Coming Soon: Dried Plasma for Hemorrhagic Trauma in the Prehospital Setting

Uncontrolled bleeding continues to be the leading cause of preventable death in victims of trauma. Whether it’s a civilian or a wartime combatant, the primary field management goal for an individual experiencing severe acute hemorrhage is to restore blood pressure and maintain perfusion of vital organs. Most hemorrhagic trauma victims with survivable injuries can be stabilized with infusions of crystalloids alone until they reach surgery. It is only in a minority of cases — mainly rapidly bleeding individuals facing a hospital transport time well exceeding 20 minutes — in which there is meaningful survival benefit from prehospital transfusion of red blood cells (RBCs).*

Yet too often in cases of severe acute trauma-related blood loss when blood pressure has been quickly restored in the field and surgeons successfully control bleeding at the site or sites of vascular injury, death ensues anyway over the next several hours. A seminal 1982 study of major abdominal vascular injuries in 123 patients found that 89 percent of mortality was attributable to bleeding, yet half of these hemorrhage-related deaths occurred after mechanical control of bleeding sites.¹ The cause of this early mortality is seriously deranged coagulation function, or what leading specialists now call trauma-induced coagulopathy (TIC). While tissue injury, shock and other variables play a role in this complex and incompletely understood phenomenon, a key contributor is extensive hemodilution resulting from prehospital administration of saline or other crystalloid solutions.²

Crystalloid resuscitation has been confirmed in several large case series to be an independent risk factor for coagulopathy.^3,4 In an analysis of 8,700 multiply injured patients, increasing amounts of intravenous fluids administered prior to ER admission were associated with an increasing incidence of coagulopathy. Coagulopathy was observed in more than 40 percent of patients who had received greater than 2,000 mL of intravenous fluids, in more than 50 percent of those who had received greater than 3,000 mL and in more than 70 percent in those administered greater than 4,000 mL.³

Particularly concerning is the effect of crystalloid hemodilution on the circulating levels of fibrinogen. Fibrinogen is the most abundant coagulation factor in blood, whose conversion to fibrin clots and facilitation of platelet aggregation at bleeding sites is crucial for hemostasis. Despite its high circulating concentrations, fibrinogen is the first coagulation factor to reach critically low levels in severely bleeding patients.⁵ Blood loss, consumption of fibrinogen by clot formation at wound sites and increased degradation due to acidosis all act to reduce circulating fibrinogen. Hemodilution resulting from large-volume administration of crystalloids also drives down the fibrinogen level, but in this case there is an alternative: transfusing fibrinogen-rich donor human plasma instead.

The Superiority of Early Prehospital Plasma

Recently with support from the U.S. Army Medical Research Command, the concept of transfusing plasma in the prehospital setting was put to the test. Its landmark multicenter, cluster-randomized PAMPer trial compared the administration of two units of thawed plasma plus standard-care resuscitation with standard-care resuscitation only during air medical transport of 501 hypotensive, tachycardic trauma patients. Mortality at 30 days was sharply lower in the plasma group than the standard-care group: 23.2 percent vs. 33.0 percent. Notably, the median prothrombin-time ratio was also lower in the plasma group after arrival at the trauma center, indicative of better overall hemostatic function.⁶

A body of research from experience in the Iraq and Afghanistan military conflicts has also shown that early transfusion of plasma together with RBCs in a ratio approaching 1:1 also improves long-term outcomes in severely bleeding combat casualties. A chart review of 246 patients requiring massive transfusion at a U.S. Army combat support hospital documented dramatically lower overall and hemorrhage-related mortality rates in patients transfused at a higher plasma-to-RBC ratio (Figure 1).⁷

Figure 1. Mortality in Massively Transfused Trauma Patients as a Function of Plasma-to-Red Blood Cell (RBC) Transfusion Ratio

Source: Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 2007 Oct;63(4):805-13. All results p < 0.001.

A separate review of 708 patients admitted to a combat support hospital who received blood products similarly found that each transfused unit of plasma was independently associated with increased survival (odds ratio 1.17; 95 percent confidence interval 1.06 to 1.29; p = 0.002).⁸

But a number of logistical constraints have limited the number of regional trauma systems that have incorporated thawed plasma on their evacuation helicopters. Prehospital transfusion is even more problematic for civilian ground ambulances, as well as rural or remote hospitals without blood banks.⁹ Plasma stored in the frozen state takes about 30 minutes to thaw using conventional equipment, then must be stored in the refrigerated state and transfused within five days; most of this plasma must be rotated back to the hospital blood bank before expiry or discarded. Consequently, the transport, storage and inventory management requirements to routinely carry thawed plasma on helicopters or ground ambulances is very costly, and payment policies for these services rarely compensate blood product costs.

Past Experience with Dried Plasma

A far better option for carrying plasma on air or ground ambulances is a dried plasma product that can be stored for an extended period without refrigeration, and rapidly reconstituted with the appropriate volume of sterile water. But this idea is not new. Decades before most specific coagulation factors were even discovered, it was intuited that the protein-rich plasma running through our arteries and veins was the ideal early resuscitative fluid to give to severely bleeding trauma victims during transport to the hospital.

