges exist in the use of conventional cryoprecipitate (CC) in the battlefield and even in many civilian centers. CC is also stored frozen and thus requires time and specialized equipment to thaw. Once thawed, shelf life is limited to 4-6 hours. Recognizing this gap and the risk of disease transmission with all blood products, a pathogen-reduced long post-thaw (5-day) shelf life cryoprecipitate (5PRC) and a pathogen-reduced lyophilized (powdered form) of cryoprecipitate (LPRC) are in development that could provide early cryoprecipitate-based resuscitation en route (Focus Area 1) and in the forward environment (Focus Area 2). The major objective of this effort is to define the role of 5PRC and LPRC using two different small animal models of HS to examine the effect of these novel products on both hemostasis and endothelial cell (cells lining blood vessels) protection. The long-term goal is Food and Drug Administration (FDA) approval of these products for clinical and field use after HS. The Navy Blood Program has expressed interest to manufacture and provide 5PRC directly to the Armed Services Blood Program for use by military blood services. Cerus expects to complete the registration study for 5PRC by end of 2019 and then file with the FDA for approval. This product is expected to be commercially available possibly by mid-2020. The plan is to submit LPRC for FDA review in 2021. It may then be available for commercial release as early as 2022. We hypothesize that pathogen-reduced cryoprecipitate-based interventions will decrease both early hemorrhagic deaths and later multiple organ failure through their dual effects on hemostasis and endothelial stability. To test this hypothesis, the early use of 5PRC and LPRC will be compared to CC, plasma, and standard-of-care Hextend in two different rodent models of trauma/HS applicable for multi-domain operations in the following specific aims (SA): SA1: Determine the effect of early cryoprecipitate on hemostasis, organ function, and mortality in a short-term mouse model of trauma and uncontrolled hemorrhage (UCH). A well-established mouse liver transection model of UCH will be utilized followed by resuscitation with the described blood products or Hextend and compared to shams. Hemostasis, coagulation, lung function, endothelial integrity, and short-term mortality will be assessed. SA2: Determine the effect of early cryoprecipitate on endothelial protection, multiple organ failure, and mortality in a mouse model of sustained hypotensive resuscitation (long periods of low blood pressure [SHR]). Our established mouse model of trauma/HS and SHR will be used with the described blood products or Hext
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010406
Entities
People
- Rosemary Kozar
Organizations
- United States Army
- University of Maryland, Baltimore