Methods to lyophilize plasma were first developed and successfully tested in animals and humans in the 1930s.^10,11 Large-scale production and use of freeze-dried plasma began in World War II with the distribution of more than six million units of pooled, lyophilized plasma to U.S. fighting personnel. However, attempts with different pathogen reduction strategies to resolve the inevitable problem of hepatitis transmission by these pooled units were unsuccessful, and by the 1960s, dried pooled plasma was essentially abandoned.¹²

But beginning in the 1990s, improved donor screening and the advent of effective pathogen reduction technologies gave new life to the possibility of dried plasma. Today, three modern dried plasma products are manufactured and available in France, Germany and South Africa (Table). The German and French products are stable for 15 months and two years, respectively, at room temperature, and require just a few minutes to reconstitute. Limited quantities of the dried plasma product manufactured by the French Military Blood Institute have been purchased by the U.S. military since 2018 under an emergency use authorization.⁷

Table. Dried Plasma Products Commercially Available Outside the U.S.

FFP: fresh frozen plasma
UV: ultraviolet

Investigational Products in the Pipeline

While no dried plasma products are approved for civilian use, several companies are actively developing investigational lyophilized or spray-dried plasma products, including Teleflex, Velico Medical, Terumo Blood and Cell Technologies and Octapharma. To facilitate their efforts, the U.S. Food and Drug Administration (FDA) recently published a guidance document providing specific recommendations for plasma sourcing, manufacturing and product quality assurance.¹³

Two companies in particular — Velico Medical and Teleflex — have advanced their dried plasma products into clinical testing on healthy volunteers. If proven safe and shown to have acceptable coagulant and anticoagulant activities, one or both could be approved for marketing in the very near future.

EZ-PLAZ Freeze Dried Plasma (Teleflex). With annual sales of $3 billion, Teleflex manufactures and sells a diverse range of medical technologies for use in surgery, vascular access, anesthesia, emergency medicine and other areas. Its investigational single-donor, freeze-dried plasma (FDP) product was originally developed by researchers at Vascular Solutions, which Teleflex acquired in 2017.

In collaboration with the U.S. Army Medical Research and Materiel Command, the safety and tolerability of up to three units of this FDP, produced from each study participant’s own plasma, was evaluated in a Phase I clinical trial involving 24 healthy subjects; the comparator was autologous fresh frozen plasma (FFP) administered to the same study participants.¹⁴

FDP coagulation factors, clotting times and product quality following lyophilization were all preserved, with slight prolongation of mean clotting times and minimal or modest reductions in the mean content of fibrinogen, factors I, V, VII, VIII, IX, XI, XII, protein C, protein S, plasmin inhibitor, plasminogen, antithrombin III and von Willebrand factor antigen compared with the FFP control. Infusions of up to 810 mL per subject were found to be safe, with no instances of serious adverse events. Remarkably, the average time to reconstitute FDP with sterile water supplied with the product was just over one minute (67 ± 15 seconds) (Figure 2). Based on findings from this study, Teleflex submitted a biologics license application to FDA in early 2021; the product’s current regulatory status is uncertain.

Figure 2. Teleflex’ Investigational Freeze-Dried Plasma Kit Including Sterile Water and Administration Kit

If approved, Teleflex intends to acquire plasma from type AB donors and/or type A donors with low anti-B titers and manufacture its FDP at its own facility for commercial sale.

FrontlineODP Spray Dried Plasma (Velico Medical). In contrast to Teleflex’ manufacturing and commercialization strategy, Massachusetts-based Velico Medical has designed its proprietary technology — the FrontlineODP system — for use by regional blood centers to manufacture dried plasma along with other blood components they routinely distribute. Velico is developing the FrontlineODP system with support from the federal government’s Biomedical Advanced Research and Development Authority.

The spray-dried FrontlineODP product is rapidly reconstituted with 200 mL of sterile water and stable for extended periods in ambient conditions. A Phase I dose-escalation study in healthy adult volunteers is currently in progress to assess FrontlineODP’s safety, quality and hemostatic function indicators. This trial is expected to be completed in May. If the results are good, it is possible that FDA will accept these findings as acceptable to review an application for marketing approval of Velico’s FrontlineODP system.

While the process of securing approval for a dried plasma product might seem straightforward at first blush, in reality it is not. Development of these products has been slowed or stymied by a number of regulatory and logistical challenges, among which are the following:¹⁵

• Uncertainty regarding clinical trial requirements to gain approval
• Need to demonstrate container integrity over a one- to two-year shelf life in a range of environmental conditions
• Limited availability of universal type AB plasma, the ideal blood type for prehospital administration
• Need for sufficient investment capital to fund scale-up and commercialization phases through initial product launch
• Testing of single-donor units for potency, purity and other product parameters that is not unduly burdensome or costly

Some experts in the field had anticipated that the first dried plasma product might be licensed and available by now,11 but that projection has proven too optimistic. Nevertheless, it now appears likely that one or more dried plasma products will be approved and available commercially in the near future.

The Eagerly Awaited Return of Dried Plasma

It is now well-established that prehospital transfusion of plasma, with its balanced mix of coagulation proteins, counters the hemodilution and progressive derangement of hemostatic mechanisms caused by crystalloid-based resuscitation, improving the chances of survival in severely bleeding trauma victims.

Thanks to its long shelf life in lyophilized form and its readiness for reconstitution and transfusion in minutes, dried plasma is conceptually ideal to meet this need. Eight decades ago, dried plasma worked to save the lives of severely hemorrhaging servicemen in WWII, and with its return in the form of new pathogen-safe dried plasma products, it will work again on air and ground ambulances to save lives here at home.